Advances in Hepatitis C Virus Treatment for HIV-Infected Persons: Have We Reached the End of the Rainbow? Kara W. Chew, MD, MS Assistant Clinical Professor of Medicine David Geffen School of Medicine at UCLA Los Angeles, California FLOWED: 04/18/2016 Los Angeles, California: April 25, 2016 From KW Chew, MD, MS, at Los Angeles, CA: April 25, 2016, IAS-USA.

After attending this presentation, participants will be able to: Learning Objectives After attending this presentation, participants will be able to: Conduct the initial evaluation for hepatitis C virus (HCV) including hepatic fibrosis assessment Select between treatment options for genotype 1 HCV in HIV/HCV-coinfected patients List treatment options for genotype 2, 3, or 4 HCV infection

Evaluation for advanced fibrosis is recommended for all Necessary to determine the appropriate HCV treatment strategy Impacts treatment options Depending on the genotype and regimen: Treatment duration may need to be extended Addition of ribavirin may need to be considered Additional management necessary for advanced fibrosis/cirrhosis Screening for hepatocellular carcinoma Screening for esophageal varices Monitoring of hepatic function Counseling to avoid NSAIDs, limit acetaminophen use, avoid raw shellfish

Recommended approach for fibrosis assessment Combining direct biomarkers and transient elastography is most efficient If discordant, consider liver biopsy If direct biomarkers or transient elastography not available, combine indirect serum biomarkers If indeterminate, consider liver biopsy Use multiple measures. Clinical evaluation + indirect and direct, TE next, and then liver biopsy if needed – if it would impact treatment decisions/management AASLD/IDSA, hcvguidelines.org, Boursier Hepatology 2012

Key considerations when choosing between HCV treatment regimens Drug interactions between ART and HCV DAAs Drug interactions between HCV DAAs and drugs for comorbidities E.g. PPIs, statins, anticonvulsants, dihydropyridines, rifampin, digoxin Comorbidities: Cardiac disease (anemia with RBV, drug interactions with cardiac meds) Renal insufficiency (limited data for most DAAs with advanced kidney disease/ESRD, increased tenofovir levels with coadministration of ledipasvir with TDF) Potent p-gp inhibitors-sofosbuvir levels decreased – rifampin, St. John’s wort CYP3A inhibitors and inducers - daclatasvir dose adjustment Daclatasvir is an inhibitor of P-gp, OATP1B1 And 1. B3, BCRP increased atorvastatin (OATP and BCRP). Max 20 mg atorva with elbasvir/grazoprevir. Ledipasvir inhibitos P-gp and/or BCRP- atorvastain levels may increase. May get increased amlodipine through P-gp inhibitiron CYP3A4 inhibition (weak) by grazoprevir and mild P-gp inhibition by elbasvir may increase amlodipine. Ritonavir in PrOD inhibits CYP3A4 and paritaprevir OATP1B1 - > increased atorvastatin levels. European advice no coadministration Amlodipine inhibits CYP3A4- may increase daclatasvir concentrations CYP3A4 inhibition by ProD – consider dose reduction of amlodipine Statins, buprenorphine- monitor for toxicity, digoxin levels may increase Beta-blocker levels may increase (P-gp inhibition by DAAs)

Drug-drug interactions between ART and HCV treatment HCV regimen Allowed ART Comments Ledipasvir/sofosbuvir (LDV/SOF) Most ART allowed Interaction between ledipasvir and TDF, ledipasvir and cobicistat LDV increases tenofovir levels – avoid coadmin with TDF if CrCL <60 mL/min and avoid LDV + TDF with ritonavir- or cobicistat-boosted ART Elbasvir/grazoprevir Raltegravir, dolutegravir, rilpivirine, tenofovir, abacavir, emtricitabine, enfuvirtide, lamivudine, NO HIV-1 protease inhibitors or efavirenz Paritaprevir/ritonavir/ombitasvir + dasabuvir Atazanavir, dolutegravir, raltegravir, emtricitabine, lamivudine, tenofovir, enfuvirtide NO efavirenz If ritonavir in ART regimen, hold ritonavir in ART for dose due with HCV treatment Simeprevir Raltegravir, (dolutegravir), rilpivirine, maraviroc, abacavir, emtricitabine, tenofovir, lamivudine, enfuvirtide Daclatasvir (DCV) -Note standard DCV dose is 60 mg No restrictions Dose adjustment with select ART DCV dose to 30 mg with r/ATV, IDV, NFV, SQV, cobi-containing ART (except DRV-cobi).  DCV dose to 90 mg with efavirenz, etravirine, nevirapine With the addition of ledipasvir/sofosbuvir, tenofovir levels (when given as TDF) are increased with efavirenz, rilpivirine, DTG, r/ATV, r/DRV. With HIV PIs, TDF levels exceed what’s felt to be safe TAF may be OK – 20% of levels seen with TDF in healthy volunteers Doyle 16th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy, May 26-28, 2015, Washington, DC, USA - R/F/TAF or E/C/F/TAF may be coadministered with LDV/SOF without dose modification Cobicistat trough levels increased 4-fold by ledipasvir – Stribild contraindicated on label Elbasvir/grazoprevir – no efavirenz. With CYP3A induction, decreased EBV/GZR levels No HIV Pis - May increase the risk of ALT elevations due to a significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition. PrOD – label no DRV. May get decreased DRV levels. European recs OK if no extensive PI resistance. May need to do BID DRV. Daclatasvir dose modification – reduced to 30 mg with strong CYP3A inhibitors, increase to 90mg with moderate CYP3A inducers  

