Disclosures. Hepatitis C: the 2016 Perspective. The Take Home. Glossary 12/9/16

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1 Disclosures Hepatitis C: the 2016 Perspective Annie Luetkemeyer, MD Division of HIV, ID and Global Medicine ZSFG, UCSF I have received research grant support to UCSF related to HCV from the following: Abbvie Bristol Myers Squibb (BMS) Gilead Merck Pfizer ACTG (NIH) The Take Home HCV treatment is not that hard Great guidelines and resources available Very well tolerated & highly effective More straightforward than HIV care!! Curing patients of HCV is incredibly rewarding for both you and your patients Try it you will like it! Glossary DAA: Directly Acting Agents (i.e. oral HCV drugs) Fibrosis Staging: Metavir F0-F4 HCV Genotype: strain of HCV (1-6), not a drug resistance test RASs : Resistance associated substitutions (no longer RAVs) SVR: Sustained virologic response: undetectable HCV RNA weeks after stopping treating (= cure) 1

2 The big picture in years since the approval of Our current HCV arsensal & what s on the horizon Does HIV/HCV coinfection matter? What populations remain special in 2016? HBV reactivation with HCV treatment Challenges after HCV cure HCV elimination? ARS: Why are we talking about HCV? 1) ~10% of HIV+ patients in US have HCV coinfection 2) HCV is major global public health issue with 50 million infected worldwide 3) HCV has surpassed all other infectious diseases as the leading cause of infectious disease related death in the US 4) The names of HCV medicines are so darned fun to say(-buvir)! HCV Deaths vs. Other Notifiable Infectious Diseases (including HIV, TB & HBV) in US Globally HCV ~ million ~ 3.5 million Ab+ (2.7 HCV RNA, likely underestimate ) HIV 36 million 1.2 million HIV-HCV > 2 million ~ 25% US Ly CID 2016 Answers: Why are we talking about HCV? 1) ~25% of HIV+ patients in US have HCV coinfection 2) HCV is major global public health issue with million infected worldwide 3) HCV has surpassed all other infectious diseases as the leading cause of infectious disease related death in the US 4) The names of HCV medicines are so darned fun to say(-buvir)! 2

3 2016 HCV Report card Whom to treat: everyone 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. Patients with short life expectancies owing to liver disease should be managed in consultation with an expert. (AASLD/IDSA guidelines) First pangenotype, single pill therapy approved Duration for most patients: 8-12 weeks >95% cure in vast majority of patients Most do not require ribavirin Effective options for historically hardest to treat populations Cost & Access Wholesale Price /Ledipasvir 94,500 (Harvoni) Viekira Pak 83,319 Elbasvir/grazoprevir (Zepatier) /velpatasvir (Epclusa) 54,000 74,760 Prices coming down NO ONE actually pays these prices Most cost effectiveness analysis find HCV cure cost effective Cost still an important barrier AASLD 2016: VA HCV Cures Skyrocket Direct-acting agents have explosive impact -- when money is available (Moon 2016 #227) DAA Prescribing Restrictions Emerging epidemic of hepatitis C virus infections among young nonurban persons who inject drugs in the United States, Suryaprasad CID 2014 Younger, IDU population 57% of HCV+ women: childbearing age 3

4 Direct Acting Agents (DAA) HCV Arsenal and principles of therapy s à Target viral protease à -previr Grazoprevir(Zepatier) Paritaprevir (Viekira) P = Previr NS5b Inhibitors à Target viral RNA polymerase à -buvir NS5b Nucleotide i.e. NS5b Non Nucleotide i.e. Dasabuvir B = Buvir Inhibitors à Target viral assembly and release à -asvir Ledipasvir Velpatasvir Ombitasvir (Viekira) Elbasvir (Zepatier) Daclatasvir A = Asvir based therapy based therapy Backbone Backbone Ledipasivir/ (Harvoni): GT 1 & 4 Velpatasvir/ (Epclusa): pangenotype NS5b Non-Nuke NS5b Non-Nuke Daclatasvir + : Pangenotype 4

