Hepatitis C Virus Management

Transcription

1 Hepatitis C Virus Management FORMATTED: 04/20/17 New York, New York: February 24, 2017 Marion G. Peters, MD John V. Carbone, Endowed Chair Professor of Medicine University of California San Francisco San Francisco, California Slide 3 of 36 Learning Objectives After attending this presentation, participants will be able to: Describe current treatment of hepatitis C virus (HCV) infection Assess the degree of liver fibrosis Describe benefits to liver post cure and ongoing management Identify who needs long-term monitoring Slide 4 of 36 Liver Fibrosis stage is NOT assessed by Transient elastography Liver biopsy APRI FIB-4 Ultrasound New York, New York: February 24,

2 Patients after 5 years (%) Patients after 5 years (%) Slide 5 of 36 Liver Fibrosis stage is NOT assessed by Transient elastography Liver biopsy APRI FIB-4 Ultrasound 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 Slide 8 of HIV-HCV 36 > 2 million ~ 25% US Ly CID 2016 Effects of SVR on the risk of liver transplant, hepatocellular carcinoma, death and re-infection: meta analysis, 129 studies, 34,563 patients Hill AASLD year risk of death (all-cause) by SVR General Cirrhotic Co-infected Gen 18 stud n=29,269 Avg. FU=4.6 years SVR No SVR Cirr 9 stud n=2,734 Avg. FU=6.6 years HIV/HCV: 5 stud n=2,560 Avg. FU=5.1 years General: 21 stud n=12,496 Avg. FU=6.1 years Benefits may be offset by re-infection over 5 years 0.9% in low-risk persons 8.2% in persons who inject drugs 23.6% in persons coinfected with HIV 5-year risk of hepatocellular carcinoma by SVR 9.3 SVR 5.3 No SVR General Cirrhotic Co-infected Cirrhotic: 18 stud n=4,987 Avg. FU=6.6 years HIV/HCV: 3 studies n=2,085 Avg. FU=4.7 years Slide 9 of 37 New York, New York: February 24,

3 HCV Therapy is Associated with Better Renal, Cardiovascular Outcomes in Diabetic Patients End-stage renal disease (3 cohorts) Cumulative Incidence (% over time) No Rx Ischaemic stroke (3 cohorts) Rx HCV No HCV HCV Rx HR (95% CI) 0.16 for ESRD, 0.53 for ischemic stroke, and 0.64 for ACS Slide 10 of 36 Hsu YC, et al. Hepatology 2014 Steps in Assessing Fibrosis 1. Noninvasive markers E.g. APRI: Fib 4: use AST, platelets: ALT, age 2. Non invasive assessment of fibrosis Transient elastography ARFI MR fibrosis assessment 3. If further delineation is needed Liver biopsy Not needed in many/ most situations with HCV Slide 11 of 36 Whom to treat: everyone Slide 12 of HCV Overview 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 New York, New York: February 24,

4 Approved DAAs From Multiple Classes: Basis of 2016 Combination HCV Regimens Structural Domain Nonstructural Domain 5 UTR Core E1 E2 P7 NS2 NS3 4A NS4B NS5A NS5B 3 UTR Protease Polymerase Ribavirin (RBV) Slide 13 of 36 NS3 Protease Inhibitors Grazoprevir (GZR) Paritaprevir/Ritonavir (PTV/RTV) Simeprevir (SMV) NS5A Replication Complex Inhibitors Daclatasvir (DCV) Elbasvir (EBR) Ledipasvir (LDV) Ombitasvir (OBV) Velpatasvir (VEL) NS5B NUC Inhibitors Sofosbuvir (SOF) Slide credit: clinicaloptions NS5B Non-NUC Inhibitors (NNI) Dasabuvir (DSV) Slide 14 of 36 Current All-Oral Regimens for HCV Infection Regimen Component Classes Approved Genotypes Grazoprevir/elbasvir Ombitasvir/paritaprevir/ritonavir Ombitasvir/paritaprevir/ritonavir + dasabuvir Sofosbuvir + daclatasvir Sofosbuvir/ledipasvir Protease inhibitor + NS5A inhibitor Protease inhibitor + NS5A inhibitor Protease inhibitor + NS5A inhibitor + polymerase inhibitor Nucleotide polymerase inhibitor + NS5A inhibitor Nucleotide polymerase inhibitor + NS5A inhibitor Simeprevir + sofosbuvir Nucleotide polymerase inhibitor + protease inhibitor 1 Sofosbuvir/velpatasvir References in HCV guidelines on line Nucleotide polymerase inhibitor + NS5A inhibitor Slide credit: clinicaloptions 1, , 3 1, 4, 5, 6 1, 2, 3, 4, 5, 6 Slide 15 of 36 Major New Developments in 2016 Elbasvir/grazoprevir FDA approved for GT1a/b and 4 With renal disease (crcl <30) Lower SVR12 rates in pts with BL NS5A RAVs associated with > 5-fold loss of EBR susceptibility (2/9, 22%) Sofosbuvir/velpatasvir FDA approved for GT1-6: 97% SVR Use for genotype 2 Ombitasvir/paritaprevir/ritonavir/dasabuvir RBV RBV not needed for GT1b (TURQUOISE-III) Ombitasvir/paritaprevir/ritonavir/dasabuvir once daily coformulation FDA approved for GT1 Feld NEJM 2015; Foster NEJM 2015 New York, New York: February 24,

