6/2/2015. Interactive Case-Based Presentations and Audience Discussion

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1 Interactive Case-Based Presentations and Audience Discussion Arthur Y. Kim, MD Assistant Professor of Medicine Harvard Medical School Director, Viral Hepatitis Clinic Massachusetts General Hospital Boston, Massachusetts FORMATTED: Chicago, IL: May 19, 2015 (INTRODUCTORY) Slide 2 of 37 HCV Sequence Diversity Relative to Hepatitis B and HIV Ray SC, Thomas DL. In: Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas, and Bennett s principles and practice of infectious diseases, 7th ed. Philadelphia, PA: Churchill Livingstone/Elsevier; Courtesy Stuart Ray, JHU What makes Genotypes 2/3 special? Slide 3 of 37 Virology cell culture system is JFH-1 (GT2 strain) Epidemiology GT 3 particularly common in India, young PWID Natural history GT3 affects lipid metabolic pathways 1, higher rates of steatosis 2 GT3 more rapid cirrhosis in some studies 3 Treatment Higher response rates to PEG-IFN/ compared to GT1 For GT2/3: fibrosis staging was optional in IFN-era 1 Piodi et al. Hepatology 2008;48: Rubbia-Brandt et al. Gut 2004;53: Kanwal et al. Hepatology 2014;60:

2 /2/2015 Case Slide 5 of y/o woman, G2P1SAB1, immediately postpartum HIV negative, HBSAg negative, prior injection drug use age Diagnosed during first pregnancy Bilirubin 0.8 mg/dl, platelets 325K, SGOT 22 SGPT 23 HCV: genotype 2b, never treated, VL 3,300,000 IU/mL No alcohol, BMI 19, Desires to get pregnant again Should she breastfeed? 56% 1. Yes 2. No 44% Mother to child transmission Slide 6 of 37 Rates from mother to child ~ 5% (range quoted 2-8%) HIV/HCV coinfected mothers are higher risk 19% (range 10-35%) More recent systematic review suggests 1 in HIV coinfection Related to magnitude of viral titer Transmission much lower when <10 6 or when HCV RNA negative Possibly increased risk: active injection drug use, premature rupture of membranes Breastfeeding not associated with increased risk of neonatal HCV Amniocentesis not associated with higher rates of vertical transmission, but very few studies have been done Avoid inserting needle through the placenta Ohto et al. NEJM 1994, Thomas et al. Int J Epidemiol 1998, Benova et al. Clin Infect Dis 2014 Case Slide 8 of y/o woman, G2P1SAB1 HIV negative, HBsAg negative, prior injection drug use age Diagnosed during first pregnancy Bilirubin 0.8 mg/dl, platelets 325K, SGOT 22 SGPT 23 HCV: genotype 2b, never treated, VL 3,300,000 IU/mL No alcohol, BMI 19, Desires to get pregnant again Do you offer her treatment? 1. Yes 2. No 2

3 Slide 9 of 37 Slide 11 of y/o woman, G2P1SAB1 HIV negative, HBsAg negative, prior injection drug use age Diagnosed during first pregnancy Bilirubin 0.8 mg/dl, platelets 325K, SGOT 22 SGPT 23 HCV: genotype 2b, never treated, VL 3,300,000 IU/mL No alcohol, BMI 19 Does she need staging? 78% 1. Yes everyone needs staging! 2. No, she has a negligible risk of cirrhosis 22% Slide 12 of 37 sofosbuvir GS-7977 Sofosbuvir is a potent, specific HCV nucleotide Safe and well-tolerated 400 mg once daily, with or without food Broad HCV genotype coverage High barrier to resistance, no known breakthrough if adherent to date Adherent patients suppress on treatment, all failures are relapses 3

4 Slide 13 of 37 Sofosbuvir + for GT2 infection /26 6/10 7/9 Naive with cirrhosis Tx Exp, cirrhosis Naive, no cirrhosis Tx-Exp, no cirrhosis Tx Exp, cirrhosis (16 wks) Lawitz et al. NEJM 2013, Jacobson et al. NEJM 2013 Sofosbuvir + x 12w for GT2 infection VALENCE Slide 14 of /30 2/2 30/33 7/8 Naive, no cirrhosis Naive with cirrhosis Tx-Exp, no cirrhosis Tx Exp, cirrhosis Zeuzem et al. NEJM 2014; 370: Slide 15 of 37 Genotype 2 Treatment-naive accessed 1/7/15 4

5 Slide 16 of 37 Genotype 2 Treatment-Experienced accessed 1/7/15 Case Slide 17 of y/o woman, G2P1SAB1 HIV negative, HBSag negative, prior injection drug use age Diagnosed during first pregnancy Bilirubin 0.8 mg/dl, platelets 325K, SGOT 22 SGPT 23 HCV: genotype 2b, never treated, VL 3,300,000 IU/mL You elect to treat with /. How do you counsel about risks of this treatment? Ribavirin teratogenicity Slide 18 of 37 Category X due to animal model data Human data over 5 years of registry (n=49 direct exposure, n=69 indirect) did not see increased birth defects in women exposed not powered Roberts SS et al. Birth Defects Res A Clin Mol Teratol

