Microsoft Word - hiv_treatment_guidelines_south_africa_2004.doc by John Snow, Inc

ANNEX I

CLINICAL GUIDELINES FOR THE MANAGEMENT OF HIV & AIDS IN HEALTH FACILITIES

National Department of Health South Africa 2008

FINAL DRAFT 30 MAY 2008

TABLE OF CONTENTS FOREWORD................................................................................................................................................. 5 PREFACE 6 ABBREVIATIONS ....................................................................................................................................... 7 SECTION 1 ANTIRETROVIRAL TREATMENT (ART) IN ADULTS .............................................. 11 A.

GOALS OF ART .......................................................................................................................... 11

B. SELECTION CRITERIA.................................................................................................................... 11 C.

ASSESSMENT FOR TREATMENT READINESS.................................................................. 12

RECOMMENDED ART REGIMENS IN ADULTS ................................................................ 15

1. FIRST LINE ART REGIMENS .......................................................................................................... 15 2. RECOMMENDED DOSING SCHEDULE AND COMBINATIONS FOR FIRST LINE DRUG REGIMENS ................................................................................................................................... 16 3. APPROACH TO DRUG SUBSTITUTION IN FIRST LINE REGIMENS.................................... 17 4. MONITORING DRUG BENEFITS AND TOXICITY FOR FIRST LINE ART REGIMENS ..... 18 5.

CONSIDERATIONS FOR CHANGING ART REGIMEN 1 ......................................................... 19

6. SECOND LINE ART REGIMENS .................................................................................................... 20 7. RECOMMENDED DOSING SCHEDULE AND COMBINATIONS FOR.................................... 21 SECOND LINE DRUG REGIMENS...................................................................................................... 21 8. CLINICAL AND LABORATORY MONITORING FOR PATIENTS ON SECOND LINE ART REGIMENS........................................................................................................................................ 21 9.

MANAGEMENT OF TREATMENT FAILURE AFTER THE SECOND LINE REGIMEN23

10.

CLINICAL AND LABORATORY MONITORING FOR PATIENTS ON ART.................. 23

11.

THE IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS) ................ 26

12.

MANAGEMENT OF PATIENTS PREVIOUSLY TREATED WITH................................... 26

ANTIRETROVIRAL THERAPY (OR NON NAÏVE PATIENTS)....................................................... 26 13. ART AND PROPHYLAXIS OF OPPORTUNISTIC INFECTIONS.............................................. 26 14. ART AND CONCOMITANT TUBERCULOSIS (TB) IN ADULTS ............................................. 27 15. PREGNANCY AND ANTIRETROVIRAL TREATMENT........................................................... 29 SECTION 2: MANAGEMENT OF HIV & AIDS INFECTION IN CHILDREN............................... 34 1. INDICATIONS FOR ART IN CHILDREN....................................................................................... 34

1.1 Clinical Criteria ............................................................................................................................. 34 2. TREATMENT OF MOTHERS/ CAREGIVERS/OTHER FAMILY ............................................. 34 MEMBERS 34 3.

RECOMMENDED PAEDIATRIC ART REGIMENS............................................................ 35

4. SINGLE DRUG SUBSTITUTION OF STAVUDINE WITH ABACAVIR..................................... 35 SECTION 3: ADHERENCE TO ART...................................................................................................... 36 1.

GENERAL CONSIDERATIONS ............................................................................................... 36

ADHERENCE SUPPORT, ASSESSMENT AND MONITORING ........................................ 36

DEFINITION OF ADHERENCE TO ART............................................................................... 37

ISSUES WHICH IMPACT ON ADHERENCE ........................................................................ 37

STRATEGIES TO PROMOTE ADHERENCE........................................................................ 38

PRE-TREATMENT ADHERENCE PACKAGE...................................................................... 38

7. ADHERENCE MEASURING TOOLS: (SEE ADULT PATIENT ADHERENCE RECORD & MONITORING FORM – PARMF [APPENDIX 2])........................................................................... 39 8.

ADHERENCE PACKAGE FOR PATIENTS ON TREATMENT.......................................... 39

9. STEP-UP ADHERENCE PACKAGE FOR PEOPLE WITH REDUCED ADHERENCE OR VIROLOGICAL FAILURE ...................................................................................................................... 40 SECTION 4: DIAGNOSIS AND MANAGEMENT OF ADVERSE EVENTS .................................... 41 1.

PRINCIPLES OF MANAGING ADVERSE EVENTS ............................................................ 41

IMPORTANT ADVERSE REACTIONS................................................................................... 41

SPECIFIC ADVERSE REACTIONS......................................................................................... 42

4. DRUG INTERACTIONS ....................................................................................................................... 54 5.

SUBSTITUTES FOR INTOLERANCE IN ADULTS .............................................................. 56

IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS) ......................... 56

SECTION 5: MANAGEMENT OF OPPORTUNISTIC ........................................................................ 58 DISEASES IN HIV POSITIVE ADULTS ................................................................................................ 58 1.

GENERAL PRINCIPLES ........................................................................................................... 58

2. HIV COMPLICATIONS ANTICIPATED AT VARIOUS DEGREES OF IMMUNOSUPPRESSION ......................................................................................................................... 58 3. RECOMMENDED PREVENTION OF OPPORTUNISTIC INFECTIONS IN HIV POSITIVE ADULTS .................................................................................................................................. 59 4.

MANAGEMENT OF OPPORTUNISTIC DISEASES IN HIV POSITIVE ADULTS.......... 65

SECTION 6: POST-EXPOSURE PROPHYLAXIS (PEP)..................................................................... 82 1. PROPHYLAXIS AFTER ACCIDENTAL OCCUPATIONAL OR NON-OCCUPATIONAL (INCLUDING SEXUAL ABUSE/RAPE) EXPOSURE TO HIV ........................................................... 82 2.

PROPHYLAXIS AFTER OCCUPATIONAL (EXCLUDING RAPE)................................... 82

3. PROPHYLAXIS AFTER SEXUAL ASSAULT .................................................................................. 83 APPENDIX 1: WHO CLINICAL STAGING OF HIV & AIDS FOR ADULTS WITH CONFIRMED HIV INFECTION (2006)............................................................................................................................ 86 APPENDIX 2 : ADULT PATIENT ADHERENCE RECORD & MONITORING FORM [PARMF]88 APPENDIX 3: TB PROPHYLAXIS ......................................................................................................... 92 EXCLUSION OF ACTIVE TB.................................................................................................................. 93 ELIGIBILITY FOR TB PREVENTIVE THERAPY.............................................................................. 94 APPENDIX 4: FORM FOR DOWN REFERRAL .................................................................................. 98 SOME DEFINITIONS.............................................................................................................................. 100

FOREWORD Guided by the Operational Plan for the Comprehensive HIV & AIDS Care, Management and Treatment Plan (The Comprehensive Plan) and the National Strategic Plan for HIV & AIDS and STIs 2007-2011 (NSP), South Africa continues to intensify the fight against HIV&AIDS. To date South Africans can access a comprehensive package of care including Antiretroviral Treatment (ART) from accredited Comprehensive Plan service points that are available in all health districts. Much experience has been gained since we started implementing this Plan in April 2004. The science of HIV treatment is evolving and treatment guidelines have to keep up to date with developments. Updating the previous guidelines has taken into consideration the need to minimise the risk of drug toxicity whilst optimizing treatment outcomes. Ongoing treatment education and support are essential elements of the National HIV and AIDS treatment programme. A comprehensive section on the management of opportunistic diseases has been included, as well as a short reference to Paediatric HIV & AIDS treatment These clinical guidelines are provided as a resource for use by all health care providers and should be used in conjunction with other relevant guidelines. Regular use by health care providers should ensure uniform, equitable, safe, sustainable and effective (principles outlined in the Comprehensive Plan master document) management of patients with HIV&AIDS. The NSP 2007-2011 recommends regular reviews in keeping with emerging evidence from active and passive surveillance, pharmacovigilance, monitoring and evaluation. The Department of Health will strive to follow this recommendation, whilst supporting research on the development of alternative and adjunctive approaches to treatment of HIV & AIDS. In order to enhance continuity and accelerate access, it is hoped that the private sector and civil society including not-for-profit organizations will as much as possible, follow these guidelines.

DR MANTO TSHABALALA-MSIMANG MINISTER OF HEALTH DATE:

PREFACE Four years into the implementation of the Operational Plan for Comprehensive HIV and AIDS Care, Management and Treatment, with some outstanding successes and formidable health systems challenges, large numbers of people living with HIV and AIDS gained access to the various elements of the package of treatment and care recommended in the Plan. Establishing an adequate cadre of well-trained health care professionals, laboratory technicians, pharmacists, doctors, social workers, nutritionists and community workers is critical for the success of this programme. Adherence to ART is of paramount importance to reaping the long-term benefits and avoiding development of resistance. Maximum adherence requires community mobilization with patients supported by health care providers, family and the community to participate and fully understand the benefit and limitations of ART. The national public health sector boasts one of the largest treatment programmes in the world. In order to optimise treatment outcomes and reduce the risks of drug toxicity and resistance, it is imperative that this remarkable achievement is sustained. Responding to the changes and development in the science of ART, these clinical guidelines aim to set the standard for the use of ART and the management of opportunistic diseases, HIV and AIDS in South Africa. Providing the best possible and safest care for those with HIV&AIDS in South Africa is possible. All health care workers in the public and private sectors as well as not for profit organizations are urged to familiarize themselves with these guidelines so that we, together, provide the best possible and safest care for those with HIV&AIDS.

MR TD MSELEKU DIRECTOR-GENERAL DEPARTMENT OF HEALTH

ABBREVIATIONS 3 TC

Lamuvidine

ABC

Abacavir

AIDS

Acquired immune deficiency syndrome

ALT

Alanine Transaminases

ART

Antiretroviral Therapy

ARV

Antiretroviral

AZT

Zidovudine (anti-retroviral drug)

BCG

Bacille Calmette Guerin

Twice-daily

BMI

Body Mass Index

CD4

CD4 cell or T4 ‘helper’ lymphocyte

Creatinine

CSF

Cerebrospinal fluid

Cryptococcal meningitis

CMV

Cytomegalovirus infection

CPT

Cotrimoxazole Preventive Therapy

CT scan

Computerised Tomography Scan

ddI

Didanosine

D4T

Stavudine

DOT

Directly observed treatment

Ethambutol

EBV

Epstein-Barr Virus

EFV

Efavirenz

ELISA (HIV)

Enzyme-linked Iimmunosorbent Assay – A type of HIV antibody laboratory test

EPTB

Extrapulmonary tuberculosis

FBC

Full Blood Count

FTA

Fluorescent treponemal antigen â&#x20AC;&#x201C; specific laboratory test for syphilis

GFR

Glomerular Filtration Rate

GIT

Gastro-Intestinal Tract

GUD

Genital Ulcer Disease

HAD

HIV Associated Dementia

ART

Antiretroviral Therapy

Haemoglobin

HBc

Hepatitis B core

HDL

High density Lipoproteins

HepBsAg

Hepatitis B Surface Antigen

HIV

Human Immunodeficiency Virus

HPV

Human papillomavirus

HSV8

Herpes Simplex Virus 8

HSV

Herpes simplex virus

INH

Isoniazid

IPT

Isoniazid Preventive Therapy

IRIS

Immune Reconstitution Inflammatory Syndrome

Kaposiâ&#x20AC;&#x2122;s Sarcoma

LDH

Lactose Dehydrogenase

LFT

Liver Function Tests

LOW

Loss of Weight

LPV/r

Lopinavir/ritonavir

MAC

Mycobacterium avium complex

MCC

Medicines Control Council

MCS

Microscopy, Culture and Sensitivity

MDR TB

Multi-drug resistant tuberculosis

NHL

Non Hodgkinâ&#x20AC;&#x2122;s Lymphoma

NNRTI

Non-nucleoside reverse transcriptase inhibitor (anti-retroviral drug)

NRTI

Nucleoside reverse transcriptase inhibitor (anti-retroviral drug)

NVP

Nevirapine

Once daily

OHL

Oral hairy leukoplakia

Opportunistic Infecion

P24

HIV antigen test

PAP smear

Papanicolaou test

PCP

Pneumocystis jiroveci pneumonia

PCR

Polymerase chain reaction (a laboratory HIV detection test)

PEP

Post Exposure Prophylaxis

PGL

Persistent generalised lymphadenopathy

Protease inhibitor (anti-retroviral drug)

PID

Pelvic inflammatory disease

PMTCT

Prevention of Mother to Child transmission

PML

Progressive multifocal leukoencephalopathy

PPD

Purified Protein Derivative

PTB

Pulmonary tuberculosis

PLWHA

Person living with HIV/AIDS

QID

6 hourly

Rifampicin

RBC

Red Blood Count

RPR

Rapid plasma reagin â&#x20AC;&#x201C; a non specific test for syphilis

Streptomycin

SIL

Squamous intraepithelial lesion

STI

Sexually Transmitted Infection

Helper lymphocyte

TCA

Trichloroacetic acid

TMP-SMX

Trimethoprim/sulphamethoxazole also known as cotrimoxazole or Bactrim ® or Septran ®

Toxoplasma encephalitis

Tuberculosis

TBM

Tuberculous meningitis

TDF

Tenofovir

TID

8 hourly - 3 times a day

TPHA

Treponema pallidum haemagglutination assay – a specific laboratory test for syphilis

URTI

Upper respiratory tract infection

VAS

Visual Analog Scale

Viral Load (HIV)

VZV

Varicella-Zoster Virus

VZIG

Varicella-Zoster Immune Globulin

VDRL

Venereal diseases research laboratory (a non-specific test for syphilis)

WBC

White Blood Count

WHO

World Health Organization

XDR-TB

Extensively Drug resistant Tuberculosis

Pyrazinamide

ZAP

Zoster-associated pain

ZDV

Zidovudine (anti-retroviral)

SECTION 1 ANTIRETROVIRAL TREATMENT (ART) IN ADULTS A.

GOALS OF ART

The primary goal of ART is to decrease HIV&AIDS-related morbidity and mortality  The patient should experience fewer HIV-related illnesses  The patient’s CD4 count should rise and remain above the baseline count  The patient’s viral load should become undetectable (<400 copies /ml), and remain undetectable on ART

The secondary goal is to decrease the rate of new HIV infections through:  Reducing the risk of HIV transmission from mother to child

B. SELECTION CRITERIA 1.

Medical indications o CD4 count ≤ 250 cells/mm3 irrespective of WHO Clinical stage OR

o WHO Clinical Stage IV irrespective of CD4 count (with the exception of tuberculosis, when the CD4 criterion of ≤ 250 cells / mm3 should be applied) OR o Other severe HIV-related conditions or co-morbidity. This group of conditions requires specialist diagnosis and recommendation. Examples of conditions in this category include:     

Immune Thrombocytopenic Purpura and Thrombotic Thrombocytopenic Purpura Severe manifestations of the diffuse infiltrative lymphocytic syndrome (e.g. lymphocytic interstitial pneumonitis, polymyositis) MDR or XDR tuberculosis Severe hidradenitis suppurativa Patients being treated for non-HIV-related metastatic or disseminated malignancies

Psychosocial considerations (not exclusion criteria):

      



Demonstrated reliability, i.e. patient has attended three or more scheduled visits to an HIV clinic No active alcohol or other substance abuse No untreated active depression Disclosure: it is strongly recommended that patients have disclosed their HIV status to at least one friend or family member OR have joined a support group If possible the patient should identify a treatment supporter who should also receive information and be educated on ART Insight: patients need to have accepted their HIV positive status. They need to have insight into HIV infection, the role of ART and the consequences of non-adherence before commencing therapy Patients should be able to attend the antiretroviral treatment facility on a regular basis or have access to services that are able to maintain the treatment chain. Where access is problematic for patients due to distances for example, clinic staff need to ensure that arrangements be made for these patients to facilitate access to care Patient expresses willingness and readiness to take ART

N.B. Patient selection: The final decision to initiate ART should be taken by a multidisciplinary team (community adherence supporters, counsellors, nurses, pharmacists, doctors, nutritionists and social workers) at the treatment point once the patient has accepted the treatment option. The clinician in charge will initiate treatment. Table 1: Summary of criteria for ART initiation in adults

CD4 ≤250 cells/ mm3 irrespective of WHO Clinical stage OR WHO Clinical Stage IV*, irrespective of CD4 count OR Other severe HIV-related conditions or co-morbidity (specialist-initiated) AND Patient expresses willingness and readiness to take ART Note: see WHO staging tables in Appendix 1 * Except tuberculosis, when the CD4 criterion of ≤ 250 cells / mm3 should be applied

ASSESSMENT FOR TREATMENT READINESS

ART Readiness Assessment and Preparation The first 2 – 4 weeks:

1.1

First visit:  Confirm the selection criteria: clinical staging and laboratory (CD4)

 

     



  1.2

Identify those with TB (symptom screening and tests, see section 14) and pregnant women (history, examination, pap smear where applicable and pregnancy test) Perform the following baseline investigations: o FBC o ALT o Hepatitis B surface antigen Perform a Pap smear for all women if not done in the last twelve months Take comprehensive history & examine the patient including weight, height and BMI Treat any opportunistic infection Patients must meet with members of the multi-disciplinary team individually or as a group for information and one on one counselor Treatment adherence counselor will discuss issues around the need for treatment, the rationale for adherence and strategies that will overcome barriers to adherence with the patient The patient advocate or community adherence supporter will do a basic psychosocial assessment to document the patient’s social issues and current psychological state, focusing on factors which might have an impact on the patient’s adherence. This is to evaluate issues that might impact on long term adherence. In some cases, it may be necessary to do a home visit A 28-day supply of co-trimoxazole is given to the patient as part of long term prophylaxis against PCP and other bacterial infections as well as a measure of their adherence (patient must be informed of potential side effect of cotrimoxazole) The patient is given a set of dates to return for more adherence counselling, training and education Confirm correctness of the contact details

Second visit  Clinical assessment and review of results • Elevated ALT Results  If the baseline ALT is elevated, repeat this to confirm the result  If ALT is less than two and a half times the upper limit of normal, ART can be commenced and ALT monitored monthly for three months  Patients with ALT higher than this should be referred for specialist opinion  Hepatitis B surface Ag positive  If the hepatitis B surface antigen is positive, the patient should be commenced on Tenofovir, 3TC and EFV (or Kaletra in pregnancy and women of childbearing age).  Serum creatinine and creatinine clearance tests must be done prior to initiating patients on Tenofovir  Perform a Pap smear for all women if not done in the last twelve months  Information and education session  Adherence check using co-trimoxazole pill count

This should not take more than 4 weeks. Patients with CD4 counts of <50 cells / mm3 should be considered for a shorter assessment and preparation period. In all cases, long term ongoing education on adherence should be given during the course of treatment. 1.3

Assessing patient readiness: multidisciplinary team discussion ART readiness criteria may include the following:  Patient’s acceptance of their HIV status and the need for ART  Medical and psychosocial criteria met  Absence of severe medical contra-indication (active disease that is not stabilized, including depression)  Patient’s understanding of the importance of adherence and attendance to all scheduled pre-treatment visits and educational sessions Patients who, on nonmedical grounds, do not meet the treatment readiness criteria should be referred for further counselling and education.

