5/2/2016. Kara W. Chew, MD, MS Assistant Clinical Professor of Medicine David Geffen School of Medicine at UCLA Los Angeles, California

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1 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 Financial Relationships With Commercial Entities Dr Chew has received a research grant awarded to the University of California Los Angeles from Merck & Co, Inc. (Updated 04/24/16) Slide 2 of 39 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 Slide 3 of 39 1

2 Case 53 yo woman with HIV/HCV co-infection referred for HCV treatment HCV genotype 1a, HCV treatment-naïve HCV diagnosed 15 years ago. No h/o GI bleeding, jaundice, encephalopathy, ascites, edema, rash +EtOH, up to ½ bottle of wine once a week, no tobacco, +remote marijuana, no other illicit drug use. No herbal or OTC meds, no NSAIDs or acetaminophen HIV well-controlled on atazanavir/ritonavir + abacavir/lamivudine Severe esophagitis with Barrett s esophagus on omeprazole Attempts to switch ART have been unsuccessful Slide 4 of 39 Case PMH HIV/AIDS, h/o disseminated MAC, PCP, CD4 nadir 0 Severe esophagitis with Barrett s esophagus and antral ulcer Stage IV diffuse large B cell lymphoma in remission since 2011 Opiate dependence Bacterial pneumonia Depression H/o tobacco use Hip fracture s/p ORIF Necrotizing fasciitis Hepatitis A and B immune Medications Atazanavir/ritonavir + ABC/3TC Buprenorphine Omeprazole 20 mg daily MVI NKDA Slide 5 of 39 Case Physical Exam Vital signs normal, BMI 30 Well-appearing Anicteric Abdomen with normal liver edge, no hepatosplenomegaly No lower extremity edema No spider nevi, palmar erythema, rash Labs Wbc 7.3, hgb 13.5, plt 315 Creatinine 0.8 T.bili 1.4, AST 37, ALT 31, Alk phos 31, albumin 4.4 INR 1.1 CD4 615 (21%), HIV RNA <20 HCV RNA 14,500,000 IU/mL HCV genotype 1a Fibrosure: fibrosis score of 0.74 = F3-F4 Slide 6 of 39 2

3 Does this patient have advanced fibrosis? 45% 1. Yes, her Fibrosure score is consistent with 10% advanced fibrosis 2. No, the Fibrosure test is not reliable 17% 3. I m not sure; I need to do more tests 28% 4. It is not necessary to determine degree of fibrosis; the treatment will be the same Slide 7 of 39 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 Slide 8 of 39 Clinical assessment: Liver fibrosis assessment Signs on exam of cirrhosis: spider nevi, palmar erythema, nodular, firm liver Laboratory signs: thrombocytopenia, hypoalbuminemia, elevated bilirubin, elevated INR Abdominal ultrasound sensitivity of ~65-80% for surface nodularity Note other findings such as splenomegaly that suggest portal HTN Slide 9 of 39 Choong, J Clin Imaging Sci

4 Non-invasive measures of fibrosis Indirect serum biomarkers FIB-4: age, plt, ALT, AST APRI: AST, plt FibroSURE TM : age, gender, alpha-2-macroglobulin, alpha-2-globulin, gamma globulin, apolipoprotein A1, GGT, ALT, total bilirubin - not reliable for patients on atazanavir APRI >2.0 or FIB-4 > high specificity for advanced fibrosis/cirrhosis Direct serum markers (extracellular matrix) FIBROSpect II: hyaluronic acid (HA), TIMP-1, alpha-2-macroglobulin ELF Test: TIMP-1, procollagen III amino-terminal peptide, HA Not sufficiently sensitive used alone for detection of advanced fibrosis Perform best at extremes of scores, indeterminate in intermediate range Slide 10 of 39 Chou, Ann Intern Med 2013; Sterling, Hepatology 2006; Lin, Hepatology 2011; Thompson, Hepatology 2012 Slide 11 of 39 Liver fibrosis assessment Vibration-controlled transient elastography Noninvasively measures liver stiffness >9.5 correlates with F3, >12.5 kpa with F4 Overlap in kpa ranges between stages Results affected by hepatic inflammation, obesity, ascites, central venous pressure, food Liver biopsy gold standard, but Subject to sampling error Understaging if tissue samples too small Up to one-third of bilobar biopsies with difference of at least 1 stage between the lobes Can evaluate for other causes of liver disease Bedossa, Hepatology 2003, Castera Invasive Gastroenterology 2005, Rockey, AASLD Liver Biopsy Guidelines, Hepatology 2009 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 Slide 12 of 39 AASLD/IDSA, hcvguidelines.org, Boursier Hepatology