5 based therapy NS5b Non-Nuke Ledipasivir/ (Harvoni) GT 1 & 4 Velpatasvir/ (Epclusa) Daclatasvir + for hard to treat: Decompensated Retreatment GT3 based therapy Backbone NS5b Non-Nuke Elbasvir/ Grazoprevir (Zepatier): GT 1&4 Pibrentasavir/ glecaprevir (in development): Pangenotype based therapy based therapy Backbone Backbone NS5b Non-Nuke Elbasvir/ Grazoprevir (Zepatier): GT 1&4 Pibrentasavir/ glecaprevir (in development): pangenotype for hard to treat: GT1A with resistance (Zepatier) Backbone NS5b Non-Nuke PrOD : Pariteprevir/ ombitasvir/ ritonavir, dasabuvir (Viekira Pak) 5

6 based therapy Backbone NS5b Non-Nuke for hard to treat: GT1A PrOD : Pariteprevir/ ombitasvir/ ritonavir, dasabuvir (Viekira Pak) Coming soon Next generation dual therapy Triple therapy NS5b Nuke (Almost) One size fits all, pangenotypic regimens 8 weeks for non-cirrhotic, treatment naïve Triple therapy effective for failures, regardless of presence of resistance Caveat: Drug interactions will limit compatible ART with these HCV PIs More is not better, better is better HIV/HCV Coinfection ARS: HCV in setting of HIV 1) s should be changed to an alternative agents prior to HCV treatment to avoid drug interactions 2) HCV cure rates are approximately 10% lower in HIV/HCV compared to HCV monoinfection 3) Risk of HCV reinfection in HIV+ men who have sex with men (MSM) is reported as high as 25% 4) Tenofovir (TDF or TAF) should not be coadministered with -based treatment 6

7 Answer: HCV in setting of HIV 1) s should be changed to an alternative agents prior to HCV treatment to avoid drug interactions 2) HCV cure rates are approximately 10% lower in HIV/HCV compared to HCV monoinfection 3) Risk of HCV reinfection in HIV+ men who have sex with men (MSM) is reported as high as 25% 4) Tenofovir (TDF or TAF) should not be coadministered with -based treatment Good news about HIV/HCV Excellent and generally equivalent cure rates. Generally same treatment recommendations & duration Equipoise about 8 weeks of sofosbuvir/ledipasvir in HIV/HCV coinfection ALLY-2: 8 weeks sofosbuvir/daclastasvir -> 76% SVR in HIV/HCV Data from German cohort support 8 weeks in selected HIV/HCV with HCV RNA < 6 million IU/ml HCV treatment options available for nearly every ART regimen Wyles DL NEJM 2015;373; Inglitz CID 2016;63(10):1302 Less Good News Managing ART /DAA drug interactions can be complex Good data available and many excellent resources AASLD/IDSA Guidelines: University of Liverpool HCV Drug interactions: ART + DAA Scorecard SOF Ledipasvir VEL Daclatasvir P/r/O + D EBR/GZP ATV/r No data LDV ; ATV a VEL ; ATV a DCV * ATV ; PAR GZP & EBV, ATV DRV/r SOF ; DRV LDV ; DRV a VEL ; DRV a DCV, DRV DRV ; PAR / GZP & ELB ; DRV LPV/r No data No data VEL ; LPV a DCV, LPV LPV ; PAR GZP & EBR ; DRV EFV SOF ; EFV LDV EFV VEL ; EFV DCV ** No PK data** GZP & EBR, EFV RPV SOF ; RPV LDV ; RPV VEL ; RPV No PK data (clinical trial data ok) PAR ; RPV GZP & EBR ; RPV ETV No data No data No Data DCV ** No data No data RAL SOF ; RAL LDV ; RAL VEL ; RAL No PK data (clinical trial data ok) PrOD ; RAL GZP & EBR ; RAL ELV/cob Cobi ; SOF a LDV ; SOF a VEL ; COBI No data No data GZP & EBV, ATV DTG No data LDV ; DOL VEL ; RAL DCV ; TFV PAR ; DOL GZP & EBR ; DOL MVC No data No data No Data No data No data No data TDF SOF ;TFV LDV ; TFV VEL ; TFV DCV ; TFV PrOD ; TFV GZP & EBR ; TFV TAF SOF ;TFV LDV ;TFV VEL ;TFV No Data No Data No Data Decrease DCV dose to 30mg QD, **Increase DCV dose to 90mg QD, *** 3D + EFV led to premature study discontinuation due to toxicities, a only of concern when coadministered with TDF Adapted from Jennifer Kiser 7