ART commencement visit The clinicians should:  Assess patient’s condition and readiness  Check Baseline laboratory results including Pap smear result  Confirm absence of pregnancy in female of childbearing age  Elevated ALT Results • If ALT is less than two and a half times the upper limit of normal, ART can be commenced and ALT monitored monthly for three months • Patients with ALT higher than this should be referred for specialist opinion  Hepatitis B surface Ag positive 1. If the hepatitis B surface antigen is positive, the patient should be commenced on Tenofovir and 3TC 2. Note that these antiretrovirals must not be stopped, even if the patient fails first line therapy, as severe flares of hepatitis B may occur  Elevated Creatinine levels • All patients with elevated creatinine level require assessment by a doctor trained in ART before commencing treatment that includes Tenofovir • Tenofovir is contraindicated if GFR <50ml/min or with a creatinine clearance of < 50ml/min (refer patient for specialist opinion) • Dose modification for AZT, d4T, 3TC and ddI is necessary with elevated creatinine   

Prescribe appropriate ART regimen Provide detailed description and dosing of the antiretroviral drugs Discuss further information and adherence issues with the patient and his/her counselor or advocate

The pharmacist should:

    

Re-assess patient’s readiness Do a co-trimoxazole pill count Provide detailed description and dosing of the antiretroviral drugs Ensure that dosing instructions are clearly written on the container with a permanent marker Discuss further information and adherence issues with the patient and his/her counselor or advocate

RECOMMENDED ART REGIMENS IN ADULTS

Antiretroviral drugs are often used in triple therapy combinations in order to enhance efficacy and to prevent or delay the emergence of drug resistance. Selection of a combination should be individualized. Patients who are already on ART and who are doing well with their treatment should not be changed to a new regimen unless their condition requires the clinician to do so (ie onset of severe side effects, pregnancy, treatment failure, etc) The following new regimens refer to new patients requiring to start ART 1. FIRST LINE ART REGIMENS Regimen 1a : Stavudine/Lamivudine/ Efivarenz Unless it is contra-indicated, all patients should be commenced on Regimen 1a: Contraindications to the use of Regimen 1a: • Contra-indications to Efavirenz o First trimester of pregnancy o Patients on psycho-active drugs o Female of childbearing age who want to conceive or are not using effective and consistent contraception • Contra-indications to Stavudine (d4T) o Female with BMI > 28 o Patients with symptoms of pre-existing neuropathy o Previous history of severe d4T toxicity • Patients with positive Hepatitis B surface Ag Regimen 1b: Stavudine/Lamivudine/ Nevirapine Indications: Unless contra-indicated, all women of child-bearing age as well as women who are in the first trimester of pregnancy on regimen 1a should be commenced on regimen 1b. Contraindications to the use of Nevirapine • Grade 3 or more of ALT elevation (>5 times upper limit of normal) • Avoid using with Rifampicin during the treatment of TB Contraindications to the use of Stavudine (see 1a)

Regimen 1c: Zidovudine/Lamivudine/Efivarenz orNevirapine Indications: Recommended for women with a Body Mass Index > 28 and in case of d4T toxicity (severe peripheral neuropathy, mild hyperlactatemia without lactic acidosis) Contraindications to the use of Zidovudine â&#x20AC;˘ Hb below 6.5g / dl or Neutrophil count below 0.5 X 10 9 / l especially if also on cotrimoxazole Contraindications to the use of Efavirenz and Nevirapine (see 1a and 1b) Regimen 1d: Tenofovir/Lamivudine/Efivarenz or Nevirapine Indications: Recommended for patients who experience d4T toxicity (with moderate or severe lactic acidosis, significant lipoatrophy, diabetes) and those with a positive Hepatitis B surface Ag serology result. All cases of severe d4T toxicity must be reported through an Adverse Drug Reaction report. ADR forms must be filled prior to initiating Tenofovir. Contra-indications to the use of Tenofovir â&#x20AC;˘ Contraindicated if GFR <50ml/min or with a creatinine clearance of < 50ml/min. Contraindications to the use of Efavirenz and Nevirapine (see 1a and 1b) 2. RECOMMENDED DOSING SCHEDULE AND COMBINATIONS FOR FIRST LINE DRUG REGIMENS Regimen 1a Stavudine (d4T) 30 mg 12 hourly (this dose should be given regardless of weight or BMI) AND Lamivudine (3TC) 300mg, daily or Lamivudine 150mg 12 hourly AND Efavirenz (EFV) 600 mg at night (400 mg if <40 kg) Regimen 1b Stavudine (d4T) 30 mg 12 hourly (this dose should be given regardless of weight or BMI) AND Lamivudine (3TC) 300mg, daily or Lamivudine 150mg 12 hourly AND Nevirapine 200 mg daily for the first 2 weeks, increasing to 200 mg every 12 hours after this( unless there are contraindications)

Regimen 1c Zidovudine(AZT) 300mg 12hrly AND Lamivudine (3TC) 300mg, daily or Lamivudine 150mg 12 hourly AND Efavirenz (EFV) 600 mg at night (400 mg if <40 kg) OR Nevirapine 200 mg daily for the first 2 weeks, increasing to 200 mg every 12 hours after this( unless there are contraindications) Regimen 1d Tenofovir (TDF) 300mg daily AND Lamivudine (3TC) 300mg daily, or Lamivudine 150mg 12 hourly AND Efavirenz 600 mg at night (or 400 mg if <40 kg) OR Nevirapine 200 mg daily for the first 2 weeks, increasing to 200 mg every 12 hours after this( unless there are contraindications) 3. APPROACH TO DRUG SUBSTITUTION IN FIRST LINE REGIMENS The management of patients who have previously been on ART and any switching of drugs needs to be discussed with a HIV clinician. All Adverse effects or suspected toxicities must be reported through ADR forms before the switch is made . Table 2: Summary of considerations for substitutions in first line therapy. Clinical indication Substitution Known toxicity and benefits Peripheral neuropathy AZT for d4T Women with body mass index >28 AZT for d4T Liver disease EFV for NVP Hepatitis B surface antigen positive TDF for d4T

Psychosis or untreated depression

NVP for EFV

Symptomatic hyperlactataemia

TDF for d4T

Significant lipoatrophy

TDF for d4T

Stavudine causes peripheral neuropathy Stavudine is higher risk for symptomatic hyperlactataemia/lactic acidosis Nevirapine is higher risk for hepatitis Tenofovir and lamivudine are active against hepatitis B and HIV – the combination protects against hepatitis B resistance. Specialist initiated Efavirenz has neuropsychiatric side effects Tenofovir has a low potential for mitochondrial toxicity – see Section 4 Tenofovir has a low potential for mitochondrial toxicity – see Section 4

4. MONITORING DRUG BENEFITS AND TOXICITY FOR FIRST LINE ART REGIMENS Table 3: Routine monitoring for ART First line Regimens Regimen Drugs Monitoring tests 1a

d4T / 3TC / EFV

d4T / 3TC / NVP

AZT / 3TC / EFV or NVP

Frequency



CD4



Staging, 6 monthly



@3 months, then 6 monthly



ALT



Baseline

 

FBC Hep BsAg

 

Baseline Baseline



CD4



Staging, 6 monthly @3 month then 6 monthly



ALT



Baseline, week 2, 4, 8, 12 thereafter 6 monthly

 

FBC Hep BsAg

 

Baseline Baseline



CD4



Staging, 6 monthly @3 month then 6 monthly



ALT (if NVP use)



Baseline, week 2, 4, 8, 12 thereafter 6 monthly



FBC



Hep BsAg



Baseline then monthly for 3 months then at 6 months then 6monthly Baseline



CD4



ALT (if NVP use)



Baseline, week 2, 4, 8, 12 thereafter 6 monthly



Creatinine clearance



Baseline, monthly x3, 6 months, then 6 monthly

 •

FBC Hep BsAg

 

Baseline Baseline

TDF / 3TC / EFV or NVP

Staging, 6 monthly @3 month then 6 monthly

CONSIDERATIONS FOR CHANGING ART REGIMEN 1

Treatment failure can be defined as virologic, immunologic or clinical • • • •

Treatment failure results from failure to suppress viral replication with the development of viral resistance Secondary virologic failure is a 1-log (10 fold) increase in the lowest recorded level The immunologic failure is defined as a 50% drop in CD4 count from peak value, or a return to pre-ART baseline or lower Clinical failure is progression of disease with development of opportunistic infections or malignancy occurring three months or more after initiation of ART

The commonest cause of the virological failure is poor adherence to treatment. All efforts and attempts should always be made to improve adherence before changing regimens is considered (see section 3 on adherence). Patients who have experienced virological failure with good adherence may be changed to second-line therapy Table 4: Viral load monitoring for patients in regimen 1

Viral load (VL) <400 copies/ml 400-1000 copies/ml

>1 000 copies/ml

Response  6-monthly viral load monitoring  Routine adherence support. Repeat viral load in 6 months  Begin step-up adherence package. Review at next 6-month viral load check.  If <400, return to routine 6-monthly monitoring and adherence support.  If still between 400 and 1 000, continue with step-up adherence package. Repeat viral load at 6 months.  If >1 000, despite stepped-up adherence support, switch to second-line therapy only if adherence is >80%. Repeat viral load in 3 months  Begin step-up adherence package. Review at next 6-month viral load check.  If <400, return to routine, 6-monthly monitoring and adherence support.  If between 400 and 1 000, continue with step-up adherence package. Repeat viral load again after a further 6 months.  If >1 000, despite stepped up adherence support, switch to second-line therapy only if adherence is >80%.

6. SECOND LINE ART REGIMENS Indications for switching to second line regimen: Second line regimens should only be considered for patients who have experienced virological failure in spite of a good drug adherence record. Specifically, the following patients should be considered for second line regimens: â&#x20AC;˘ Failure to suppress viral load to (<400 copies/ml) within 6 months of starting any first line regimen. â&#x20AC;˘ If viral load >1 000copies/ml despite stepped up adherence support Regimen 2a: Zidovudine/Didanosine/Lopinavir/ritonavir All patients with virological failure on regimen 1 should be switched to regimen 2a unless contraindicated. Women with BMI > 28 initiated on AZT as well as pregnant women should continued with AZT in the second line regimen.

Regimen 2b: Tenofovir/Lamivudine/Lopinavir/ritonavir Recommended for patients who have developed severe toxicity to d4T and with virological failure on Regimen 1. N.B. Didanosine must never be combined with Tenofovir! N.B Patients who are hepatitis B surface antigen positive must not stop Tenofovir and 3TC as severe flares of hepatitis B may occur. Patients in this situation should be discussed with an HIV clincician. Regimen 2c: Zidovudine/Didanosine AND double dose Lopinavir/ritonavir Recommended for patients who are on antiTB drugs containing Rifampicin and with virological failure to regimen 1. It is important to monitor liver function tests (ALT) monthly whilst on Rifampicin.

7. RECOMMENDED DOSING SCHEDULE AND COMBINATIONS FOR SECOND LINE DRUG REGIMENS Regimen 2a • Zidovudine (AZT) 300 mg every 12 hours AND • Didanosine (ddI) 400mg once a day (250mg daily if <60kg), taken alone, dissolved in water, on an empty stomach AND • Lopinavir/ritonavir (LPV/r) 400mg/100 mg every 12 hours N.B Didanosine must be taken alone, on an empty stomach, at least an hour before, or at least 2 hours after a meal. Less than 50% is absorbed if taken immediately after a meal. Tablets should be dissolved in at least 30 ml of water. No other liquids may be used to dissolve the tablets. There is no need to dissolve the enteric-coated version.

Regimen 2b • Tenofovir 300mg daily • •

AND Lamivudine (3TC) 300mg daily OR Lamivudine 150mg 12 hourly AND Lopinavir/ritonavir (LPV/r) 400mg/100 mg every 12 hours

Regimen 2c • Zidovudine (AZT) 300 mg every 12 hours AND • Didanosine (ddI) 400mg once a day (250mg daily if <60kg), taken alone, dissolved in water, on an empty stomach AND • Lopinavir/ritonavir (LPV/r) 800mg/200 mg every 12 hours 8. CLINICAL AND LABORATORY MONITORING FOR PATIENTS ON SECOND LINE ART REGIMENS  

The patient's response to therapy will be monitored by CD4 count. Assessment will be after 6 months.

8.1 Scheduled visits Patients starting ART Regimen 2 need to be seen by a doctor at least once a month for the first 3 months. Thereafter the visits should be once in six months or as required. Drugs need to be collected every month.

Table 5: Summary of adult ART Regimen 2 and routine monitoring

Regimen

Drugs

AZT / ddI / lopinavir / ritonavir

TDF/3TC/lopinavir/ritonav ir

AZT / ddI / double dose lopinavir /ritonavir

Monitoring tests

Frequency



CD4



6-monthly



FBC



Baseline, then monthly for 3 months, at 6 months then 6monthly



Fasting cholesterol and triglyceride



Baseline, 3 months and thereafter every 12 months



Fasting glucose



CD4



Baseline, 3 months and thereafter every 12 months 6-monthly



Creatinine Clearance



Baseline, monthly X3 , 6 months, 6 monthly



Fasting cholesterol and triglyceride



Baseline, 3 months and thereafter every 12 months



Fasting glucose



Baseline, 3 months and thereafter every 12 months



CD4



6-monthly



FBC



Baseline, then monthly for 3 months, at 6 months, 6monthly



Fasting cholesterol and triglyceride



6-monthly Baseline, 3 months and thereafter every 12 months



Fasting glucose



6-monthly Baseline, 3 months and thereafter every 12 months

8.2 Unscheduled visits for patients under regimen 2 ď&#x201A;§ Clinical judgment will be used to assess the need for additional safety investigations depending on the presenting adverse event. 9. MANAGEMENT OF TREATMENT FAILURE AFTER THE SECOND LINE REGIMEN Salvage therapy is currently not available in the public health sector. The drugs needed for salvage therapy are not yet available in South Africa. Studies have shown clinical benefit in continuing on Regimen 2 despite virologic failure. The CD4 count typically continues to increase or remain stable provided the viral load is less than 10 000. Therefore patients failing after the second line regimen should receive increased adherence support. ART should be continued until there is no frther clinical benefit from treatment. If paients experience AIDS-defining (WHO stage 4) illnesses on second-line therapy, they should be referred to an HIV clinician to discuss stopping ART and starting palliative care. Table 6: Recommended adult ART regimens in summary Regimen 1a 1b 1c 1d 2a 2b 2c

Drugs d4T/3TC/EFV d4T/3TC/NVP AZT /3TC/EFV or NVP (women with BMI>28) TDF/3TC/EFV or NVP (d4T toxicity) AZT/ddI/lopinavir/ritonavir TDF/3TC/lopinavir/ritonavir (d4T toxicity and virological failure on regimen 1) AZT/ddI/double dose lopinavir/ritonavir (on antiTB drugs and virological failure on regimen 1)

10. CLINICAL AND LABORATORY MONITORING FOR PATIENTS ON ART 10.1 Scheduled visits Patients should attend clinics monthly to collect medication. The pharmacy must play a role in adherence counselling. Patients should be seen by the professional nurse who should assess drug tolerance, adverse events and adherence. Ideally pills should be counted by the relevant health worker, nurse, doctor, pharmacist, pharmacy assistant or the counsellor at each scheduled visit. Patients that are on nevirapine should, in addition to the regular schedule, be seen two weeks after initiation of ART in order to monitor: ď&#x201A;§ for adverse events

 

ALT levels ensure the correct dosing

10.2 Down referrals All patients should be seen monthly for the first 6 months. Patients that are well and have responded well to ART can be considered for referral to a lower level of care within the same service point. Patients who are not well, should be seen more frequently as determined by the doctor or nurse responsible for care. 10.2.1 Indications for “down-referral” 10.2.1.1 Adult ‘down-referral’ Criteria from initiation to maintenance site: a) b) c) d) e)

Clinically stable (as determined by the clinician / s that care for the patient). Patient has completed at least six months of ART. No current serious side effects and adverse drug reactions. Undetectable viral load (less than 400 RNA copies per mL). No serious co-morbidities (e.g. kidney transplant, lymphoma, etc).

Table 7 summarizes the time events schedule for patients eligible for ART CD4 counts are done 6-monthly while patients are on Regimen 1. Viral loads are done at 3months and at 6 months after initiation and 6-monthly thereafter while patients are on Regimen 1. Viral load is not done for patients on regimen 2

Table 7: Time events schedule Baseline tests for all patients on regimen 1: FBC, ALT, Mantoux test, Pregnancy test, papsmear and Hep B s Ag. See below for additional baseline tests for specific regimens Baseline Assessment

Screening week 4

Commen ce ART week 0

Education/ Therapeutic Counsellor visit Treatment Readiness assessment History Physical exam Complete registers Safety bloods Regimen 1b with NVP Safety bloods Regimen 1d with TDF Safety bloods Regimen 2a

Safety bloods Regimen 2b With TDF

Safety bloods Regimen 2c

Viral load CD4 count Adverse events Adherence check

Week 2

Week 4 (M1)

Week 8 (M2)

Week 12 (M3)

Month 4

Month 5

month 6

6 Month ly

D N

Whole team D D N

D D N

ALT

Cr FBC,

Fasting cholesterol& triglyceride

Fasting glucose FBC, Cr Fasting cholesterol& triglyceride Fasting glucose FBC,

Fasting cholesterol& triglyceride

Fasting glucose

Nb Cr

Nb D N/P P/N TC / D

D/P P/N TC / D

N/P P/N TC / D

N N/P

C = counsellor; D = doctor; N = nurse; TC = therapeutic counsellor; PA = patient advocate; P = pharmacist For information on a, b, c, see below a. b. c.

N TC/N

Nb Cr

For patients on nevirapine, ALT will be taken at baseline, Week 2, 4 and 8, 12 then 6 monthly. For patients on ART Regimen 2, FBC will be done monthly for the first 3 months, then 6 monthly. Fasting cholesterol, triglycerides and fasting glucose will be done as in Table 6. Calculate monthly adherence = (tablets dispensed â&#x20AC;&#x201C; tablets returned)/ (tablets prescribed), e.g. (30 â&#x20AC;&#x201C; 5)/28 = 25/28 = 0.9 (90%).

D N D/P P/N TC/ D

11. THE IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS) IRIS occurs when improving immune function unmasks a previously occult opportunistic infection which subsequently presents with an unusually aggressive inflammatory presentation, or causes paradoxical deterioration of an existing opportunistic disease. Patients with advanced HIV disease, particularly those with a CD4 count < 50 cells mm3, may become ill with an immune reconstitution inflammatory syndrome (IRIS) during the first 3 months of ART. Tuberculosis is the commonest presenting IRIS reaction in South Africa. About a third of patients starting ART when on treatment for tuberculosis will experience recurrence of their TB symptoms/signs or worsening or new manifestations. The commonest of these presentation is with enlarging lymph nodes, often with extensive caseous necrosis. It is important to exclude multidrug resistance in these cases. Also, opportunistic infections may present in atypical ways during this phase of immune reconstitution. Patients need to be referred to an experienced HIV clinician for advice regarding investigation and management. IRIS is not indicative of drug failure or drug side effects. It is not a reason to stop ART, or to change the antiretroviral regimen.

12. MANAGEMENT OF PATIENTS PREVIOUSLY TREATED WITH ANTIRETROVIRAL THERAPY (or non naïve patients) Patients who are already on ART within the public sector and who are doing well with their treatment should not be changed to a new regimen unless their condition requires the clinician to do so Patients who commenced ART in the private sector and have stopped their treatment should be discussed with an HIV clinician before any treatment regimen is commenced.  Those patients who stopped for several reasons, but who were responding well, could recommence appropriate therapy and be monitored as per schedule. Patients who commenced ART in the private sector and are still on treatment should be discussed with an HIV clinician before any treatment regimen is commenced.  Those patients controlled on their antiretroviral medication should continue on their treatment or swap to the appropriate treatment protocol. Those patients who have failed a previous regimen should ideally be started on appropriate drugs they have not been exposed to before. 13. ART and PROPHYLAXIS OF OPPORTUNISTIC INFECTIONS 

Co-trimoxazole prophylaxis (or CPT) is indicated for all symptomatic HIV infected patients with WHO clinical stage 2,3 or 4 or HIV infected patients with CD4 < 200 cells/ mm3. CPT must be continued in all patients on ART until the CD4 count is >200 cells/mm3 for 6 months. It should be recommenced if the CD4 count drops to ≤ 200 cells/ mm3 when therapy fails.

 

Patients who have had cryptococcal meningitis must continue taking Fluconazole prophylaxis until the CD4 count is >200 cells/ mm3 for 6 months. Patients on Isoniazid preventive therapy (IPT) who start ART should complete their 6 month IPT regimen (together with pyridoxine to reduce the risk of developing peripheral neuropathy).

14. ART and CONCOMITANT TUBERCULOSIS (TB) IN ADULTS Tuberculosis is a common co-morbid illness with HIV. If an HIVpositive patient has symptoms suggestive of TB, 2 sputum specimens should be collected for 2 smears and a TB culture. It is very important to investigate patients for tuberculosis before starting ART: Suspect TB if 2 or more of the following are present: Observed weight loss of ≥ 1.5 kg over the past 4 weeks Cough >2 weeks Night sweats >2 weeks Fever >2 weeks Other symptoms may include loss of appetite, general feeling of illness (malaise) and tiredness, shortness of breath and/or chest pain

If TB is diagnosed, there are two scenarios to consider: 14.1 The patient that develops tuberculosis while on ART ART should be continued throughout TB treatment, with changes to ART regimens (for patients on Rifampicin containing TB treatment) and monitoring as follows:  ART Regimen 1: A change to Efavirenz is recommended for patients on Nevirapine wherever possible. If this is not possible (e.g. intolerant of efavirenz or significant risk of falling pregnant), nevirapine may be continued in selected cases, with monthly ALT monitoring.  ART Regimen 2: Double dose lopinavir/ritonavir is recommended as in Regimen 2c. This should be accompanied with monthly ALT monitoring. 14.2 The patient that presents with TB before commencing ART  

If the patient has no history of WHO Stage IV illness, and has a CD4 count > 250 cells/ mm3, ART is not indicated. o The need for ART should be reassessed on completion of TB treatment. If the patient has a history of WHO Stage IV illness (other than TB), and/or a CD4 count ≤ 250 cells/mm3, complete 2 to 8 weeks of TB therapy before commencing ART. o Patients with a very low CD4 should be started on ART as soon as ready and stable with TB treatment o Patients in this group should be started on first-line therapy – Regimen 1a.

