5/11/2017. Arthur Y. Kim, MD Associate Professor of Medicine Harvard Medical School Boston, Massachusetts

Transcription

1 Hepatitis C Virus Infection Management: Curing Is Caring Arthur Y. Kim, MD Associate Professor of Medicine Harvard Medical School Boston, Massachusetts FORMATTED: 04/07/17 Slide 2 of 53 Financial Relationships With Commercial Entities Dr Kim has no relevant financial affiliations to disclose. (Updated 04/07/17) In this presentation I will discuss the off-label use of investigational direct-acting agents Acute HCV infection treatment Glecaprevir/pibrentasvir Slide 2 of 53 Learning Objectives After attending this presentation, learners will be able to: Describe modifiable risks for liver disease progression in HIV/HCV-coinfected individuals Optimize choice of antiviral regimens Describe rationale for enhanced screening, prevention, and treatment for HCV infection Slide 3 of 53 1

2 Audience response Slide 4 of 52 Slide 4 of 53 How long have you been involved in the treatment of HCV? 1. I have not treated HCV and we defer to hepatology 2. I have not treated HCV but others in my practice do 3. I have just started treating HCV within the last 2 years 4. I have been treating HCV for 2-5 years 5. I have been treating HCV for 5-15 years 6. I have been treating HCV for >15 years Slide 5 of 53 Slide 5 of 53 Estimates of prevalence in the United States Slide 6 of 53 NHANES - household based survey - ~ 3.2 million % unaware of infection Not included or underestimated in NHANES estimate: Homeless (142, ,610) Incarcerated (372, ,826) Veterans (1,237,461-2,452,006) Active military (6805) Healthcare workers (64, ,234) 2.7 to 5.0 million living with chronic HCV in the United States Number of Cases, millions Baby boomers Estimated HCV Cases account for >65% of cases 7.1 Conservative estimate Upper limit estimate Total Not Included in NHANES NHANES 0. CDC data. Ann Intern Med 2006 Denniston M, et al. Ann Intern Med. 2014;160: Chak E, et al. Liver Int. 2011;31: Zalesak M, et al. PLoS One. 2013;8:e63959; Edlin B, et al. Hepatology

3 HCV deaths exceed those from 60 infectious conditions (death certificate data) Slide 7 of 53 (including HIV, pneumococcus) Ly et al. CID 2016 MMWR: Age distribution of newly reported confirmed cases of hepatitis C virus infection --- Massachusetts, 2002 and 2009 Slide 8 of 53 * N = 6,281; excludes 35 cases with missing age or sex information. N = 3,904; excludes 346 cases with missing age or sex information. Source: Onofrey et al MMWR: May 6, 2011 / 60(17); HIV outbreak among PWID in the U.S. Overlaid upon a network of HCV transmission 135 cases as of report Investigation triggered by HIV surveillance Injection of oxymorphone Multigenerational use of injection drugs 84.4% (114/135) diagnosed with HCV infection Slide 9 of 53 Need for HCV prevention and vaccine! 3

4 A perfect storm for sexual HCV transmission: HIV+MSM Slide 9 of 52 Slide 10 of 53 Bloody practices Semen exposure Other STDs Sex Drugs Crystal methamphetamine Sildenafil Internet HIV Higher levels of virus in plasma and semen Immune deficiency, especially at GI mucosa Take home points: screening Slide Slide 109 of of 52 Slide 11 of 53 HCV is a common chronic infection and a candidate for screening Mostly asymptomatic Major cause of liver disease and leading cause of mortality in US Screening is effective, life-saving for those with advanced liver disease, also costeffective Whom to screen? Baby boomers born between 1945 / 1965 Those with past and ongoing risk factors (see prior list) Injection drug use (people who inject drugs) HIV+ men who have sex with men Screen highest risk patients yearly to identify early and prevent onward transmission HCV RNA for those already HCV Ab positive Slide 12 of 53 Goal of Treatment The goal of treatment of HCV-infected persons is to reduce all-cause mortality and liver-related health adverse consequences, including end-stage liver disease and hepatocellular carcinoma, by the achievement of virologic cure as evidenced by a sustained virologic response. Recommendations for When and in Whom to Initiate Treatment 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. Adapted from 4

