Advances in the Management of Hepatitis C. Managing Infections in the 21 st Century and Beyond November 8, 2014 Leslie Cockerham, MD

Transcription

1 Advances in the Management of Hepatitis C Managing Infections in the 21 st Century and Beyond November 8, 2014 Leslie Cockerham, MD

2 Disclosures None

3 Hepatitis C

4 Outline Brief overview of HCV epidemiology, diagnosis, goals of treatment Who to prioritize for treatment Fibrosis evaluation HCV Treatment Genotype 1 HIV/HCV co-infection and drug-drug interactions Genotypes 2 and 3

5 Impact of Chronic HCV on Mortality Ly, K, et al. Annals of Internal Medicine. 2012

6 Epidemiology Estimated prevalence of HCV RNA-positive persons in the US is 3.2 million, likely higher Only 55% of persons ever infected with HCV report an exposure risk. Armstrong, G, et al. Ann Int Med CDC. MMWR 2012;61(No. RR-4).

7 HCV Treatment Cascade Yehia BR, et al. The Treatment Cascade for Chronic Hepatitis C Virus Infection in the United States: A Systematic Review and Meta-Analysis. PLoS ONE 2014

8 Bottom Line: Testing - What should you do? Test: Persons born during without a previous test Current/previous IVDU Others with risk exposure who haven t been tested HIV+ Unexplained liver disease or chronic hepatitis

9 Next steps If positive, check a Hep C viral load to confirm acute/chronic HCV No need to routinely check HCV viral load if known to have chronic HCV Screen and vaccinate if needed for HAV & HBV Reduce alcohol consumption Counsel on transmission risk Drug use: avoid sharing needles or nasal straws Sexual counseling: MSM or HIV infected partner Household precautions: no shared toothbrushes or razor Check a HCV genotype when considering/referring for treatment

10 Distributions of HCV genotypes United States: ~75% Genotype 1

11 Case 1 65 y/o M c well-controlled HIV, but multiple other co-morbidities including likely ILD, BPH, anal dysplasia, and compensated hepatitis C cirrhosis. His main complaint is overwhelming fatigue He even says some days doc, I think about just throwing in the towel I bring up hepatitis C treatment He says, What? Why would I do that?

12 Goals of Treatment Viral Eradication Achieve Sustained Virologic Response (SVR) undetectable HCV RNA weeks after therapy Durable response SVR means cure in 99% of patients 1,2 Prevent Disease Progression Histologic regression Improvement in fibrosis, 49% resolution of cirrhosis 3 Reduces risk of HCC, liver transplant & liver-related mortality 4,5, and all-cause mortality Improved Quality of Life/Decreased symptoms 6 1 Swain MG, et al. Gastroenterology Manns MP, et al. J Viral Hepat Poynard T, et al. Gastroenterology Morgan RL, Ann Intern Med van der Meer AJ, et al. JAMA Younossi ZM, et al. Clin Gastroenterol Hepatol

13 Who to prioritize for treatment? Advanced fibrosis (Metavir F3) or compensated cirrhosis (Metavir F4) HIV+ and/or other liver disease (HBV, NASH) Symptoms related to HCV Renal disease Cryoglobulinemia Debilitating fatigue Individuals with HCV negative partner HCV+ women desiring pregnancy Genotype 2

14 Fibrosis assessment Laboratory markers Platelets, INR, Albumin Serologic tests: APRI, FIB-4, Fibrosure Best at distinguishing adv fibrosis/cirrhosis (Stages F3-F4) from non-cirrhosis Physical Exam Palmar erythema, telangectasia, gynecomastia, splenomegaly Imaging: U/S reasonable first step CT and MRI usually unnecessary- would avoid radiation and save as follow-up tests Elastography: Fibroscan Excellent option when available: now FDA approved Biopsy: rarely necessary

15 Hepatitis C Treatment

16 Liang, T and Ghany, M. NEJM 2013;368:

17 The Toolbox Categories of HCV Direct Acting Agents (DAAs): NS3/4A Protease inhibitors: e.g. Simeprevir 2 nd generations ABT-450/r, Asunaprevir NS5b Polymerase inhibitors Nucleoside inhibitors: eg. Sofosbuvir Non-Nucleoside inhibitors: Dasabuvir, GS-9669 NS5A Inhibitors: e.g ledipasvir, daclatasvir, ombitasvir Fixed dose combinations

18 Treatment approaches Three treatment approaches emerging: 1) Nucleoside containing NS5b additional drugs (NNI, NS5a, PI) 2) Nucleoside sparing Triple therapy (NNI, NS5a, PI) 3) Nucleoside sparing dual therapy: 2 nd generation HCV Protease inhibitors + 2 nd drug (NS5a)

19 Nucleos(t)ide analogue-based strategies NI NS5B NNI NS5B PI NS5A Gilead Sofosbuvir GS-9669 Vedroprevir, GS-9857 Roche Mericitabine Setrobuvir Danoprevir/r Ledipasvir, GS Nucleoside-free triple combo strategies Abbvie Dasabuvir Paritaprevir/r Ombitasvir BMS BMS Daclatasvir BI/Presidio Faldaprevir PPI-668 Janssen/GSK GSK Simeprevir GSK Nucleoside-free, second-generation double combo strategies Merck MK-3682 Grazoprevir Elbasvir Achillion Sovaprevir, ACH-2684 ACH-3102 Adapted from Pawlotsky, JM, Gastroenterology 2014; 146(5):