Table 8: Common shared side-effects of TB and ART Side effects ART Nausea didanosine, zidovudine,

Tuberculosis treatment pyrazinamide

protease inhibitors Hepatitis

nevirapine, efavirenz

rifampicin, isoniazid, pyrazinamide

Peripheral neuropathy

stavudine, didanosine

isoniazid

Rash

nevirapine, efavirenz

rifampicin, isoniazid, pyrazinamide

14.3

Recommended dosing schedule and combinations in patients with commitant TB disease

Patients should be counselled about the following:  Treatment for TB together with ART involves taking a large number of tablets.  When ART is commenced, the patient’s TB symptoms may temporarily worsen as part of immune reconstitution. Scenario 1: TB develops while on ART Continue ART throughout TB treatment. Patients on first-line therapy containing nevirapine should generally be swapped to efavirenz as follows: First-line therapy: • • •

Stavudine 30 mg every 12 hours AND Lamivudine 300mg or 2X 150mg daily or 150 mg every 12 hours AND Efavirenz 600 mg at night

Second-line therapy: • Zidovudine (AZT) 300 mg every 12 hours AND • Didanosine (ddI) 400 mg once a day (250 mg daily if <60 kg) on an empty stomach AND • Double dose lopinavir/ritonavir 800/200 mg every 12 hours Scenario 2: TB disease before ART is started: a) CD4 cell count >250 cells/mm3 (and no other HIV-related symptoms): Start TB treatment. Assess the need for ART after completing TB therapy, using CD4 and clinical criteria. b) CD4 cell count <250 cells/mm3: Delay ART until after 2 - 8 weeks intensive phase of TB therapy. Then start on regimen 1a as below: First-line therapy:

• • •

Stavudine 30 mg 12 hourly AND Lamivudine 300mg or 2X 150mg daily AND Efavirenz 600 mg at night

c) CD4 cell count of <50 cells/mm3 or other serious HIV illness: Introduce ART as soon as the patient is stabilized on TB therapy (no less than 2 weeks between starting TB therapy and starting ART). N.B In these patients, intensive education, counselling and support is a critical predictor of adgerence and treatment outcomes. 15. PREGNANCY AND ANTIRETROVIRAL TREATMENT 15.1 PRINCIPLES OF MANAGEMENT • •

•

The current SA guidelines for ART recommend initiating ART in patients with WHO clinical stage 4 or CD4 ≤ 250 cells/mm3. A woman who becomes pregnant whilst on ART should have EFV switched to NVP in the first trimester. After the first trimester there is no need for the switch. Adverse event monitoring (including foetal anomaly scans) is critical in all cases. Nevirapine-based regimen is not recommended in women with a CD4 cell count >250cells/ mm3 because of the increased risk of toxicity.

15.2 COUNSELLING AND TESTING FOR PREGNANT WOMEN • • • • •

All pregnant women should be offered HIV testing at their initial booking visit.(i.e. all should be pre-test counselled and then offered an HIV test). Finger pricks should be performed at the same time as routine antenatal booking blood specimens are taken. Women who test HIV positive on the rapid test should have a CD4 count taken on the same day. The result of this CD4 should be checked within a week and documented. Women who decline an HIV test should, at every antenatal visit, be encouraged to take the test. Women who tested HIV negative in pregnancy should be offered a repeat HIV test at 34 weeks gestation.

15.3 ART FOR PREGNANT WOMEN

Women with medical indications for ART should be intiated on treatment regardless of the gestational age of the pregnancy. In cases where this is not possible, the PMTCT Regimen should be given while preparations are made to start with ART as soon as possible after delivery. The approach to rediness preparation is the same as for non-pregnant adults. However, pregnant women who are eligible and are willing to take ART should not be on a waiting list. 15.4 RECOMMENDED ART REGIMENS a) Initiation regimen – Regimen 1b (CD4 ≤ 250 mm3, ALT < 100 U/L and Hepatitis B sAg negative) •

Monitor the patient closely during the first few months, including with ALT tests at weeks 2, 4 and 8. Then monitor the patient according to pregnancy requirements.

b) Pregnant women for special consideration Note nevirapine should be replaced with lopinavir/ritonavir if: • There is clinical evidence of liver disease • Hepatitis B surface Ag positive Commence on a mixed regimen, and avoid NVP Stavudine (d4T) 30mg 12 hourly AND Lamivudine (3TC) 300mg daily OR 150 mg 12 hourly AND Lopinavir/ritonavir 400/100 every 12 hours • • •

Request fasting cholesterol, triglycerides and glucose tests Monitor 4 weekly unless pregnancy or medical condition requires more frequent monitoring, or patient experiences side effects. Tenofovir should be considered post delivery if not breastfeeding.

c) Women who become pregnant whilst on ART • These women should continue ART throughout the pregnancy. • Women who become pregnant on an efavirenz-containing regimen should have efavirenz substituted with Nevirapine , monitoring ALT closely • Test VL at least once during pregnancy; at least after two months of ART. If the VL is greater than 1 000 copies/ ml intensive adherence counselling should be given with a repeat VL 1 month later. If there is no reduction in VL, the ART regimen should be changed to an appropriate regimen 2. (Note:It is not necessary to introduce nevirapine graduallly if previously on efivarenz) d) Regimen 2 in pregnancy - Regimen 2a

• Zidovudine (AZT) 300 mg every 12 hours AND • Didanosine (ddI) 400mg once a day (250mg daily if <60kg), taken alone, dissolved in water, on an empty stomach AND • Lopinavir/ritonavir (LPV/r) 400mg/100 mg every 12 hours 15.5

CLINICAL AND LABORATORY MONITORING DURING ANTENATAL CARE

•

Monitor pregnant women on ART at least once every 4 weeks and according to: o The antiretroviral drugs used o The underlying medical condition o Obstetric considerations.

•

At each follow-up visit: o Determine patient adherence to ART o Determine whether patient is experiencing any adverse reactions to ART

• • •

Monitor pregnant women initiated on Regimen 1b more closely Request ALT at weeks 2, 4, 8 and 12 then 6 monthly if normal Couple ALT elevation with a symptom directed evaluation.

15.5.1 MANAGEMENT OF ELEVATED ALT IN PREGNANCY • Stop ART if: o Grade 3 or more ALT elevation occurs (>5 times upper limit of normal)  AND/OR o Patient develops symptoms of hepatitis  AND/OR o Patient develops grade 3 or 4 rash, • Continue with co-trimoxazole prophylaxis. • Restart with lopinavir/ritonavir based ART once the patient’s symptoms and enzymes have returned to at least 2 times upper limit of normal.

15.6

ART DURING CHILD BIRTH • Offer HIV testing to women who did not take up the test during pregnancy. This should be done during first stage of labour or shortly after childbirth. • An elective Caesarean section done for obstetric indications before 38 weeks should offer additional benefit for PMTCT. • Continue ART during labour and after delivery. • Ensure that pregnant women on the PMTCT regimen do not miss doses around the time of delivery. • Keep an emergency stock of ART in the Labour ward for women who present to the labour ward after hours and do not have their medication with them.

15.7 TREATMENT STRATEGY FOR INFANTS BORN TO HIV POSITIVE WOMEN • Administer sdNVP as soon after birth as possible but within 72hours period • Commence AZT soon after birth o For 7 days o For 28 days to infants born to women who received suboptimal PMTCT or ART  where no maternal ARVs were taken  where maternal ARVs (PMTCT or ART regimen) were taken for less than 4 weeks  where women only received sdNVP Table 9: PMTCT Infant Dosing Guide

Drug

Weight

Dose

Notes

NVP syrup (10mg/ml)

>2kg

0.6ml (6mg) stat 0.2ml/kg stat (2mg/kg) 1.2ml 12 hrly (12mg 12 hrly)

To be administered as soon after birth as possible as a single dose(sdNVP)

< 2kg AZT syrup (10mg/ml)

>2kg

For 1 week if mother received 28 days of AZT or ART, otherwise for 4 weeks. Administered with a 2ml syringe

15.8 POSTPARTUM CARE • Offer HIV testing to women who were not tested during pregnancy or around time of childbirth. • Provide infant feeding counselling, assessment for indications for ART and other HIV-related care to HIV positive women. • Provide women who plan on leaving the geographic area of the clinic following delivery with: o A referral letter containing all relevant clinical details o Details of clinic that offers PCR testing o Sufficient antiretroviral medication to ensure that she will not run out of medication before reaching the referral clinic. • Discuss family planning choices. • Request women to return at six weeks post delivery for: o Cervical cancer screening,

o For infant diagnosis (if not performed by the baby wellness clinic) o To ensure the infant has been initiated on co-trimoxazole prophylaxis. • Request women to return for cervical smear results, infant HIV diagnosis and appropriate referral for ongoing care. • Refer women who have completed postnatal care to a Comprehensive Care Management and Treatment service point. 15.9

ART IN PREGNANT WOMEN WITH TUBERCULOSIS Screen pregnant HIV positive women for signs and symptoms of tuberculosis. o Collect sputum for microscopy and TB culture, and o Do a safe chest radiograph If TB is diagnosed (clinically as above or microbiologically) there are two scenarios to consider:

a) The pregnant women who develop tuberculosis while on ART Regimen 1a: If beyond her first trimester should continue on this regimen. Regimen 1b: Continue on this regimen and monitor ALT every two weeks. Regimen 2: Change to regimen 2c until two weeks after completion of antiTB treatment b) The pregnant women who qualify for ART and are diagnosed with TB before commencing ART • Prioritise treatment of TB • Start ART only after patient has stabilized on TB treatment (at least two weeks later). • Delay starting ART in the first trimester, unless there is severe morbidity or a very low CD4 count < 50 cells/ mm3. • Use Nevirapine only with tight toxicity monitoring • Consider replacing Efivarenz with Lopinavir/2Xritonavir

SECTION 2: MANAGEMENT OF HIV & AIDS INFECTION IN CHILDREN Guidelines for the management of HIV and AIDS in Children are available on print and have been posted on the DOH website. This section seeks to addresss the ART aspects of HIV and AIDS management in children. 1. INDICATIONS FOR ART IN CHILDREN 1.1 Clinical Criteria o Confirmation of diagnosis of HIV infection o Recurrent (> 2 admissions per year) hospitalizations for HIV complications or prolonged hospitalization for HIV (> 4 weeks) OR Table 10: Clinical criteria Child less than 1 year

1 – 5 years >5 years

Symptomatic ( WHO stage II, III, IV) or CD4 ≤ 35% or absolute count below 1500 Symptomatic (stage III, IV) or CD4 ≤ 20% Symptomatic (stage III, IV) or CD4 <15% or CD4 <250 cells.

1.2 Social criteria • These criteria are about ensuring adherence to treatment: o At least one identifiable caregiver who is able to supervise the child for administering medication (all efforts should be made to ensure that the social circumstances of vulnerable children, e.g. orphans, are addressed so that they too can receive treatment) o Disclosure to another adult living in the same house is encouraged so that there is someone else who can assist with the administration of medication 2. TREATMENT OF MOTHERS/ CAREGIVERS/OTHER FAMILY MEMBERS • Always ask about the caregiver’s health, and the health of other members of the family • Ensure that mothers and other family members access medical care timeously, including ART if needed • Attend mothers or caregivers at the same time as their children where possible HIV positive mothers in order to decrease the number of clinic visits and associated costs and time away from work.

3. RECOMMENDED PAEDIATRIC ART REGIMENS • Start all infants less than 6 months of age who require antiretroviral therapy on treatment under supervision by a doctor trained in ART. • Stavudine solution requires refrigeration. If no ‘fridge’ is available, stavudine capsules may be opened and dissolved, and the required amount administered to the child. The rest can be discarded. • Substitute stavudine capsules with Zidovudine suspension may if the caregiver experiences difficulty • Recommend lopinavir/ritonivir for: o Children under 3 years as one can assume that most in this age group will have received nevirapine for PMTCT. Resistance mutations have been shown to occur in almost half of children exposed to nevirapine in this fashion. Most resistance mutations fade within the first year. It is still unknown whether children with resistance mutation will have achieved resistance and therefore inadequate response to therapy with a regimen including an NNRTI. o Children under 3 years have higher viral loads and often have adherence problems and this makes lopinavir/ritinovir preferable. • Switch to tablets or capsules from syrups or solutions as soon as possible. • Keep lopinavir/ritonavir at (< 25º C) Refrigerate till dispensing.(can be kept out of the fridge for 42 days). Table 11: Recommended Paediatric ART Regimens

0 months up to 3 years

Over 3years and >10 kg

1st Line

2nd Line

Stavudine

Lamivudine (3TC)

Lopinivir/ritonavir

Efavirenz

Zidovudine (AZT)

Didanosine (ddI)

Nevirapine/ Efavirenz*

Lopinivir/ritonavir

* Efavirenz if the child is over 3 years and nevirapine if <3years

4. SINGLE DRUG SUBSTITUTION OF STAVUDINE WITH ABACAVIR Children who develop resistance or toxicity to Stavudine should be switched to Abacavir. 4.1 Toxicity warranting a switch: o Lactic acidosis o Peripheral neuropathy o Lipodystrophy. o Other manifestations like insulin resistance, hyperglycemia, hypertriglyceridaemia, hypercholesterlaemia and low HDL levels. o Viral load >400 copies/ml – continue o Viral load > 1000 copies/ml switch to 2nd line

SECTION 3: ADHERENCE TO ART 1. GENERAL CONSIDERATIONS •

The Adequate Preparation of patients; support of patients during treatment initiation and ongoing adherence monitoring and support are all critical to ensuring maximum sustained adherence

•

Adherence to ART is essential to maintain long-term health benefits and avoid development of drug resistance.

•

It is not possible for health care providers to reliably predict which individuals will ultimately be adherent to their treatment plan. This is because adherence does not correlate with gender, cultural background, socio-economic or education level nor does it correlate with language barriers between provider and patient.

•

It is therefore essential to provide all patients with a comprehensive strategy to support adherence that includes education, training, counselling, appropriate tools and community support.

•

The plan must make use of all members of the health care team, as well as the patient’s family and the community the patient comes from.

2. ADHERENCE SUPPORT, ASSESSMENT AND MONITORING 2.1 Role of the health care team • There is evidence that adherence to treatment and positive lifestyle choices decreases as time progresses. • Thus, monitoring and ongoing support of adherence is essential both at the clinic level as well as in the community. • New diagnoses, unexplained symptoms, opportunistic infections and high pill regimens are barriers to adherence. • Patients might have to be reassured and treated symptomatically if they experience minor symptoms like nausea and vomiting, on treatment initiation advise them on the transient nature of these. • Patients with depression might require referral and long-term management as depression impacts negatively on adherence. • A supportive and trusting relationship between the patient and members of the health care team is essential. • Optimal adherence requires full participation of the multi-disciplinary health care team: the patient, their family members and the community. • Every patient interaction with staff at the clinic is an opportunity for reinforcement of positive behaviour change. • Supportive and non-judgmental attitudes and behaviours will encourage patient honesty regarding adherence and problems.

2.2 The clinic team should commit to the following: • Communication between clinic visits, referral points as appropriate. • Ongoing adherence support with evaluation, monitoring and appropriate interventions • Timely response in the form of ongoing counselling and reassurance to any barriers such as adverse events, interim illness, issues around stigma and disclosure. • Interim management during holidays or other absences must be discussed with the patient. • If there is sub-optimal adherence, there should be extra support e.g.: o Investigate these barriers and assist with overcoming these o Recommend more visits with more frequent adherence checks o Enlist support of family/friends/ partners/ support group members o Review teaching approach o Increase home visits o Use reminders and reinforce with adherence tools 3. DEFINITION OF ADHERENCE TO ART • • •

Success of ART hinges on the correct medication-taking behavior. Ideal adherence means a patient must take more than 95% of their doses (i.e. missing less than 3 doses in a month) If a patient is taking less than 95% of their doses, they are at risk for developing viral resistance and ultimately virological failure.

Patients taking <80% of their doses are unlikely to have any durable virological suppression. They should be targeted urgently for adherence improvement and 3month follow-up as discussed in strategies to promote adherence below. 4. ISSUES WHICH IMPACT ON ADHERENCE 4.1

Personal: o Internalized stigma; external discrimination o Unresolved grief reaction o Lack of Disclosure

4.2

Environmental: o Pill burden and side effects o Income and food insecurity – underlying starvation o Negative staff attitudes o Lack of training of staff o Shift work

5. STRATEGIES TO PROMOTE ADHERENCE • •

• • • • •

The whole clinic team needs to support adherence at all points of intervention. Adherence counsellors (where possible, patient advocates; community health care workers, treatment supporters) need to:o Spend time with the patient and explain the goals of therapy and need for adherence to ensure virological suppression as many times as is necessary. o Consider monitoring of medications such as co-trimoxazole prior to ART initiation. o Negotiate a treatment plan that the patient can understand and to which he/she commits. o Tailor pill taking time to suite the patient’s lifestyle. o Encourage disclosure to family or friends who can support the treatment plan. o Inform the patient of potential side-effects – severity, duration and strategies for management of these. o Establish ‘readiness’ to take medications before ART initiation. o Provide adherence tools where available: written calendar of medications, tick sheets, patient diaries and patient self care ‘contracts’ etc. o Encourage use of pill boxes, alarms, pagers or other available mechanical aids for adherence. o Explain to patients how to avoid adverse drug-drug interactions. The patient must disclose any over-the-counter drugs and traditional medicines. Other medications as well as some traditional medicines cannot be taken concurrently with ART because they may result in poor ART therapeutic levels in the blood leading to viral resistance. Herbs and other over the counter preparation can lead to renal and liver toxicity, complicating the clinical picture of adverse events. Anticipate, monitor and treat side-effects. Include adherence discussions in support groups. Develop links with community-based organizations to support adherence. Encourage links with support groups. Create links with patient advocates.

6. PRE-TREATMENT ADHERENCE PACKAGE • Provide pre-treatment information and education as per visit schedule is critical for all patients. • Specific strategies are needed for young patients. • Introduce patient to the therapeutic counsellor and patient advocate if available and if agreed to or treatment buddies nominated by patient. • Arrange home visit if available to be undertaken by the nominated community care giver, or trained home based carer or other volunteer health care worker. • Use an assessment questionnaire to investigate potential adherence barriers and investigate strategies to overcome these like; o Access to drug and alcohol counseling o Social welfare for grant access. o Emergency relief for nutritional support. o Support with disclosure.

•

• •

Take co-trimoxazole count one month prior to commencing therapy. This is not to be used to exclude people from ART. It is meant to reinforce daily medication-taking behaviour from the beginning. It is also meant to identify potential problems before starting ART. Encourage attendance and participating in a support group. These should be ideally run by community members but might need to be supported by the clinic staff or adherence/ therapeutic counselors or social workers. Consider reward mechanisms for >95% adherent patients e.g. less waiting (faster queues)

7. ADHERENCE MEASURING TOOLS: (SEE ADULT PATIENT ADHERENCE RECORD & MONITORING FORM – PARMF [Appendix 2]) • • • • •

Pick up dates with variance to actual appointment dates need to be recorded, and followed up with the patient immediately if there is a significant variance Return of pills used to calculate pill usage Use 7 or 30 day recall of missed pills to assess non-adherence Visual analogue scales can also be used to measure the patient’s assessment of their own adherence according to a scale used by the treatment site. Set questions on adherence can also be asked at times of pill pick up to further monitor adherence

8. ADHERENCE PACKAGE FOR PATIENTS ON TREATMENT At each visit the following needs to be done: • Count ART pill-returns count (% doses missed) .Adherence goal is >95% doses taken. Patients with adherence <80% require increased adherence support (see below). • Do tablet count before the patient sees the doctor (can be done by the Pharmacist Assistant, Nursing Assistant or Community Care worker). • Doctor should review the count to evaluate adherence. • Missed/late clinic visits should trigger concerns about adherence. • Include <95% adherence patients in list for discussion and follow-up. • Intervene when a historical review of pill pick up dates against actual dates since last viral load testing highlights nonadherence trends Routine adherencediscussion (education) with the adherence counsellor is of value. • Avail yourself for questions and counseling patients when nonadherence occurs • Get a better profile of the patient and their environment through feedback from the therapeutic and adherence counselors. • Encourage participation in a support group where there is indication of failing adherence. • Continue monthly visit with therapeutic counsellors for first three months and quarterly thereafter. • Arrange regular community visits by patient advocates or community adherence workers for follow-up of patients who have shown non-adherent behaviour.

9. STEP-UP ADHERENCE PACKAGE FOR PEOPLE WITH REDUCED ADHERENCE OR VIROLOGICAL FAILURE •

•

• • • • • • • • •

This is necessary when the adherence assessment is <80% at any visit, with or without viral or clinical failure to: o Establish the cause and suggest appropriate interventions. o Re-educate the patient (and their buddy) about the importance of adherence. o To re-emphasize long-term benefits o To assign a community adherence worker or patient advocate to patient if not attached. Evaluate the support structures in place. o Are they appropriate? o How can they be improved? o What alternatives are there? Reinforce the use of adherence tools e.g. pillboxes and/or daily dosing diary. Insist on participation in a support group or link with a patient advocate/ community adherence worker. Consider doing a psychological profile and respond appropriately. Check the family situation (social worker and therapeutic counsellor). Redo the CAGE Assessment for alcohol abuse and other abused drugs. CAGE = Cutback; Anger; Guilt, Eye Opener. Increase home visits by therapeutic counsellors/patient advocates to daily or weekly, at a minimum (spot pill counts to be done at home). Consider directly observed therapy for an agreed period. Promote self-efficacy training.

SECTION 4: DIAGNOSIS AND MANAGEMENT OF ADVERSE EVENTS 1. PRINCIPLES OF MANAGING ADVERSE EVENTS • • • • •

•

Establish whether the adverse event is due to antiretroviral agents, other medication or other illness. Never stop only one antiretroviral drug. If there is a need to discontinue ART, all antiretroviral medications must be stopped together. Individual drugs may be switched due to intolerance as shown on Table 2 . A single drug switch should not be made if the patient is known to be virologically failing. Clinicians may continue ART if there is a mild or moderate adverse reaction. Adequate symptomatic therapy, counselling to reassure patients and monitoring are essential if this is done. Potentially life-threatening side effects of ART are: lactic acidosis, severe druginduced hepatitis, kidney toxicity, pancreatitis, severe drug rash and abacavir hypersensitivity reactions. All therapy should be interrupted immediately in these situations. Adverse events should be recorded and reported regularly to the HIV&AIDS programme at Head Office. Serious adverse events (SAEs) and deaths should be reported within 48-72 hours to the MCC National Adverse Drug Event Monitoring Centre, phone (012) 312-0000 Pretoria; or (021) 447-1618, fax: (021) 448-6181 Cape Town.

