Learning Objectives • Demonstrate knowledge of the efficacy and safety of current DAA therapies • Offer interdisciplinary consultation on DAA management related to comorbidities and drug-drug interactions • Provide longitudinal pharmacy-based care and harm-reduction– informed counseling for patients before and after HCV treatment
Treatment Rationale: HCV Is Deadly The Natural History of the Disease Years 20−25 Years Normal Liver
HCV INFECTION
Chronic Hepatitis
Fibrosis Cirrhosis
25−30 Years • HCC • ESLD • Death
55−85 will develop chronic HCV if untreated
20−30 will develop cirrhosis
1−5 will die from HCC or ESLD
OF EVERY 100 PERSONS INFECTED WITH HCV
ESLD, end-stage liver disease. Lingala S, Ghany MG. Gastroenterol Clin North Am. 2015;44(4):717-734; 2. Image adapted from Hepatitis C Online. 2015. https://www.hepatitisc.uw.edu/go/evaluation-staging-monitoring/natural-history/core-concept/all. Accessed May 27, 2019.
HCV Guidance Recommendations Testing, Management, and Treatment • Recommendations for When and in Whom to Initiate Treatment – Treatment is recommended for all patients with chronic HCV infection, except those with short life expectancies that cannot be remediated by treating HCV, by transplantation, or by other directed therapy
• Goal of Treatment – Reduce all-cause mortality and liver-related adverse health consequences, including ESLD and HCC, by the achievement of virologic cure
AASLD/IDSA. When and in Whom to Initiate HCV Therapy. Last updated September 2017. https://www.hcvguidelines.org/evaluate/when-whom. Accessed May 27, 2019.
Evolving HCV Therapies
Increased Efficacy and Cure Rates 1986 100 90
SVR Rate, %
80
1998
2001
2002
• SVR = sustained virologic response = undetectable virus • SVR12 = SVR at ≥12 weeks after completion of HCV treatment • SVR12 = HCV cure
2011
2013 >90
Present >95
~75
70 60
54−56
50
42
40
34
39
30 16
20 10
6
0
IFN 6 Months
IFN 12 Months
IFN/RBV 6 Months
IFN/RBV 12 Months
PEG-IFN 12 Months
PEG-IFN/RBV PIs 12 Months BOC/TVR Addon Therapy
2nd Gen DAAs IFN-free 12 weeks
BOC, boceprevir; DAA, direct-acting antiviral; Gen, generation; IFN, interferon; PEG, pegylated interferon; PI, protease inhibitor; RBV, ribavirin; TVR, telaprevir. Adapted from Strader DB, Seeff LB. Clin Liver Dis. 2012;1(1):6-11.
Pangenotypic DAAs: 8−12 weeks
Introduction to Current First-line DAA Regimensa Initial Treatment
Retreatment Options for NS5A‒DAA-TE Patients
EBR/GZR Zepatier®
GLE/PIBb Mavyret®
GLE/PIB Mavyret®
SOF/VEL/VOXc Vosevi®
Pangenotypic
Pangenotypic
LDV/SOF Harvoni® SOF/VEL Epclusa® Pangenotypic
TE, treatment experienced. aRegimens listed alphabetically within columns by generic DAA; bNS5A−TE patients without prior NS3 exposure; cAll NS5A−TE patients. AASLD/IDSA. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. http://www.hcvguidelines.org/evaluate/when-whom. Accessed June 25, 2019.
HCV Is Not Only Curable Decreased All-Cause Mortality
35
10-Year Cumulative Incidence Rate, %
30
SVR (n=192) No SVR (n=338)
29.9 26.0
25
21.8
20 15 10
8.9 5.1
5
2.1
0 All-Cause Mortality
HCC
530 patients with advanced fibrosis: treated with interferon-based therapy and followed for 8.4 years (interquartile range 6.4−11.4 years). Van der Meer AJ, et al. JAMA. 2012;308(24):2584-2593.
Liver Failure
Putting HCV Test Results in Clinical Context Sequence for Identifying HCV Infection REFLEX HCV TESTING HCV Ab Plus HCV RNA If HCV Ab+ Ab Negative
Ab Reactive HCV RNA
No HCV Ab Detected
Not Detected
Detected
STOP
No Current HCV Infection
Current HCV Infection
Additional Testing as Appropriate
Link to Care
Caution: Consider recent exposure and Ab-negative window period
Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2013;62(18):362-365.