5 Components of HCV care Slide 13 of 53 Coffee tied to lower mortality in French HIV/HCV coinfected patients Slide Slide 139 of of Slide 14 of 53 French ANRS HEPAVIH cohort n=1035 followed for median 5 years deaths (N=77) HCV-related causes 42.8% non-aids, non-hcc cancer 11.7% AIDS 10.4% ahr for death: Unstable housing 3.7 CD4 =< HCV cured 0.2 female gender or fewer EtOH drinks or more coffee 0.5 Carrieri et al. CROI 2016 Abstract #549 Take home points: evaluation Slide 15 of 53 Care for HCV is not all about treatment Preventing transmission (and harm reduction) critical to avoid re-infection Preventing liver progression Avoid alcohol Avoid weight gain (fatty liver) Coffee probably beneficial Avoid HIV Anticipating toxicities, managing drug/drug interactions Prognosis Noninvasive liver staging is now available ID doctors (and PCPs) will be critical in addressing the provider shortage 5

6 Identifying and Managing Interactions Slide 16 of 53 Kiser JJ, Burton JR, Jr, Everson GT. Nature Reviews Gastroenterol Hepatol 2013;10: Slide 17 of 53 HBV reactivation Slide 18 of 53 HBV flares (abrupt increase in ALT) preceded by HBV DNA increase institution or withdrawal of immunosuppression HBV core IgM may be positive Steroids, transplant, chemotherapy / biologics (esp. anti-cd20 Ab) Rare cases with HCV antiviral therapy (8-12 weeks into treatment) Reported with core-ab only but rate is likely extremely low Monitoring versus prophylaxis Treat HBSAg positive patients who meet AASLD criteria Prophylaxis or closely monitor those who do not meet AASLD criteria Monitor cab only, LFTs 8 and 12 weeks Lok et al. AASLD Guidelines 2009; Hammond et al. Biol Blood Marrow Transplant 2009; Wright et al. Am J Transplant 2014; Sulkowski et al. CID 2016; Wang et al. Clin Gastro Hep

7 Potential Therapeutic Targets in the HCV Replication Cycle Slide 20 of 53 Transport and release Fusion and uncoating HCV RNA Viral assembly Translation RNA replication NS5B polymerase inhibitors NS5A inhibitors Polyprotein processing NS2 NS4B NS3/4A protease inhibitors CypA NS5B NS3 NS5A NS4B NS2 NS3 NS5A NS5B HCV NS proteins NS5A inhibitors Adapted from slide courtesy Ray Chung Worldwide genotype distribution Slide 21 of 53 Possible combinations of HCV treatments then are applied to different viral genotypes Slide 22 of 53 PEG IFN GT3 10% GT4 4% GT2 9% BOC TLV SMV LDV VOX VEL PRV/r OBV DCV GZR EBR GCV PBV GT1 77% DSV Abbreviations: GT = genotype; PEG IFN = pegylated interferon; = ribavirin PIs: BOC = boceprevir, TLV = telaprevir, SMV = simeprevir; VOX = voxilaprevir; PRV = paritaprevir; GZR = grazoprevir; GCV = glecaprevir. Pharmacologic booster: r = ritonavir; NS5A: LDV = ledipasvir; VEL = velpatasvir; OBV = ombitasvir; DCV = daclatasvir; EBR = elbasvir; PBV = pibrentasvir; NS5B nonnucleoside: DSV = dasabuvir; NS5B nucleotide: = sofosbuvir 7

8 Predictors of relapse to sofosbuvir-based regimens Slide 23 of week FISSION POSITRON FUSION VALENCE n= week VALENCE n=247 PEG 12 week ATOMIC NEUTRINO n=339 Who will do poorly with currently-available based regimens? SVR12= undetectable HCV RNA at 12 weeks after cessation of therapy Six factors associated with relapse: Treatment-experienced IL28B non-cc Male sex Weight > 75 kg Cirrhosis High viral load >800,000 IU/mL Foster et al. EASL 2014 Abstract 66 Antiviral HCV treatments (FDA-approved as of June 28, 2016) Slide 24 of 53 Monotherapies IFN-2a IFN-2b PEG-IFN 2a Combination Therapies Daclatasvir (DCV) + Sofosbuvir () IFN-2a + Ribavirin (GT1,3)* IFN-2b + Ribavirin Elbasvir (EBR) / Grazoprevir (GZR) PEG-IFN 2a + Ribavirin* PEG-IFN 2b + Ribavirin (FDC GT1,4)* PEG-IFN 2b PEG-IFN + ribavirin plus either: Boceprevir (GT1) Telaprevir (GT1) Simeprevir (GT1) In combination with other agents: Sofosbuvir Ledipasvir (LDV) / Sofosbuvir () (FDC, GT1,4,5,6)* Paritaprevir / ritonavir / ombitasvir (FDC) + dasabuvir PrOD (GT1) Paritaprevir / ritonavir / ombitasvir (FDC) PrO (GT4) Simeprevir (SMV) + Sofosbuvir () *approved for HIV/HCV coinfection (GT1) approved for GT1 - decompensated and post-liver transplant Sofosbuvir () / Velpatasvir (VEL) approved for decompensated (FDC, All GTs) Antiviral HCV treatments (FDA-approved as of June 28, 2016) Slide 25 of 53 LDV Combination Therapies Daclatasvir (DCV) + Sofosbuvir () (GT1,3)* Elbasvir (EBR) / Grazoprevir (GZR) (FDC GT1,4)* Ledipasvir (LDV) / Sofosbuvir () (FDC, GT1,4,5,6)* Paritaprevir / ritonavir / ombitasvir (FDC) + dasabuvir PrOD (GT1) Paritaprevir / ritonavir / ombitasvir (FDC) PrO (GT4) EBR GZR PTV/r OBV DSV VEL Simeprevir (SMV) + Sofosbuvir () (GT1) Sofosbuvir () / Velpatasvir (VEL) (FDC, All GTs) 8

