Antiviral treatment in Unique Populations

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1 Antiviral treatment in Unique Populations Atif Zaman, MD MPH Oregon Health & Science University Professor of Medicine Division of Gastroenterology and Hepatology

2 Unique HCV Populations HIV/HCV co-infected Renal failure Decompensated cirrhotics

3 Key Considerations in HIV/HCV Coinfection

4 PHOTON-1: SOF + RBV for Wks in HIV/HCV Coinfection Wk 0 Wk 12 Wk 24 Wk 36 Wk 48 GT2/3 TN GT2/3 TE SOF + RBV (n = 68) SOF + RBV (n = 41) SVR12 SVR24 Allowable ARVs included: boosted atazanavir, boosted darunavir, efavirenz, raltegravir or rilpivirine in combination with NRTI backbone of TDF/FTC Naggie S, et al. CROI Abstract 26. Sulkowski MS, et al. JAMA. 2014;312: SVR24 (%) n/n = / / 42 GT2 GT3 Treatment-Naive Pts

5 TURQUOISE-I: Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV in HIV/GT1 HCV Pts Open-label phase II/III trial; compensated cirrhosis (Child-Pugh A) allowed; DAA naive but pegifn/rbv naive or experienced DAA-naive HIV-infected pts with GT1 HCV infection (N = 63) Wk 12 Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV (n = 31) Wk 24 Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV (n = 32) SVR12 (%) n/n = / 31 29/ 32 15/ 16 12/ 12 14/ 15 17/ 20 Overall Atazanavir Raltegravir Sulkowski MS, et al. JAMA. 2015;313: Eron JJ, et al. Glasgow HIV. Abstract O222. VF with RAVs in all 3 HCV target genes occurred in 2 pts with GT1a HCV, previous null response to pegifn/rbv, and cirrhosis VF (posttreatment) without RAVs occurred in 2 HCV treatment-naive pts with GT1a HCV Genetic analysis strongly supported HCV reinfection with different isolate Both pts MSM who reported high-risk sexual practices posttreatment

6 ION-4: LDV/SOF in HIV/GT1 or 4 HCV Coinfection Multicenter, open-label phase III study; GT1 or 4 HCV; tx-naive or tx-exp d pts; compensated cirrhosis allowed SVR12 (%) Treatment: LDV/SOF for 12 wks % on EFV, 44% on RAL, 9% on RPV; cirrhosis: 20%; HCV tx exp d: 55%; previous HCV PI therapy: 29%; n = 8 with GT4 HCV / / / 185 Overall No Yes 258/ 268 No 63/ 67 Yes Previous HCV Tx Cirrhosis Cooper C, et al. EASL Abstract P1353. Naggie S, et al. CROI Abstract 152LB. SVR12 in tx-exp d pts with cirrhosis: 98% (46/47) Black (vs nonblack) race assoc. with significantly lower SVR12 rate (by multivariate) 10 relapses, all in black pts No gr 3/4 creatinine abnormalities nor gr 3/4 AEs in renal or urinary category 4 pts had change in creatinine 0.4 mg/dl: 2 completed tx with no ART change: 1 d/c TDF, 1 had TDF dose reduction

7 ALLY-2: Daclatasvir + Sofosbuvir for HIV/HCV Coinfection Multicenter, randomized phase III study; almost all pts received ART (ATV/RTV, DRV/RTV, LPV/RTV, EFV, NVP, RPV, RAL, DTG, or NRTIs only) SVR12 (%) HCV treatment-naive, HCV/HIV-coinfected pts (n = 151) HCV treatment-experienced, HCV/HIV-coinfected pts (n = 52) / 31/ 43/ 98/ 38/ 51/ n/n = Genotype 1 All Treated Wyles DL, et al. EASL Abstract LP01. Daclatasvir + Sofosbuvir (n = 101) Daclatasvir + Sofosbuvir (n = 50) Wk 8 Daclatasvir + Sofosbuvir (n = 52) 28 of 32 pts with NS5A RAVs achieved SVR12 Wk 12 Among 4 pts with NS5A RAVS who did not achieve SVR12, 3 were in 8-wk arm Emergent NS5A Q30 RAVs detected in 3 of 13 pts with virologic failure

8 SVR12 (%) C-EDGE Coinfection: Grazoprevir/Elbasvir for Pts Coinfected With HCV/HIV Multicenter, single-arm, open-label phase III trial; HCV treatment-naive pts coinfected with HIV and GT1, 4, or 6 HCV n/n = 0 Treatment: Grazoprevir/elbasvir for 12 wks ART regimen components: ABC: 21.6%; TDF: 75.2%; RAL: 51.8%; DTG: 27.1%; RPV: 17.4% / / / 44 27/ 28 All Pts GT1a GT1b GT4 Rockstroh JK, et al. EASL Abstract P0887. No subgroup provided an efficacy advantage or disadvantage New NS3, NS5A RAVs detected at failure in 5 of 6 pts who relapsed Short-lived HIV-1 RNA increases occurred in 2 pts on ART during treatment: both resuppressed HIV-1 RNA without ART change Grazoprevir/elbasvir well tolerated: no pt discontinued for AEs and no serious treatment-related AEs

9 EASL Guidance on HCV/HIV Drug Drug Interactions NRTIs NNRTIs Protease Inhibitors Entry/ Integrase Inhibitors Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir DF Zidovudine Efavirenz Etravirine Nevirapine Rilpivirine ATV; ATV/RTV DRV/RTV; DRV/COBI Fosamprenavir Lopinavir Saquinavir Dolutegravir Elvitegravir/cobicistat Maraviroc Raltegravir SMV SOF OMV/PTV/ LDV/ RTV SOF + DSV DCV No clinically significant interaction expected Potential interaction may require dosage adjustment, altered timing of administration or additional monitoring Do not coadminister EASL clinical practice guidelines.