Treatment recommendations - HCV genotype 3 Treatment naïve and PEG-IFN/RBV experienced non-cirrhotic Treatment naïve compensated cirrhotic PEG-IFN/RBV treatment experienced compensated cirrhotic Sofosbuvir/RBV experienced non-cirrhotic or cirrhotic Daclatasvir + sofosbuvir x 12 weeks (IA) Sofosbuvir + WBR + PEG-IFN x 12 weeks (IA) Sofosbuvir + WBR + PEG-IFN x 12 weeks (IIaC) Daclatasvir + sofosbuvir +/- WBR x 24 weeks (IIaB) Daclatasvir + sofosbuvir + WBR x 24 weeks (IIaB) Daclatasvir + sofosbuvir + WBR x 24 weeks (IIaC) WBR = weight-based ribavirin, RBV = ribavirin; Strength of recommendation provided by Class (I, IIa/b, III) and Level (A, B, C), PEG-IFN= pegylated interferon ALLY-2 SVR 12 GT 3 10/10 ALLY-3 – 12 weeks daily DCV + SOF- 101 naïve – SVR12 90% Naïve non-cirrhotic 97% SVR12 Naïve with cirrhosis 58% SVR12 Experienced with cirrhosis – limited data. 12 weeks of SOF+DCV = SVR12 69% SOF-experienced treated with SOF/DCV x 12 weeks = 71% (n=7) SVR12. Extend duration + add RBV. European compassionate use – SVR12 cirrhotics - 86% with 24 weeks vs 70% 12 weeks Role of RBV not clear. Adding to 24 weeks doesn’t seem to increase SVR12 rates. Duration for naïve GT 3 compensated cirrhosis not known: ALLY-3+ SOF+DCV+ RBV 12 vs 16 weeks in naïve and experienced with stage 3 and compensated cirrhosis. SVR12 86% in cirrhotics, most experienced. Extending to 16 weeks not much difference 88% vs 89% n=17 and 18) FDA label –SOF/DCV + RBV x 12 weeks for GT 1 and 3 cirrhotics In ALLY-1,2,3, HCV GT1a and 3presence of NS5A polymorphisms Y93H associated with reduced SVR12 – very few N =6 1a and n=4 GT3. BOSON study: TN and TE GT3 to SOF/RBV x 16 vs 24 weeks or SOF+PEG+RBV x 12 weeks. SVR12 naïve 77% vs 88% vs 95%. In cirrhotics n=23 SVR12=91% with PEG C-SWIFT Elbasvir/GZR + SOF x 8-12 week TN w/ and w/o cirrhosis. 93% SVR12 with 8 weeks non-cirrhotics. 100% SVR 12 with 12 weeks. Cirrhotics 91% with 12 weeks (n=11) AASLD/IDSA HCV Guidance

Determining treatment response and post-treatment follow-up Quantitative HCV RNA at week 4 on treatment and 12 weeks after treatment completion (SVR12 determination) Can consider HCV RNA at end of treatment and 24 weeks after end of treatment (SVR24) >99% concordance between SVR12 and SVR24 Remind patients that treatment cure does not = HCV immunity High rates of reinfection in HIV/HCV co-infected persons HIV+ MSM without IDU, 2-year cumulative reinfection rates 25-33% Continue to review risk factors Ongoing cirrhosis/chronic liver disease management Positive VL at week 4- repeat at week 6. If increased >1 log (10-fold), d/c treatment The significance of a positive HCV RNA test result at week 4 that remains positive, but lower, at week 6 or week 8 is unknown. No recommendation to stop therapy or extend therapy can be provided at this time. Yoshida et al, Hepatology 2015, Martin et al, AIDS 2013, Lambers et al, AIDS 2011, AASLD/IDSA HCV guidance

Management of treatment failures Optimal retreatment strategy unknown If urgent to retreat: Resistance testing for NS3 and NS5A resistance mutations Include RBV on retreatment Consider PEG-IFN Consider a clinical trial RAVs make a difference. NS5A inhibitor RAVs on retreatment with longer duration LDV/SOF = more failures. Also then developed S282T/NS5B RAVs AASLD/IDSA HCV Guidance, hcvguidelines.org