Adverse event forms should be available at all centres. 2. IMPORTANT ADVERSE REACTIONS Table 12: Important ART adverse reactions and safety monitoring Antiretroviral Adverse Reactions Abacavir (ABC)

   

Recommended safety monitoring A potentially fatal hypersensitivity reaction Clinical develops in approximately 3% -5% of patients. Symptoms usually appear within 6 weeks of treatment initiation. Suspect reaction if symptoms from 2 or more of the following groups are present: Fever maculopapular pruritic generalised rash gastro-intestinal symptoms other symptoms (including pharyngitis, dyspnoea, cough, musculoskeletal disorders, malaise, fatigue, lymphadenopathy and paraesthesia) Never give abacavir to a patient who has previously developed an abacavirhypersensitivity reaction

Antiretroviral

Adverse Reactions

Recommended safety monitoring

Didanosine (ddI)

Pancreatitis, peripheral neuropathy, GIT effects (bloating, flatulence, nausea, diarrhoea), hyperlactataemia, lactic acidosis. CNS disturbances (dysphoria, vivid dreams, distractedness, dizziness) Skin rash, hepatitis Congenital anomalies – avoid during 1st trimester of pregnancy. Generally well tolerated. GIT symptoms (mainly diarrhoea), lipid and glucose abnormalities, lipodystrophic changes.

Clinical

Efavirenz (EFV)

Lamivudine (3TC) Lopinavir/ Ritonavir Nevirapine (NVP)

Ritonavir

Stavudine (d4T) Tenofovir (TDF) Zidovudine (AZT)

Clinical

Clinical Fasting cholesterol and triglycerides and glucose at baseline, 6 months and thereafter every 12 months. ALT at baseline and at week 2, 4, and 8, and 12 and any time hepatitis symptoms occur Fasting cholesterol and triglycerides and glucose at baseline, 6 months, and thereafter every 12 months. Clinical

Skin rash (16%), nausea, vomiting, hepatitis (can be fatal). Toxic hepatitis: avoid in females with CD4>250 cells/mm3 and in males with CD4>400 cells/mm3 Bad taste, GIT symptoms, especially diarrhoea. Raised liver enzymes, raised cholesterol and triglycerides and glucose intolerance, lipodystrophic changes. Peripheral neuropathy, hepatic steatosis, hyperlactataemia, lactic acidosis, pancreatitis. Nephrotoxicity, bone demineralisation Check creatinine at baseline and 6-monthly Bone marrow suppression (anaemia, neutropenia), Hb and neutrophils count at GIT symptoms, myopathy, headaches, baseline, then at months 1, 2, hyperlactataemia, and lactic acidosis. 3 and 6. Anaemia: avoid in Hb < 6.5 g/dl

3. SPECIFIC ADVERSE REACTIONS 3.1 Symptomatic hyperlactataemia and lactic acidosis •

Lactate is normally produced by all the body’s cells as part of anaerobic metabolism. Nucleoside reverse transcriptase inhibitors (NRTIs) have the potential to directly inhibit the human enzyme mitochondrial DNA polymerase gamma, which is responsible for mitochondrial DNA synthesis. Reduced DNA synthesis results in less synthesis of essential mitochondrial proteins. The consequence is the formation of mitochondria which are structurally and functionally impaired, resulting in decreased oxidative capacity of each mitochondrion. Anaerobic metabolism with lactate overproduction and cellular dysfunction is the result.

•

Different NRTIs have different risk profiles for causing hyperlactataemia. These drugs have only been implicated if used in combination with higher risk drugs or in patients with co-morbidities. Their risk is directly proportional to their inhibitory effect on polymerase chain reaction in the following order (highest to lowest risk): o Combination of didanosine (ddI) and stavudine (d4T) o ddI

o o o o o •

d4T Zidovudine (AZT) Lamivudine (3TC) Abacavir (ABC) Tenofovir (TDF).

Other manifestations of NRTI mitochondrial toxicity are: o Hepatic steatosis o peripheral neuropathy o lipoatrophy o Pancreatitis o Myopathy o Cardiomyopathy o HIV-associated neuromuscular weakness syndrome (a Guillain-Barre like syndrome that occurs secondary to NRTIs) and o cytopaenias.

3.1.1 Hyperlactataemia and lactic acidosis • •

• •

•

• • •

A normal venous lactate is less than 2, 5 mmol/l and arterial lactate less than 2, 0 mmol/l. Hyperlactataemia is present when: o Lactate is raised, but o Blood pH is > 7.35 and o Standard bicarbonate > 20, It may be asymptomatic or symptomatic. Asymptomatic hyperlactataemia is common when using NRTIs (occurs in up to 25% of patients on NRTIs), but does not predict for the symptomatic form of the disease. Routine monitoring of lactate is not recommended if the patient is asymptomatic. Lactic acidosis is diagnosed when: o Standard bicarbonate <20 together with • Raised lactate. • Lactate > 5. To reach this stage, significant failure of the physiological compensating mechanisms is present, and this carries a much worse prognosis. In lactic acidosis the pH may be in the normal range (due to respiratory compensation) but the standard bicarbonate is always <20. Symptomatic hyperlactataemia occurs in 0.4 - 9% of patients on NRTI therapy whereas lactic acidosis occurs in 0.1-0.4%.

3.1.2 Risk factors The following have been identified as risk factors: • High body mass index (>28) and rapid weight gain. • Female gender. • Pregnancy. • Underlying liver disease. • Age – symptomatic hyperlactataemia/lactic acidosis appears to be unusual in younger children.

3.1.3 Diagnosis Apply the rule: if you consider the diagnosis, do the laboratory investigations immediately. Delays in diagnosis may be life-threatening. •

• •

•

• •

•

Many other conditions may result in raised lactic acid. Examples are: o Sepsis o Severe anaemia o Hepatic failure o Renal failure o Pancreatitis, o severe cardiac failure o Severe dehydration o Thiamine deficiency o Treatments like metformin for diabetes mellitus. Hyperlactaemia/lactic acidosis secondary to NRTIs is thus a diagnosis that should be made only once these other possible explanations for raised lactate have been excluded. Symptoms may be very non-specific and vague, and generally have been present and getting worse for weeks or months. Key symptoms and signs include: o Unintentional loss of weight (especially > 5%) o Gastro-intestinal symptoms, including nausea, vomiting, loss of appetite, abdominal pain. o Weakness and fatigue o Dyspnoea, tachypnoea without respiratory cause o Unexplained tachycardia o Myalgia o Peripheral oedema o Peripheral neuropathy o Lipoatrophy Symptomatic hyperlactataemia/lactic acidosis usually occurs after: o Patients have been on NRTIs for several months (median 10 months). o Initially experiencing resolution of HIV and opportunistic infection related symptoms, o Patient has gained weight in the months after starting ART o Patient is virologically suppressed then experiences deterioration o Onset of hyperlactataemia and its associated weight loss and symptoms. It is unusual for symptomatic hyperlactataemia/lactic acidosis to develop after 2 years on therapy. Clinical assessment should include: o Evaluation of the respiratory rate o Abdominal examination (for associated fatty liver and pancreatitis) o Assessment for peripheral neuropathy. o Evaluation for metabolic acidosis (tachypnoea in the absence of a respiratory cause is suggestive of metabolic acidosis). Make the diagnosis by measuring venous or arterial lactate. The venous blood sample should be taken without the use of a tourniquet in a sodium fluoride tube.

Use point-of-care devices for lactate measurement where access to a laboratory that is able measure lactate is difficult. Check lipase, liver functions and glucose in all patients with confirmed symptomatic hyperlactataemia/lactic acidosis to assess for co-existent pancreatitis, steatohepatitis and diabetes. A blood gas should also be checked in all patients with symptomatic hyperlactataemia to confirm or exclude metabolic acidosis.

• • •

3.1.3.1 Differential diagnosis •

Other causes for LOW to consider are: o Opportunistic infections (ask about TB symptoms) o Chronic diarrhoea with malabsorption o Virological failure o Depression o Malignancy o Undiagnosed diabetes o Poor diet

3.1.4 Confounders •

•

HIV positive patients frequently present with infective gastroenteritis with diarrhoea and vomiting. If severe this may result in profound dehydration with poor tissue perfusion and a raised lactate. In this situation once the patient is resuscitated with fluids the lactate will normalise. If the lactic acidosis is incorrectly attributed to the NRTIs in this situation an inappropriate interruption and switch in therapy may result. This may compromise future ART options. Similarly, septicaemic illnesses may result in lactic acidosis that will resolve with fluid resuscitation, appropriate antibiotics and other supportive therapies and it may not be necessary to stop or change ART in this situation.

3.1.5 Prevention •

•

Start women with a body mass index (BMI) > 28 (high risk group) on AZT rather than D4T or switch them to AZT if they gain weight to a BMI > 28 on ART. If such women have an Hb < 6.5g/dl the switch from D4T to AZT should be deferred until Hb has normalized. Recognize the syndrome before the person becomes acidotic as the most effective prevention by : o Educating patients to report any loss of weight, abdominal pain or vomiting lasting more than a few days, excessive fatigue, lipoatrophy or peripheral neuropathy symptoms. o Monitoring weight should be monitored at every clinic visit and when they drop by > 5% a lactate should be done, even if no other symptoms are present o Measuring lactate of any patient with a severe or rapidly progressive NRTI-induced neuropathy (typically due to D4T or ddI)

Avoid using ddI and D4T in the same ART regimen as this combination carries the highest risk for mitochondrial toxicity. Symptoms tend to occur long before severe laboratory abnormalities are present. The mortality and morbidity of the condition dramatically increases in the presence of acidosis. The mortality rate with severe lactic acidosis is 30-60%.

• • • •

3.1.6 Management Once the diagnosis is confirmed (raised lactate and EXCLUSION of other causes), the following guidelines are suggested: o Stop the regimen even before the diagnosis is biochemically confirmed if you have a high index of suspicion. o Do not stop the NRTIs alone, stop the entire regimen. It is better to interrupt a regimen for a short period than to continue a toxic regimen in the presence of suspected lactic acidosis.

•

3.1.6.1 In patients with mild hyperlactataemia and minimal symptoms (lactate 2.5-5 and no metabolic acidosis – standard bicarbonate > 20) o o o o

The D4T should be switched to AZT and The lactate rechecked within 3 days and then weekly until normalized. Stop ART If the lactate cannot be monitored in the way described Stop ART and follow the guidelines below if symptoms are severe or the lactate continues to rise or symptoms get worse despite the switch.

3.1.6.2 Patients with moderately severe hyperlactataemia/moderate metabolic acidosis (lactate 5-10 and/or standard bicarbonate 15-20) o o o o o o o

Stop ART and observe as inpatient for 1-2 days and Give oral vitamins (vitamin BCo 2 tablets bd and thiamine 100mg bd) , Hydrate well (orally or IVI) Exclude sepsis Exclude OIs. Recheck lactate and discharge for outpatient follow-up if clinically stable. Recommence ART Regimen 1d (Tenofovir, 3TC, EFV) only when lactate and bicarbonate has normalized (this may take months).

3.1.6.3 Patients with severe hyperlactataemia (lactate > 10 without metabolic acidosis) or significant lactic acidosis (raised lactate regardless of level and significant metabolic acidosis – standard bicarbonate < 15) •

The mortality is high in this scenario (up to 60%). These patients should preferably be managed in a high care facility as such: o Stop ART o IVI Thiamine 100mg 12hrly and BCo 1 amp 12hrly o IVI fluids o Blood culture/ urine culture/ septic search AND

o Broad-spectrum antibiotic (e.g. third-generation cephalosporin or coamoxyclav). This is important because sepsis may mimic or precipitate NRTI-associated lactic acidosis. o IVI NaHCO3 if profound acidosis o Ventilation if respiratory fatigue occurs o Dialysis, o Inotropes and o Other supportive measures as necessary • Monitor: o Lactate o Blood gas o Lipase o ALT and o Alkaline Phosphatase. • Recommenced on ART Regimen 1d (Tenofovir, 3TC, EFV) kaletra when lactate has significantly decreased and they are clinically improved (this may take weeks to months). NOTE: Neither d4T nor ddI should be used ever again in any patient who has had symptomatic hyperlactataemia/lactic acidosis. 3.2 Nausea and vomiting • Actively manage nausea due to antiretroviral medication, or adherence will suffer. The common causative agents are AZT and ddI. • Administering anti-emetics half an hour before the antiretroviral dose up to 3 times daily may be helpful. If the nausea does not settle, refer to a doctor trained on ART. • Check for jaundice and take blood for ALT as nausea and vomiting may be the first symptoms of drug-induced hepatitis 3.3 Drug Rashes • Drug rashes are typically associated with Nevirapine (and the Abacavir hypersensitivity syndrome which is covered above). Less commonly they are associated with Efavirenz and rarely with other antiretrovirals. A number of other drugs used in patients with HIV (e.g. Co-trimoxazole and TB medications) may also result in drug rashes. • About 15% of patients started on Nevirapine will develop a drug rash. This typically occurs in the first 3 months. It typically presents with a morbiliform or maculo-papular eruption but may progress to blistering, desquamation and a Stevens-Johnson syndrome. • Most Nevirapine skin rashes are mild and will settle despite continuing the drug. However, about 1/3 of patients require that Nevirapine is stopped. • Check the following in patients presenting with a Nevirapine skin rash: o ALT o Temperature o Asked about systemic symptoms. • Stop Nevirapine (together with the rest of the ART regimen) immediately: o Any mucosal involvement (conjunctival, oral and/or genital) o Any angio-oedema

• • • • • • • • • • •

o Fever or systemic symptoms such as myalgia o Blistering, desquamation or ulceration o Associated hepatitis (rise in ALT) o Associated arthritis Continue Nevirapine if patients have a mild rash with none of the above features (but the 2 week dose escalation from 200mg daily to 200mg b.d. should not be made until the rash has settled). Use topical steroids and oral antihistamine for milder cases and the patients should Review in 2-3 days. Warn patients to come earlier if any of the above severe manifestations occur. Avoid systemic steroids. Re-initiate ART with Efavirenz in place of Nevirapine once the rash has resolved. Consult a doctor trained in ART when re-initiating ART in patients who have had a life threatening Stevens Johnson syndrome on Nevirapine. The management of Efavirenz rash follows the same principles Consult a doctor trained in ART when re-initiating ART in patients if ART was stopped due to EFV rash Exclude rash caused by IRIS as not all rashes presenting on ART are drug rashes. A number of skin rashes may worsen or first manifest during immune recovery (eg. acne, molluscum contagiosum, warts, folliculitis).

3.4 Abdominal pain • Abdominal pain in a patient on ART can be caused by a number of serious problems, and should never be ignored. Important causes to consider are: o Symptomatic hyperlactataemia and lactic acidosis (check lactate o Pancreatitis (check lipase) o Hepatitis / steatohepatitis (check liver functions and assess for hepatomegaly) o Opportunistic infections or IRIS (e.g. abdominal TB) o Gastrointestinal intolerance of medication o Unrelated causes (e.g. pregnancy, diabetic ketoacidosis, appendicitis, peptic ulcer disease, pelvic inflammatory disease, urinary tract infections) 3.5 Peripheral neuropathy • Peripheral neuropathy may herald the development of symptomatic hyperlactataemia in patients on d4T • Peripheral neuropathy may result from: o HIV infection o INH o d4T o ddI

NOTE: If a new neuropathy develops or an existing neuropathy rapidly worsens after d4T or ddI initiation then a d4T/ddI induced neuropathy is likely

•

• • •

Symptoms of peripheral neuropathy are: o Nocturnal pain in the toes and feet usually the first symptoms o Paraesthesia (burning and tingling) o Sensory loss and motor impairment (may occur later) If peripheral neuropathy is due to mitochondrial toxicity resulting from ddI or d4T initial treatment should involve: o Symptomatic therapy with simple analgesia o Amitriptyline o Vitamin supplementation (B6 and BCo). If the symptoms progress despite this and particularly if there is any sensory loss or motor deficit the d4T should be switched to AZT. Switch to AZT provided there is no neutropaenia or anaemia (Hb below 6.5 g / dl ) or neutropenia (Neutrophil count below 0.5 X 10 9 / l) Use Tenofovir in patients who have severe neuropathy and anaemia or neutropaenia .

3.6 Efavirenz neurological side effects • Efavirenz may cause CNS disturbances (dysphoria, vivid dreams, distractedness, dizziness, depression etc.) • In the majority of patients this is self-limiting despite the drug being continued • Switch to Nevirapine if these symptoms do not resolve after a few weeks and are disabling (if a switch from Efavirenz to Nevirapine is made the lead-in dose is not required and nevirapine should be started at a dose of 200mg bd). 3.7 Pancreatitis Causes of Pancreatitis may be: o ddI or o d4T o 3TC in children o Hypertriglyceridaemia due to Kaletra in patients on ART Regimen 2.(usually the triglyceride level is above 15 mmol/l) • Patients present with typical clinical features of pancreatitis (upper abdominal pain, vomiting, etc) • Confirm the diagnosis by measuring lipase (amylase is non-specific in patients with HIV as HIV-related salivary disease may result in elevation). • Lipase should be > 4 x upper limit of normal for the diagnosis to be made. • Management o Stopping ART regimen o Admission o IVI fluids o Keep patient nil per mouth until clinically improved. 3.8 AZT-related anaemia and neutropaenia Table 13: Grading of anemia and neutropaenia in adults

ITEM Hemoglobin

GRADE I TOXICITY 8.0-9.4 g/dL neutrophil 1 - 1.5 x 109/L

Absolute count

• • • • • • •

GRADE II TOXICITY 7.0-7.9 g/dL

GRADE III TOXICITY 6.5-6.9 g/dL

0.75 - 0.99x 109/L 0.5 109/L

0.749

GRADE IV TOXICITY <6.5 g/dL x < 0.5 x 109/L

These side effects typically occur within the first 3 months of initiating AZT Check Hb and neutrophil upon starting or switching to AZT then after 1, 2, 3 and 6 months. Reduce the dose to 200mg 12 hourly if the patient develops grade I or II anaemia or neutropaenia on zidovudine. Replace AZT with Tenofovir if there is no improvement after dose adjustment. Repalce AZT with Tenofovir in patients who present with grade III or IV anaemia or neutropenia. Blood transfusion may be required for severe anemia Neutropaenia may be complicated by neutropaenic sepsis

3.9 Hepatitis • Each class of antiretrovirals is associated with a unique pattern of drug injury • Nevirapine is the commonest cause of drug-induced hepatitis among the antiretrovirals resulting in clinically significant hepatitis (ALT>200 with symptoms) in 2% of patients. • The NNRTIs (Nevirapine > Efavirenz) cause an immune-mediated hypersensitivity hepatitis that almost exclusively occurs within 3 months of initiating the drug • Patients may present with: o acute onset of nausea and vomiting o malaise o jaundice and/or o Right upper quadrant pain. o LFTs show predominantly a transaminitis (ALT and AST elevation). o Immune-mediated hypersensitivity phenomena (e.g. drug rash, drug fever and eosinophila) which occur simultaneously. • Women with CD4 count > 250 and men with CD4 count> 400 are greater risk of developing Nevirapine hepatitis (and rash). • Check ALT at baseline then at 2, 4, 8 and 12 weeks for patients on Nevirapine. • Protease inhibitors (Kaletra) may also result in drug-induced hepatitis usually presenting with a predominant transaminitis. • Exclude causes other than the antiretrovirals in patients with hepatitis diagnostic. These include: o Alcohol abuse o Chronic viral hepatitis (B and C).(ART-induced immune reconstitution may result in an acute flare of viral hepatitis in such patients - a form of IRIS) o Other drugs (eg. INH, Rifampicin, PZA, Co-trimoxazole, Fluconazole, antibiotics and alternative remedies)

•

o HIV cholangiopathy o TB involvement of the liver (granulomatous hepatitis) or porta hepatis nodes resulting in bile duct obstruction Check ALT and HepBsAg before initiating ART in all patients

An approach to managing patients with hepatitis on ART: • Consider all possible causes • Continue therapy and repeat in 1 week if ALT elevated to 50-200 and patient is asymptomatic • Stop ART and other drugs that could be causing hepatitis (eg. TB treatment) and monitor ALT if ALT elevated 50-200 with symptoms of hepatitis (nausea and vomiting, jaundice, right upper quadrant pain) and in all in whom ALT elevated > 200 even if no symptoms,. • Assess patients with severe ALT derangement for features of liver failure (confusion, metabolic flap and raised INR). Admit these patients and manage appropriately for liver failure. • Patients with drug-induced hepatitis have often been on a host of drugs that could possibly cause the hepatitis. Re-introduction of medication should only be done when ALT has normalized and jaundice has resolved. Drugs should be rechallenged in the following order as a general rule, while monitoring ALT closely: o Rechallenge treatments of active OI’s (e.g. TB drug rechallenge according to local guidelines) o Re-introduce of safer ART regimen (eg. substituting Nevirapine with Efavirenz if Nevirapine was in the ART regimen when hepatitis occurred. o Rechallenge with prophylactic medication (eg. Co-trimoxazole) o Manage patients with fatty liver/steatohepatitis according to protocols for the associated hyperlactaemia 3.10 Hyperlipidaemia •

• • •

•

Kaletra or ritonavir may cause hypertriglyceridaemia and hypercholesterolemia thus at initiation, at 6 months then annually check : o Fasting triglycerides o cholesterol o glucose The main risk associated with hypertriglyceridaemia is pancreatitis (usually when level is >15 mmol/l) Hypercholesterolemia may result in atherosclerotic vascular disease particularly in patients with other risk factors such as smoking, hypertension and diabetes. Address: o Dietary advice (low fat diet)refer to a dietician o Vascular risk factors (stop smoking, weight loss, increase exercise and treat hypertension and/or diabetes) in patients with elevated cholesterol and/or triglycerides. Treat patients with hypertiglyceridaemia where the triglyceride level is >10 mmol/l medical therapy with a fibrate (e.g. Bezafibrate 400mg daily after food

• • •

Treat patients with hypercholsterolaemia after an assessment of overall cardiovascular risk and the cholesterol level. Treat patients with a fibrate if their Framingham risk for MI is calculated to be 20% over 10 years. Simvastatin and most other statins are contra-indicated for use with PIs because of drug interactions. However, Pravastatin and low dose Atorvastatin are safe.