9 >90% cure rates for Genotype 1 Slide 26 of 53 PTV/r SVR ~95% of genotype 1 patients can be cured with current regimens 455/473 OBV DSV 286/ / /214 LDV 102/ /215 SAPPHIRE-I SAPPHIRE-II TURQUOISE-II ION-1 ION-2 ION-3 LDV ION-1 and 2: arms not shown but did not enhance SVR, therefore not necessary for many receiving LDV/ Cirrhotics (TURQUOISE) 24 weeks 95.9% SVR Tx-Exp (ION-2) 24 wks LDV/ 108/109 SVR no cirrhosis naive no cirrhosis null responder 55% 100% cirrhosis 16% cirrhosis naive 20% cirrhosis Tx-Exp no cirrhosis naive SAPPHIRE 1 Feld et al. NEJM 2014, SAPPHIRE 2 Zeuzem et al. NEJM 2014, ION 1 Afdhal et al. NEJM 4/12/2014, ION 2 Afdhal et al. NEJM 2014; 370(16):1483, ION 3 Kowdley et al. NEJM 4/12/2014. SAPPHIRE/TURQUOISE are 12 week arms only. ION studies are sparing arms only Major considerations for ledipasvir/sofosbuvir Slide 27 of 53 Few data for patients with egfr<30 Cirrhosis: No dose adjustment or for treatment-naive patients Drug interactions: Avoid coadministration with amiodarone - life-threatening bradycardia Avoid with oxcarbazepine, carbamazepine, rifampin, St. John s wort Antacids lower absorption of ledipasvir Avoid PPIs if possible Maximum dose omeprazole 20 mg If on omeprazole, take LDV/ with something acidic Shortening ledipasvir/sofosbuvir to 8 weeks Slide 28 of 53 ION-3 trial established 94% cure rate with eight weeks of therapy with ledipasvir/sofosbuvir for patients naive to therapy; non-cirrhotic Most relapses occurred in those with HCV RNA > 6,000,000 IU/mL Real-world (non-rct) data confirm efficacy of 8 weeks 94-98%,? selecting favorable patients Generally African-Americans under-represented Subanalysis showed ~91% SVR rate in African Americans using 8 weeks Caution regarding those with HIV, black patients, or certain characteristics Few data in HIV/HCV coinfection, especially African- American455/ / / / / /215 Care with F3 patients as they may be harboring F4 From adherence and cost standpoint, 8 weeks is attractive ION 3 Kowdley et al. NEJM 2014; Wilder et al. compared to 12 weeks Hepatology 2016; Ingiliz et al. ClD 2016; Lai et al. Drugs 2017; Kowdley et al. Hepatology 2017; 9

