No More Special Populations!?

No More Special Populations!? Mark Sulkowski, MD Professor of Medicine Johns Hopkins University School of Medicine Medical Director, Viral Hepatitis Center Divisions of Infectious Diseases and Gastroenterology/Hepatology Baltimore, Maryland

Disclosures PI for research grants: Funds paid to Johns Hopkins University AbbVie, BMS, Gilead, Janssen, Merck DSMB member: Funds paid to Johns Hopkins University Gilead Scientific advisor/consultant: The terms of these arrangements are being managed by the Johns Hopkins University in accordance with its conflict of interest policies AbbVie, BMS, CoCrystal Pharma, ContraVir, Gilead, Janssen, Merck, Trek

SVR12 (%) Sofosbuvir/Velpatasvir FDC daily for 12 weeks is highly effective in persons infected with any HCV genotype 100 99 99 99 95 100 97 100 80 60 40 20 0 1015 1035 323 328 237 238 264 277 116 116 Total GT1 GT2 GT3 GT4 GT5 GT6 34 35 41 41 Jacobson et al. HEP DART 2015

No more special populations? Are expert clinicians obsolete in the era of HCV DAAs?

Hepatitis C virus and People with chronic infection are diverse and HCV Diversity complicated Human Diversity

Persons for whom HCV treatment warrants special consideration of risk:benefit Altered drug metabolism and/or safety Decompensated liver disease, transplant, chronic kidney disease, HIV Risk for HCV re-infection following cure HIV-infected men who have sex with men (MSM) Person who inject drugs (PWID) Unsuccessful treatment with DAAs Resistance associated variants Limited data Children, pregnant women

Persons with decompensated cirrhosis 68 year-old man with HCV infection and no prior treatment (had repeatedly declined interferonbased treatment) Presents with moderate ascites and LE edema (CTP B) ALT 103; AST 156; platelet count 55k ;Hemoglobin 13.6; Cr 2.4, total bili 2.1, INR 1.5, albumin 3.1 Esophageal varices s/p banding FibroScan = 59.3 kpa Meds: Furosemide, spironolcatone HCV RNA 445,000 IU/mL Genotype 1a

DAAs in persons with decompensated liver disease and/or transplant DAA Primary Metaboli c Pathway Suitable in Patients With Cirrhosis CTP-A CTP-B CTP-C Interaction Calcineurin Inhibitors Sofosbuvir Renal Yes Yes Yes Yes Simeprevir Hepatic Yes No No No Grazoprevir Hepatic Yes No No No Paritaprevir/ RTV Hepatic Yes No No No Ledipasvir Hepatic Yes Yes Yes Yes Ombitasvir Hepatic Yes No (as combo) No (as combo) No (as combo) Daclatasvir Hepatic Yes Yes Yes Yes Dasabuvir Hepatic Yes No No No Bifano M, et al. AASLD 2011. Abstract 1362. Garimella K, et al. Clinical Pharm 2014. Abstract P43. Sofosbuvir [package insert]. Simeprevir [package insert]. Khatri A, et al. AASLD 2012. Abstract 758. German, et al. AASLD 2013. Abstract 467. Kirby R, et al. Clinical Pharm 2013. Abstract PO20.

Persons with CTP B/C are difficult to treat and the clinical benefit is debated NS3 inhibitors are not recommended and may cause drug-induced liver injury SOF/NS5As (LDV or DAC) combinations may be used www.hcvguidelines.org

Risk:Benefit considerations for persons with decompensated liver disease Clinical status -- ascites, varicies, albumin, platelet count, CTP and MELD score? Risk of drug induced liver injury? Is the patient a transplant candidate? Anticipated time to transplant? Risk of death on the transplant list? Viral cure Healthy liver Avoid transition to an undesirable state of alive but sick

Persons with chronic kidney disease 66 year-old man with HCV infection and ESRD on hemodialysis thrice weekly ALT 53; AST 36; platelet count 243k ;Hemoglobin 9.6; Cr 3.1 FibroScan = 13.3 kpa Meds: Lisinopril, metoprolol HCV RNA 2.4 million IU/mL Genotype 1b

HCV is common and problematic in persons with end-stage renal disease HCV-infected persons are more likely to die on HD HCV+ donated kidneys are routinely discarded Kwon E, et al. PLoS One. 2015;10:e0135476. Reese PP, et al. N Engl J Med. 2015;373:303-305.

DAAs in persons with chronic kidney disease CrCl 30 ml/min: No dosage adjustment required for ledipasvir/sofosbuvir, sofosbuvir, ombitasvir/paritaprevir/ritonavir + dasabuvir, simeprevir, or grazoprevir/elbasvir CrCl < 30 ml/min: Sofosbuvir is not recommended Ribavirin dose adjustment in patients with renal dysfunction Creatinine clearance RBV dose daily > 50 ml/min <75 kg = 1000 mg 75 kg = 1200 mg 30-50 ml/min Alternate 200 mg & 400 mg QD < 30 ml/min 200 mg QD Hemodialysis 200 mg QD Copegus (ribavirin) tablets [package insert]. South San Francisco, CA: Genentech USA; August, 2011. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021511s020lbl.pdf. Accessed September 15, 2015. See prescribing information. Desnoyer A, et al. Presented at: 16 th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy; May 26-28, 2015; Washington, DC.