3.11 Glucose intolerance and diabetes • • • • •

Glucose intolerance and diabetes may complicate therapy with d4T or Kaletra Monitor fasting glucose in patients on Kaletra at baseline, 6 months then annually. Check glucose if symptoms of diabetes occur in patients on d4T Manage the diabetes as per standard protocols Consider switching d4T to Tenofovir if diabetes develops on d4T

3.12 Lipodystrophy •

• • •

HIV-associated lipodystrophy includes fat loss and/or fat accumulation in distinct regions of the body. This includes increased fat around abdomen, buffalo hump and breast hypertrophy in women (lipohypertrophy), and fat loss from limbs, buttocks and face (lipoatrophy). Lipoatrophy is closely associated with NRTI use (especially d4T, and to a lesser extent AZT). Lipohypertophy may occur with NRTI’s and/or PI’s. Switch from d4T to Tenofovir if significant lipoatrophy occurs. Encourage exercise to reduce fat accumulation for lipohypertrophy

3.13 Gynaecomastia • • •

Less than 5 % of men on ART will develop gynaecomastia which may be bilateral or unilateral.This is most strongly associated with Efavirenz and ddI use In most cases it resolves spontaneously over 1-2 years Switch drugs if its effects are severe (e.g. psychological distress).

3.14 Tenofovir nephrotoxicity • • •

• • •

A minority of patients on Tenofovir with underlying renal disease and those also exposed to other nephrotoxic drugs experience deterioration in renal function. In most cases it is reversible on stopping Tenofovir. Tenofovir has also rarely been associated with Fanconi’s syndrome, resulting from tubular dysfunction and wasting of phosphate, amino acids and other substances from the renal tubules. Patients present with non-specific symptoms such as malaise. Before starting a patient on Tenofovir check their renal function and creatinine clearance calculated (see Cockgraft-Gault formula). If creatinine clearance is < 50ml/min Tenofovir should not be used Check creatinine levels monthly until 6 months after initiation of Tenofovir. Never combine Tenofovir with didanosine because of increased side effects and poorer virological outcomes

Table 14: Recommended substitutions for specific side-effects Regimen Toxicity Drug substitution 1a. D4T/3TC/EFV

• •

1b. D4T/3TC/NVP

• • • •

1c. AZT / 3TC / EFV

• • • •

1d Tenofovir / 3TC / EFV or NVP     2a. AZT/ ddI / lopinavir / ritonavir      

d4T-related neuropathy or pancreatitis Persistent EFV-related CNS toxicity d4T-related neuropathy or pancreatitis NVP-related severe hepatotoxicity NVP-related severe rash (but not life-threatening) NVP-related life-threatening rash Stevens-Johnson syndrome Lactic acidosis AZT related anaemia or neutropenia Persistent EFV-related CNS toxicity nephrotoxicity Persistent EFV-related CNS toxicity NVP-related severe hepatotoxicity NVP-related severe rash (but not life-threatening) AZT related anaemia or neutropenia ddI related pancreatitis LPV/r related GIT symptoms LPV/r related hypercholesterolaemia Lipodystropy Impaired glucose tolerance

• •

Switch d4T to Tenofovir Switch EFV to NVP

•

Switch d4T to Tenofovir

• •

Switch NVP to EFV (except first trimester pregnancy) Switch NVP to EFV

•

Switch NVP to Tenofovir

• • • •

Switch NVP to Tenofovir Switch d4T to Tenofovir Switch AZT to Tenofovir Switch EFV to NVP



Consult doctor trained in ART Switch EFV to NVP Switch NVP to EFV (except first trimester pregnancy) Switch NVP to EFV

   

    

2b. Tenofovir / 3TC / lopinavir /  ritonavir    

Nephrotoxicity



LPV/r related GIT symptoms LPV/r related hypercholesterolaemia Lipodystropy Impaired glucose tolerance

    

Switch AZT to d4T (monitor closely for peripheral neuropathy and lactic acidosis) Consult doctor trained in ART Antidiarrhoeals and other symptomatic therapy Diet +/- fibrate Advise exercise Antidiabetic agents (warning: metformin may increase risk of lactic acidosis). Consult doctor trained in ART Consult doctor trained in ART Antidiarrhoeals and other symptomatic therapy Diet +/- fibrate Advise exercise Antidiabetic agents (warning: metformin may increase risk of lactic acidosis).

4. DRUG INTERACTIONS

• • •

Drugs belonging to the NNRTI and PI classes have a number of important drug interactions that need to be considered. These result from the fact that they are substrates of the cytochrome P450 enzyme system in the liver and intestine. PIs are generally inhibitors of these enzymes; Nevirapine an inducer and Efavirenz may be an inducer or inhibitor. Exceptions do, however, occur. Drugs that are commonly involved in these interactions are:

4.1 Inducers Carbamazepine, Phenytoin, Phenobarbitone Rifampicin 4.2

Inhibitors Macrolides Cimetidine Azoles (e.g. Itraconazole, Fluconazole) Substrates Warfarin Carbamazepine, Phenytoin, Phenobarbitone Oral contraceptive Statin Benzodiazepines, especially Midazolam Ergot alkaloids Calcium channel blockers • When prescribing other drugs with antiretrovirals it is important to check for interactions. • In some cases the combinations are contraindicated (e.g. ergotamine and PI’s) and in others dose adjustments are required (e.g. Warfarin and Nevirapine guided by INR). • The interactions may be bi-directional, for example carbamazepine and nevirapine may reduce each others levels. A useful source of ART drug interaction information is the University of Cape Town Medicines Information Centre (021-4066829). • •

Other drug combinations share toxicities and should not be used together, for example acyclovir and AZT because both drugs are bone marrow suppressants. Traditional remedies, phytotherapeutics, as well as other complimentary medicines, when used together with ART, could cause liver enzyme induction or inhibition. They could also bind the drug in the gut, leading to decreased blood levels of ART drugs and ultimately resistance.

Table 15 shows examples of drugs that should be avoided when administered with efavirenz, nevirapine, lopinavir/ritonavir or all 3 drugs. N.B. Beware of other drug interactions that may require dosage adjustment (i.e. anticonvulsant, psychiatric, anti-infective, cholesterol lowering drugs etc.). Seek expert advice if your patient is taking one of these drug combinations.

Table 15: Prohibited drug combinations with specific ART Agent by class

Agents prohibited with lopinavir/ ritonavir Anti-arrhythmic agents Fleicanide Propafenone Anti-histaminics

Astemizole Terfenadine

Anti-infectives Cholesterol lowering Simvastatin agents GI motility Cisapride Psychiatric medications St. John’s Wort (Hypericum perforatum) Sedative/hypnotics Midazolam Triazolam Other Dihydroergotamine Ergonovine Ergotamine

Agents prohibited with ritonavir Amiodarone Fleicanide Propafenone Quinidine Astemizone Terfenadine

Cisapride

Midazolam Triazolam Pimozide Ergot derivatives Disulfiram Metronidazole

Agents prohibited with NVP and EFV

Astemizone Terfenadine Systemic Ketoconazole

Cisapride St. John’s Wort (Hypericum perforatum) Midazolam Triazolam Dihydroergotamine Ergotamine Methylergonovine

5. SUBSTITUTES FOR INTOLERANCE IN ADULTS All switches should be made by a doctor trained in ART. 6. IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS) • • • • •

A rapid reduction in HIV viral load and a rise in CD4 count may occur after ART is commenced in patients with advanced HIV disease, particularly those with a CD4 count < 50 cell mm3 This is accompanied by a restoration of pathogen specific immunity. Inflammatory reactions in the first three months after starting ART may result as a consequence of the recovering immune system which may be dysregulated. This is termed IRIS. This is often in response to a high burden of microbial antigen related to an OI that was present prior to ART. Before diagnosing IRIS it is important to exclude other possible explanations for clinical deterioration such as: o drug resistance to the treatment for the OI (especially MDR-TB) o drug reactions o additional bacterial o Opportunistic infections. Forms of IRIS are described as:

• • • • •

• • •

o “Unmasking” IRIS – this describes an inflammatory and often atypical presentation of an OI soon after starting ART that was untreated prior to ART commencement o Paradoxical reactions – patients experience recurrence or worsening of OI symptoms and signs after starting ART despite being on appropriate treatment for the OI. The reaction here is thought to result from an immune response directed towards residual antigen o Sarcoidosis and auto-immune diseases (e.g. Grave’s disease is described as an IRIS phenomenon) Kaposi’s sarcoma may worsen with an increase in lesions or inflammation of existing lesions in 5% of patients (most KS lesions regress on ART) IRIS may result from reactions to inert foreign materials (e.g. tattoos) IRIS most commonly occurs in association with OIs such as TB, cryptococossis, MAC, CMV and HBV. An example of a CMV unmasking IRIS is a patient presenting with an inflammatory CMV uveitis after starting ART. TB paradoxical reactions are seen in up to 45% of patients starting ART while on TB treatment manifesting as: o recurrence of fever and o TB symptoms o enlarging lymphadenopathy o recurrent pulmonary infiltrates o Dermatological IRIS manifestations (e.g. flare of acne) Exclude multi-drug resistance in these cases. IRIS is not indicative of drug failure or side effects. IRIS is not a reason to stop ART, or to change the antiretroviral regimen.

Management o o o o o o

Diagnosing the OI exclude additional OI’s Exclude antimicrobial resistance. Continue ART Start and / or continue effective OI therapy Consider steroids (eg. prednisone 1mg/kg, duration dependent on response) in severe cases o Stop ART if the reaction is life threatening (e.g. CNS involvement) and not responding to steroids.

SECTION 5: MANAGEMENT OF OPPORTUNISTIC DISEASES IN HIV POSITIVE ADULTS 1. GENERAL PRINCIPLES • HIV causes immune system damage through various mechanisms. • The rate at which the disease progresses differs from individual to indvidual. • Treatment for HIV & AIDS as well as any opportunistic infections needs to be done in the context of treating the patient in a holistic manner, taking into account the micro- and macro-nutritional status of the patient, assisting the patient with the means to address this. 2. HIV COMPLICATIONS ANTICIPATED AT VARIOUS DEGREES OF IMMUNOSUPPRESSION CD4 count

>500cells /mm3

200 – 500cells/mm3

Infectious complications

Non-infectious complications

Acute retroviral syndrome Candidal vaginitis

Persistent generalized lymphadenopathy (PGL) Guillain-Barré syndrome Myopathy Aseptic meningitis Cervical intraepithelial neoplasia Cervical cancer B-cell lymphoma Anemia Mononeuronal multiplex Idiopathic thrombocytopenic purpura Hodgkin’s lymphoma Lymphocytic interstitial pneumonitis

Pneumococcal and other bacterial pneumoniae Pulmonary TB Herpes zoster Thrush Candidal oesophagitis Cryptosporidiosis self-limited Kaposi’s sarcoma Oral hairy leukoplakia 3 <200cells /mm P. jiroveci pneumonia Wasting Peripheral neuropathy Disseminated/chronic Herpes HIV-associated dementia CNS simplex Toxoplasmosis lymphoma Cardiomyopathy Cryptococcosis Vacuolar myelopathy Progressive Disseminated histoplasmosis and polyradiculopathy Immunoblastic coccidioidomycosis lymphoma Cryptosporidiosis, chronic Microsporidiosis Miliary/extrapulmonary TB Progressive multifocal leukoencephalopathy (PML) Candidal esophagitis <50cells /mm3 Disseminated CMV Disseminated M. avium complex * Most complications occur with increased frequency at lower CD4 counts. Some conditions listed as “Noninfectious” are probably associated with transmissible microbes: examples are lymphoma (EBV) and cervical cancer (HPV).

3. RECOMMENDED PREVENTION OF OPPORTUNISTIC INFECTIONS IN HIV POSITIVE ADULTS Agent/intervention

Dosage/schedule

Indication

Disease prevented

TrimethoprimSulfamethoxazole (TMP-SMX also known as Co-trimoxazole or Bactrim ® or Septran ®)

2 single strength (80/400mg) po daily for life or 1 double strength tablet (160/ 800 mg) po daily for life or 1 single strength tablet (80/400 mg) po daily for life (which is better tolerated by some but is not effective as prophylaxis for toxoplasmosis)

Pneumocystis carinii pneumonia, toxoplasmosis, bacterial pneumonia, diarrhoea

PAP smear

At first presentation and annually thereafter. HPV vaccine has the greatest benefit when it is given before a person becomes sexually active, thus their use in positive women is under investigation.1

All symptomatic HIV positive individuals (WHO clinical stage 2, 3 or 4) or CD4 count below 250 cells / mm3 or if there has already been an active infection of PCP, or HIV associated thrush, unexplained fever x2 weeks or Toxoplasmosis. Treatment no longer needed once patient is on ART and their CD4 >250 for 6 months All HIV positive women

Hepatitis B vaccine

0.5 mL IM injection x 3 doses according to manufacturer’s instructions, given to well patients not needing ART. Where patients are ill, vaccinate only once on ART and are well 0.5 mL IM injection annually prior to the influenza season for patients who are well and not need ART. Where patients are ill, vaccinate only once on ART and are well

All susceptible (HBc or Hep BsAb negative) HIV positive individuals

Hepatitis B

All HIV positive individuals. (The use of this vaccine in severely immunocompromised patients is not recommended)

Influenza

Influenza vaccine

To detect human papillomavirusassociated genital epithelial cancersabnormal PAP smear results should be followed up in accordance with current accepted best practices.

1 Nam publication, Derek Thaczuk, Thursday, December 14, 2006; AIDS:Volume 20(18)28 November 2006p 2381-2383

3.1 Prevention of Pneumocystis jiroveci pneumonia (PCP) Note: Shaded sections are interventions that are recommended at primary care level. Comments / Condition Management Indications Rationale Primary Prophylaxis for PCP

Trimethoprim/sulphamet hoxazole (TMP-SMX single strength 80/400 mg) 2 tablets po daily for life or TMP-SMX double-strength (160/800 mg) 1 tablet po daily for life or TMPSMX 1 single-strength tablet po daily for life (which is better tolerated by some but is not effective as prophylaxis for toxoplasmosis).

Adults and adolescents who are HIV positive (including pregnant women and those on ART) with: • Symptomatic HIV disease (WHO clinical stage 2, 3 or 4) • CD4 count less than 200 cells/ mm3 • or if there has already been an active infection with Pneumocystis

Prophylaxis for PCP in individuals who are sensitive to TMP-SMX

Consider re-introduction of TMP-SMX, if feasible (see note) Alternative Dapsone 100mg po daily Dapsone 50mg/day plus pyrimethamine 50mg/week plus leucovorin 25mg/week Atovaquone 1500mg POqd with meals2

As above

TMP-SMX at a dose of one double-strength tablet per day confers cross-protection against toxoplasmosis and some common respiratory bacterial infections. Intolerance to TMPSMX is experienced by 25-50%, mostly as skin rashes ± fever. Secondary prophylaxis Chronic maintenance therapy should be continued after treating a confirmed episode of PCP using the same protocol as for primary prophylaxis, except this should only be discontinued once the patient has a CD4>200 for 6 months while on ART. For patients who have an adverse reaction that is not life-threatening, treatment with TMPSMX should be continued if clinically feasible; for those who have discontinued such therapy because of an adverse reaction, reinstitution of TMPSMX should be strongly considered after the adverse event has resolved. Patients who have experienced adverse events, especially fever and rash, might better tolerate reintroduction of

2 Bartlett JG and Gallant JE Medical Management of HIV Infection 2005-2006 pg 50. Suggested regimens not available in public sector.

Condition

Discontinuation of Primary Prophylaxis for PCP

Restarting Primary Prophylaxis for PCP

Management

Indications

Once patients are on ART and their CD4 > 200cells/mm3 for 6 months

It may be possible to discontinue prophylaxis when patients have sustained a CD4 count of greater than 200 cells / mm 3 for at least 3-6 months

As for Primary Prophylaxis recommendations.

PCP Prophylaxis for Pregnant Women

As for other adults.

Primary Prophylaxis for Toxoplasma encephalitis (TE)

Advise against eating undercooked meats, about safe food handling procedures and appropriate pet care for cats Trimethoprim/ sulphamethoxazole (TMP-SMX single strength 80/400 mg) 2 tablets po daily or TMPSMX 1 double-strength tablet po daily

Toxoplasma seropositive adults and adolescents who are HIV positive (including pregnant women and those on ART) with CD4 count less than 100 cells/ mm3 who are not taking PCP Prophylaxis with a double strength TMPSMX dosage.

Comments / Rationale the drug with a gradual increase in dose (desensitization) or reintroduction of TMPSMX at a reduced dose or frequency; up to 70% of patients can tolerate reinstitution of therapy in this way. Beware of severe SJ reaction. Do not re expose these patients. Mostly advised when discontinuation of primary prophylaxis (no prior episode of PCP) is considered for individuals on ART who meet the criteria described. No data available to demonstrate that this should differ from primary prophylaxis. TMP-SMX may exacerbate folate deficiency and increase the risk of neural tube defects. For this reason, pregnant women should preferably be given TMP-SMX after the first trimester and should also receive folate supplements. The double strength TMP-SMX regimens advised for PCP Prophylaxis are also effective against Toxoplasma. Individuals who do not know their Toxoplasma serology status, or are seronegative, who are not taking a PCP prophylactic regimen known to be active against TE should be retested for IgG antibody to Toxoplasma when their CD4 count declines

Condition

Management

Prophylaxis for Toxoplasma in individuals who are sensitive to TMPSMX

Non-drug measures, as above. Dapsone 50mg po daily (Âą pyrimethamine 50 mg po weekly) plus leucovorin 25mg/week.

Discontinuation of Primary Prophylaxis for Toxoplasmosis

discontinuing prophylaxis for patients as per guidelines for PCP Pregnant HIV positive women who have evidence of prior Toxoplasma exposure can be administered TMP-SMX for prophylaxis against TE as described for PCP. Treat with Amphotericin B 1mg/kg/dose ivi in dextrose for 2 weeks followed by fluconazole 400mg po daily x 8weeks and then fluconazole 200mg/day for life or until CD4>200cells/mm3 >6months on ART (total of 12 months fluconazole)

Toxoplasma Prophylaxis for Pregnant Women

Cryptococcosis

Indications

Adults and adolescents who are HIV positive (including pregnant women and those on ART) with CD4 count less than 100 cell / mm3 and are Toxoplasma seropositive.

ART is critical Primary prophylaxis is indicated for special cases only: CD4 count less than 50 cells / mm3 with unusually high additional risk of Cryptococcosis, or if considered as part of the decision to treat other concomitant fungal infections.

Comments / Rationale

below 100 cell/ mm3 to determine whether they have seroconverted and are therefore at risk for TE. Secondary Prophylaxis Individuals who have had TE should be administered lifelong suppressive therapy (secondary prophylaxis / chronic maintenance therapy) with drugs active against Toxoplasma to prevent relapses. Prophylactic monotherapy with dapsone, pyrimethamine, azithromycin, or clarithromycin cannot be recommended on the basis of current data. It is advisable to check Toxoplasma serology in these patients to guide therapy. Prophylaxis for PCP should continue if it is still indicated.

NB: Primary toxoplasma infection or active toxoplasmosis (including TE) should be evaluated and managed during pregnancy in consultation with appropriate experts. Fluconazole and Itraconazole should be avoided in pregnancy and effective birth control measures should be recommended to all HIV positive women on prolonged azole therapy.

Condition

Mycobacterium tuberculosis Isoniazid Preventive Therapy (I PT)

Herpes Simplex Virus (genital or orolabial)

Varicella-Zoster Virus (VZV)

Human Papilloma virus Infection

Management Management of raised intracranial pressure (>20cmCSF) is through the draining of 20-30ml of CSF prn to reduce opening pressure by 50%). Daily LPs may be required When indicated: Isoniazid 5 mg/kg daily is to be given for 6 months + pyridoxine 50mg po daily for 6 months.

Indications

Comments / Rationale

HIV positive adults with no signs or symptoms of TB and a normal chest x-ray. Tuberculin skin test-positive patients show greater benefit. It is extremely important to rule out active TB before initiating I PT to prevent the development of isoniazid resistance.

The feasibility of providing I PT in TB prevention is of proven value in low income countries in individuals at a risk due to conditions like HIV and for health workers. For more information about I PT see Appendix 2 / 3 / 4 below.