10 Extension of therapy beyond 12 weeks of PrOD necessary for cirrhotic patients with GT1a Slide 29 of weeks 24 weeks TURQUOISE II 100% cirrhosis PTV/r OBV DSV PTV/r OBV DSV SVR /64 14/15 13/13 52/56 11/11 10/10 40/50 39/42 Partial Null Naive Relapse not necessary for 1b FDA Warning issued regarding rare cases of decompensation in CTP-A cirrhosis Poordad et al. TURQUOISE II, NEJM PrOD for 8 weeks for 1b patients with easier characteristics: GARNET Slide 30 of 53 PRV/r OBV DSV 8 weeks SVR / / /162 ITT mitt-gt mitt-gt-nvf ITT = intention to treat mitt-gt (3 excluded for not having 1b) mitt-gt-nvf (denominator excludes non 1b and 1 premature discontinuation Welzel et al.easl Special Conference 2016 Major considerations for PrOD Slide 31 of 53 For treatment-naive patients, generally unnecessary for GT1b 12 weeks for most patients 8 weeks for treatment naive, GT1b without cirrhosis Cirrhosis: Naive patients still may receive 12 weeks Safety concern with cirrhosis raised in post-marketing phase Avoid with decompensated cirrhosis Drug interactions: Multiple ritonavir-related drug interactions 10

11 Slide 32 of 53 C-EDGE: elbasvir/grazoprevir is a and nucleoside/nucleotide sparing 12- week regimen for GT 1/4 HCV EBR GZR 12-wks Treatment naive Mean age 52 46% women 37% nonwhite 22% cirrhosis % SVR12 50 Serious AE n=12, none drug-related / / /131 18/18 8/10 All Patients GT 1a GT 1b GT 4 GT6 9 relapsers, 1 breakthrough in 1a Similar SVR for n=218 HIV co-infected individuals on DTG/RAL/RPV Zeuzem et al. Ann Intern Med 2015; Rockstroh et al. Lancet HIV 2015 Cirrhosis does not impact SVR rates for 12 weeks of EBR/GZR Slide 33 of 53 GZR EBR No cirrhosis Cirrhosis AEs are similar between cirrhotic and non cirrhotic patients in these trials % SVR /246 68/70 34/35 32/34 175/183 35/35 C-EDGE C-SALVAGE HIV C-EDGE Zeuzem et al. Ann Intern Med 2015; Rockstroh et al. Lancet HIV 2015; Buti et al. CID 2016; Jacobson et al. AASLD 2015 EBR/GZR - Resistance Associated Variants (RAVs) at NS5A positions 28, 30, 31, 93 associated with lower SVR Slide 34 of 53 EBR GZR } 28,30,31 } 93 Baseline testing for NS5A resistance recommended if using this regimen Jacobson et al AASLD 2015, San Francisco 11

12 EBR/GZR - extension of therapy to 16 weeks and addition of overcame resistance Slide 35 of 53 GZR EBR Jacobson et al AASLD 2015, San Francisco Major considerations for elbasvir/grazoprevir Slide 36 of 53 For treatment-naive patients, genotypes 1 and 4 12 weeks for most patients Extend 16 weeks and add for GT1a harboring NS5A resistance-associated substitutions NS5A mutations: M28A/G/T Q30D/E/H/G/K/L/R L31F/M/V Y93C/H/N/S Cirrhosis: Avoid with decompensated cirrhosis Drug interactions: Transporter issues with oxcarbazepine, carbamazepine, rifampin Excellent safety and efficacy in stage 4/5 chronic kidney disease Response rates for pangenotypic regimen: Genotypes 1-6 Slide 37 of weeks for GT1,2,4,5,6 19% compensated cirrhosis 32% nonresponders VEL weeks for GT3 No cirrhosis Cirrhosis SVR / / /116 34/35 41/41 GT1 GT2 GT4 GT5 GT6 8 week arms of phase II trial: lower SVRs at 100 mg VEL dos (81-88%) 0 160/163 Best available option for genotype 2/3 40/43 GT3 Naive 40/43 31/34 33/37 GT3 Tx Exp Feld et al. NEJM 2015; Foster et al. NEJM 2015; Everson et al. Ann Intern Med

13 Glecaprevir and pibrentasvir (G/P): novel pangenotypic regimen Slide 38 of 53 Glecaprevir (GCV) is a pangenotypic next-generation HCV protease inhibitor Pibrentasvir (PBV) is a pangentoypic next-generation NS5A inhibitor GCV PBV ENDURANCE-1 examined 8 versus 12 weeks in GT1 non-cirrhotic patients with or without HIV Zeuzem et al. AASLD 2016 Glecaprevir and pibrentasvir (G/P): novel pangenotypic regimen Slide 39 of 53 ENDURANCE-1 examined 8 versus 12 weeks in GT1 non-cirrhotic patients with or without HIV Zeuzem et al. AASLD 2016 A menu of options Slide 40 of 53 Due to regulations, no alcohol will be served Primo Protease boceprevir 44 telaprevir 12 grazoprevir 12 / 16 paritaprevir +ritonavir 12 / 24 simeprevir 12 / 24 NS5A inhibitors daclatasvir 12 / 24 elbasvir 12 / 16 ledipasvir 8 / 12 / 24 ombitasvir 12 / 24 Polymerase inhibitors dasabuvir 12 / 24 sofosbuvir 8 / 12 / 24 Notice: The consumption of raw or undercooked eggs, meat, poultry, seafood or shellfish, and certain combinations are not approved by the FDA for Hepatitis C Please ask your server whether Ribavirin 40 is suggested 13