8 ART with least interactions with DAAs SOF Ledipasvir VEL Daclatasvir P/r/O + D EBR/GZP ATV/r No data LDV ; ATV a VEL ; ATV a DCV * ATV ; PAR GZP & EBV, ATV DRV/r SOF ; DRV LDV ; DRV a VEL ; DRV a DCV, DRV DRV ; PAR / GZP & ELB ; DRV LPV/r No data No data VEL ; LPV a DCV, LPV LPV ; PAR GZP & EBR ; DRV EFV SOF ; EFV LDV EFV VEL ; EFV DCV ** No PK data** GZP & EBR, EFV RPV SOF ; RPV LDV ; RPV VEL ; RPV No PK data (clinical trial data ok) PAR ; RPV GZP & EBR ; RPV ETV No data No data No Data DCV ** No data No data RAL SOF ; RAL LDV ; RAL VEL ; RAL No PK data (clinical trial data ok) PrOD ; RAL GZP & EBR ; RAL ELV/cob Cobi ; SOF a LDV ; SOF a VEL ; COBI No data No data GZP & EBV, ATV DTG No data LDV ; DOL VEL ; RAL DCV ; TFV PAR ; DOL GZP & EBR ; DOL MVC No data No data No Data No data No data No data TDF SOF ;TFV LDV ; TFV VEL ; TFV DCV ; TFV PrOD ; TFV GZP & EBR ; TFV TAF SOF ;TFV LDV ;TFV VEL ;TFV No Data No Data No Data The bad news: Reinfection in HIV+ MSM Meta-analysis of 5 year HCV reinfection risk High and equivalent SVR rates Risk for reinfection NEAT European Cohort HIV+ MSM 25% reinfection rate over 12 yrs 7.3/100py Not Just HIV+ MSM at risk: MSM on PREP with sexually acquired HCV Decrease DCV dose to 30mg QD, **Increase DCV dose to 90mg QD, *** 3D + EFV led to premature study discontinuation due to toxicities, a only of concern when coadministered with TDF Adapted from Jennifer Kiser Simmons CID March 2016, Inglitz J Hep 2016, Volk CID 2015:60 Still hard to treat? Good news Challenges Still hard to treat? Good news Challenges Genotype 3 SOF/VEL cure rates 90-95%, better than SOF/RBV (Astral-3) Worse outcome in cirrhotics & treatment experiences, especially if RASs at baseline Genotype 3 SOF/VEL cure rates 90-95%, better than SOF/RBV (Astral-3) Worse outcome in cirrhotics & treatment experiences, especially if RAVs at baseline Renal Failure/ ESRD Grazoprevir/Elbasvir an option (no ritonavir, no RBV, potentially even in GT1a) (C-SURFER) Consider timing of treatment if transplant candidate 8