5 Case 53 yo woman with HIV/HCV co-infection, no clinical or routine laboratory signs of cirrhosis FIB-4 score: 0.96 APRI: FIBROSpect II: 25 Abdominal US: Normal-appearing liver, normal spleen FIB-4 <1.45, NPV=90% for advanced fibrosis APRI <0.5, NPV in different studies >70-95% Fibrosis serum panel index <25: probability of F4=0.6% Slide 13 of 39 Sterling, Hepatology 2006, Lin Hepatology 2011 Determined she does not have cirrhosis. She has genotype 1a HCV. What would you treat her with? 1. 70% Ledipasvir/sofosbuvir 90mg/400mg once daily x 12 weeks 2. Elbasvir/grazoprevir 50mg/100mg once daily x 12 weeks 10% 0% 7% 13% 3. Paritaprevir/ritonavir/ombitasvir (150/100/25mg) once daily + dasabuvir 250mg BID + weight-based RBV x 12 weeks 4. Simeprevir 150mg plus sofosbuvir 400mg once daily x 12 weeks 5. Daclatasvir 30mg plus sofosbuvir 400mg daily x 12 weeks Slide 14 of 39 Slide 15 of 39 Treatment recommendations HCV Genotype 1a Treatment naïve and PEG- Treatment naïve compensated PEG-IFN/RBV experienced IFN/RBV Review experienced of GT1a noncirrhotic and 1b options, cirrhotic naïve, non-cirrhotic compensated vs cirrhotic cirrhotic (include level of data) Elbasvir/grazoprevir x 12 weeks - if Elbasvir/grazoprevir x 12 weeks - if Elbasvir/grazoprevir x 12 weeks - no significant NS5A RAVs* no significant NS5A RAVs* if no significant NS5A RAVs* Ledipasvir/sofosbuvir x 12 weeks Paritaprevir/ritonavir/ombitasvir + dasabuvir + WBR x 12 Simeprevir + sofosbuvir x 12 weeks Daclatasvir + sofosbuvir x 12 weeks (IB and IIaB) Ledipasvir/sofosbuvir x 12 weeks Ledipasvir/sofosbuvir x 24 weeks Ledipasvir/sofosbuvir + WBR x 12 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; *Significant RAVs at AA positions 28, 30, 31, 93 FOR RECOMMENDED REGIMENS FOR DAA-EXPERIENCED, SEE AASLD/IDSA HCV GUIDELINES AASLD/IDSA HCV Guidance, hcvguidelines.org 5

6 Patients with SVR12 (%) 5/2/2016 Treatment recommendations HCV Genotype 1b Treatment naïve and PEG- Treatment naïve compensated PEG-IFN/RBV experienced IFN/RBV Review experienced of GT1a noncirrhotic and 1b options, cirrhotic naïve, non-cirrhotic compensated vs cirrhotic cirrhotic (include level of data) Elbasvir/grazoprevir x 12 weeks no resistance testing needed Elbasvir/grazoprevir x 12 weeks no resistance testing needed Elbasvir/grazoprevir x 12 weeks no resistance testing needed Ledipasvir/sofosbuvir x 12 weeks Paritaprevir/ritonavir/ombitasvir + dasabuvir x 12 Simeprevir + sofosbuvir x 12 Daclatasvir + sofosbuvir x 12 weeks (IB) Ledipasvir/sofosbuvir x 12 weeks Paritaprevir/ritonavir/ombitasvir + dasabuvir x 12 * Ledipasvir/sofosbuvir x 24 weeks Ledipasvir/sofosbuvir + WBR x 12 Paritaprevir/ritonavir/ombitasvir + dasabuvir x 12 * 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; *risk of drug-induced liver injury FOR RECOMMENDED REGIMENS FOR DAA-EXPERIENCED, SEE AASLD/IDSA HCV GUIDELINES Slide 16 of 39 AASLD/IDSA HCV Guidance, hcvguidelines.org Grazoprevir/elbasvir in HCV/HIV Co-infection (C-EDGE CO-INFECTION) Single-arm safety and efficacy study GT1 or 4 12 week treatment 218 treatment naïve 38 (17%) Black 35 (16%) F4 0 Median CD4 568 All GT1a GT1b GT4 N=218 N=144 Genotype N=44 N=28 ART: RAL, DTG, RPV, Pooled analysis of HCV trials, 12 wk duration: ABC, TDF, 3TC, FTC NS5A RAVs at amino acid positions 28, 30, 31, or 93 SVR12 70% vs 98% in absence of RAVs Rockstroh et al, Lancet HIV 2015;2:e Slide 17 of 39 Figure adapted from University of Washington Hepatitis Web Study Daclatasvir + Sofosbuvir in HCV/HIV Co-infection (ALLY-2) Phase 3, open-label GT1-4 8 or 12 weeks treatment Treatment naïve and experienced 30 (30%) Black 24 Cirrhosis Median CD4 >500 Slide 18 of 39 ART: DRV/r, ATV/r,LPV/r, EFV, NVP, RPV, DTG, RAL, MCV, TDF, FTC, ABC, 3TC, AZT, enfuvirtide -high SVR rates across ART Wyles et al, NEJM 2015; 373:

7 Patients with SVR12 (%) 5/2/ Ledipasvir/Sofosbuvir in HCV/HIV Co-infection (ION-4) Open-label, phase 3 12 week treatment Treatment naïve and experienced GT1 or (34%) Black 67 (20%) cirrhotic 8 GT4 Median CD4 628 N=335 N=150 N=185 N=268 N=67 ART: 13 non-svr, 10 with relapse all black, 8/10 on efavirenz 160 (48%) EFV/TDF/FTC --No differences in PK analysis 29 (9%) RPV/TDF/FTC Limited data on 8 wk duration with lower HCV viral load in HCV/HIV, 146 (44%) RAL+TDF/FTC not recommended (Christensen AASLD 2015, Ain HepDart 2015) Slide 19 of 39 Naggie et al, NEJM 2015;378:705-13, Figure from University of Washington Hepatitis Web Study 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) Slide 20 of 39 Drug-drug interactions between ART and HCV treatment HCV regimen Allowed ART Comments Ledipasvir/sofosbuvir (LDV/SOF) Elbasvir/grazoprevir Paritaprevir/ritonavir/ ombitasvir + dasabuvir Simeprevir Daclatasvir (DCV) -Note standard DCV dose is 60 mg Slide 21 of 39 MostART allowed Interaction between ledipasvir and TDF, ledipasvir and cobicistat Raltegravir, dolutegravir, rilpivirine, tenofovir, abacavir, emtricitabine, enfuvirtide, lamivudine, Atazanavir, dolutegravir, raltegravir, emtricitabine, lamivudine, tenofovir, enfuvirtide Raltegravir, (dolutegravir), rilpivirine, maraviroc, abacavir, emtricitabine, tenofovir, lamivudine, enfuvirtide No restrictions Dose adjustment with select ART LDV increases tenofovir levels avoid coadmin with TDF if CrCL <60 ml/min and avoid LDV + TDF with ritonavir- or cobicistat-boosted ART NO HIV-1 protease inhibitors or efavirenz NO efavirenz If ritonavir in ART regimen, hold ritonavir in ART for dose due with HCV treatment NO HIV-1 protease inhibitors or efavirenz DCV dose to 30 mg with r/atv, IDV, NFV, SQV, cobi-containing ART (except DRVcobi). DCV dose to 90 mg with efavirenz, etravirine, nevirapine 7

8 Acid-suppressing agents may reduce efficacy of LDV/SOF Ledipasvir solubility decreases with increasing ph Current FDA label allows max omeprazole dose 20 mg daily given simultaneously under fasted conditions HCV-TARGET: no baseline PPI aor 2.48 (p<0.001) for achieving SVR Slide 22 of 39 Terrault et al, HCV-TARGET, AASLD November 13-17, 2015 Degree of renal impairment Treatment in renal impairment Genotype Recommendation CrCl ml/min All genotypes No dose adjustment needed for Daclatasvir Ledipasvir/sofosbuvir Paritaprevir/ritonavir/ombitasvir, dasabuvir Simeprevir Sofosbuvir CrCl <30 ml/min* including HD GT 1a or 4 GT 1b Usual dose Elbasvir (50 mg)/grazoprevir (100mg) x 12 weeks Usual dose Elbasvir/grazoprevir x 12 weeks Paritaprevir/ritonavir/ombitasvir + dasabuvir x 12 weeks GT 2, 3, 5, 6 PEG-IFN + dose-adjusted RBV (200 mg daily) *High urgency to treat, no immediate option for kidney transplantation Slide 23 of 39 AASLD/IDSA HCV Guidance Case 53 yo woman with HIV, HCV genotype 1a, on atazanavir/ritonavir + abacavir/lamivudine, severe esophagitis, gastric ulcer, Barrett s esophagus, on omeprazole. Omeprazole dose increased to 40 mg daily. Intolerant of change in ART. Slide 24 of 39 8