Pretreatment Evaluation • HCV assessment (any time prior to initiation of treatment) – Quantitative HCV RNA = viral load (VL) – HCV genotype (GT) and subtype: GT 1a, 1b, 2, 3, 4, 5, 6 – Treatment history: regimen and treatment outcome; have they been reinfected?
• Liver disease assessment (within 12 weeks of initiation of treatment) – – – –
• • • •
Complete blood count (CBC) International normalized ratio (INR) Complete metabolic panel (CMP) Estimated glomerular filtration rate (eGFR)
Liver fibrosis staging: F0−F4 Cirrhosis evaluation (if present) HCV comorbid conditions and extrahepatic manifestations Patient readiness
F0−F4, liver fibrosis stages 1−4. AASLD/IDSA. Monitoring Patients Who Are Starting HCV Treatment, Are on Treatment, or Have Completed Therapy. Last updated May 2018. https://www.hcvguidelines.org/evaluate/monitoring. Accessed May 27, 2019.
Liver Fibrosis Staging 101 For ALL Patients With HCV1,2
• History and physical exam • Elastography3,4 – F3 = severe fibrosis: 9.5−12.5 kPa – F4 = cirrhosis: >12.5 kPa
• Serum biomarkers of fibrosis: APRI and FIB-4 to rule out cirrhosis5
• Imaging (CT, MRI, US) – Cirrhotic morphology – Portal hypertension
• Liver biopsy
– Consider, if conflicting data or concomitant liver disease
– No cirrhosis: APRI <1.0 or FIB-4 <1.45 – Commercial tests – FibroSURE; Hepascore; FIBROSpect • Employ ≥1 testing modality—as needed for the given patient— to accurately determine the presence and extent of fibrosis • The presence of cirrhosis determines therapy and follow-up APRI, aspartate aminotransferase (AST) to platelet ratio index; CT, computed tomography; FIB-4, fibrosis-4 index for liver fibrosis; kPa, kilopascal: a unit of pressure; MRI, magnetic resonance imaging; US, ultrasound. 1. AASLD/IDSA. Monitoring Patients Who Are Starting HCV Treatment, Are on Treatment, or Have Completed Therapy. Last updated May 2018. https://www.hcvguidelines.org/evaluate/monitoring. Accessed May 27, 2019; 2. Cox-North PP, Shuhart MC. Hepatis C Online. Last updated May 2018. https://www.hepatitisc.uw.edu/go/evaluation-staging-monitoring/evaluation-staging/core-concept/all. Accessed May 27, 2019; 3. Barr RG, et al. Radiology. 2015;276(3):845-861; 4. Castera L, et al. J Hepatol. 2008;48(5):835-847; 5. Schmid P, et al. PLoS ONE. 2015;10(9):e0138838.
HCV Comorbidities
Assess for Disease Manifestations Beyond the Liver Psychiatric Depression
Blood
Anemia Impaired blood clotting Blood cancers
Immune system
Abnormal immune responses Connective tissue disease
Kidney
Acute/chronic kidney inflammation/dysfunction Excess fluid retention Slide courtesy of Stacey Trooskin, MD, PhD.
Eye
Inflammation Ulcerations
Blood Vessels
Immune-triggered damage resulting in skin, joint, muscle, gastrointestinal tract, heart, kidney, and nervous system manifestations
Skin
Photosensitivity Immune-triggered skin rash, lesions, or ulcerations
Nerves and Muscles Muscle weakness/pain Joint inflammation/pain
Other Factors to Address Prior to HCV Treatment Initiation • Pregnancy status of women of childbearing age • HIV status • Hepatitis B virus (HBV) status • Hepatitis A virus (HAV) status • Potential drug-drug interactions (DDIs)
AASLD/IDSA. Monitoring Patients Who Are Starting HCV Treatment, Are on Treatment, or Have Completed Therapy. Last updated May 2018. https://www.hcvguidelines.org/evaluate/monitoring. Accessed May 27, 2019.