5 Slide 16 of 36 PPI and DAA LDV and VEL less soluble in high ph with PPIs LDV use lower doses of PPI: comparable to 20 mg omeprazole under fasted conditions VEL- don t use PPI If needed give SOF VEL with food 4 hrs before omeprazole 20 mg Data on other PPIs unknown Treatment naive PEG RBV Recommended Regimens for HCV Genotype 1a Slide AASLD/IDSA. 17 of 36 HCV guidance.october Recommended no Cirrhotic 12 wks EBV/GRZ (no RAVs) 12 wks LDVSOF 12 wks PRoD 12 wks SIM + SOF 16 wks EBV/GRZ (NS5A RAVs) 12 wks EBV/GRZ (if no RAVs) 12 wks PRoD + RBV 12 wks SIM + SOF 16 wks EBV/GRZ (NS5A RAVs) Recommended Compensated Cirrhotic 12 wks EBV/GRZ (no RAVs) 12 wks EBV/GRZ (no RAVs) 16 wks EBV/GRZ (NS5A RAVs) Slide 18 of 36 Recommended Regimens for HCV Genotype 1b Tx Experienced Recommended non cirrhotic Recommended Compensated Cirrhotic naive PEG RBV 12 wks EBV/GRZ 12 wks PRoD 12 wks SIM + SOF 12 wks EBV/GRZ 12 wks PRoD + RBV 12 wks SIM + SOF AASLD/IDSA. HCV guidance. September wks EBV/GRZ 12 wks PRoD 12 wks EBV/GRZ 12 wks PRoD New York, New York: February 24,

6 Recommended Regimens for HCV Genotype 1 failures Tx Experienced Recommended non cirrhotic Recommended Cirrhotic SOF RBV +/- PEG NS3 SIM +SOF + RBV 24 wks LDV/SOF + RBV 12 wks EBV/GRZ (16 w if EBV RAV) + RBV 24 wks LDV/SOF 24 wks DCV + SOF +/- RBV 12 wks EBV/GRZ + RBV (16 if EBV RAV) wait Test NS5A NS3 resistance Chose best available Add ribavirin Extend to 24 wks NS5A Slide 19 of 36 wait Test NS5A NS3 resistance Chose best available Add ribavirin Extend to 24 wks AASLD/IDSA. HCV guidance. September Recommended Regimens for HCV Genotype 2 Tx Experienced Recommended non cirrhotic Recommended Cirrhotic naive wks DCV + SOF PEG RBV SOF + RBV 24 wks DCV + SOF wks DCV + SOF 24 wks DCV + SOF Slide 20 of 36 AASLD/IDSA. HCV guidance. September Recommended Regimens for HCV Genotype 3 Tx Experienced Recommended non cirrhotic Recommended Cirrhotic naive 24 wks DCV + SOF +/- RBV PEG RBV SOF + RBV 24 wks DCV + SOF +RBV + RBV 24 wks DCV + SOF + RBV 24 wks DCV + SOF +RBV Slide 21 of 36 AASLD/IDSA. HCV guidance. September New York, New York: February 24,