9 What would you treat her with now? 11% 1. Ledipasvir/sofosbuvir 90mg/400mg once daily x 12 weeks 11% 11% 11% 56% 2. Elbasvir/grazoprevir 50mg/100mg once daily x 12 weeks 3. Paritaprevir/ritonavir/ombitasvir (150/100/25mg) once daily + dasabuvir 250mg BID + weight-based RBV x 12 weeks 4. Simeprevir 150mg plus sofosbuvir 400mg once daily x 12 weeks 5. Daclatasvir 30mg plus sofosbuvir 400mg daily x 12 weeks Slide 25 of 39 Treatment recommendations - HCV genotype 2 Treatment naïve and PEG-IFN/RBV experienced noncirrhotic Sofosbuvir + WBR x 12 Treatment naïve and PEG-IFN/RBV experienced compensated cirrhotic Sofosbuvir + WBR x weeks (IIaC, IIaB) Sofosbuvir/RBV experienced noncirrhotic or cirrhotic Sofosbuvir + WBR + PEG- IFN x 12 weeks (IIaC) Daclatasvir + sofosbuvir x 12 weeks if not eligible for RBV (IIaB) Slide 26 of 39 Daclatasvir + sofosbuvir x weeks if not eligible for RBV (IIaB) Daclatasvir + sofosbuvir +/- WBR x 24 weeks if PEG-IFN and/or RBV ineligible (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 AASLD/IDSA HCV Guidance Treatment recommendations - HCV genotype 3 Treatment naïve and PEG-IFN/RBV experienced noncirrhotic Daclatasvir + sofosbuvir x 12 Treatment naïve compensated cirrhotic Sofosbuvir + WBR + PEG-IFN x 12 PEG-IFN/RBV treatment experienced compensated cirrhotic Sofosbuvir + WBR + PEG-IFN x 12 Sofosbuvir/RBV experienced noncirrhotic or cirrhotic Sofosbuvir + WBR + PEG-IFN x 12 weeks (IIaC) Sofosbuvir + WBR + PEG-IFN x 12 Daclatasvir + sofosbuvir +/- WBR x 24 weeks (IIaB) Daclatasvir + Daclatasvir + sofosbuvir + WBR x sofosbuvir + WBR x 24 weeks (IIaB) 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 Slide 27 of 39 AASLD/IDSA HCV Guidance 9

10 Sofosbuvir/velpatasvir for HCV genotype 1-6 GENOTYPE SVR12 1a 98% (206/210) 1b 99% (117/118) 2 100% (104/104) / 99% (133/134) 3 95% (264/277) *NS5A RAVs still impact SVR 4 100% (116/116) 5 97% (34/35) 6 100% (41/41) Slide 28 of 39 ASTRAL-1, -2, and -3 trials, Feld, NEJM 2015; Foster, NEJM 2015 Treatment recommendations - HCV genotype 4 Treatment naïve noncirrhotic or cirrhotic PEG-IFN/RBV treatment experienced noncirrhotic PEG-IFN/RBV experienced compensated cirrhotic Paritaprevir/ritonavir/ombita Paritaprevir/ritonavir/ombita Paritaprevir/ritonavir/ombita svir + WBR x 12 weeks (IA, svir + WBR x 12 svir + WBR x 12 cirrhotics-ib) Elbasvir/grazoprevir x 12 weeks (IIaB) Prior relapse: Elbasvir/grazoprevir x 12 weeks Prior virologic failure: 16 weeks + WBR (IIaB) Ledipasvir/sofosbuvir x 12 Ledipasvir/sofosbuvir x 12 weeks (IIaB) weeks (IIaB) 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 Slide 29 of 39 AASLD/IDSA HCV Guidance Treatment regimen may differ based on cirrhosis status, HCV subtype, prior treatment, baseline resistance Depending on the genotype and regimen: Treatment duration may need to be extended or RBV added for prior cirrhotics and prior treatment failures Baseline resistance-associated variants (RAVs) have the greatest impact on genotype 1a and 3 treatment response Genotype 1a is harder to treat than 1b - ribavirin may need to be added or resistance testing done with implications for treatment extension Slide 30 of 39 10