Women of Reproductive Age: A Critical HCV Population
Updated AASLD/IDSA Recommendations RECOMMENDATION FOR UNIVERSAL HCV SCREENING IN PREGNANCY • All pregnant women should be tested for HCV; ideally at the initiation of prenatal care RECOMMENDATION FOR HCV TREATMENT AND PREGNANCY • For women of reproductive age with known HCV infection, antiretroviral therapy is recommended before considering pregnancy, whenever practical and feasible, to reduce the risk of transmission to future offspring NOT RECOMMENDED REGARDING HCV TREATMENT AND PREGNANCY • Treatment during pregnancy is not recommended due to lack of safety and efficacy data AASLD/IDSA. 2017. Last updated May 2018. https://www.hcvguidelines.org/unique-populations/pregnancy. Accessed May 27, 2019
RATING IIb, C RATING I, B RATING IIb, C
Treatment of HCV in Pregnancy
A Single-Center Phase 1 Trial of LDV/SOF, 2019 • Recruitment: October 2016 to October 2018 • N=170 HCV+ pregnant women • Enrollment criteria – HCV-positive; 18‒39 years of age – Enrollment at 23 to 24 weeks gestation – Singleton gestation without fetal anomalies – Non-genotype 2 or 3 – No HBV, cirrhosis, or clinically significant drug use – Not at high-risk of spontaneous preterm birth
29 patients screened
9 enrolled 9 completed study medication and delivered
Screen fails (n=20) • • • • •
Genotype 2: 5 patients Genotype 3: 5 patients Ongoing drug use: 4 Declined participation: 3 Not delivering at study hospital: 2 • APRI score >1
8 completed SVR assessment; 1 remained in follow-up
Chappell CA, et al. Conference on Retroviruses and Opportunistic Infections.(CROI) 2019. March 4−7, 2019; Seattle, WA. Abstract 87.
9 infants enrolled 5 infants completed 1-year follow-up; 4 remained in follow-up
Pregnancy and Delivery Outcomes Single-Center Phase I Trial
Outcome
n (%) or Median (Low, High)
Maternal-related adverse events
5 (56)
Maternal-related adverse events > grade 2
0 (0)
Vaginal delivery
5 (56)
Gestational age at delivery (weeks+days)
39+2 (36+6, 41+0)
Birth weight (grams)
3290 (2600, 4160)
Infant length of hospital stay
3 (2, 12)
Infant-related adverse events
0 (0)
Infant HCV-RNA at last visit
0 (0)
Chappell CA, et al. Conference on Retroviruses and Opportunistic Infections.(CROI) 2019. March 4â&#x2C6;&#x2019;7, 2019; Seattle, WA. Abstract 87.
Assessing HIV/HCV Coinfection Status Prior to HCV Treatment
• CD4 cell count • HIV viral load • HIV disease status – Duration of disease – Treatment naïve vs treatment experienced – Duration of treatment – Long-term viral suppression – AIDS‒defining events or opportunistic infections
• Current and past ART – Adherence history – Potential for drug-drug interactions?
• HIV/HCV DDI resources – Pharmacy interaction checkers • Lexicomp, Micromedex, Epocrates
– Directed resources • Liverpool Hep interaction checker
HIV/HCV coinfection does not impact selection of HCV therapy or SVR. ART, antiretroviral therapy; CD4, T lymphocytes involved in regulation of immune responses; DDI, drug-drug interactions. AASLD/IDSA. Patients With HIV/HCV Coinfection. Last updated May 2018. https://www.hcvguidelines.org/unique-populations/hiv-hcv. Accessed May 27, 2019.
