DR-TB in India: MSF's experience

Exploring how India’s problems with drug-resistant TB evolved: MSF’s experience of treating drug-resistant TB in India

Petros Isaakidis Medical Epidemiologist Senior Operational Research Fellow

TB/DR-TB Epidemiology in India • 2.000.000 new TB cases/year ; 300.000 deaths

• 25% of the global MDR-TB burden – 100.000 new MDRTB cases ( WHO)

• Reported MDRTB prevalence : 4,1% – 3% new cases 17% retreated

• Other sources on MDRTB prevalence – – – –

Chandigarh: 17,4% (9,9% NC 27,6% RC) Mumbai D'Souza et al, 2009: 24% NC and 41% RC Hinduja lab: 70,1% FQ resistance MSF OR first data: 25% NC and 51% RC in HIV+

– Mumbai Sewri GTBH: 14% MDR, 60% pre-XDR, 20% XDR, 6% XXDR

HIV Epidemiology in India • Low prevalence in the general population (0.1%) •BUT the third largest population living with HIV, after South Africa and Nigeria : 2,390,000 people •Unknown HIV/DR-TB co-infection burden

MDR-TB epidemiology in India DR-TB epidemic not linked to HIV High burden

Heterogeneity Amplification of resistance profiles ("Mumbai TDR 2012")

Why an MDR-TB epidemic in India?

•Large reservoir of TB/ Social factors (poverty, slums, malnutrition) •"Unknown" burden of disease

•Under-resourced public sector •Unregulated private sector •Over the counter medications •Erratic TB drugs prescriptions •Quality of TB drugs •Lack of Infection Control •Intermittent Tx/DOTS (?)

•Lack of patient support/adherence •Delayed DR-TB diagnosis •Laboratory capacity •Challenging current MDRTB regimens

Does notification help?

After notification made compulsory in Mumbai in 2012 1407 MDR-TB patients were identified from the 6561 screened in 6 weeks compared to 181 of 354 in all 2011 Udwadia ZF, Reddy D: J Epidemiology Community Health, 2012

TB diagnosis is big money...

India has 30,000 labs: only 250 with any accreditation

TB diagnosis in India is a lucrative industry: 1.5 million serology tests were carried out annually RNTCP diagnostic spending = $38,000,000 Non-RNTCP spending

= $138,000,000

Recent bans in serology have brought other unindicated tests: IGRA’s, In-house PCRs to the fore

Only 3 labs accredited for 2nd line DST in the country None in Mumbai: Hinduja Microbiology Lab is a state-ofthe-art laboratory but not accredited

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Serological assays for tuberculosis on the Indian market

Dowdy DW, Steingart KR, Pai M (2011) Serological Testing Versus Other Strategies for Diagnosis of Active Tuberculosis in India: A Cost-Effectiveness Analysis. PLoS Med 8(8): e1001074. doi:10.1371/journal.pmed.1001074 http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001074

Tuberculosis Management by Private Practitioners in Mumbai, India: Has Anything Changed in Two Decades?

1991 study of prescribing behavior of private practitioners in Mumbai : •100 doctors provided 80 different prescriptions 1998 study in Mumbai and rural Pune: •105 doctors provided 79 different prescriptions 2009 study in Dharavi, Mumbai: •106 doctors provided 63 different prescriptions •6 only with correct drugs/regimen •no significant differences between Western medicine and alternative systems Udwadia ZF, Pinto LM, Uplekar MW (2010) PLoS ONE

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Table 4. Analysis of the physicians' prescriptions for MDR TB.*

Udwadia ZF, Pinto LM, Uplekar MW (2010) Tuberculosis Management by Private Practitioners in Mumbai, India: Has Anything Changed in Two Decades?. PLoS ONE 5(8): e12023. doi:10.1371/journal.pone.0012023 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0012023