Risk:Benefit considerations in patients with chronic kidney disease Is kidney transplant with HCV+ organ should an option? Liver disease stage? Options for treatment after transplant? If treatment in the setting of stage 4 or 5 CKD, which DAAs can be used Limited DAAs -- Grazoprevir/Elbasvir or Ombitasivir/Paritaprevir/r + Dasabuvir Nucleos(t)ide analogues are not recommended (SOF) or are difficult to use safely (RBV)

Persons with HIV coinfection 53 year-old man with HCV infection and well-controlled HIV infection ALT 53; AST 36; platelet count 243k;Hemoglobin 14.6; Cr 1.3 FibroScan = 10.3 kpa Meds: atazanavir/ritonavir + tenofovir/emtricitabine HCV RNA 2.4 million IU/mL Genotype 1a Risk behaviors no IDU but reports ongoing unprotected sex with other HIV-infected men

DAA and HIV antiretroviral drug interactions SMV + SOF SOF LDV/SOF DCV + SOF OMV/PTV/RTV + DSV Atazanavir + ritonavir Darunavir + ritonavir Lopinavir/ritonavir Tipranavir + ritonavir Efavirenz Rilpivirine Etravirine X X Raltegravir Elvitegravir + cobicistat X X X Dolutegravir Maraviroc Tenofovir DF Monitor for nephrotoxicity No clinically significant interaction expected Potential interaction may require adjustment to dosage, altered timing of administration, or additional monitoring Do not coadminister AASLD/IDSA/IAS USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org.

HIV may reduce HCV cure rates in persons with with other negative host, viral or regimen factors ION-4 Sofosbuvir/Ledipasvir ALLY-2 Sofosbuvir + Daclatasvir Naggie et al. NEJM 2015; Wyles et al NEJM 2015

Persons with HIV infection may be a greater risk for HCV re-infection following curative treatment Risk of HCV reinfection following SVR: meta-analysis of 66 studies in 11,071 patients HIV-infected male partners with re-infection with telaprevir resistant HCV (V36M) Franco et al. Gastroenterology 2014; Hill et al CROI 2015 (#654)

Risk:Benefit considerations for persons with HIV infection Are there clinically important drug-drug interactions? Expert consideration of HIV disease Expert consideration of HCV disease One expert or two experts? If two, will they communicate? Can treatment be shortened? HCV triplet will increase drug interactions Will re-infection be prevented following cure?

Persons who inject drugs 18 year-old woman with HCV genotype 3 acquired through injecting heroin She is in recovery and receiving methadone Her partner was injecting heroin 3 x daily until he was jailed two months ago No liver disease (FO) She is anxious to undergo treatment, and is getting her life on track Taking community college classes Working in retail

PWID with HCV are represent an important population in the community and prisons Increasing incidence of HCV among young adults (USA) 1.9 million HCV + incarcerated persons are reservoir for new infections (USA) MMWR Morb Mortal Wkly Rep. 2015;64:453-8. Rich JD et al. N Engl J Med

HCV treatment is effective in persons who are currently using drugs C-EDGE CO-STAR: GZV/EBR C-EDGE CO-STAR: Active drug use had no impact on HCV cure Efficacy: SVR12 (Full Analysis Set) 80 60 40 20 0 % SVR12 (95% CI) 100 91.5 93.5 93.3 91.7 20.0 Dore G, et al. AASLD 2015, San Francisco. #40

HCV care cascade does not end with cure Ongoing harm reduction is required for persons at risk for reinfection 60% 50% 50% (1.6M) 40% 30% 20% 10% 0% 32%-38% (1.0-1.2M) 7%-11% (220,000-360,000) 5%-6% (170,000-200,000) Diagnosed Referred to Care Treated Cure Reinfected? Adapted from Holmberg SD, et al. N Engl J Med. 2013;368:1859-61.