HBV Reactivation An Emerging Concern
• Patients with a history of HBV require clinical monitoring while receiving DAA therapy – FDA Report, May 20171,2
• Consider HBV reactivation if – Clinical symptoms occur – There is a rise in transaminase levels while on HCV treatment
• Vaccinate if no HBV seromarkers are present to suggest immunity
Algorithm:3 Testing, Treating, and Monitoring for HBV Reactivation if HBV Seromarkers Are Present HBsAg positive HBV DNA detectable HBV DNA meets AASLD criteria for HBV treatment Treat with HBV drug
HBsAg negative; anti-HBc positive (± anti-HBs)
Low or undetectable HBV DNA Initiate prophylactic antiviral therapy OR monitor HBV DNA levels during and immediately after DAA therapy
Insufficient data to provide recommendations; consider HBV reactivation if clinical symptoms or ALT rise occurs
ALT, alanine transaminase; DNA, deoxyribonucleic acid; FDA, US Food and Drug Administration. 1. Bersoff-Matcha SJ, et al. Ann Intern Med. 2017;166(11):792-798; 2. AASLD/IDSA. Monitoring Patients Who Are Starting HCV Treatment, Are on Treatment, or Have Completed Therapy. Last updated May 2018. http://www.hcvguidelines.org/evaluate/monitoring. Accessed May 27, 2019; 3. Graphic adapted from: Jacobson IM. American Association for the Study of Liver Diseases. The Liver Meeting® 2016 – AASLD. November 11‒15, 2016; Boston, MA.
Evaluating HAV Status1,2
An Opportunity for Pharmacy-Based Immunization Anti HAV IgM Anti HAV IgG
Possible Interpretation/ Stage of Infection
Negative
• No current or previous HAV infection • No immunity: vaccination recommended • Caveat: Possibly in the window period
Negative
Positive
• No active infection • Immunity due to prior HAV infection or HAV vaccination
─
Positive
• HAV exposure: infection or vaccination • Does not rule out acute infection
Negative
IgG, immunoglobulin G. 1. CDC. Hepatitis A, Acute: 2019 Case Definition. 2019. https://wwwn.cdc.gov/nndss/conditions/hepatitis-a-acute/case-definition/2019/. Accessed May 27, 2019; 2. Dynacare. Interpretation of Hepatitis Test Results. 2016. https://www.dynacare.ca/DYN/media/DYN/Pdf/HCP/Interpretation-of-Hepatitis-Test-Results.pdf. Accessed May 27, 2019.
What Does Your Patient Need to Know About HCV? • HCV is a serious and potential deadly disease that is associated with high risk of cirrhosis and liver cancer • The virus can be transmitted to others through – Shared use of drug paraphernalia or other blood-contaminated objects (eg, razors) – Sexual activity, especially among men who have sex with men (MSM) – Pregnancy; maternal-child transmission
• Cost should not be a barrier to initiating HCV treatment! • HCV treatment is highly effective, including in PWID on MAT or continuing injection drug use; and in HIV/HCV coinfection – – – – –
Treatment will be managed by an HCV-care provider Treatment may be as simple as 1 to 3 pills per day, and as brief as 8 to 12 weeks in duration The medications are well tolerated The full treatment course must be completed Posttreatment follow-up is essential
• HCV reinfection is possible — risk reduction following treatment is critical! MAT, medication-assisted treatment; PWID, people who inject drugs. AASLD. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Last updated September 2017. http://www.hcvguidelines.org/evaluate/when-whom. Accessed May 27, 2019.
Benefits of Achieving HCV Cure The Individual and the Community1-3
Decreased Transmission
CURE Improved Clinical Outcomes
Hepatic
Extrahepatic
Cirrhosis Decompensation HCC Transplantation
Improved quality of life All-cause mortality Malignancy Diabetes Cardiovascular disease Renal manifestations Neurocognitive manifestations
HCC, hepatocellular carcinoma. 1. Image adapted from: Smith-Palmer J, et al. BMC Infect Dis. 2015;15:19; 2. Negro F, et al. Gastroenterology. 2015;149(6):1345-1360; 3. George SL, et al. Hepatology. 2009;49(3):729-738.
Patient Readiness Pretreatment Checklist
• The patient . . . Wants HCV treatment Generally keeps scheduled medical appointments; but if highly motivated, 1 or 2 missed appointments should not preclude treatment Can be contacted by phone and/or other reliable means Has other active medical issues (eg, HIV, diabetes) that are stable and has good adherence to other prescribed medications Knows incarceration status, if applicable Understands harm-reduction measures and can articulate a plan to avoid HCV reinfection after treatment Slide courtesy of Stacey Trooskin, MD, PhD.