20 Case 2 67 y/o M c HIV (CD4 587, VL<40, on epzicom/dolutegravir) Previously attempted therapy with Peg/Riba in 2006 multiple complications PMHx: HIV, CAD mild CRI , a fib on digoxin, apixaban Geno 1a, tx-naive, no clinical evidence of cirrhosis or history of decompensation Plts 154, AST/ALT 82/84, Alb 4.2, INR 1.1 U/S: unremarkable liver without definite evidence of contour nodularity

21 Geno 1: Current Tx options Sofosbuvir + PEG/Ribavirin x12 weeks: ~80-90% cure Generally avoiding now due to more tolerable options Sofosbuvir + Ribavirin x24 weeks: ~75% cure, less in cirrhotics Not recommending due to decreased efficacy Sofosbuvir + Simeprevir x12 weeks: ~90-95% cure rate Results based on a smaller study, but in more difficult to treat populations Sofosbuvir + Ledipasvir x12 weeks: >95% cure

22 Sofosbuvir + Simeprevir Slide courtesy of Annie Luetkemeyer With RBV No RBV With RBV No RBV 100% 79% 93% 93% 96% 93% 93% 93% 90% 94% 12 weeks of SIM/SOF 24 weeks of SIM/SOF Overall Conclusions: Cohort 1: non-responders, F0-F2 No clear benefit to 24 weeks over 12 weeks Cohort 2: NRs, or naïve + F3-F4 No clear benefit to addition of RBV Advanced fibrosis (F3-4) did just as well, with high SVR (93-100%) SEs: HA, nausea, fatigue, 20% rash COSMOS, Lawitz Lancet 2014

23 Sofosbuvir + Ledipasvir (Harvoni) 97% overall SVR As short as 8 weeks for txnaïve, noncirrhotics (if VL<6 million per package insert)

24 Sofosbuvir: NS5b inhibitor Pan-Genotype activity Metabolism: Not a cytochrome P450 substrate/inducer/inhibitor. Substrate of P-gp. No food requirement, H2/PPI s OK Renal Impairment: Avoid if CrCl <30 or on HD Hepatic impairment: no dosage adjustments req d, but no data in decompensated cirrhosis Side effects: minimal nausea, HA Opiate replacement: OK to co-administer

25 Simeprevir: PI Activity in GT 1, 2, 4, 5, 6: approved for GT1 in US Metabolism: CYP P450 substrate. Inhibits P-gp and OATP Take with food, H2/PPI s OK Renal Impairment: Avoid if CrCl <30 or on HD Hepatic impairment: Ok in CTP A, but levels increased CTP B, C - not recommended Side effects: photosensitivity, skin rash (may be severe), elevated bilirubin Opiate replacement: OK to co-administer

26 Ledipasvir: NS5A inhibitor Activity in GT 1, 3, 4: approved for GT1 only in US, Metabolism: substrate/inhibitor of P-gp Renal Impairment: Avoid if CrCl <30 or on HD Hepatic impairment: No dose adjustments required Side effects: Nausea, HA Opiate replacement: OK to co-administer

27 What about drug interactions with ART? HIV DRUG CLASS MEDICATION SIMEPREVIR SOFOSBUVIR LEDIPASVIR Protease Inhibitors NNRTIs Integrase Inhibitors Atazanavir/r Darunavir/r Rilpvirine Nevirapine Efavirenz Etravirine Dolutegravir Raltegravir Elvitegravir/cobi NOT COMPATIBLE NOT COMPATIBLE (decreased SIM) COMPATIBLE NOT COMPATIBLE COMPATIBLE COMPATIBLE COMPATIBLE CCR5 Inhibitor Maraviroc COMPATIBLE COMPATIBLE MAY INCREASE TDF LEVELS COMPATIBLE NO DATA COMPATIBLE COMPATIBLE COMPATIBLE MAY INCREASE LDV LEVELS NRTIs ABC, TDF, 3TC/FTC COMPATIBLE COMPATIBLE COMPATIBLE

28 HIV/HCV Co-Infection Most compatible ART for HCV treatment: Truvada, Epzicom, Raltegravir, Dolutegravir Rilpivirine If you need to use a PI: ATV or DRV Although most studies have been in HCV monoinfected, co-infection studies have shown good results.