Risk:Benefit considerations for persons who inject drugs (PWID) Is the persons willing and able to adhere? Will treatment be continued in the person is incarcerated? What is the risk that the persons with infect others with HCV before, during or after unsuccessful therapy? Linked to addiction treatment Treat others in their injecting network What care should PWID receive after HCV cure? Access to clean injecting equipment Opioid substitution therapy On Demand Preexposure Prophylaxis (PrEP) with oral DAAs? Molina J-M et al. On-Demand Preexposure Prophylaxis in Men at High Risk for HIV-1 Infection. NEJM 2015

Persons in whom HCV was not 63 year-old man with compensated cirrhosis and portal hypertension HCV genotype 1a; HCV RNA 6.5 million IU/mL IL28B TT; Black race Platelet count 43,000 CTP A; MELD =12 2002: PegIFN + RBV = Null 2013: LDV/SOF x 12 weeks = Relapse 2014: SIM/SOF + RBV x 24 weeks = relapse cured After his second failure, he underwent HCV resistance testing NS5B = wild-type NS3/4A = Q80K; R155K NS5A = Q30R, H58D His brother died waiting for liver transplant and he is highly motivated to achieve HCV cure

~ 5 out of every 100 adherent patients treated with DAAs are not cured Patient-related factors Cirrhosis IL28B TT genotype High viral load Genotype 1a or 3 RAVs Poor adherence DAA-related factors Suboptimal pharmacokinetics due to variable absorption (PPIs), metabolism or penetration (cirrhosis) Suboptimal course of treatment [outside expert guidelines] OPTIMIST-2: Simeprevir NS3 RAV + Cirrh LDV/SOF: NS5A RAV + IL28B non-cc Kwo et al. EASL 2015; Zuezem AASLD 2015

Risk:Benefit considerations for persons who did not achieve HCV cure with DAAs What is the urgency of re-treatment? Advanced liver disease Persons at risk to infect others with HCV enriched with DAA RAVs? Are RAVs present, and how should the data be interpreted? Can another regimen be constructed with at least two active DAAs? Can ribavirin be added to the DAA regimen? Can the patient be treated for longer duration ($$$$)?

Persons who are children 8 year-old girl presents with her adoptive parents Originally for China Found about 4 years ago to have HCV genotype 1b and stage 2 fibrosis Treated with peginterferon/ribavirin in a clinical trials --- response followed by relapse Currently, serum ALT levels between 100 and 180 IU/mL and recent biopsy stage 3 fibrosis

PegIFN alfa-2a: Nine years between the definitive studies in adults and children 2002: PegIFN-2a + RBV is more effective than 2011: PegIFN-2a + RBV is more effective t PegINF-2a alone in adults PegINF-2a alone in children Fried MW et al NEJM 2002; Schwarz KB et al. Gastroenterology. 2011

Search of clinicaltrials.gov for HCV and children or pediatric Safety and Efficacy of Sofosbuvir + Ribavirin in Adolescents and Children With Genotype 2 or 3 Chronic HCV Infection; NCT02175758 First received: June 24, 2014 Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed Dose Combination in Adolescents and Children With Chronic HCV-Infection; NCT02249182 First received: September 23, 2014

Risk:Benefit considerations for the treatment of children Correct dose and/or treatment regimen with oral regimens is not known Liver disease stage is important Validity of non-invasive tests? Defer or enroll in clinical trials Up To Date (2015) by Maureen M. Jonas, MD, Professor of Pediatrics, Harvard Medical School we suggest deferring treatment until an interferon-free regimen is available. Clinicaltrials.gov search HCV and children or pediatrics

Women who are pregnant 26 year-old woman in her second trimester of pregnancy HIV infection was diagnosed 3 years ago and she is doing well on antiretroviral therapy (HIV RNA < 20 copies/ml) HBsAg negative HCV antibody reactive; HCV RNA = 9.5 million IU/mL

Mother-to-child transmission in 77 prospective cohort studies of at least 10 mother-infant pairs If 35% of 170 million persons infected with HCV are women of childbearing age, given an annual fertility rate of 2%, 10,000 60,000 babies will be infected each year Roberts and Yeung. Hepatology 2002

Reducing risk for mother-to-infant transmission of hepatitis C virus A systematic review for the U.S. Preventive Services Task Force No intervention has been clearly demonstrated to reduce the risk for mother-to-infant HCV transmission Given limited evidence of an association between prolonged rupture of membranes and increased transmission risk, clinicians may consider avoiding prolonged rupture of membranes For prenatal screening to be effective, there must be an effective intervention Persons for Whom Routine HCV Testing Is Not Recommended (unless they have risk factors for infection): Pregnant women Cottrell et al. Ann Intern Med. 2013 Jan 15;158(2):109-13;.

Risk:Benefit considerations in woman who are pregnant Mother to child transmission occurs but is this being recognized? No recommendations for testing during pregnancy If tested, who will follow the woman and her child after delivery? HCV treatment in the 3 rd trimester: Cure mother; protect child? Interferon and ribavirin are no longer necessary No adverse effects were observed in the reproductive and development studies, and the NOAELs were 10-fold relative to the mean clinical exposure at SOF 400 mg Other DAAs may be safe in late pregnancy

Conclusions Multiple interferon-free regimens offer the opportunity for HCV cure to nearly all persons Challenges remain for specific patient populations Decompensated liver disease, CKD, HIV, PWID, children, pregnant woman Persons in whom HCV cure was not achieved RAVs HCV care cascade does not end with cure, and must include prevention of reinfection Large burden of HCV disease in resource constrained settings Far from obsolete, HCV expert clinicians are just getting started