7 Slide 22 of 36 DAA and ART: where to find guidance Managing ART /DAA drug interactions can be complex Good data available and many excellent resources AASLD/IDSA Guidelines: University of Liverpool HCV Drug interactions: Slide 23 of 36 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) ELV/co b PrOD ; RAL GZP & EBR ; RAL 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 issue when using TDF Adapted from Jennifer Kiser Slide 24 of 36 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) ELV/co b PrOD ; RAL GZP & EBR ; RAL 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 Adapted from Jennifer Kiser: HCV guidelines.org/ report New York, New York: February 24,

8 SVR12 (%) Good news Challenges Genotype 3 Renal Failure/ ESRD NS5a failures with NS5a RASs Decompensated cirrhosis Slide 25 of 36 SOF/VEL cure rates 90-95%, better than SOF/RBV (Astral-3) 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) Worse outcome in cirrhotics & treatment experiences, especially if NS5a RAVs at baseline 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 n/n = Slide 26 of IFN-Free DAA Therapy: OST vs Non-OST PTV/RTV/OMB + DSV + RBV [1,2] References in slidenotes No OST OST + DSV PTV/RTV/OMB + RBV [3] SOF/LDV + RBV [4] SOF/VEL [5] GZR/ELB [6,7] 1. Feld JJ. N Engl J Med Puoti M AASLD A Lalezari J J Hepatol Grebely J Clin Infect Dis Grebely J. Clin Infect Dis Zeuzem S Ann Intern Med Dore GJ Ann Intern Med Slide credit: clinicaloptions Recommendations Related to HCV Medication Interactions with HIV Antiretroviral Medications Rating: Class I, Level A ART switches, when needed, should be done in collaboration with the HIV practitioner. Rating: Class IIa, Level B DAC requires decrease with ritonavir-boosted atazanavir (30 mg/d) and increase with efavirenz or etravirine (90 mg/d) Elbasvir/grazoprevir FDC: should be used with ART without clinically significant interactions: abacavir, emtricitabine, enfuvirtide, lamivudine, raltegravir, dolutegravir, rilpivirine, and tenofovir. Simeprevir should be used without clinically significant interactions: abacavir, emtricitabine, enfuvirtide, lamivudine, maraviroc, raltegravir, (and probably dolutegravir), rilpivirine, and tenofovir. Sofosbuvir/velpatasvir cannot be used with efavirenz (increases TDF- check CrCl) or etravirine. Slide 27 of 36 New York, New York: February 24,

9 Recommendations Related to HCV Medication Interactions with HIV Antiretroviral Medications Rating: Class IIa, Level C Ledipasvir (90 mg)/sofosbuvir (400 mg) FDC: most antiretrovirals. Check Cr Cl with TDF as ledipasvir increases tenofovir levels. Avoid LDV with TDF in ritonavir-boosted or cobicistat-boosted regimens, or use TAF PrOD: should be used with antiretroviral drugs with which they do not have substantial interactions: atazanavir, dolutegravir, emtricitabine, enfuvirtide, lamivudine, raltegravir, and tenofovir. Dose of ritonavir used for boosting of HIV protease inhibitors may need to be adjusted (or held) when administered with paritaprevir/ritonavir/ombitasvir plus dasabuvir and then restored when HCV treatment is completed. The HIV protease inhibitor should be administered at the same time as the fixed-dose HCV combination. Slide 28 of 36 Regimens Not Recommended for Patients with HIV/HCV Coinfection Antiretroviral treatment interruption to allow HCV therapy is Not Recommended. Rating: Class III, Level A Elbasvir/grazoprevir should NOT be used with cobicistat, efavirenz, etravirine, nevirapine, or any HIV protease inhibitor. Rating: Class III, Level B Sofosbuvir/velpatasvir should NOT be used with efavirenz, etravirine, or nevirapine. Rating: Class III, Level B Sofosbuvir-based regimens should NOT be used with tipranavir. Rating: Class III, Level B PRoD should NOT be used with darunavir, efavirenz, ritonavir-boosted lopinavir, ritonavir-boosted tipranavir, etravirine, nevirapine, cobicistat, or rilpivirine. Rating: Class III, Level B PRO with or without dasabuvir should NOT be used in HIV/HCV-coinfected individuals who are not taking antiretroviral therapy. Rating: Class III, Level B Ribavirin should NOT be used with didanosine, stavudine, or zidovudine. Rating: Class III, Level B Simeprevir should NOT be used with cobicistat, efavirenz, etravirine, nevirapine, or any HIV protease inhibitor. Rating: Class III, Level B Slide 29 of 36 Slide 30 of 36 HBV Reactivation Risk in HBV/HCV Coinfected Pts on DAAs Case reports of HBV reactivation in pts treated with SMV + SOF + ASV, [3,4] and LDV/SOF [5] Observational study of Chinese pts treated with DAAs (N = 327 screened) [6] 3/10 HBsAg+ pts experienced hepatitis due to HBV reactivation Of 124 HBsAg-/HBcAb+ pts, none experienced hepatitis due to HBV reactivation Analysis of open-label phase IIIb trial [7] RBV, [1,2] DCV No evidence of HBV reactivation in HBsAg-/HBcAb+ pts receiving LDV/SOF (n = 103) Led FDA to require boxed warning for certain DAAs regarding the risk of HBV reactivation and need for HBV screening/monitoring [8] 1. Collins JM, et al. Clin Infect Dis. 2015;61: ; 2. Ende AR, et al. J Med Case Rep. 2015;9:164; 3. Hayashi K, et al. Clin J Gastroenterol. 2016;9: ; 4. Takayama H, et al. Hepatol Res. 2016;46: ; 5. De Monte A, et al. J Clin Virol. 2016;78:27-30; 6. Wang C, et al. Clin Gastroenterol Hepatol. 2016;[Epub ahead of print]; 7. Sulkowski MS, et al. Clin Infect Dis. 2016;[Epub ahead of print]; 8. FDA. Drug Safety Communication New York, New York: February 24,