10 Take-Home Points: HCV/HIV Coinfection HIV/HCV pts achieve SVR at same rates as monoinfected In HCV/HIV coinfection, treat HCV as though HCV monoinfected, but consider drug drug interactions OMV/PTV/RTV + DSV: adjust or withhold RTV if receiving a boosted PI LDV/SOF: avoid with tenofovir DF if CrCl < 60 ml/min or if also receiving tenofovir with RTV-boosted PIs; monitor for nephrotoxicity if using LDV/SOF and tenofovir DF with ARVs DCV + SOF ± RBV is recommended when ART regimen changes cannot be made to accommodate other DAAs Tools to help identify drug drug interactions: aidsinfo.nih.gov/guidelines, hiv-druginteractions.org, hep-druginteractions.org

11 AASLD/IDSA: When and in Whom to Initiate HCV Therapy ALL pts are candidates for HCV therapy, regardless of disease stage In regions where limited resources preclude treatment of all pts, the following groups should be prioritized for therapy: Highest Priority (based on highest risk for disease complications) Advanced fibrosis (F3) or compensated cirrhosis (F4) Organ transplant Type 2 or 3 essential mixed cryoglobulinemia with end-organ manifestations Proteinuria, nephrotic syndrome, or membranoproliferative glomerulonephritis High Priority (based on high risk for disease complications) HIV-1 coinfection Other coexistent liver disease (eg, NASH) Fibrosis (Metavir F2) Type 2 DM (insulin resistant) HBV coinfection Porphyria cutanea tarda Debilitating fatigue AASLD/IDSA. HCV Management.

12 Key Considerations in Patient with Renal Disease

13 Ineffective Treatment in the Past Tantalizing Prospects Successful treatment = Sustained Virological Response (SVR) Treatments Not so good: - Mediocre SVR rates - Adverse Events (AE) - IFN associated graft loss = Cure

14 Which CKD Patients to Consider Treating Now Renal transplant (RT) ineligible patients All mild, moderate, severe genotype 1 and 4 CKD ~ non- CKD pts Mild, Moderate genotype 2 and 3 CKD ~ non-ckd pts

15 Which CKD Patients to Consider Treating Now RT candidates - Pros for treating before RT: - Possible decrease risk of progressive liver disease, post-tx GMN, new onset DM post-rt - Avoid DDI - Public health risk reduction, reduced risk of spread in HD unit - Cons for treating before RT: - May limit choice of deceased donors - May lose Tx opportunity Compensated cirrhotics who are being considered for SLK

16 Genotype 1 and 4 with Severe Kidney Disease Grazoprevir + Elbasvir - GZR- NS3/4A Protease Inhibitor - EBR- NS5A Inhibitor - April FDA granted Breakthrough Designation status for treatment in GT 1,4 patients on HD - Viekira Pack (PrOD) in GT 1,4 - FDA approved in patients with any renal impairment including HD patients

17 Recommendation for mild to moderate renal impairment For patients CrCl 30 ml/min-80 ml/min, no dosage adjustment is required when using Recommendation for severe renal impairment (CrCl<30 ml/min) for whom the urgency to treat is high and kidney transplant is not an immediate option For patients with genotype 1a, or 1b, or 4 infection daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100mg) for 12 weeks is a Recommended regimen. Rating: Class IIb, Level B For patients with genotype 1b infection daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twicedaily dosed dasabuvir (250 mg) for 12 weeks is a Recommended regimen. For genotype 1a should add ribavirin. However, caution is recommended in this group, owing to the potential for hemolytic anemia due to impaired renal clearance in this population, and RBV should be restricted to those with a baseline hemoglobin concentration above 10 g/dl. Rating: Class IIb, Level B For patients with HCV genotype 2, 3, 5, or 6 infection PEG-IFN and dose-adjusted RBV* at 200 mg daily is a Recommended regimen.

18 Pangenotypic Agents for Severe Kidney Disease Glecaprevir/Pibrentasivr (Mavyret) -A pangenotypic combination - NS3/4A Protease Inhibitor - NS5A Inhibitor - EXPEDITION-4 trial noted an SVR rate of 99% (103 of 104 patients) of which 82% were on hemodialysis

19 Considerations in Decompensated Cirrhosis

20 Key Considerations for Genotype 1 or 4 Decompensated Cirrhosis Treatment options are more limited than for pts without cirrhosis or with compensated cirrhosis SVR rates are generally lower Protease inhibitors are not recommended for CTP B or C Continuing role for ribavirin Low dose for CTP C; weight based for CTP B with SOF/VEL Extend duration to 24 wks if RBV ineligible AASLD/IDSA. HCV guidance. September 2016.

21 AASLD/IDSA Guidance for Pts With GT1 HCV and Decompensated Cirrhosis Refer to experienced HCV provider (ideally liver transplant center) GT1 Population DCV + SOF LDV/SOF SOF/VEL RBV eligible 12 wks + low-dose RBV* *Initial dose: 600 mg/day, increase as tolerated. 12 wks + low-dose RBV* 12 wks + RBV (weight based for CTP B; low dose* for CTP C) RBV ineligible 24 wks 24 wks 24 wks AASLD/IDSA. HCV guidance. September 2016.

HIV-HCV coinfection. Mark Sulkowski, MD Professor of Medicine Johns Hopkins University School of Medicine Baltimore, Maryland

HIV-HCV coinfection. Mark Sulkowski, MD Professor of Medicine Johns Hopkins University School of Medicine Baltimore, Maryland HIV-HCV coinfection Mark Sulkowski, MD Professor of Medicine Johns Hopkins University School of Medicine Baltimore, Maryland Disclosures Principal investigator for research grants Funds paid to Johns Hopkins