6 Case Slide 19 of y/o man with HIV, prior injection drug use on tenofovir/ftc r/atazanavir, HIV ND, CD4 331 cells/mm 3 bilirubin 1.6 mg/dl, platelets 203K, SGOT 36 SGPT 49, liver bx 13 years ago shows 1/6 fibrosis and steatosis HCV: genotype 3a, IL28B CT, failed PEG-IFN/ 6 years prior, VL 6,300,000 IU/mL Slide 21 of y/o man with HIV, prior injection drug use on tenofovir/ftc r/atazanavir, HIV ND, CD4 331 cells/mm 3 bilirubin 1.6 mg/dl, platelets 203K, SGOT 36 SGPT 49, liver bx 13 years ago shows 1/6 fibrosis and steatosis HCV: genotype 3a, IL28B CT, failed PEG-IFN/ 6 years prior Which of the following is most likely to influence response to currently-available therapies for genotype 3? 79% 1. IL28B CT 2. Prior treatment failure 3. HIV status 4. Prior steatosis on biopsy 5. Injection drug use history 5% 5% 11% Slide 22 of 37 Sofosbuvir + for GT3 infection, naïve patients Naïve, no cirrhosis Naïve with cirrhosis Naïve, no cirrhosis 12 weeks 24 weeks Naïve, cirrhosis Lawitz et al. NEJM 2013; 368: , Jacobson et al. NEJM 2013; 368: , Antiviral Drugs Advisory Committee Meeting, Gilead Review 10/25/13; Zeuzem et al. NEJM 2014;370:

7 SVR12 6/2/2015 Sofosbuvir + for GT3 infection treatment experienced patients Slide 23 of RB V SO F Tx Exp, no cirrhosis Tx Exp, cirrhosis Tx Exp, no cirrhosis Tx Exp, cirrhosis 12 weeks 24 weeks Lawitz et al. NEJM 2013; 368: , Jacobson et al. NEJM 2013; 368: , Antiviral Drugs Advisory Committee Meeting, Gilead Review 10/25/13; Zeuzem et al. NEJM 2014;370: Sofosbuvir for HIV/HCV coinfection PHOTON-1 Slide 24 of 37 Treatment naïve, cirrhosis permitted ART included: rilpivirine, raltegravir, efavirenz, boosted PIs Wk 0 Wk 12 Wk 24 Wk 36 GT 1 TN n=114 +, n=114 SVR12 GT 2/3 TN n=68 +, n=68 SVR12 GT 2/3 TE n=41 +, n=41 SVR12 SAE 7% Sulkowski et al. JAMA 2014; 312: PHOTON SVR12 results Slide 25 of RB SO V F 88 GT1 GT3 GT GT1 TN GT2 TE GT3 TE 87/114 22/24 16/17 /R 24 weeks 0 GT2 TN 23/26 GT3 TN 28/42 /R 12 weeks Sulkowski et al. JAMA 2014; 312:

8 /2/2015 Slide 27 of y/o man with HIV, prior injection drug use on tenofovir/ftc r/atazanavir, HIV ND, CD4 331 cells/mm 3 bilirubin 1.6 mg/dl, platelets 203K, SGOT 36 SGPT 49, liver bx 13 years ago shows 1/6 fibrosis and steatosis HCV: genotype 3a, IL28B CT, failed PEG-IFN/ 6 years prior What would you choose for repeat liver staging? 1. APRI score (already available) 2. Fibrosure/Fibrotest 3. Fibrosure/Fibrotest after change in medications 31% 38% 4. Fibroscan 5. Liver biopsy 6% Slide 29 of 37 During last treatment course with PEG-IFN there was not an RVR, stopped at 16 weeks due to nonresponse. Patient suffered moderate fatigue and mild cytopenias not requiring growth factors For the co-infected individual with genotype 3 infection, repeat biopsy shows 2/4 fibrosis. Which of the following currently available regimens would you recommend? 1. Await something better 53% 2. Paritaprevir/ritonavir + ombitasvir + dasabuvir + x 12 weeks 3. PEG-IFN + + sofosbuvir x 12 weeks 29% 4. Sofosbuvir + x 24 weeks 5. Ledipasvir + sofosbuvir (FDC) + x 12 weeks 18% Slide 31 of 37 During last treatment course with PEG-IFN there was not an RVR, stopped after 16 weeks due to nonresponse. Patient suffered moderate fatigue and mild cytopenias not requiring growth factors For the co-infected individual with genotype 3 infection, repeat biopsy shows 3.5/4 fibrosis. Which of the following currently available regimens would you recommend? 1. Await something better 65% 2. PEG-IFN + x 48 weeks 3. PEG-IFN + + sofosbuvir x 12 weeks 4. Sofosbuvir + x 24 weeks 5. Ledipasvir + sofosbuvir (FDC) + x 12 weeks 18% 18% 8