10 Slide 31 of 36 HBV Reactivation during DAA Rx for HCV Cases were not receiving HBV antiviral treatment In 8 cases, when transaminases started to rise, DAA hepatotoxicity was initial diagnosis - DAA discontinued. As patients deteriorated or failed to improve, HBV reactivation was considered among the likely diagnosis 12 cases eventually received HBV antiviral treatment Treatment for HBV was delayed in at least five of the 12 cases, and one patient died. With HBV treatment, most patients had improvement in HBV DNA, and other signs and symptoms FDA.gov HBV reactivation on DAA therapy 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 ) Slide 32 of 36 CJ Chu Journal of Gastroenterology and Hepatology 23 (2008) Slide 33 of 36 DAAs and HCC in HCV SVR patients Reig 103 prior treated HCC received DAAs 53 complete HCC response 3 died, 16 recurrence within 5.7 months post SVR ANRS 3 cohorts receiving prior HCC treatment No difference in HCC whether received DAA or IFN Conti 344 DAA, 59 prior HCC Recurrence 17/59 (28.8%) 9/285 (3.2%) within 24 w post SVR AURIC (Austrian) 182 SVR (8 prior HCC) 16 developed HCC within 1-13 months post SVR 8.1% overall, 7.7% de novo Kobayashi 77 DAA; 528 IFN; no difference at 3 and 5 years FIB-4>3.25 5y HCC 9.66% in DAA rx, 8.37% in IFN rx(ns) Recurrence 8-30% Incidence % Within 1y post SVR J HEP 2016 Reig; ANRS; Kozbial; Conti. Kobayashi J Med Virol 2016 New York, New York: February 24,

11 Slide 34 of 36 HCC surveillance post SVR in cirrhotics? HCV cure reduces the risk of HCC Transient elastography may not be accurate post SVR in diagnosing cirrhosis If you want to stop screening you need to do liver biopsy Increased risk of HCC in non HIV with Chronic and heavy alcohol intake, Metabolic syndrome and diabetes mellitus Unclear if need to screen All F3 Older age Less HIV control Continued surveillance with q 6 month imaging and AFP Conclusions HCV treatment options for HIV/HCV patients are excellent DDIs with DAAs prove the most problematic However excellent tools are available online After HCV cure: continue HCC surveillance and assess for reinfection Stay vigilant in this rapidly changing field: HBV reactivation can occur with DAA therapy It is easier to treat and there are greater needs for us all to treat We have the tools and the vision to work towards global elimination by 2030 Slide 35 of 36 HCV Treatment is essential but not sufficient US HCV care cascade, pre-daa era, DIAGNOSIS ACCESS to HCV CARE ACCESS to HCV MEDICATIONS PREVENTION OF REINFECTION Slide 36 of 36 New York, New York: February 24,