Market promotes irrational treatment DRUG/ DRUG COMBINATION

No. of Brands

PYRAZINAMIDE

40

ETHAMBUTOL

40

RIFABUTIN

2

RIFAMPICIN

22

ETHIONAMIDE

13

ISONIAZID

6

PAS

5

PROTHIONAMIDE

7

STREPTOMYCIN

7

CYCLOSERINE

6

RIFAMPICIN + ISONIAZID

87

87

RIFAMPICIN + ISONIAZIDE + ETHAMBUTOL

40

RIFAMPICIN + ISONIAZIDE + ETHAMBUTOL + PYRAZINAMIDE

54

RIFAMPICIN + ISONIAZIDE + PYRAZINAMIDE

45

ISONIAZIDE + AMINO SALICYLIC ACID

1

ISONIAZID + PYRIDOXINE

4

RIFAMPICIN + ISONIAZIDE + ETHAMBUTOL + PYRAZINAMIDE + PYRIDOXINE

10

PYRAZINAMIDE + ISONIAZID + RIFAMPICIN + PYRIDOXINE

4

ISONIAZIDE + ETHAMBUTOL

12

Total

405

Will PPM (Public-Private Mix) help to take TB control ahead?

– RNTCP recommended since 2002 – No more than 24 PPM projects countrywide: not even a drop in the ocean Deewan P, BMJ 2010

How patients see the DOTS? 150 patients with TB Only 14% had heard of DOTS Only 1% can say what it stands for 66% found DOTS unacceptable Visits 3 x a week time consuming (62%) Humiliating having a doctor watch me swallow (45%) Lack of trust in government facilities (24%) Intrusion of privacy (10%) Pinto L, Udwadia ZF. The politics and economics of DOTS in India. Chr Resp Dis 2007

Does DOTS fit all?

1. Verifiable address mandatory - - homeless, slum dweller, migrants 2. Women more hesitant to attend - - stigma 3. DOTS clinics too obtrusive for a people secretive about TB 4. Difficult patients weeded out - - alcoholics, drug abusers - 5. Private patients excluded - 6. Inflexible: clinic hours do not suit the daily wage laborer, the sick, invalid, poor 7. Eventual workload 8. Inadequate for MDR 9. Inadequate for the HIV co-infected

TB in MSF projects in India

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Mumbai – complicated resistance profiles – co-morbidities, co-infections, HIV – Pediatrics/adolescents – psychosocial aspects – hospitalization of severe cases CG – accessibility – insecurity – continuity of care – community perception /cultural beliefs Nagaland – severe cases and unusual presentations – community perception / cultural beliefs – remote tribal area Manipur – accessibility – cross border patients – HIV co-infection

MSF in Manipur A Description of Diagnosis and Admission into treatment cohort: Home Based Care All newly diagnosed sputum positive patients and all patients clinically suspected of having TB but with negative microscopy are screened with Genexpert

If Genexpert reveals Rifampicin resistance samples sent to LRS laboratory in Delhi for culture and DST

Patient and family counseling is provided. Housing conditions, social support, and willingness to start on MDR treatment is assessed Once consent is obtained patients are started on a presumptive standard MDR treatment and later the regimen is tailored to the sensitivity results. ** Treatment is home based care and drugs are administered daily by health care workers.

Patients are visited by counselors and doctors at least twice in a month. Blood samples and sputum cultures are repeated monthly.

MSF in Manipur Table: 1 Clients with MDR TB stratified according to Gender and HIV status Whole Cohort

Males

Females

Total clients

51 (100)

35 (68.62)

16 (31.37)

Mean age

37 (11-70)

40 (14-70)

30 (11-50)

POS

NEG

POS

NEG

POS

NEG

6

45

5

30

1

15

HIV Status

*All values in parenthesis except mean age (range) are percentages

Cohort consists of :

Outcomes:

Isoniazid mono-resistance: 4 patients

13 cured

Poly drug resistance: 1 patient

4 died

MDR TB 42 patients: 14 of these patients are Pre XDR

3 LFU

XDR TB: 2 patients

31 alive on treatment

MSF in Mumbai Médecins Sans Frontières (MSF) has been operating an HIV-clinic in Mumbai since May 2006

Treating HIV-infected patients with DR-TB since May 2007 (MoH 2010)

HIV-infected patients with suspected MDR-TB are referred by public ART-centers by a network of NGOs

MSF in Mumbai Diagnosis confirmed/ not confirmed ďƒ individualized / empirical regimen (8+ months injectable /20+ months continuation) One-stop-service, ambulatory and under DOT Treatment and care is free of charge This is the first cohort of HIV/MDR-TB co-infected patients in India and among the first reported globally >120 co-infected patients to-date

Final outcomes 2007, 2008, 2009 and 2010 cohorts 57% successfully treated 25% died 14% LFU 4% failed treatment

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Time to death under MDR-TB treatment.