11 FDA warnings Sofosbuvir + amiodarone serious symptomatic bradycardia When sofosbuvir given with another HCV DAA (e.g. ledipasvir, daclatasvir, simeprevir) Fatal cardiac arrest reported Bradycardia occurs within hours to days, to up to 2 weeks Beta blockers or underlying cardiac disease and/or advanced liver disease may increase risk Paritaprevir/ritonavir/ombitasvir +/- dasabuvir Serious liver injury with advanced liver disease Hepatic decompensation, liver failure, including liver transplantion or death Most often within 1-4 weeks of treatment initiation CONTRAINDICATED in Child-Turcotte-Pugh (CTP) B or C disease Simeprevir combination therapy Hepatic decompensation and failure with advanced and/or decompensated cirrhosis Grazoprevir/elbasvir contraindicated in CTP B and C Slide 31 of 39 Slide 32 of 39 Monitoring on treatment Monitor for adherence, adverse events, and potential new drug-drug interactions by clinic or telephone visits CBC, creatinine/gfr, and LFTs at week 4 10-fold ALT increase d/c treatment <10-fold ALT increase + symptoms/signs of decompensation d/c treatment <10-fold ALT increase + asymptomatic repeat LFTs at weeks 6 and 8 More frequent CBC monitoring if receiving RBV Grazoprevir/elbasvir: LFTs at week 8 (and 12 if 16 week course) late ALT elevations noted Paritaprevir/ritonavir/ombitasvir +/- dasabuvir and CPT A cirrhosis LFTs at weeks 2 and 4 if decompensation develops, d/c HCV treatment TSH q12 weeks if receiving IFN Renal monitoring with ledipasvir + TDF, closer if TDF+ritonavir-boosted HIV protease inhibitor Serum creatinine, electrolytes including phosphorus, urinary protein and glucose AASLD/IDSA HCV Guidance, hcvguidelines.org 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 Slide 33 of 39 Yoshida et al, Hepatology 2015, Martin et al, AIDS 2013, Lambers et al, AIDS 2011, AASLD/IDSA HCV guidance 11

12 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 Slide 34 of 39 AASLD/IDSA HCV Guidance, hcvguidelines.org Next-generation, pan-genotypic regimens on the horizon Sofosbuvir/velpatasvir/GS-5897 ABT-493/ABT-530 MK-3682/grazoprevir/MK-8408 Genotypes 1-6 Fixed-dose combination single tablet daily No need for ribavirin Higher barrier to resistance Activity against common RAVs Improved efficacy in cirrhotic patients Slide 35 of 39 No longer a gap in HCV treatment responses between HCV/HIV and HCV Treatment responses similar between HCV/HIV and HIV Similar safety profile between HCV/HIV and HIV Recommended regimens are the same for HCV/HIV and HCV Real-world data thus far demonstrate similar high effectiveness as seen in clinical trials Slide 36 of 39 12

13 Summary Treatment is not always straightforward due to drug-drug interactions with ART, other meds, and comorbidities Use drug interaction references ( Treatment regimens may need to be extended or ribavirin added based on HCV subtype, cirrhosis status, prior treatment experience, and presence or absence of baseline NS5A resistance associated variants Optimal treatment for select populations (e.g. GT3 cirrhotics) still to be determined Optimal approach to retreatment of DAA failures not yet known More agents are on the horizon that will address treatment gaps Check the guidelines frequently! Slide 37 of 39 Recommended resources AASLD/IDSA HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. University of Liverpool hepatitis drug interactions database: Hepatitis C Online and Hepatitis Web Study, University of Washington: AASLD Practice Guidelines for management of cirrhosis Management of Hepatocellular Carcinoma (HCC screening recommendations) Prevention and Management of Gastroesophageal Varices and Variceal Hemorrhage in Cirrhosis Slide 38 of 39 Thank you! Slide 39 of 39 13