14 Prix fixe menus? Slide 41 of 53 Due to regulations, no alcohol will be served Notice regarding protease inhibitors boceprevir and telaprevir will no longer be offered due to high calories, dysgeusia and/or allergic reactions Grilled Goose 8 weeks of GS-9857, pan-seared topped with velpatasvir flakes on a sofosbuvir backbone Abalone Veloute 12 weeks of paritaprevir, slow-boosted, infused with ombitasvir, served with twice-dosed dasabuvir chutney Mesclun Medley (nuc-free option) 12 weeks of sous-vide grazoprevir topped with fresh elbasvir salsa Notice: The consumption of raw or undercooked eggs, meat, poultry, seafood or shellfish, and some of these choices are not approved by the FDA for Hepatitis C Please ask your server whether Ribavirin 41 is suggested Slide 42 of 53 The continuum of care in HCV infection in the U.S. At least 3 million persons infected Slide 45 of 53 50% 38% Improving cascade necessary to reduce transmission, morbidity and mortality 23% 11% 6% 1% Adapted from Holmberg et al. NEJM

15 Incidence, prevalence and sustaining an epidemic Slide 46 of 53 Rising opiate use Lack of prevention services Asymptomatic infection Unknown serostatus Barriers to care, access restrictions and cost of treatment Can PWID be cured with novel HCV regimens? Slide 47 of 53 Dore et al. Ann Intern Med 2016 Treatment of recently active PWID with elbasvir/grazoprevir; on opiate agonist therapy, made 80% appointments 4 8 Dore et al. Annals of Internal Medicine

16 Dutch lifted restrictions on treatment in Nov 2015 Achieving 70% cure in HIV/HCV patients Slide 49 of 53 Women, former IDU less likely to be treated Boerekamps et al. CROI 2017 Abstract 136 What were the effects of de-restricting access to DAAs in the Netherlands? Slide 50 of 53 Late 2015: unrestricted access with very rapid uptake in Dutch HIV/HCV coinfection - ~70% treated No associated decrease in syphilis or LGV so behavior is an unlikely explanation indirect evidence of cure as prevention for HCV Rijnders et al. CROI Abstract 137LB Take home points regarding treatment Slide 51 of 53 Novel interferon-free and ribavirin-free paradigms Potent combinations can overcome biologic / host barriers to response 12 week regimens available for many patients Shortened courses for certain regimens if favorable traits present Pangenotypic 8-week regimen coming Special populations are being addressed: Treating high-risk populations may be a component of reducing incident infections Improving cascade of care and removing restrictions to access will be critical to maximize the impact of treatment 16

17 Resources Slide 52 of 53 Guidelines: IDSA Webinars: Hepatitis C Online Course: Liverpool website for drug interactions: Glossary Slide 53 of 53 baby-boomer = those born between 1945 and 1965 DAA = direct-acting antiviral DCV = daclatasvir DSV = dasabuvir EBR = elbasvir EtOH = alcohol GCV = glecaprevir GT = genotype LDV = ledipasvir HCC = hepatocellular carcinoma IFN = interferon IL28B CC = host genotype associated with response to interferon-based therapy IL28B non-cc = host genotypes associated with lower response to interferon-based therapy NHANES = National Health and Nutrition Examination Survey NS3/4A = protease NS5A = NS5A nonstructural protein NS5B = HCV nonstructural protein polymerase OBV = ombitasvir pangenotypic = activity and/or efficacy against all major HCV genotypes PEG IFN = pegylated interferon PBV = pibrentasvir PRV = paritaprevir r = ritonavir PWID = people who inject drugs = ribavirin SMV = simeprevir VOX = voxilaprevir GZR = grazoprevir VEL = velpatasvir = sofosbuvir Hepatitis C Virus Infection Management: Curing Is Caring Arthur Y. Kim, MD Associate Professor of Medicine Harvard Medical School Boston, Massachusetts FORMATTED: 04/07/17 17