Primary infection can be prevented through safer sex (condom usage) at all times and specific avoidance of contact with herpetic lesions (genital or orolabial). Drug prophylaxis of initial episodes of HSV disease is not recommended. Individuals who have no history of chickenpox or shingles, or seronegative for VZV should avoid exposure to persons who are infected with chickenpox or shingles. Prevent exposure: safer sex practices (use of condom at all times) should be advised. Prevention of HPVassociated Genital Epithelial Cancers in HIV positive Women: Pelvic examination and a

Individuals with frequent or severe recurrences can be administered daily suppressive therapy with oral acyclovir 400mg bid or famciclovir 250mg bid or valacyclovir 0.51gqd3.

All HIV positive women

Pregnant women: VZIG (Varicella Zoster Immune Globulin) 125U per 10kg up to 625U IM is recommended for VZV-susceptible, HIVpositive pregnant women within 96 hours after exposure to VZV. Abnormal PAP smear results should be followed up in accordance with current accepted best practices.

3 These drugs are all clinically equivalent Br J Dermatol 2001;144:188

Condition

Management

Indications

Comments / Rationale

Pap smear at first presentation and annually thereafter if this is normal. Influenza Virus

Influenza vaccine 0.5ml intramuscularly annually

Hepatitis B Virus

Hepatitis B Vaccine 0.5 mL IM injection X 3 doses according to manufacturerâ&#x20AC;&#x2122;s instructions.

All HIV positive individuals annually prior to the Influenza season. (The use of this vaccine in severely immuno-compromised patients is not recommended) All susceptible (AntiHBc and HepBs Ab negative) HIV positive individuals. (The use of this vaccine in severely immunocompromised patients is not recommended)

Amantadine 100mg po twice a day is an alternative for selected susceptible (unimmunised) individuals who are acutely exposed to Influenza.

4. MANAGEMENT OF OPPORTUNISTIC DISEASES IN HIV POSITIVE ADULTS 4.1 Management of common respiratory infections associated with HIV Condition

Recommended treatment

Comments

Community acquired Pneumonia

Exclude PCP and active pulmonary TB. In many cases, empirical therapy needs to be started, pending the results of investigations. Severe infections require hospitalisation for Parenteral antibiotics and supportive therapy (Bed rest, oxygen, IV fluids and nutrition) Frequent monitoring of temperature, blood pressure, respiratory and pulse rates in order to detect complications early and to monitor response to therapy. CXR and pre-treatment cultures of blood and sputum are required. Treatment of specific organism is ultimately guided by the results of investigations and culture sensitivities, as well as clinical response to first-line treatment. Initiating treatment is with Ceftriaxone 1g ivi bid. Changed to Amoxycillin 500mg pO tid once the fever has settled. Antibiotics are given for 2 weeks in total.

‘Usual’ pneumonia pathogens suspected (S. pneumoniae / H. influenzae)

Oral: Amoxicillin 250-500mg 8 hourly until infection resolves. Duration of antibiotic therapy is guided by clinical response, but should not be less than 7–10 days. Where there is likely Penicillin/Ampicillin resistance: Amoxicillin/clavulanic acid (eg Augmentin®) 250/125 mg (375 mg tablet) po 8 hourly should be first choice Penicillin allergic patients: Erythromycin 500mg po 6 hourly Parenteral antibiotic therapy Depends on the causative organism. Empirical treatment could be started with Benzyl penicillin, IV, 2 MU 6 hourly for 10 days (or combination therapy with Gentamicin IV, if a gram negative infection is suspected; or an appropriate Cephalosporin) Erythromycin 500mg po 6 hourly for 10-14 days.

Severe infections are suggested when there is: Moderate/severe respiratory distress; fever higher than 39.50C; hypoxia; confusion; dehydration; hypotension; heart rate >120; extensive pneumonia (bilateral / more than 1 lobe involved on CXR) or complicated pneumonia (such as empyema). Blood cultures need to be done. A control post treatment chest X-ray is always indicated to ensure complete resolution of the pneumonia. With an uncomplicated clinical course this should only be done after 4–6 weeks, as radiological resolution may be delayed. Followup X-rays are indicated earlier only when complications are suspected (e.g. empyema, abscess or pneumothorax). At the onset of the pneumonia the X-ray changes may be unimpressive, and may only develop fully after a few days. Prolonged fever and clinical signs may be due to any of the complications, to the incorrect choice of antibiotic, or due to an underlying bronchus obstruction (foreign body or carcinoma). These patients should be further investigated. Common at all stages of HIV infection. Clinically lobar or bronchopneumonia ± effusion. Penicillin/Ampicillin resistance is increasing, so alternative treatment might be required.

Suspected ‘atypical’ pneumonia (Mycoplasma/ Legionella)

4.2 Treatment of Pneumocystis jiroveci pneuomonia (PCP) Condition

Recommended treatment

Comments

Acute PCP Infection

Trimethoprim/sulphamethoxazole, 20/100 mg/ kg/day in 4 divided doses equivalent to Co-trimoxazole 1tab/4kg body weight /day in 3 to 4 doses (max of 16tabs/d). The duration of treatment is 21 days, followed by 2 tablets daily for life or until CD4>200cells/mm3 for >6m when on ART. If at all possible, this should be given orally. IV Trimethoprim/sulphamethoxazole may be used in patients not able to swallow.

Hypoxic patients

Prednisone, 40 mg 12hourly for 5 days, followed by 40mg daily for 5 days and then 20mg for 11 days

PCP often presents as an acute/sub-acute nonproductive cough, fever with 1-2 weeks dyspnoea, marked respiratory distress. Diagnosis further suggested by: CD4 < 250 cell / mm3; normal-looking X ray in early stages, or ‘ground-glass’ interstitial infiltrates and other atypical radiological findings; Relative hypoxia (p02 <10) on ABG or desaturation on exercise (if sats are normal at rest, check patienst sats with a sats probe before and after a 30m walk or less if the patient reaches maximum heart rate- a drop of more than 5% is significant Diagnosis is usually made empirically but can be confirmed with a DFAT on induced sputum Moderately severe or severe disease is present when the patient is hypoxic (pO2<10). Steroid therapy can further compromise the individual’s immunity and other opportunistic infections (such as Candidiasis, TB, CMV and Herpes) should be anticipated.

Patients intolerant to Trimethoprim/ Sulphamethoxazole

Trimethoprim 300mg 8hourly + dapsone 100mg daily or Clindamycin 450 mg po 8 hourly plus primaquine 15mg po daily (exclude G6PD deficiency when giving primaquine) (atovaquone can be substituted)

4.3 Management of common oral and oesophageal conditions associated with HIV Condition

Recommended treatment

Comments

Candidiasis (Thrush) Oropharyngeal Milder topical forms

Nystatin lozenges 100 000 IU, to be sucked 4 times daily or Nystatin 100 000 IU/mL 1-2 mL 4 times daily for 10 days If no improvement after 2 weeks, nystatin can be replaced with: Miconazole 2% oral gel twice daily for 10 days or Amphotericin B lozenges 10 mg suck 1 slowly 4 times daily, up to 8 lozenges in severe cases .Where there is retrosternal odynophagia treat with fluconazole 200mg daily for 2 weeks Fluconazole 200mg po daily for 5-14 days. As a secondary option: Ketoconazole, oral, 150mg- 400mg po daily for at least 14 days or Itraconazole 200mg po daily for 14 days For patients who cannot take oral medications: Fluconazole 200mg IV daily for 5-14 days.

Chlorhexidine gluconate 0.2% mouthwash may be used for secondary infections. ART is recommended to be commenced as soon as patient is stable to ensure recovery of natural immunity that will prevent recurrence

Oesophageal or invasive candidiasis Severe or recurrent

Aphthous ulcers

Oral hairy leukoplakia

Gingivitis/ periodontitis

Topical steroids such as hydrocortisone cream 1% or Kenalog® in Orabase® or a steroid inhaler such as beclomethasone or budesonide applied directly to the lesions or Tetracycline 250 mg tablet dissolved in water 4 times daily Severe or refractory cases, including oesophageal ulcers: Prednisone 40 mg po daily for 1-2 wks, then reduce incrementally This usually does not require treatment – if symptomatic in selected cases: Acyclovir 800 mg po 5 times a day for 2-3 wks or valaciclovir 1g 8hrly x 28days gives temporary respite.

Curettage and debridement of involved tissue + topical antiseptic such as povidine-iodine solution and chlorhexidine mouth rinses. Selected cases: Metronidazole 200mg three times a day or 400 mg po twice a day for 7-14 days or clindamycin 300 mg three times a day for 7-14 days.

WHO has recommended that fluconazole should replace ketoconazole as the prototype drug since it is more cost-effective and is associated with fewer adverse effects. Referral to a specialist centre may be required. Patients should be worked up for ART to ensure treatment initiation as a matter of urgency Consider discontinuing any medications that might be causing the ulcers. Where patients are on the standard ART regimens, treat ulcers symptomatically. This might be an IRIS4 as a consequence of ART initiation in severely immune compromised patients and might need to be biopsied in refractory cases Most lesions are asymptomatic and do not require therapy. Most treated cases relapse and may require maintenance high-dose acyclovir if problematic. OHL is a sign that the patient may have a low CD4 count often <200c/ml and should be worked up for ARTdespite the often appearance of being well Four clinical phases are described: gingival erythema, necrotizing gingivitis, necrotizing peridontitis, and necrotizing stomatitis Usual presenting complaints are oral pain and bleeding.

4 IRIS is Immune reconstitution inflammatory syndrome often seen in patients with CD4<50 cells/mm3 within a few weeks of commencing ART. They present with either new illnesses or exacerbation of diseases they are currently receiving treatment for like TB, CMV, KS, NHL, MAC etc

4.4. Management of common skin conditions associated with HIV HIV positive patients are more prone to a wide variety of skin problems. Conditions that usually occur in non-HIV infected individuals should generally be managed in the same way, in accordance with Standard Treatment Guidelines. Condition

Recommended treatment

Comments

Molluscum contagiosum

Topical application of tincture of iodine or 1% phenol to individual lesions or Cryotherapy with liquid nitrogen or Surgical excision / curettage or electrosurgery. Skin biopsy might be required to rule out cryptococcal skin rash or cutaneous lymphoma in cases where the clinical picture is unclear

For extensive lesions, which usually indicate severe immunodeficiency and are too widespread for topical treatment, systemic retinoid may be effective. This requires specialist supervision. The best outcomes are seen when patients are started on ART. Response then to the standard treatments improve and recurrence slows eventually disappearing over time as the immune system strengthens

Seborrhoea

Skin Steroid cream (hydrocortisone 1%) and/or topical azole cream (e.g. Miconazole 2% cream), or Terbinafine cream, applied twice a day Scalp 2% selenium sulphide suspension - apply weekly by lathering on scalp and rinse off after 10 minutes or Shampoos (e.g. Selsun速 Head and Shoulders速, Gill shampoo速) containing selenium sulfide, zinc pyrithiore, ketoconazole, salicylic acid or coal tar, used daily.

Folliculitis (including S. Aureus; Eosinophilic inflammation; Pityrosporum ovale)

Depends on aetiology Staphylococcal folliculitis: Topical cleansing with antiseptic lotions (e.g. chlorhexidine gluconate 2% or Hibiscrub速); Topical 2% sulphur cream twice a day. Consider short course antibiotic therapy: Flucloxacillin 500 mg po four times a day for 10 days In pregnant and/or penicillin-allergic patients: Erythromycin 500 mg 4 times daily for 10 days Recurrent disease: chronic antibiotic (clindamycin 150 mg four times a day or TMP-SMX 1 DS four times a day)+/-nasal mupirocin Fungal: Miconazole 2% cream applied twice daily or other topical antifungal or systemic antifungal agents Eosinophilic: Topical steroids and anti-pruritics (such as promethazine or hydroxyzine) Phototherapy with UVB and/or PUVA is sometimes effective.

A group of acne-like conditions that present as pruritic follicular papules and pustules on face, trunk and extremities at lower CD4 counts. Spontaneous remissions and exacerbations occur. This is a strong indication to commence ART even in cases where the CD4>250

Condition

Recommended treatment

Comments

Fungal skin / nail infections

Skin: 6% benzoic acid and 3% salicylic acid ointment twice daily for 4 weeks or 2% miconazole cream applied topically twice daily for 4 wks or other topical antifungal agents such as clotrimazole For severe nail infections, consider: itraconazole 400 mg po daily for 7 days repeated monthly x 2 months (fingernails) and 3 months (toenails); fluconazole 200mg weekly for three months for finger nails and 6 months for toenails.

Where infections are persistent or severe consider commencing ART

Drug-related skin reactions

Depends on severity and the need for the implicated drug. Discontinue suspected drug. Antihistamines such as chlorpheniramine 4 mg po 3-4 times daily Âą topical steroids such as hydrocortisone 1% cream applied twice daily. Severe reactions: discontinue all drugs. Systemic steroids are not useful.

Psoriasis

Salicylic acid 2% in white soft paraffin 3 times daily to local plaques or other topical treatments with emollients, topical steroids, coal tar, vitamin A, vitamin D derivatives, salicylic acid. Phototherapy.

Morbilliform exanthema are more common; most frequent onset 7-10 days after starting new drug. Diagnosis on basis of clinical features, past history of drug eruptions and history of new drug exposure. Response to stopping drug should be noticed within 3-5 days. It may be possible to re-introduce the drug, if necessary, if the reaction was not severe. Nevirapine and cotrimoxazole are the commonest causative agents where these are used but reactions to efavirenz are not uncommon, often not as severe. Most cases can be treated symptomatically but ARV drugs might need to be changed where symptoms worsen or where there is involvement of conjunctiva and mucous membranes Avoid methotrexate and prednisone.

Kaposiâ&#x20AC;&#x2122;s sarcoma

If HIV positive commence ART, despite CD4 count. Investigate for other OIs especially TB. Patients need to be referred to a treatment centre where treatments will be individualized based on the extent of disease, rate of growth, symptoms, CD4 count and general health. Local therapy can be used for small skin and oral lesions which include intralesional chemotherapy (vinblastine), local radiotherapy, liquid nitrogen cryotherapy or topical aliretinoin 0.1%gel. Cytotoxic chemotherapy for extensive disease is recommended where; Multiple skin lesions Progressive disease

Treatments should be performed at a site where there is the capacity to manage this disease. ART should be commenced even before chemotherapy as this improved response to chemotherapy. Where lesions increase on ART (IRIS) continue on ART with ongoing chemotherapy

Condition

Recommended treatment

Comments

Visceral involvement Extensive oedema B symptoms (fever, night sweats, significant constitutional symptoms Failure to respond to local therapy and ART

4.5 Treatment of herpes virus infections Condition

Recommended treatment

Comments

Herpes simplex virus (HSV) Initial treatment of mild skin or genital HSV

Aciclovir 400 mg po 3 times a day or Famciclovir 250 mg po 3 times daily or Valaciclovir 1 gm po twice a day All administered for 7-10 days

Recurrent HSV

Aciclovir 400 mg po three times a day or 800 mg po twice a day or Famciclovir 125 mg po twice daily or Valaciclovir 500 mg po twice daily All administered for 5 days.

Severe or refractory HSV Infection

Consider Aciclovir 5-10 mg/kg IV 8 hourly infused over 1 hour for 5-7 days or Aciclovir 400-800 mg po 5 times a day for 7-14 days or Valaciclovir 1 gm po 3 times a day for 7-14 days

Varicella zoster virus (VZV)/ Shingles

Aciclovir 800 mg po 5x/day at least 7 days (until lesions crust) or Famciclovir 250 mg po tid or Valaciclovir 1 gm po tid

Dermatomal VZV

Acyclovir 800 mg po 5x/day at least 7 days (until lesions crust) or Famciclovir 250 mg po tid or Valaciclovir 1 gm po tid

Herpes is a recurrent viral disease that has no cure. Two serotypes of HSV have been identified: HSV-1 and HSV-2. Most cases of recurrent genital herpes are caused by HSV-2. Genital herpes is a sexually transmitted disease. Antivirals do not cure the infection or prevent transmission. These drugs may shorten the time to clinical remission. Early treatment of initial infections is much more effective than treating recurrent infections. Most patients with first episode genital HSV-2 infection will have recurrent episodes of genital lesions. Initiate therapy at first sign of prodrome or genital lesions. Relapses after treatment of acyclovir-resistant strains often involve acyclovir-sensitive strains. • If failing to respond, or for disseminated HSV, give aciclovir 30 mg/kg/day IV and test sensitivity of isolate to acyclovir; • Resistant HSV: foscarnet 40 mg/kg IV 8 hourly, topical trifluridine, oral valaciclovir, or high-dose IV aciclovir (12-15 mg/kg IV 8 hourly or by continuous infusion). VZV infections in immunocompromised patients should be treated with appropriate anti-viral drugs. However drug therapy is expensive and unlikely to be of advantage to patients with lesions that have healed (crusted phase). VZV also seen in patients well and stable on ART and does not indicate a failing regimen. Treatment is the same • Treatment can be started long as new lesions are forming • Postherpetic neuralgia is less common in young patients • No maintenance therapy is recommended • Antiviral therapy has not been

Condition

Recommended treatment

Comments shown to be effective beyond 7 days of acute therapy

Disseminated, opthalmic nerve involvement, corneal or visceral infection (life or vision threatening) VZV

Pain control Acute phase of infection

Chronic management of Zoster Associated Pain

Acyclovir, IV, 5-10 mg/kg over 1 hour at 8 hourly intervals for at least 7 days or Foscarnet 40 mg/kg IV 8 hourly or 60 mg/kg 12 hourly. For corneal disease in addition to parenteral (IV therapy): Topical acyclovir eye drops 3% ointment, 4 hourly for 14 days. For VZV pneumonia consider adding: Hydrocortisone 200 mg IV 6 hourly for 7 days. Ibuprofen 400 mg po 3 times daily or Paracetamol 1 000 mg po (4–6 hourly) plus Amitriptyline 25–50-75 mg po at night.

To be prescribed by a specialist only. The dose must be adjusted according to renal function.

Amitriptyline 25-50-75 mg po at night +/- Carbamazepine 100-400 mg po twice daily.

If pain remains severe after 4 weeks, refer.

Pain is often very severe and requires active control usually with a combination of nonsteroidal, opiate analgesics and amitriptyline.

4.6 Management of human papillomavirus infection Condition

Recommended treatment

Comments

Non-drug treatment

Surgical removal - tangential scissor excision, tangential shave excision, curettage, or electrosurgery. Or Cryotherapy with liquid nitrogen or cryoprobe. Repeat applications every one to two weeks

Drug Treatment for warts in general

Podophyllin resin 10–25% in compound tincture of benzoin. A small amount should be applied to each wart and allowed to dry. To avoid the possibility of problems with systemic absorption and toxicity, some experts recommend that application be limited to <0.5 mL of podophyllin or <10 cm2 of warts per session. Repeat weekly if necessary. or Trichloracetic acid (TCA) or bichloracetic acid (BCA) 80–90%. Apply a small amount only to warts and allow to dry, at which time a white “frosting” develops; apply talc or sodium bicarbonate to remove unreacted acid if an excess amount is applied. Repeat weekly if necessary.

This is a sexually transmitted disease. Note: The removal of warts does not necessarily decrease infectivity. It is advisable to treat sexual partners as well. Surgical removal of warts has the advantage over other modalities of rendering the patient wart-free, usually with a single visit. An expert should do this. The use of podophyllin is contraindicated during pregnancy. Podophyllin is caustic and should be used with care. Avoid contact with healthy skin. After visible genital warts have cleared, follow-up is not mandatory. Re-occurrence is most frequent during the first three months. Patients should be warned that scarring in the form of persistent hypo-or hyperpigmentation is common with ablative modalities. Patients with severe cutaneous HPV infections respond poorly to these treatment modalities despite in many cases being stable on ART.New treatments are continually being developed

Vaginal warts

TCA or BCA 80–90% applied only to warts. Apply a small amount only to warts and allow to dry at which time a white “frosting” develops; apply talc or sodium bicarbonate to remove unreacted acid if an excess amount is applied. Repeat weekly if necessary. or Podophyllin 10–25% in compound tincture of benzoin applied to a treated area that must be dry before removing the speculum. Treat less than or equal to 2 cm2 per session. Repeat application at weekly intervals.

Cervical warts

Urethral meatus warts

Anal warts

Oral warts

Podophyllin 10–25% in compound tincture of benzoin. The treatment area must be dry before contact with normal mucosa. Podophyllin must be applied weekly if necessary. Or Cryotherapy with liquid nitrogen or cryoprobe. TCA or BCA 80–90% applied to warts. Apply a small amount only to warts and allow to dry at which time a white “frosting” develops; apply talc or sodium bicarbonate to remove unreacted acid if an excess amount is applied. Repeat weekly if necessary. or Cryotherapy with liquid nitrogen or surgical removal. Cryotherapy with liquid nitrogen or surgical removal.

The use of a cryoprobe in the vagina is not recommended because of the risk of vaginal perforation and fistula formation. Because of concern about potential systemic absorption, some experts caution against vaginal application of podophyllin. Podophyllin is contraindicated during pregnancy.

For women with exophytic cervical warts, a high-grade squamous intraepithelial lesion (SIL) must be excluded before treatment is begun. Management should be carried out in consultation with an expert. The use of podophyllin is contraindicated in pregnancy. To be performed by a specialist only.

Management of warts on rectal mucosa should be referred to an expert.