Isaakidis P, Cox HS, Varghese B, Montaldo C, et al. (2011) Ambulatory Multi-Drug Resistant Tuberculosis Treatment Outcomes in a Cohort of HIV-Infected Patients in a Slum Setting in Mumbai, India. PLoS ONE 6(12): e28066. doi:10.1371/journal.pone.0028066 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0028066

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CD4 evolution over time in MDR-TB/HIV co-infected patients under ART and MDRTB treatment, Mumbai, India.

Isaakidis P, Cox HS, Varghese B, Montaldo C, et al. (2011) Ambulatory Multi-Drug Resistant Tuberculosis Treatment Outcomes in a Cohort of HIV-Infected Patients in a Slum Setting in Mumbai, India. PLoS ONE 6(12): e28066. doi:10.1371/journal.pone.0028066 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0028066

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Adverse events (episodes) and time of occurrence.

Isaakidis P, Varghese B, Mansoor H, Cox HS, et al. (2012) Adverse Events among HIV/MDR-TB Co-Infected Patients Receiving Antiretroviral and Second Line Anti-TB Treatment in Mumbai, India. PLoS ONE 7(7): e40781. doi:10.1371/journal.pone.0040781 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040781

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Mumbai HIV/MDR-TB co-infected adolescent cohort, 2007–2013.

Isaakidis P, Paryani R, Khan S, Mansoor H, et al. (2013) Poor Outcomes in a Cohort of HIV-Infected Adolescents Undergoing Treatment for Multidrug-Resistant Tuberculosis in Mumbai, India. PLoS ONE 8(7): e68869. doi:10.1371/journal.pone.0068869 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0068869

Trends in 2011-2013 cohorts •increasing pre-XDR, XDR, XXDR (a TDR case) >70% FQ resistance •severely ill patients • high pre-treatment mortality •overall on-treatment mortality stable •Loss-to-follow-up rates stable despite improved support

‘Worse than the illness itself : side

effects I have to take them daily. And I cry every day.

Every day I cry for an hour....the place where they give the injection becomes stone hard.

When I take the injection, I can‘t lift my legs, my legs hurt a lot and I am unable to walk.

Stigma and loss of support „They say [you should] „be separate, eat

separately, keep your water separate, and stay separately or stay far away‟. I am very sad in my heart, my heart aches because of this…. What can I do?‟

The burden of care “I take care of him all day and I even stopped going to work and stayed home for 3 months”

Staying on Treatment: �...so he gave me the pills to take at home� “The doctor has helped by giving me the pills to take home and to take them later otherwise I get dizzy. Otherwise they say the pills have to be taken at the doctors place itself.

Findings Family financial and emotional resources depleted

Two-year daily DOT seemed unrealistically demanding Adverse-events were severe and debilitating.

Frustration, anxiety and desperation due to burden of care and stigma Family caregivers were exhausted

MSF-providers: barriers to patient adherence were social not only medical

Conclusions Satisfactory outcomes can be achieved in HIV/MDR-TB co-infected patients treated ambulatory with individualized regimens

Despite free care, counselling, and psychosocial support, retention-in-care and adherence to treatment is challenging.

Specific interventions are needed to support children, adolescents, families and caregivers New, safe, low pill-burden, and significantly shorter treatment regimens are urgently required, and alternative to DOT strategies should be explored.

Current treatment regimens and case-holding strategies are resource-intensive and demanding, suggesting that scale-up of diagnosis and treatment for drug-resistant tuberculosis and HIV may remain challenging

Thank you Illustrations by George Butler