9 Still hard to treat? Good news Challenges Still hard to treat? Good news Challenges Genotype 3 SOF/VEL cure rates 90-95%, better than SOF/RBV (Astral-3) Still worse outcome in cirrhotics & treatment experiences, especially if RASs Genotype 3 SOF/VEL cure rates 90-95%, better than SOF/RBV (Astral-3) Worse outcome in cirrhotics & treatment experiences, especially if RAVs at baseline Renal Failure/ ESRD failures with RASs Grazoprevir/Elbasvir an option (no ritonavir, no RBV, potentially even in GT1a) (C-SURFER) High cure rates with current DAAs + RBV Some triple therapies will be RBV-sparing Timing of treatment if transplant candidate Current options require RBV Expense and access to medications for retreatment Renal Failure/ ESRD failures with RASs Decompensated cirrhosis Grazoprevir/Elbasvir an option (no ritonavir, no RBV, potentially even in GT1a) (C-SURFER) High cure rates with current DAAs + RBV Some triple therapies will be RBV-sparing SVR 95% with SOF/VEL/RBV (Astral-4) Real world : CPT A up to 94% SVR vs CPT B-C 78% (Fernando-Carillo 2016) Consider timing of treatment if transplant candidate Current options require RBV Expense and access to medications for retreatment Best outcomes with RBV Better outcome with less advanced disease Medically complex: treat with liver expert, discuss transplantation ARS : After attaining an HCV cure, what hepatocellular carcinoma (HCC) surveillance do cirrhotic patients need? None, as HCV cure reduces the risk of HCC Continued HCC surveillance as long as remain cirrhotic by Fibroscan or other marker of fibrosis, can stop if cirrhosis regresses Continued surveillance with q 6 month imaging Continued HCC surveillance only if other risk factors for HCC are present Answer: After attaining an HCV cure, what hepatocellular carcinoma (HCC) surveillance do cirrhotic patients need? None, as HCV cure reduces the risk of HCC Continued HCC surveillance as long as remain cirrhotic by Fibroscan or other marker of fibrosis, can stop if cirrhosis regresses Continued surveillance with q 6 month imaging Continued HCC surveillance only if other risk factors for HCC are present 9

10 After the cure HCV cure reduces but doesn t eliminate HCC risk in cirrhotics Continue to screen cirrhotic patients for HCC after SVR El Serag Hepatology 2016;64(1):130 After the cure: Reinfection Sexual (re)infection in MSM HIV+ MSM 7.3 reinfection/100 person-years (NEAT) STDs at an all time high in US, with MSM highly impacted HIV-uninfected MSM on PREP with HCV sexual acquisition Surveillance with HCV RNA in cured patients with ongoing risk Targeted education and prevention for MSM population Active IDU High SVR rates 4 reinfections/ 100 person-years 81% used clean needles all the time (C-Edge CO-STAR) Inglitz J Hep 2016, CDC 2015 STD Surveillance Report Press Release, Volk CID 2015, Dore AIM 2016, Dore AASLD % used injecting equipment after someone else used ARS: Which is true about HBV in the setting of HCV DAA treatment? HCV treatment makes patients more susceptible to new HBV infection HBV reactivation occurs when HBV virus develops resistance to HBV-active HCV drugs HCV treatment has been associated with HBV reactivation in HBV DNA (-) patients HBV reactivation during HCV treatment only occurs in HIV+ or otherwise immunosuppresed patients Answer: Which is true about HBV in the setting of HCV DAA treatment? HCV treatment makes patients more susceptible to new HBV infection HBV reactivation occurs when HBV virus develops resistance to HBV-active HCV drugs HCV treatment has been associated with HBV reactivation in HBV DNA (-) patients HBV reactivation during HCV treatment only occurs in HIV+ or otherwise immunosuppresed patients 10

11 HBV reactivation 29 cases of HBV reactivation on HCV therapy Including HBsAg (-), HBV DNA (-) patients Mechanism-? Viral interference HCV can have known suppressive effect on HBV in dually infected patients Check HBV serologies before HCV treatment (HBsAb, sag, core Ab) Very unlikely in HIV+ patients on HBV active ART (3TC/FTC Tenofovir ) HCV Elimination CJ Chu Journal of Gastroenterology and Hepatology 23 (2008) HCV Elimination Active initiatives in Egypt, Australia, Republic of Georgia, at global level (WHO), and here in the US What will it take to eradicate HCV in the US? Base Case: - Risk based & Baby boomer screening - Treatment ramps up Ideal - Universal Screening - Treatment capacity unlimited KabiriAIM 2014 Aug 5;161(3):

12 12/9/16 Treatment is essential but not sufficient US HCV care cascade, pre-daa era, DIAGNOSIS PREVENTION OF REINFECTION ACCESS to HCV CARE ACCESS to HCV MEDICATIONS Conclusions HCV treatment options for HIV/HCV patients are better than ever Excellent highly curative options for even the hardest to treat populations Our work is not done after HCV cure: HCC surveillance and prevention of reinfection Stay vigilant in this rapidly changing field: HBV reactivation Have the tools and the vision to work towards global elimination We need HIV providers of all kinds to treat HCV to realize the enormous potential of these new drugs Than Thank you! 12