Management of warts should be referred to an expert.

4.7 Management of genital and sexually transmitted conditions • Sexually transmitted infections in HIV positive individuals should be managed syndromically following the Department of Health’s Protocols for the management of a person with sexually transmitted diseases with the following considerations: o Urethral discharge syndrome – cefixine 400mg po stat o Genital ulcer syndrome(GUS) – Add Acyclovir 400mg po 8 hourly for all GUS o Vaginal discharge syndrome – Cefixine 400mg oral stat. vulvo-vaginal candidiasis unchanged and if vulval irritation present Clotrimazole cream applied bd X 3 days.

Condition Genital Herpes Simplex Virus Vulvo-vaginal Candidiasis (Thrush)

Pelvic Inflammatory Disease (PID)

Recommended treatment See ‘Treatment of herpes virus infections. Clotrimazole vaginal tablets 100 mg or vaginal cream, nightly for 7–10 nights. For more severe cases, use systemic therapy with Fluconazole 150mg po x 1. As a secondary option: Ketoconazole, oral, 200-400 mg daily, for 5-7 days.

All patients with stage II-IV and severely ill patients with stage I must be hospitalised for parenteral antibiotic therapy. All patients must receive adequate therapy for both gonococcal and chlamydial infection.

Pelvic Inflammatory Disease (PID) (Continued)

PID: Stage I Acute (uncomplicated) salpingitis

Stage II Salpingitis + peritonitis

Ciprofloxacin 500 mg as a single oral dose (Alternative to ciprofloxacin: Ceftriaxone 250 mg IM single dose) plus Doxycycline, 100 mg po 12 hourly (with meals) for 14 days plus Metronidazole 400 mg po 12 hourly for 14 days. Cefoxitin 2 g IV 6 hourly plus Doxycycline 100 mg IV 12 hourly plus Metronidazole, 400 mg po 12 hourly, if there is no vomiting, otherwise per rectum 500 mg 8 hourly initially for 3-5 days. This regimen is given for at least 48 hours after the patient clinically improves. After discharge from hospital, the patient continues with oral therapy with: Doxycycline 100 mg po 12 hourly plus Metronidazole 400 mg po 12 hourly until a total of 14 days of therapy has been completed.

Comments More prolonged therapy may be required in severely immunedeficient women. WHO has recommended that fluconazole should replace ketoconazole as the prototype drug since it is more costeffective and is associated with fewer adverse effects. Consider early ART initiation in intractable cases. Adequate fluid replacement, analgesics and antipyretics should be provided. Patients should be tested for syphilis and other STDs. In stage III, surgery is indicated if the diagnosis is uncertain, if rupture seems imminent, if there is no adequate response after 48 hours of appropriate therapy, if the patient deteriorates on treatment or if after 4–6 weeks there still is a large or symptomatic pelvic mass. Contact tracing. Remember that PID is usually sexually transmitted and that sexual partners should be offered treatment for their own health and to prevent re-infection and spread of the infection to other partners. Intrauterine contraceptive devices are a risk factor for PID and should be removed after commencement of antibiotic therapy. Alternative contraceptive choices should be offered. Characterised clinically by local adnexal tenderness, but no peritoneal tenderness. As the prevalence of resistant GC increases, ceftriaxone is the preferred treatment

Characterised clinically by local adnexal tenderness and peritoneal irritability (rebound, guarding, etc) Contact tracing Remember that PID is usually sexually transmitted and that sexual partners should be offered treatment for their own health and to prevent re-infection and spread of the infection to other partners.

Condition

Recommended treatment

Comments

Stage III Tubal occlusion + pus + distention

Clindamycin 900 mg intravenously 8 hourly plus Gentamicin, IV, for at least 48 hours at a loading dose of 2 mg/kg, followed by 1.5 mg/kg 8 hourly This regimen is given for at least 48 hours after the patient clinically improves. After discharge from hospital, the patient continues with oral therapy with: Doxycycline 100 mg orally 12 hourly plus Metronidazole, oral, 400 mg 12 hourly until a total of 14 days of therapy has been completed plus Clindamycin 450 mg four times daily until a total of 14 days of therapy has been completed. Antibiotics as stage III. Rapid surgical exploratory laparotomy.

Characterised clinically by peritonitis. Gentamicin therapy should preferably be monitored by blood drug levels in patients with impaired renal function. Contact tracing Remember that PID is usually sexually transmitted and that sexual partners should be offered treatment for their own health and to prevent re-infection and spread of the infection to other partners.

Condition

Recommended treatment

Comments

Primary or secondary syphilis

Benzathine penicillin, IM, 2.4 MU as a single dose or in case of penicillin allergy: Erythromycin 500mg qid X 4 weeks

Early latent syphilis

Benzathine penicillin, IM, 2.4 MU as a single dose or in case of penicillin allergy: Erythromycin 500mg qid X 4 weeks Benzathine penicillin, IM, 7.2 MU total, administered as 3 doses of 2.4 MU each, at weekly intervals Nonpregnant penicillin-allergic patients: Doxycycline, oral, 100 mg twice daily, for 2 weeks if duration of infection <one year, otherwise, for 4 weeks, with close follow-up. Benzathine penicillin, IM, 7.2 MU total, administered as 3 doses of 2.4 MU at weekly intervals.

Parenteral benzyl penicillin is the preferred drug for treatment of all stages of syphilis. The preparation(s) used (i.e., benzathine, aqueous procaine, or aqueous crystalline), the dosage, and the length of treatment depend on the stage and clinical manifestations of disease. Parenteral benzyl penicillin is effective in achieving local cure (healing of lesions and prevention of sexual transmission) and in preventing late sequelae. Partner notification Follow-up serology tests for 6 months.

Stage IV Rupture to peritoneal cavity

Characterized by septicaemia, collapse. Contact tracing Remember that PID is usually sexually transmitted and that sexual partners should be offered treatment for their own health and to prevent reinfection and spread of the infection to other partners.

4.7.1 Treatment of Syphillis

Late latent syphilis or latent syphilis of unknown duration

Tertiary syphilis

Pregnant patients with penicillin allergy: see above.

Neurosyphilis

Refer to text above

4.8 Management of neurological complications associated with HIV Condition

Recommended treatment

Comments

HIV-associated Dementia (HAD)

Possible benefit from antiretroviral regimens with agents that penetrate the CNS (AZT, d4T, ABC, nevirapine; less penetration – efavirenz, ddI, 3TC,).

AZT at higher dose for mild or moderately severe HAD has been shown beneficial. Patients respond to ART. Monitor the effectiveness of therapy with neurocognitive tests.

Myopathy (inflammatory)

Consider discontinuing AZT for 3 weeks (if applicable). Non-steroidal anti-inflammatory agents sometimes useful. Prednisone 40-60 mg/day (for severe case, preferably with biopsyproven inflammation).

Peripheral neuropathy

Neuropathic pain can be difficult to relieve. Consider Ibuprofen 400-800 mg po three times a day plus Amitriptylline 25-50-75 mg po at night or other tricyclic antidepressants. Alternatives: Carbamazepine 200-400 mg po twice a day.

Indication for treatment is proximal muscle weakness plus elevated creatine kinase. Often unclear whether due to HIV or AZT so consider changing ART and monitor clinical and CPK response. Refer for expert opinion Peripheral neuropathy may be HIVrelated but it may also be a side effect of several drugs such as isoniazid, ddI, d4T and ddC. If using Tricyclic antidepressants, increase doses incrementally (eg. Nortriptyline started at 10 mg at night, increasing the dose by 10 mg every 5 days to maximum of 75 mg daily or 10-20 mg three times a day until effective).

4.9 Management of psychiatric disorders in the presence of HIV •

• • •

Psychiatric disorders can occur prior to HIV infection, and may increase risk for infection. Alternatively, people who have never experienced mental illness may have the first onset as a complication of HIV infection, of opportunistic infections and illness and HIV-related treatments. Assess new onset major mental illness (a first episode) medically completely including an HIV screen. Rule out underlying physical cause when an exacerbation occurs even when major mental illness is recurrent. Refer patients for: o management of acute psychosis and mania o presence of dangerousness to self or others o Inability to manage the psychiatric diagnosis in the primary case setting. Psychotropic medications are effective in the presence of HIV infection, assuming urgent medical conditions have been addressed. Do a complete medical assessment on patients who enter mental health facilities with an established HIV diagnosis or those who are initially diagnosed after admission. Assessment should include staging of HIV infection and prescription of prophylaxis for opportunistic infections, (including tuberculosis in long-term patients).

• • • • •

Administer and monitor prescribed medications and arrange for appropriate medical follow-up for patients in psychiatric hospitals. Start low go slow in advanced and /or symptomatic HIV infection and elderly patients. Treat with anti psychotic medications regardless of neuropsychiatric manifestations of HIV & AIDS Treat delirium with anti psychotic medications Note the following precautions: o Patients with advanced HIV disease are very sensitive to extrapyramidal side effects and can develop severe parkinsonian symptoms, including the onset of neuroleptic malignant syndrome occuring within days and tardive dyskinesia occuring within weeks. Standard neuroleptics should thefore be used in very low doses in these patients. o Where available, newer atypical anti- psychotic medications are easier to use. o Monitor patients continuously as neuropsychiatric symptoms may improve with treatment and may wax and wane over time monitoring is recommended.

4.10 Management of central nervous system infections associated with HIV Condition

Recommended treatment

Comments

Toxoplasmosis Acute Toxoplasma infection – encephalitis

Co-trimoxazole tablet for each 8kg bodyweight per day, 12hourly for 4 weeks followed by half the dose for 8 weeks. Continue with 2tablets per day for life or until the CD4>200cells/mm3 for 6 months. OR Pyrimethamine 100-200 mg loading dose, then 50-100 mg/day po + folinic acid 10 mg /day po (or folic acid)+ sulfadiazine 4-8 gm/day po (or replace sulfadiazine with clindamycin 300-450 mg po 6 hourly) for at least 6 weeks. Corticosteroids if significant oedema/mass effect is present (Decadron® 4 mg po or IV four times a day) Consider serial lumbar puncture to lower raised intracranial pressure.

Patients who present with focal neurological signs, or depressed level of consciousness should have a CT scan of the head. When ring enhancing space occupying lesions are shown, consider tuberculoma, lymphoma or toxoplasmosis. Consider treatment for toxoplasmosis where there are several lesions. If no response to treatment consider TB treatment. If a single lesion is seen on CT scan, check Toxo serology and initiate treatment for toxoplasmosis. If positive continue, if negative LP where there is no risk or initiate TB treatment if patient has systemic TB symptoms• Anticipated response is clinical improvement within one week and improvement by CT scan within 2 weeks • Patients who respond to primary therapy should receive life-long ART.

Maintenance therapy (after successful response to treatment of acute episode of Toxoplasma infection)

Co-trimoxazole 2 tablets/day Pyrimethamine 25-50 mg/d po + folinic acid 5 mg/day (or Folic acid) + sulfadiazine 2-4 gm/ day po (or replace sulfadiazine with clindamycin 300-450 mg po 6-8 hourly). Stop when the CD4 count>250cells/mm3 for 6 months

4.10.1 Management of cryptococcal meningitis • Cryptococcal meningitis occurs in individuals who are severely immunocompromised. • Do a lumbar puncture if history of subacute meningitic illness of: o Headache o unexplained fever o nausea and vomiting o neck stiffness o confusion o seizures o abnormal behaviour o new-onset psychiatric symptoms o altered level of consciousness o focal neurological signs o diplopia o unexplained blindness o Coma • Do a CT scan if there are focal neurological signs, • CSF findings consistent with cryptococcal infection include: o Positive Cryptococcal antigen, Indian ink stain or Cryptococcal culture. • In rare instances where cryptococcus is isolated from other sites of infection, therapy should also be initiated due to the high risk of CNS dissemination. • Successfully treated cases of cryptococcal meningitis require secondary prophylaxis therapy with fluconazole until CD4 > 200 cells / mm3 for 6 months on ART. Caution should be exercised in prescribing Fluconazole to patients who are taking Rifampicin; Protease Inhibitors; Warfarin; oral contraceptives; oral Sulphonylureas or Phenytoin. Condition

Recommended treatment

Comments

Cryptococcal meningitis 5

Acute treatment (8 weeks): Induction phase: Amphotericin B 1mg/kg/day IV for up to 14 days (minimum 1 week) Consolidation phase: Fluconazole 400 mg/day for 8 weeks. Secondary prophylaxis: Fluconazole 200 mg po daily for life or until the CD4>200cells/ml for more than 6 months when on ART Subsequent episode of CC Induction phase: Amphotericin B 1mg/kg/doseivi for 2-4 weeks or until CSF is sterile Consolidation phase: Fluconazole 800mg po daily for 8 weeks with or without weekly amphotericin B

Pain and symptom management: Reduction of intracranial pressure alleviates headache and confusion. Residual pain can be managed with paracetamol and mild opiates(WHO level 1 & 2 analgesics). Non-steroidal anti-inflammatory drugs should be avoided in patients on amphotericin B as they potentiate nephrotoxicity. Laboratory diagnosis: . Definitive diagnosis by culture or presumptively by tests indicating the presence of Cryptococcal species like India ink, cryptococcal antigen detection test or mucicarmine-stained histopathological sections revealing organisms.

5 Guidelines for the prevention, diagnosis and management of cryptococcal meningitis and disseminated cryptococcosis in HIV-infected patients. The Southern African Journal of HIV Medicine, Spring 2007; 2535

Condition

Neurosyphilis

Recommended treatment

Comments

1mg/kg Secondary prophylaxis: Fluconazole 400mg podaily for life (at least 12 months fluconazole) OR weekly amphotericin B1mg/kg/dose OR weekly amphotericin B1mg/kg/dose plus daily fluconazole 400mg. Stopped when CD4>250cells/ml for more than 6 months Management of raised intracranial pressure(>20cm CSF): Serial therapeutic lumbar puncture, preferably with manometry: • Measure initial opening pressure by manometry • Remove ± 20-30ml CSF if intracranial pressure is raised (to decrease opening pressure by 2050%) at initial LP. Ongoing need for pressure relief should be dictated by recurrence of symptoms of raised intracranial pressure. Repeat daily until opening pressure is normal. Dosage and administration: Controlled infusion over 4 hours of amphotericin B at 1mg/kg in 1 litre of 5% dextrose water should be given after prehydration with 1 litre normal saline containing 20mmol KCL(1ampoule) run over 2 hours. AmphotericinB should never be mixed with normal saline or half normal saline, nor used to administer any other drugs. Infusion should not be faster than 4hrs to avoid cardiac problems.

ART should be started 2-4 weeks after initiation of antifungal therapy according national guidelines Management of suspected IRIS: Continue ART LP to exclude additional pathology, check susceptibility and measure intracranial pressure CT Head when focal neurological signs present Ensure appropriate antifungal therapy Treat culture positive cases as per guidelines, in culture negative cases continue with the consolidation phase or secondary prophylaxis Oral steroids with prednisone 1mg/kg daily for at least a week if symptoms fail to respond after appropriate management of raised intracranial pressure and symptomatic treatment or longer if needed.

Benzathine penicillin ivi 18–24 MU daily, administered as 3–4 MU 4 hourly, for 10–14 days. Alternative Regimen: Procaine penicillin imi 2.4 MU daily, for 10–14 days plus Probenecid, oral, 500 mg 4 times a day, for 10–14 days. These regimens are shorter than that of the regimen used for late syphilis in the absence of neurosyphilis. Therefore, some experts administer benzathine penicillin, IM, 2.4 MU after completion of these neurosyphilis treatment regimens to provide a comparable total duration of therapy. Parenteral penicillin is the only therapy with documented efficacy for neurosyphilis. Patients with neurosyphilis who report

Side-effects: Nephrotoxicity and electrolyte abnormalities prevented by adequate prehydration. Nephrotoxicity occurs in the second week of amphotericin B. Baseline and twice weekly monitoring of creatinine, magnesium and potassium is recommended.If creatinine doubles omit a dose of amphotericin B or hydrate with 1litre 8hourly. If creatinine remains elevated stop amphotericin B and commence fluconazole. Oral potassium and magnesium supplements may pre-empt electrolyte imbalances. Monitor Hb weekly to check for anaemia. Diagnosis is made by CSF examination showing mononuclear pleocytosis (10-200wcc/ml), mild elevation of protein and/or positive VDRL. CSF VDRL is specific but not sensitive; the CSF FTA-ABS is sensitive but not specific. Diagnosis is thus difficult due to the high rate of false negative CSF VDRLs and the pleocytosis that can be attributed to HIV in patients with high CD4 levels. If neurosyphilis cannot be excluded the patient should be treated as such.

Condition

Recommended treatment

Comments

penicillin allergy should always, if possible, be treated with penicillin, after desensitization

4.11 Chronic Diarrhoea 4.11.1 General Principles • • •

Many infective causes of diarrhoea that affect HIV negative individuals occur commonly in HIV positive patients and should be managed in the same way as they are treated in HIV negative patients. Basic food, water and personal hygiene, as well as infection control procedures should be emphasized. Ensure hydration with home-made sugar and salt solution: 1 level teaspoon of salt and 8 level teaspoons of sugar dissolved in 1 litre of boiled then cooled water.

4.11.2 Management of diarrhoeal disease in HIV Condition

Recommended treatment

Comments / Rationale

Symptomatic treatment of diarrhoea

Loperamide, oral, 4 mg immediately, followed by 2 mg after each loose stool, up to 16 mg/ day for severe diarrhoea. or Codeine syrup/tablets 15-30mg po 3-5 times a day (as required).

Diarrhoea is classified as acute if <2weeks and chronic if > 2 weeks. In acute diarrhoea send stool for bacterial MCS and in chronic diarrhoea send for this as well as coccidian parasites (microsporidiam, cryptosporidium and Isospora belli). If there is a history of recent antibiotics consider Clostridium difficile. Where there is an acute onset wth fever, blood or mucus in the stools or LIF tenderness send for stool MCS, blood cultures if febrile and treat with ciprofloxacin or ceftriaxone if vomiting. Oral rehydration should be prescribed if the diarrhoea is severe. Diet modification includes: low fat, no caffeine, no milk or milk products. Codeine usage can become addictive. Stools should be sent of for culture and microscopy that includes investigation for TB Chronic Diarroea Rehydrate and correct electrolytes and send stool for MCS and coccidian parasites. Scope if negative. If inflammatory stool found (WCC or RBCs on micro) treat with metronidazole. If does not settle do sigmoidoscopy and biopsy. If no

Condition

Recommended treatment

Infective diarrhoea

Usual infective diarrhoea should be managed in the same manner in HIV and non-HIV infected individuals.

Non-invasive bacterial infections (food poisoning)

Replace electrolytes and fluids Treat vomiting symptomatically Antibiotics are mostly of no value, except for Enterotoxic E coli and for Cholera, in which cases, treat with: Trimethoprim/sulphamethoxazole (80/400), oral, 2 tablets twice daily or Doxycycline, oral, 100 mg twice daily for 5 days. Invasive bacterial infections causing diarrhoea Trimethoprim/sulphamethoxazole (80/400), oral, 2 tablets twice daily for 7 days plus Metronidazole, oral, 400 mg 8 hourly for 7 days. Fluid and electrolyte replacement

Invasive bacterial infections causing diarrhoea

Cryptosporidial diarrhoea

Protease inhibitor associated diarrhoea

Symptomatic treatment with oral rehydration, nutritional supplements and Loperamide or Codeine. There are currently no specific treatments. Loperamide. Fibre supplements. Pancreatic supplements, as indicated.

Comments / Rationale inflammatory stool then gastro-scope for duodenal biopsy. Infective diarrhoea may be suspected, or confirmed on stool microscopy, culture and sensitivity Loperamide and codeine should not be given if infective diarrhoea is suspected (eg fever, blood in stool). Food Poisoning is a Notifiable Disease. Outbreaks often occur in institutions.

Attempt to identify the specific causative agent and antibiotic sensitivity and give antibiotics according to sensitivity. Widespread resistance to antibiotics is common. Appropriate antibiotics should preferably be selected according to sensitivity. Non-steroidal anti-inflammatory agents are sometimes useful. ART is the best treatment available

4.12 Miscellaneous conditions Condition

Cytomegalovirus Retinitis and extraocular disease

Mycobacterium avium complex (MAC) bacteremia

Recommended treatment

Comments / Rationale

Vision threatening lesion: Intraocular ganciclovir implant every 6-8 months + valganciclovir 900mg pobid x 1421 days then 900mg/day. The goal of therapy is to prevent further loss of vision and to control disease using ART. Discontinue maintenance therapy when the CD4 count is >100150cells/mm3 for more than 6 months and no active disease. Gastrointestinal disease is best treated with valganciclovir 900mg po bid with food x3 to 4 weeks if able to swallow otherwise ganciclovir 5mg/kg ivi bid for 3 to 4 weeks Clarithroymcin 500 mg po twice a day plus ethambutol 15 mg/kg/day +/rifabutin 300mg/d po. Start ART as soon as possible with in 1-2 weeks of initiation of MAC

Patients may be asymptomatic or present with foaters, visual field defects, scotomata or decreased acuity. CD4 usually <50cells/mm3. Fundoscopic exam shows perivascular yellow-white retinal infiltrates or lesions with occasional haemorrhages. Patients need urgent ART workup and commencement

Symptoms are: fever, night sweats, weight loss, diarrhoea, abdominal pain, abdominal masses etc in patients with CD4 counts<50cells/ml. Diagnosis established by culture with

Condition

Anaemia

Septicaemia

Recommended treatment

Comments / Rationale

therapy. Alternative regimen: azithromycin 500-600mg/day + ethambutol 15mg/kg/day po or Ciprofloxacin 750 mg po twice daily With ART, initial results suggest MAC treatment may be discontinued when MAC treatment is >1 yr, CD4 count is >100/mm3 for 3-6 months and the patient is asymptomatic Treat as per standard clinic guidelines

blood cultures being 90-95% sensitive using Bactec culture. . Note interactions of recommended therapy with protease inhibitors and NNRTIs.