Targeting the HCV Replication Cycle DAA Mechanisms of Action
Transport and release
Fusion and uncoating Translation
HCV RNA
NS4B
NS3
HCV NS proteins
NS5A
Viral assembly
NS5B polymerase inhibitors
Polyprotein processing NS2
RNA replication
NS5B
NS3/4A protease inhibitors
NS5A inhibitors CypA
NS3 NS5B NS4B NS2
NS5A
NS5A inhibitors
Cyp, cyclophilin; NS, nonstructural protein. Slide courtesy of Arthur Y. Kim, MD, as adapted from slide courtesy of Raymond T. Chung, MD.
Approved DAAs
Basis for Current Combination HCV Regimens Structural Domain 5’UTR
Core
E1
Nonstructural Domain
E2 P7
NS2
NS3
4A
NS4B
NS5A
Protease
NS5B
3’UTR
Polymerase
NS3
NS5A
NS5B
NS5B
Protease Inhibitors
Replication Complex Inhibitors
NUC Inhibitors
Non-NUC Inhibitors
Grazoprevir (GZR) Voxilaprevir (VOX) Glecaprevir (GLE)
Daclatasvir (DCV) Elbasvir (EBR) Ledipasvir (LDV) Pibrentasvir (PIB) Velpatasvir (VEL)
Sofosbuvir (SOF)
Dasabuvir (DSV)
RBV
PREvir = PRotEase inhibitor NUC, nucleoside/nucleotide; UTR, untranslated region. Slide courtesy of Sally Hodder, MD.
Asvir = NS5A inhibitor
Uvir = nUcleoside/tide or non-nUcleoside/tide polymerase inhibitor
DAA Selection
Criteria Associated With Treatment Choice • HCV treatment status – Treatment naïve vs treatment experienced – If TE, what drug classes has the patient been treated with?
• HCV genotype – 1, 2, 3, 4, 5, 6 – Subtype: 1a, 1b
• Liver fibrosis stage – METAVIR score F0−F4 – Cirrhosis vs no cirrhosis – Compensated cirrhosis vs decompensated cirrhosis
• Known drug-drug interactions Slide courtesy of Stacey Trooskin, MD, PhD.
FDA-Approved First-line DAA Regimens
HCV Monoinfection and HCV in HIV/HCV Coinfection Regimen
Genotype
No Cirrhosis: Duration
EBR/GZR
1, 4
12 weeksa
12 weeks
12 weeks
1 tablet daily
With or without food
GLE/PIB
1−6
8 weeks
12 weeks
8−16 weeksb
3 tablets once daily
With food
Pangenotypic
Compensated Cirrhosis: Duration
eGFR <30 mL/min/1.73 m2: Duration
Dosing
Food Requirements
LDV/SOF
1, 4, 5, 6
12 weeks
12 weeks
—
1 tablet daily
With or without food
SOF/VEL
1−6
12 weeks
12 weeksc
—
1 tablet daily
With or without food
Pangenotypic
BL, baseline; eGFR, estimated glomerular filtration rate; RAS, resistance-associated substitution. aFor GT1a without baseline NS5A RASs for elbasvir. If present, 12 weeks not recommended─can increase duration to 16 weeks with weight-based RBV (alternative); bPatients in this group should be treated as would patients without CKD. Duration of GLE/PIB should be based on presence of cirrhosis and prior treatment experience; cFor GT3, RAS testing for Y93H is recommended for patients with cirrhosis. If present, ribavirin should be included in the regimen or sofosbuvir/velpatasvir/voxilaprevir should be considered. AASLD/IDSA. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. http://www.hcvguidelines.org/evaluate/when-whom. Accessed June 25, 2019.