29 Back to our case Geno 1a, tx-naïve, no e/o advance fibrosis/cirrhosis, on epzicom, r/drv Options: Sofosbuvir + PEG/Ribavirin: past complications with IFN and ribavirin, therefore avoiding Sofosbuvir + Simeprevir: would require a change in ARVs, recommend integrase inhibitor Sofosbuvir + Ledipasvir (Harvoni) Plan: Pursue Harvoni given decreased potential for DDIs

30 A Suggested Approach to Genotype 1 patients Cirrhotic or extrahepatic manifestations: PRIORITIZE TREATMENT HCV Genotype 1 Not cirrhotic: Establish timing for treatment Simprevir+ Sofosbuvir (+/- RBV)* x 12 weeks Sofosbuvir/Ledipas vir x 12 weeks Simprevir+ Sofosbuvir x 12 weeks Sofosbuvir/Ledi pasvir x 8-12 weeks 95% cure > 95% cure 95% cure > 95% cure *consider RBV in prior nonresponders or cirrhotics Slide adapted from Annie Luetkemeyer

31 A Suggested Approach to Genotype 2 & 3 HCV Genotype Slide courtesy of Annie Luetkemeyer 2 GT2: SIM & LED not options Not cirrhotic, naïve/relapsers Cirrhotic or prior PEG non responders 12 weeks Sofosbuvir +RBV >90% cure 16 weeks Sofosbuvir +RBV 78% cure Not IFN eligible IFN eligible 12 weeks Sofosbuvir +PEG/RBV >90% Cure

32 A Suggested Approach to Genotype 2 & 3 HCV Genotype Slide courtesy of Annie Luetkemeyer 2 GT2: SIM & LED not options 3 GT3: SIM & LED not options Not cirrhotic, naïve/relapsers Cirrhotic or prior PEG non responders Treatment naive Treatment experienced 12 weeks Sofosbuvir +RBV >90% cure 16 weeks Sofosbuvir +RBV 78% cure Not IFN eligible IFN eligible 12 weeks Sofosbuvir +PEG/RBV >90% Cure 24 weeks Sofosbuvir +RBV -94% Cure: non cirrhotic -93% cure: cirrhotic IFN eligible 12 weeks Sofosbuvir +PEG/RBV >95% cure: naive 83% cure: cirrhotics Not IFN eligible 24 weeks SOF+RBV -87% Cure: non cirrhotic -60% cure: cirrhotic

33 Non-genotype 1 Summary: Simeprevir and Ledipasvir are not options for genoptype 2 and 3. We have all oral, effective, short therapies for genotype 2 available now Genotype 3 infections require longer durations of sofosbuvir + ribavirin Not great options for GT3, Tx-experienced, cirrhotics who are IFN-ineligible. Pan-genotypic options coming though.

34 Looking forward Abbvie 3D therapy: Co-formulation of paritaprevir (protease inhibitor), ritonavir 100mg and ombitasvir (NS5a inhbitor) daily Dasabuvir (non-nucleoside NS5b inhibitor) twice daily Submitted FDA application 4/2014, expected approval end of 2014 Daclatasvir: Potent once-daily, pan-genotypic NS5A inhibitor Submitted NDA for asunaprevir/daclatasvir April 2014, asunaprevir application withdrawn, approval for daclatasvir pending, likely Q New data on daclatasvir regimens to be presented at AASLD Nov 2014 Merck Grazoprevir/Elbasvir (MK-5172/MK-8742 SVR 24 results of C-WORTHy Study in GT1 to be presented Also presenting interim data of C-SWIFT, ultrashort duration

35 Abbvie Pearl III HIV-, treatment naïve, genotype 1b, non cirrhotic 12 weeks of 3 DAA +/- RBV ABT 450/r (PI) ABT 267 (NS5a) ABT 333 (NNI NS5b) Side effects Headache, fatigue, pruritus, nausea, anemia (RBV arm) 38 patients on stable methadone or buprenorphine regimen: AbbVie Triple therapy + RBV - 97% cure rate (Lalezari #662LB) Ferenci CROI 2014, #29LB

36 Turquoise-1: Triple therapy in HIV/HCV Co-infected Triple therapy: Co-formulation of ABT mg (protease inhibitor), ritonavir 100mg and ombitasvir (NS5a inhbitor) 25mg daily Dasabuvir (non-nucleoside NS5b inhibitor) 250mg twice daily Sulkowski, M, et al. IAS 2014

37 Sofosbuvir + Daclatasvir Daclatasvir: Potent, once daily, pan-genotypic Anticipated approval 11/14 Daclatasvir+ sofosbuvir 95% cure for treatment naïve, treatment experienced and prior IFN/RBV and HCV Protease inhibitor failures Dose adjustments need with atazanavir and efavirenz Sulkowski, et al. NEJM 2014

38 Summary Diagnose all chronic HCV infection Ensure all HCV Ab+ patients have an HCV RNA Identify those with with advanced fibrosis/cirrhosis using labs/imaging and prioritize those individuals for treatment Establish a timeline for treatment Can treat patients now with efficacious interferon sparing regimens, cirrhotics shouldn t wait By early 2015, should have several IFN and RBV-free options

39 Summary - treatment Both Simeprevir/Sofosbuvir and Sofosbuvir/Ledipasvir are good IFN-sparing options for GT1 with >90% cure rates Can treat GT2 and some GT3 with Sofosbuvir + RBV GT3 with cirrhosis unable to do IFN will have to wait for pan-genotypic agents

40 Hepatitis C Resources

41 Acknowledgements Annie Luetkemeyer, MD Val Robb, RN

42

43 Additional slides

44 APRI and FIB-4 Scoring Holmberg, et al. CID 2013