9 Slide 32 of 37 Peg-IFN + sofosbuvir + x 12 wks for GT3 infection LONESTAR2 included high rate of cirrhotics (55%) & nonresponders (85%) 5 2/4 nonresponders in GT3 LONESTAR2 group were lost to f/u 38/39 Naïve 20/24 Regimen achieved 96% SVR for GT2 (n=22) PEG PROTON, & ELECTRON, Lawitz et al. Lancet 2013, LONESTAR2 (Lawitz et al. AASLD 2013) Slide 33 of 37 Genotype 2 or 3 Treatment-Experienced Also alternative regimen for GT3 PEG accessed 1/7/15 Newly approved regimen for GT1: ledipasvir + sofosbuvir (FDC) Slide 34 of 37 ledipasvir 90 mg + sofosbuvir 400 mg LDV Safe and well-tolerated 90 mg / 400 mg once daily, with or without food Guidance re: antacid use, antiretrovirals Broad HCV genotype coverage (? less efficacy against GT3) High barrier to resistance, no known breakthrough to date 9

10 SVR12 (ITT) 6/2/2015 LDV RB V LDV/ +/- x 12 weeks for GT3 infection Unapproved indication 65 Naive Treatment-experienced Slide 35 of /26 no 26/26 41/50 25/28 16/22 Overall no cirrhosis cirrhosis Gane et al. EASL 2014; Abstract O6 Gane et al. AASLD 2014; LB-11. DCV/ x 12 weeks for GT3 infection ALLY-3 Slide 36 of 37 DCV /75 11/19 32/34 9/13 Naive, no cirrhosis Naive, cirrhosis Tx Exp, no cirrhosis Tx Exp, cirrhosis 12 weeks 9 of 16 relapses developed Y93H in NS5A Nelson et al. AASLD 2014; Abstract LB3. ALLY-2 had 10 cure in 14 GT3 patients Slide 38 of 37 Patient is on TDF/FTC + ritonavir / atazanavir No prior history of resistance If you are treating with LDV/+, what would you do? 1. Keep ARVs as is, close renal monitoring 87% 2. Swap TDF for ABC 3. Swap TDF for ABC, Swap r/atv for raltegravir 4. Swap r/atv for raltegravir 5. Swap r/atv for rilpivirine 7% 7%

11 Slide 39 of 37 ARV Interaction Score Card Kisergram Simeprevir 1 Sofosbuvir 2 Ledipasvir 3-5 Daclatasvir 6,7 AbbVie 3D 8-10 ATV/r No data No data LDV, ATVa DCV b ABT450 ; ATV DRV/r SIM ; DRV ; DRV LDV, DRVa DCV 3D / ; DRV LPV/r No data No data No data DCV ABT450 ; LPV TPV/r No data No data No data No data No data EFV SIM ; EFV ; EFV LDV ; EFV a DCV b No PK datac RPV SIM ; RPV ; RPV LDV ; RPV No data ABT450 ; RPV ETR No data No data No data No data No data RAL SIM ; RAL ; RAL LDV ; RAL No data 3D ; RAL EVG/cob i No data ; ELV/cobi LDV ; ELV/cobi No data No data DTG No data No data No data No data No data MVC No data No data No data No data No data TDF SIM ; TFV ; TFV LDV ; TFV DCV ; TFV 3D ; TFV a Watch renal function, TFV levels increased, b Decrease DCV dose to 30mg QD with ATV, increase DCV dose to 90mg QD with EFV, c 3D + EFV led to premature study discontinuation due to toxicities 1 Ouwerkerk-Mahadaven S IDWeek 2012, 2 Kirby B AASLD 2012, 3 ledipasvir/sofosbuvir, 4 German P 15 th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy 2014, 5 German P, CROI 2015, 6 Bifano M, et al. Antivir Ther. 2013;18(7):931-40, 7 Eley T HIVDART 2014, 8 Khatri ICAAC 2014, 9 Khatri ICAAC 2014, 10 (PrOD) Slide Courtesy of J Kiser Slide 40 of 37 Some options in pipeline for genotype 3 daclatasvir + sofosbuvir ABT ABT-493 PTV/r/OBV + sofosbuvir GS sofosbuvir Grazoprevir, MK-3682 (formerly IDX21437) + MK-8408 or elbasvir Role of not clear Ng et al. CROI 2014; clinicaltrials.gov search performed 2/20/15, NCT , NCT , NCT , NCT Slide 41 of 37 Option in pipeline for genotype 3 GS-9857 novel protease inhibitor with activity against GT3 Taylor et al. EASL

12 Slide 42 of 37 HCV Treatment for Genotypes 2,3 Novel interferon-free regimen weeks / Remains costly in U.S. Treatment-experience and cirrhosis are major predictors of response, extension of therapy warranted Future ribavirin-free paradigms for GT 2,3 Interferon may play a role with presently available options DAA-based regimens have thus far similar efficacy for HIV/HCV co-infected patients for HIV, main issue will be drug-drug interactions 12