Real-World Evidence
Feasibility and Efficacy of Treating HCV in PWID • REALITIES – Baseline drug use – Continued injection drug use during DAA therapy – Concurrent medicationassisted treatment for opioid dependence – HIV/HCV coinfection
93%−95% SVR12 among PWID with recent or ongoing injection drug use1,2 Near-identical SVR12 rates achieved in MAT vs non-MAT PWID3-10 No drug-drug interactions with MAT9,10 No negative impact of HIV/HCV coinfection on SVR11-16
SVR12, SVR 12 or more weeks after the end of treatment. 1. Rockstroh JK. European Association for the Study of the Liver. The International Liver Congress™ − EASL 2017. April 19−23, 2017; Amsterdam, The Netherlands; 2. Alimohammadi A, et al. Open Forum Infect Dis. 2018;5(6):ofy120; 3. Grebely J, et al. Clin Infect Dis. 2016;63(11):1405-1411; 4. Zeuzem S, et al. Ann Intern Med. 2015;163(1):1-13; 5. Dore GJ, et al. Ann Intern Med. 2016;165(9):625-634; 6. Grebely J, et al. Clin Infect Dis. 2016;63(11):1479-1481; 7. Grebely J, et al. J Hepatol. 2017;66(suppl 1):S513-S514; 8. Puoti M, et al. J Hepatol. 2018;69(2):293-300; 9. Kiser JJ. Top Antivir Med. 2016;24(3):106-110; 10. Drugs@FDA. 2018. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed May 27, 2019; 11. Osinusi A, et al. JAMA. 2015;313(12):1232–1239; 12. Naggie S, et al. N Engl J Med. 2015;373(8):705-713; 13. Rockstroh JK, et al. Lancet HIV. 2015;2(8):e319-e327; 14.Sulkowski MS, et al. JAMA. 2015;313(12):1223-1231; 15. Wyles D, et al. Clin Infect Dis. 2017;65(1):6-12; 16. Rockstroh JK. Clin Infect Dis. 2018;67(7):1010-1017.
Potential DAA Drug-Drug Interactions Proceed With Caution
Common Drug Class or Specific Drug
Metabolic Induction or Inhibition
Acid reducing agents
CYP
Amiodarone
BRCP
Anticonvulsants
OATB
Antiretrovirals
P-Gp
Rifamycin antimicrobials St. Johnâ&#x20AC;&#x2122;s wort Statins BCRP, breast cancer resistance protein; CYP, cytochrome P450; OATP, organic anion transporting polypeptide; P-gp, P-glycoprotein. US Food and Drug Administration (FDA). Drugs@FDA. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed July 5, 2019.
Monitoring for Common ADRs First-Line DAAs
Drug Regimena
Common ADRs, (%)
EBR/GZRb
Fatigue (11), headache (10)
GLE/PIBc
Headache (9), nausea (6), diarrhea (5)
LDV/SOFd
Headache (14), fatigue (13), nausea (7)
SOF/VELe
Fatigue (≥10), headache (≥10)
aListed
alphabetically; bADRs (all grades) reported in ≥5% of treatment-naïve (TN) patients treated with EBR/GZR for 12 weeks; cADRs reported in ≥5% of TN and TE adults without cirrhosis treated with GLE/PIB for 12 weeks; dADRs (all grades) reported in ≥5% of patients treated with LDV/SOF for 12 weeks; eADRs reported in ≥10% of patients without cirrhosis or with compensated cirrhosis treated with SOF/VEL for 12 weeks. FDA. Drugs@FDA. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed July 5, 2019.
Pharmacy Interaction Checkers • University of Liverpool: HEP drug interaction checker – https://www.hep-druginteractions.org/
• Lexicomp Online – https://www.wolterskluwercdi.com/lexicomp-online/
• Micromedex – https://www.micromedexsolutions.com/home/dispatch
Considerations for Treatment Failures After DAA Regimens • Is this relapse or reinfection? • Was initial therapy appropriate, ideal? • Was staging accurate? Is it needed again? • Was regimen adherence adequate? • Were drug interactions present? • Should I order resistance testing? If so, when?
Slide courtesy of Arthur Kim, MD. AASLD/IDSA. Last updated May 2018. https://www.hcvguidelines.org/evaluate/monitoring. Accessed May 27, 2019.
New Viremia Following Treatment
Is This Reinfection or Relapse/Treatment Failure? Different, later
Genotype/ subtype Same
Reinfection
Treat as naĂŻve Slide courtesy of Stacey Trooskin, MD, PhD.
But history consistent with reinfection
Possible reinfection Evidence of acute infection?