Ceftriaxone 1g ivi bd as initial therapy while causative organism and sensitivities are awaited

Common and usually related to HIV and OIs. If the anaemia is out of keeping with the OI presentation then investigate other causes; nutritional, haemolytic, marrow infiltrates, drugs or Parvovirus B19 infection Patients are prone to Gram positive (staphylococcus) and Gram negative (salmonella) septicaemias. Symptoms: high fever, hypotension, metabolic acidosis, source of infection might not be clear. Blood cultures are critical

SECTION 6: POST-EXPOSURE PROPHYLAXIS (PEP) 1. PROPHYLAXIS AFTER ACCIDENTAL OCCUPATIONAL OR NONOCCUPATIONAL (INCLUDING SEXUAL ABUSE/RAPE) EXPOSURE TO HIV 1.1 General principles • Compliance with infection control recommendations in handling blood products, body fluids or sharps is the mainstay in the prevention of occupational HIV infection. • Non-occupational exposure may occur as a result of sexual abuse (rape), with bite injuries or other violent actions, lay individuals assisting victims of accidents or violence where there is exposure to blood or body fluids 2. PROPHYLAXIS AFTER OCCUPATIONAL (EXCLUDING RAPE) 2.1 High Risk exposure of infection - Factors that increase the risk of seroconversion include: Exposure to large inoculum of infected blood indicated by: • a deep injury • visible blood on device • procedures involving needles especially large bore needles/biopsy needles • Source patient with terminal AIDS or known to have a high viral load, i.e 100 000 copies / ml In situations where there is a high suspicion that the patient may be in the window period, consider HIV PCR testing. 2.2 When to commence treatment • •

Commence treatment as soon as possible within 1 to 2 hours of exposure – the sooner the better. Counsel and test the injured person for HIV before initiating HIV prophylaxis. Dual or interrupted therapy could lead to resistance and endanger future treatment options.

2.3 Monitoring after occupational exposure • • •

Do laboratory monitoring to exclude acquisition of HIV infection and, for those given PEP, to monitor toxicity. Test for HIV infection using an HIV antibody test at time of exposure using ELISA, and again at 6 weeks, 3 months and 6 months. Counsel on practicing safe sex until HIV test is negative 6 months following exposure

•

Do a full blood count before initiating patients on AZT and after 2 and 4 weeks on antiretroviral therapy. Relative contra-indications to the use of AZT include significant renal or liver impairment and severe anaemia (Hb < 6, 5 g/dl).

2.4 Recommended PEP drug regimen a) For standard risk, basic two drug regimen AZT, oral, 300mg 12 hourly for 4 weeks AND 3TC, oral, 150 mg 12 hourly for 4 weeks b) For high risk, expanded three drug regimen ADD Lopinavir / ritonavir 400 / 100, oral, 12 hourly 3. PROPHYLAXIS AFTER SEXUAL ASSAULT 3.1 High risk profile rape includes: o where there have been multiple perpetrators o anal penetration o obvious trauma to the genital areas o Female menstruating at time of rape, or with genital ulcerations/sores o Known HIV positivity of one of the perpetrators 3.2 Follow guidelines on STI/Pregnancy prophylaxis • Counsell all women and men, aged 12 years and older presenting to a health facility after being raped, about the potential risks of HIV transmission postrape. • Offer PEP to prevent HIV transmission to all women and men, aged 12 years and older, presenting to a health facility within 72 hours of being raped. • Manage younger managed at specialized sites where there is the expertise in dealing with traumatized children and the prescription of ART. 3.3 The following points should be covered in the counselling: • Counsel all patients presenting after 72 hours about the possible risk of infection and the possibility of them transmitting infection during seroconversion. • Provide appropriate post trauma counselling with follow up to all patients. 3.4 Where the risk of HIV transmission is not known, but exists. • Know the victim’s HIV status prior to using any ART. • Delay but not for longer than 72 hours post-rape as it is the patient’s choice to have immediate HIV testing if she/he prefers. • Provide a 3-day starter pack for those who prefer not to test immediately, or those that are not ready to receive results immediately.

• • •

Counsell patients who request prophylaxis after 72 hours about lack of scientific evidence that the use of PEP delayed this long after the rape will have any impact on preventing HIV transmission Give patients a week supply of PEP. Give a date to return within a week for: o reassessment o ongoing counselling o Review of test results (except the rapid HIV or to obtain the confirmatory ELISA, where positive). Give the remainder of the drugs at this visit (i.e. a 3-week supply). Give a month’s treatment supply with an appointment date for those patients who cannot return for their one-week assessment due to logistical or economic reasons. Do not offer prophylaxis to patients who are either known to be HIV positive, or who test HIV positive. Refer to an appropriate health care clinic for longterm management of their HIV infection

3.5 Recommended PEP drug regimen For standard risk, basic two drug regimen AZT, oral, 300mg 12 hourly for 4 weeks AND 3TC, oral, 150 mg 12 hourly for 4 weeks For high risk, expanded three drug regimen ADD Lopinavir / ritonavir 133 / 33, oral, 3 capsules 12 hourly

Figure 1: PEP after sexual assault Patient allegedly sexually assaulted

Documentation for all patients to open folder

Medical examination for STI and pregnancy; Counselling

Assault occurred less than 72 hours ago

Yes

Counselling 3-days PEP starter pack

Consent HIV test

HIV negative

HIV positive

Baseline HIV, FBC, LFTs HIV positive

Refuse test

HIV negative

NO PEP

PEP

Routine follow-up

Patient referred for further HIV management

Follow-up blood tests 6 & 12 weeks and 6 months

APPENDIX 1: WHO clinical staging of HIV & AIDS for adults with confirmed HIV infection (2006) Clinical Stage 1 1. Asymptomatic 2. Persistent generalized lymphadenopathy (PGL)

Clinical Stage 2 3. Unexplained moderate weight loss <10% of presumed or measured body weight 4. Recurrent respiratory tract infections (e.g. bacterial sinusitis) (URTI) and/or performance Scale 2: symptomatic, normal activity. 5. Herpes zoster within the last five years 6. Angular cheilitis 7. Recurrent oral ulceration 8. Papular puritic eruptions 9. Seborrhoeic dermatitis 10. Fungal nail infections

Clinical Stage 3 11. Unexplained severe weight loss >10% of presumed or measured body weight 12. Unexplained Chronic diarrhoea >one month 13. Unexplained presistent fever (above 37.5ÂşC intermittent or constant) >one month 14. Persistent oral candidiasis 16. Oral hairy leukoplakia 17. Pulmonary TB 18. Severe bacterial infections (pneumonia, empyema, pyomyositis, bone or joint infections, meningitis or bacteraemia) 19. Acute necrotizing ulcerative stomatitis, giingivitis or periodontitis 20. Unexplained anemia (<8g/dl), Neutropaenia (<0.5 x 109 per litre) and/or chronic thrombocytopaenia (<50 x 109 per litre)

Clinical Stage 4 21. HIV wasting syndrome 22. Pneumocystis pneumonia 23. Recurrent severe bacterial pneumonia 24. Chronic herpes simplex infection (orolabial, genital or anorectal of >1 months duration or visceral at any site) 25. Oesophagael candidiasis (or candidiasis of trachea, bronchi or lungs) 26. Extrapulmonary tuberculosis 27. Kaposis sarcoma\ Cytomegalovirus infection other than liver, spleen or lymph node (CMV) 28. CNS toxoplasmosis (Toxo) 29. HIV encephalopathy (ADC) 30. Cryptococcosis â&#x20AC;&#x201C; non pulmonary 31. Disseminated mycosis (i.e. histoplasmosis, coccidiomycosis) 32. Progressive multifocal leucoencephalopathy (PML) 33. Cryptosporidiosis plus diarrhoea >one month

34. Chronic Isosporiasis plus diarrhoea 35. Herpes simplex infection; visceral or >one month mucocutaneous (HSV) 36. Atypical mycobacteriosis disseminated (MOTT) 37. Atypical disseminated leishmeniasis 38. Non-typhoidal Salmonella septicaemia 39. Extra-pulmonary tuberculosis (ETB) 40. Lymphoma 41. Kaposiâ&#x20AC;&#x2122;s sarcoma (KS) 42. Invasive cervical carcinoma and/or performance 43. Symptomatic HIV-associated nephropathy or symptomatic HIV-associated cardiomyopathy

APPENDIX 2 : ADULT PATIENT ADHERENCE RECORD & MONITORING FORM [PARMF] Please complete all sections of the PARMF unless otherwise indicated 1. Patient Details: Surname: Folder no:

First Name: Date: dd / mm / yy

D.O.B.:

2. Date of Treatment initiated: dd / mm / yy

3. Duration of treatment: Months Years

4. Pill Identification Test (PIT) Ask the patient to inspect the container and its content. The patient should then tell you the name of the medication, number of pills to take per dose, the times when the medication are taken and whether there are any additional instructions Medication Knows the name Y/ N

Knows the no of pills per dose Y/N

Time the medication is taken Morning Evening Judged hour hour correct Y/N

Knows any additional information

5. Medication Pick-Up Dates: Mon th 1 2 3 4 5 6

To Come Again (Appt. Date)

Pick Up Date

Variance Mon (days) th

To Come Pick Up Again Date (Appt. Date)

Variance (days)

7 8 9 10 11 12

6. Pill Count: Did the client return the medication containers? Yes / No If yes, check that the patient only used medication from this container since the date of the last visit. If leftover medication has been used or an emergency prescription obtained then the calculation will be invalid. Count the remaining number of pills on the collection date Calculate the Adherence as follows: % Adherence =

Dispensed

Returned / Expected to be taken × 100

Dispensed = pills remaining at last visit + pills issued at last visit Returned = pills remaining now Expected to be taken = number of pills taken per day x number of days passed since last visit Then collate Adherence Monitoring Record (%) using the table provided below: 6.1 Adherence Monitoring Record (%): Medications M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12 Date

7. Visual Analogue Scale (VAS): Insert a √ in the relevant box and then insert % Adherence (see Table below) • Ask the patient to think back over the past 4 days and identify the times when he / she either missed a dose or took it at the wrong time. • Show the patient an unmarked copy of the visual analogue scale. • While placing your finger on the appropriate place, tell the patient that if he / she had taken all medication doses to point to 10. • If the patient missed all the doses he / she would point to 0. • In the meantime you move your finger to 0. • Now give the patient an opportunity to point out their level of adherence. • The health care worker then marks the visual analogue scale. • If the scale is marked at 4, then the percentage adherence would be 40%.

Month

Date

10 %Adherence S c o r e

M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12

8. Self â&#x20AC;&#x201C; Reporting: (Insert a â&#x2C6;&#x161; in the relevant box to indicate the patientâ&#x20AC;&#x2122;s response) Month Date Question

Y N

Y N Y N

Y N

Do you sometimes find it difficult to remember to take your medicine? When you feel better, do you sometimes stop taking your medicine?

Y N Y N

Thinking back over the past 4 days, have you missed any of your doses? Sometimes if you feel worse when you take the medicine, do you stop taking it?

9. Adherence Assessment (Mark the response provided with a √) Pick Up Date Pill Count VAS Self-Reporting

0 – 2 days 3 – 5 days > 5 days > 95% 75 – 94 % < 75% > 95% 75 – 94% < 75% Answered “No” to all Answered “Yes” to 1 Answered “Yes” to questions question 2 or more questions HIGH (H) MODERATE (M) LOW (L)

OVERALL ADHERENCE

10. Fill in table provided below to show adherence per tool used per month Month

Date Pick Up Date Pill Count VAS Self-Reporting OVERALL ADHERENC E

11. Recommendations MODERATE ADHERENCE Low Intervention: Adherence Counselling

LOW ADHERENCE High Intervention: Intense Retraining and Counselling Revision of Dosage Regimens / TrainingReview with Patient Advocate Revision Re-assurance Home Visit

APPENDIX 3: TB PROPHYLAXIS Guidelines for tuberculosis (TB) preventive therapy among HIV positive patients Background • The spread of the HIV epidemic throughout sub-Saharan Africa in the past decades has been accompanied by up to a fourfold increase in the number of TB cases registered by the national TB programmes. • Strategies to control TB must now include interventions to reduce HIV infection. •

On the other hand, it is estimated that around 50% of new adult cases of TB in South Africa are co-infected with HIV.

•

TB is the commonest cause of morbidity and mortality among HIV-infected population in South Africa.

•

There is scientific evidence that shows that TB does accelerate HIV-disease progression. Therefore, preventive TB therapy should be offered in the package of care for people living with HIV.

•

TB preventive therapy is the use of one or more anti-tuberculosis drugs given to individuals with latent infection with M. tuberculosis in order to prevent the progression to active TB disease.

•

There is scientific evidence that shows that maximum benefits from TB preventive therapy are achieved in HIV positive patients with evidence of TB infection.

•

Providing IPT to these patients reduces the risk of developing TB by 60%, and their survival is also prolonged.

TB preventive therapy and health services •

Provide TB preventive therapy as part of the package of care for people living with HIV after: o voluntary counselling and testing for HIV o effective screening for active TB

EXCLUSION OF ACTIVE TB • •

• •

Exclude active TB in every patient prior to starting preventive therapy. This is critical in order to avoid giving one drug to patients with TB disease who require the full regimen. Ask patients about signs and symptoms of TB: o Cough >2 weeks o Fever >2 weeks o Night sweats o Other symptoms, like pleuritic chest pains, haemoptysis should also prompt investigations for TB o Weight loss of >1.5 kg in the past 4 weeks Investigate all patients with 1 or more signs and symptoms for active TB. These patients are not immediately eligible for TB preventive therapy until active TB has been excluded. Reassess patients with symptoms / signs after 3 months for TB preventive if they are not confirmed with TB (smear and culture are both negative), and they recover from their illness

NOTE: Symptoms are adequate to exclude active TB in advanced disease, but with CD4 > 250 symptoms are insensitive. In these patients it is suggested that sputum specimens must be collected for the following investigations: • sputum samples for microscopy • 1 sputum for culture • A chest x-ray must not be a barrier for people to access IPT. Emphasis is on sputum samples for microscopy and culture and, where appropriate, on identification of extra pulmonary TB. • Do a chest ONLY in those who are TB suspects with negative sputum smears.

ELIGIBILITY FOR TB PREVENTIVE THERAPY 1. ELIGIBILITY FOR TB PREVENTIVE THERAPY All HIV-positive people, with no signs and symptoms suggestive of active TB, with positive tuberculin skin test, are eligible for TB preventive therapy. •

Give particular attention to: o Miners o Prisoners o TB contacts o Health care workers

1.1 Who is not eligible for TB preventive therapy? • • • •

Patients with active liver disease or active alcohol abuse should not be offered TB preventive therapy. This is because of potential hepatotoxicity of the drug used for preventive therapy. Patients with history of TB treatment:Any patient, who had active TB in the past 2 years, should not be offered TB preventive therapy. Patients on ART should not be offered TB preventive therapy, as there is currently no scientific evidence of added benefit. Patients who receive TB preventive therapy, and who require to start ART, can complete their TB preventive therapy even if the ART is started. This is because there is no interaction between isoniazid and the current ART regimen used.

2. TUBERCULIN SKIN TEST • • • • • • • •

The tuberculin skin test measures the body’s immune response to an injection of tuberculin purified protein derivative (PPD). The Mantoux test is the recommended technique that injects a known amount of PPD between the layers of the skin (intradermally). The injection must go into the skin and not under the skin. The reaction is measured at the site of injection 48-72 hours later. Measure the induration (not the eventual erythema) accurately To help measure accurately, mark the edges of the induration at the widest point with a pen (two point pen method). Then measure the exact distance between the two points. Measure the diameter of the reaction at the widest points of the raised, thickened area. Record the result in millimetres.

2.1 Positive tuberculin skin test results: Tuberculin test Mantoux

Previous BCG NO previous BCG HIV positive Greater or equal toGreater or equal to >4 mm 15mm 10mm

2.2 What does a positive tuberculin skin test mean? • • •

A positive test indicates infection with TB, but not necessarily TB disease. A positive reaction occurs after BCG immunisation and remains positive for several years thereafter. This reaction is usually weaker than the reaction to natural infection with M. tuberculosis.

2.3 Conditions that may reduce or suppress the tuberculin skin test include: o HIV infection o Malnutrition o Severe viral infections (e.g. measles, chicken pox) o Cancer o Immuno-suppressive drugs (e.g. steroids) o Severe disseminated TB 3. RECOMMENDED REGIMEN The standard regimen for TB preventive therapy is: Isoniazid (INH) daily. The dose is: 5 mg/kg/day (maximum 300 mg per day). The recommended duration is: 6 months. • •

Give additional Vitamin B6 (Pyridoxine) in sufficient dosage to prevent the eventual occurrence of peripheral neuropathy. IPT protective effect is expected to last for 18 months.

Figure 2: Screening for tuberculosis preventive therapy flowchart among HIV positive patients.

HIV-positive patient

Complete patient chart

Clinical status and screening for suitability for PT Not eligible for IPT; provide co-trimoxazole prophylaxis

Previous TB treatment past 2 years

TB symptoms or signs NO

YES

PPD test

Sputum smear & culture

PPD positive

Visit 2 / Follow up Offer IPT and counselling about IPT Commence IPT

Smear negative

â&#x20AC;˘

Antibiotics

PPD negative

Good response to antibiotics

No IPT

Patient refuses IPT

Smear positive or culture

Reassess and reconsider screening for IPT after 3 months

Read result after three days (48-72 hrs)

Poor response to antibiotics

Refer for further investigations for PTB, EPTB or other possible conditions TB treatment; co-trimoxazole prophylaxis

• •

Offer TB preventive therapy if the skin test is positive Offer on-going counseling about : o HIV o Symptoms of side-effects of isoniazid (minor: peripheral neuropathy) ( major: jaundice, vomiting and confusion, due to hepatitis) o Adherence counseling o Early detection of active TB o seeking care immediately if they develop an illness Give one month at a time supply to patients starting TB preventive therapy. Give a subsequent appointment to review the condition if Tuberculin test negative

Patients should come for review if any symptoms of active TB occur. 4. CONTRAINDICATIONS TO IPT • Stop IPT and start the full TB treatment regimen if the patient develops active TB • Stop IPT immediately, and refer signs and symptoms suggestive of hepatitis 5. WHEN THE PATIENT INTERRUPTS THERAPY • Enquire about the possible reasons for interrupting. • Counsel on the importance of adherence appropriately. • Restart the therapy after assessing the reasons for bad adherence. • Ensure that the 6 months therapy is taken within a 9-month period. • Stop IPT if the patient interrupts for the second time These TB preventive guidelines may be reviewed upon evidence of new developments.

APPENDIX 4: FORM FOR DOWN REFERRAL

Referring Dr.

Maintenance site

Dear Prof/Dr/Mr/Ms REFERRAL OF PATIENT 1. GENERAL AND PERSONAL PARTICULARS: 1.1

Appointment with and/or place of appointment:

1.2

Date:

1.3

Patient:

1.4

Date of birth:

Time:

Registration:

2. REFERRAL NOTES:

SIGNATURE:

DATE:

PATIENT REPORT: REGISTRATION NO: HOSPITAL NO: Dear Prof/Dr/Mr/Ms 1. Please complete this feedback report on completion of your consultation. 2. Findings:

Orders:

Refer to

Admission to

Prescription

For follow-up at

SIGNATURE 8.

for on

with

NAME IN PRINT

DATE

Your contact telephone number please:

SOME DEFINITIONS Treatment failure results mainly from failure to suppress viral replication. The most reliable tool to measure treatment failure is the viral load. This should be suppressed (<400 copies/ml) within 6 months of starting the first line regimen. Virological failure is defined as failure to suppress, or if previously suppressed viral load rises significantly (see table 6). The CD4 count typically increases by about 100 cells / mm3 in the twelve months and by about 50 in each subsequent year, but this increase is highly variable. Treatment failure should not be defined by CD4 count criteria as a proportion of patients with a suppressed viral load will fail to increase their CD4 counts, and changing therapy will not improve this. On the other hand, a large proportion of patients will have a good increase in their CD4 cell count despite incomplete viral load suppression. In this situation resistance to antiretroviral drugs will occur. Clinical failure is progression of disease with the development of opportunistic diseases. This may occur during the first 3 months of ART before the CD4 count has increased significantly. At this point, it is not necessary to switch to another regimen. Even if a new opportunistic disease erupts, the treatment regimen should only be switched if this is accompanied by virological failure. Step-up adherence package Steps taken to promote adherence to taking more than 95% of their doses when adherence assessment is <80% at any visit, with or without viral or clinical failure. Down-referral Referral to a lower level of care of patients who for a period of six months after initiation are responding well to ART. Initiation site These are sites where patients are commenced on antiretroviral therapy.

100

List of contributors (Please acknowledge sources of all information especially around the managemnt of side effects and the management of OIs)

101