Same, early
Uncertain whether reinfection or treatment failure
Viremic before achieving SVR12
Likely treatment failure
Treat as experienced
HCV Resistance-Associated Substitutions Key Considerations
• For current first-line regimens, detection of RASs most often is NOT necessary • RASs are present at baseline in the absence of drug exposure, but may or may not be detected – Possibility of transmission
• RASs may impact treatment responses in select situations – Often worse in the presence of other treatment characteristics – Viruses with RASs may exhibit variable “fitness” compared with wild-type – Higher fitness lasts longer; lower fitness may be transient
• Resistance does NOT render treatment futile – May be overcome by longer durations, addition of ribavirin, or later-generation agents
Slide courtesy of Arthur Kim, MD. AASLD/IDSA. Last updated May 2018. https://www.hcvguidelines.org/evaluate/resistance. Accessed May 27, 2019.
Retreatment Options
NS5A DAA−Treatment-Experienced Patients Recommended SOF/VEL/VOX All NS5A−TE patients
GLE/PIB NS5A−TE patients without prior NS3 exposure
Duration
Rating
12 weeks
IA
16 weeks
IIa,B
AASLD/IDSA. Last updated September 2017. https://www.hcvguidelines.org/treatment-experienced. Accessed May 27, 2019.
Pharmacists’ Roles in HCV Treatment Offer patient education on HCV Ensure appropriate treatment selection, dosage, and duration of treatment Be aware of comorbid disease states Recognize potential DDIs • Facilitate prior authorizations • Provide financial-assistance resources • Monitor therapy and identify ADRs and DDIs • Identify barriers to care • Provide ongoing harm-reduction counseling − Know your communities harm-reduction resources − Emphasize optimal adherence − Recognize reinfection risk ADRs, adverse drug reactions. Sullivan KM, et al. P T. 2018;43(12):764-768.
Community Pharmacy
Hospital/ Inpatient Pharmacy
Ambulatory/ Outpatient Pharmacy
Prior Authorization Considerations
Know Your Medicaid and Private Insurers’ Guidelines • Common treatment restrictions – Disease-severity restrictions – Sobriety restrictions – Prescriber restrictions
• These restrictions on access to HCV treatment are NOT evidence-based or in alignment with AASLD/IDSA guidelines
Examples of Documents to Be Sent Chart notes Pretreatment labs Fibrosis score Medical necessity Patient readiness Patient attestment Illicit-drug testing Prescription insurance card
Center for Health Law and Policy Innovation of Harvard Law School and National Viral Hepatitis Roundtable. 2017. Last updated 2018. https://stateofhepc.org/. Accessed May 27, 2019.
Copay Assistance Programs
www.healthwellfoundation.org
www.copays.org
www.mygooddays.org
www.tafcares.org
www.panfoundation.org
See also manufacturersâ&#x20AC;&#x2122; coupons for financial assistance (applies only to commercial insurance plans).
Barriers to HCV Cure
Across the Pharmacy-Based Care Continuum Communication!
Communication! Additional blood test
Screened Wrong contact info
Received test results
Linked to care
Illicit drug use
Patient attestment required
Linked and received diagnostic test results
Refer to specialist
Last fill at mail order pharmacy
Initiated therapy
Alcohol abuse
Lost to follow-up? Slide courtesy of Susan MK Lee, PharmD. Adapted from: Linas BP, et al. PLoS ONE. 2014;9(5):e97317.
Communication!
Adhered to therapy
On-treatment viral load
Achieved SVR
Prior authorization extension
A Functional Definition of Harm Reduction Harm reduction is any positive change, as defined by the person at risk for harm. It is meeting people where they are and providing the tools and information they need to keep themselves and those around them healthy. Dan Biggs, Chicago Recovery Alliance
Harm Reduction Services
Support During HCV Treatment and Beyond • Information, education, counseling, and outreach • Medication-assisted treatment (MAT) • Needle and syringe programs (NSP) • Combined mental-health services/MAT/NSP • Prevention of injection-related wounds • Prevention of secondary infections (endocarditis, cotton fever) • Overdose prevention and response
• • • • • • • •
MAT, medication-assisted treatment; NSP, needle syringe program; STI, sexually transmitted infection. Harm Reduction Coalition. https://harmreduction.org/. Accessed May 27, 2019.
Safer injection technique Alternatives to injecting Immunization STI testing Safe-sex supplies Case management Addiction treatment Employment assistance
SELECTED STUDIES AND MODELS
Study: DAA Drug-Drug-Interactionsa
The Pharmacistâ&#x20AC;&#x2122;s Role in Identification and Intervention Drug Classes Identified as DDIs From Patientsâ&#x20AC;&#x2122; Baseline Medication Lists, N=664a,b Drug class Patients, n (%) PPI/H2RA agents Antacids Vitamin and herbal supplements Hypertensive agents Analgesics Psychiatric agents Anticonvulsants Steroids Others
117 (17.6) 72 (10.8) 284 (42.7) 53 (8.0) 67 (10.1) 46 (6.9) 4 (0.6) 12 (1.8) 126 (19.0)
H2RA, histamine 2 receptor antagonist; OBV/PTV/r, ombitasvir/paritaprevir/ritonavir; PPI, proton pump inhibitor; SIM, simeprevir. a57% men, average age 56.7 years, 51.5% cirrhotic; bDAA regimens: 369 patients treated with LDV/SOF, 48 with OBV/PTV/r + DSV, 114 with SIM/SOF, and 133 with SOF/RBV. Langness JA, et al. World J Gastroenterol. 2017;23(9):1618-1626.
Study: Pharmacist-Identified DDIs By Fibrosis Stage
Fibrosis Stage
Stage â&#x2030;¤2 Minimal to moderate fibrosis
Stage 3 Advanced fibrosis
Stage 4 Cirrhosis
Average Number of Medications per Patient
Average Number of Interactions per Patient
Patients, n
Total Medications, n
Total Interactions, n (%)
232
1508
249 (16.5)
6.50
1.07
72
575
91 (15.8)
7.99
1.26
341
3066
425 (13.8)
8.99
1.25
Langness JA, et al. World J Gastroenterol. 2017;23(9):1618-1626.
Indian Health Services (IHS) Facilities
The Pharmacist’s Roles in HCV Care Under Collaborative Drug Therapy Management (CDTM) • Clinical stages: diagnosis to treatment – Provide comprehensive HCV care under the supervision of a physician – Screen for and address lifestyle factors and comorbidities that may adversely affect HCV treatment outcomes – Act as case manager for patients diagnosed with HCV; link to other services – Provide other pharmacist services; eg, medication counseling, DDI identification, treatment monitoring
Geiger R, et al. J Prim Care Community Health. 2018;9:1-5.
IHS: Liver Fibrosis Scoring to Treatment Initiation
Cascade Stages Vulnerable to High Attrition Liver Fibrosis Scored? Fibrosis Scored (n=576)
YES 62%
NO 38%
Need Liver Fibrosis Scoring (n=353)
Initiated HCV Treatment Treatment in Progress or Completed (n=335) Geiger R, et al. J Prim Care Community Health. 2018;9:1-5
YES 58%
NO 42%
Need Treatment (n=241)
IHS Collaborative HCV Care: Diagnosis to Treatment Study Results and Conclusions
• Key findings: liver fibrosis scoring to treatment initiation – 576 underwent liver fibrosis scoring – 23% (137/576) had stage ≥F3 (advanced fibrosis or cirrhosis)
• These data indicate that rural clinics can be successful in providing HCV diagnosis • Pharmacists can play a key role in rural HCV clinical services
Geiger R, et al. J Prim Care Community Health. 2018;9:1-5.
Model: Multidisciplinary Team Approach HCV CDTM in an HIV Ambulatory Care Clinic
Key Points
Pharmacistsâ&#x20AC;&#x2122; Patient-Care Process
1. HCV treatment and management require an interdisciplinary patientcentered approach 2. The full potential of pharmacists in the management of chronic disease states, including HCV, is actualized through collaborative drug therapy management
Collect
Monitor and Evaluate
PatientCentered Care
Implement
Sorbera M, et al. Innov Pharm. 2018;9(1). Accessed May 27, 2019.
Assess
Plan
Concluding Comments • HCV is common and deadly—and CURABLE • Given advances in HCV antiviral therapy, elimination is a realistic target • But barriers to elimination remain – Lack of screening and diagnostic services – Lack of linkage to care and prevention services
Pharmacists are uniquely positioned to assist in testing, diagnosis, harm-reduction counseling, and linkage to care for patients with chronic HCV.