Disclosures. Outline Update on HCV management & treatment in Primary care. What role does the Family Practice Provider play in HCV care in 2014?

Transcription

1 Disclosures 2014 Update on HCV management & treatment in Primary care Annie Luetkemeyer HIV Division San Francisco General Hospital I have received research grant support to UCSF related to HCV from the following: Abbvie Bristol Myers Squibb (BMS) Gilead Pfizer Merck ACTG (NIH) What role does the Family Practice Provider play in HCV care in 2014? HCV screening & diagnosis of all HCV cases Staging of disease & appropriate management of cirrhosis Prioritizing HCV treatments with patients Where will HCV be treated? Hepatotology Infectious Disease/HIV Primary care Treatment shorter, less toxic, more effective Excellent platform to engage and support patients through treatment Outline Brief overview of HCV diagnosis, fibrosis evaluation, and cirrhosis management Whom should we treat How should we treat Addressing the treatment price tag HCV treatment and the primary care HIV provider 1

2 Our case 55 year old man, transferring to your clinic As part of your intake evaluation, you offer him HCV antibody testing Never had HCV testing and is surprised by your offer Why do I need to be tested, Doc? I never shot drugs and don t know anyone with HCV HCV treatment Cascade Screening Recommendations Yehia PLOS One 2014 Up to 50% of American with HCV unaware of their infection 45% with HCV report no known risk factor 75% of US HCV infections are in Baby Boomers born MMWR 2012: 61(4) CDC 2012 recommendations: test at least once: All baby-boomers (birth ) HIV+ IDU Hemodialysis Organ transplant or blood transfusion before 1992 People with exposure to HCV infected blood: health care workers and children born to HCV+ mothers HCV RNA testing to diagnose HCV If acute HCV suspected In advanced immunocompromise ( including HIV with low CD4 + ) 2

3 HCV Ab+: next steps HCV Genotype To his surprise, his HCV Antibody test comes back positive Confirm viremia with HCV RNA Screen and vaccinate if indicated for HAV & HBV Reduce alcohol consumption Reduce forward transmission risk Drug use avoid sharing needles or nasal straws Sexual counseling: MSM or HIV infected partner Household precautions: no shared toothbrushes or razor Genotypes 1-6 Can impact disease progression Genotype 3: associated with steatohepatitis Impacts selection and response to therapy Easiest to Cure: 2>3>4 1 (1b>1a) Genotype 1: most common in US (70%) Send genotype if considering HCV treatment Fibrosis Evaluation Key to assess for advanced fibrosis Impacts decision to screen for HCC and varices Informs risk of decompensation and mortality Affects HCV treatment response, choice & duration of therapy, and treatment initiation timeline If initial evaluation does not show fibrosis, suggest repeat imaging in 3-5 years Fibrosis assessment Serologic markers FREE! Platelets, INR, Albumin Serologic tests: APRI, Fib- 4, FibroSure/Test Physical Exam Palmar erythema, telangectasia, gynecomastia, splenomegaly Imaging: Ultrasound reasonable first step CT and MRI usually unnecessary- would avoid radiation and save as follow-on tests Transient Elastography: Fibroscan Excellent option when available -now FDA approved Biopsy: rarely necessary 3

4 When cirrhosis is present Hepatocellular carcinoma screening Imaging q 6 months U/S recommended initial screening, will need f/u with CT or MRI for some AFP no longer routinely recommended Variceal screening and prophylaxis EGD recommended to screen for varices Nonselective beta-blocker if large varices or small varices (particularly if higher risk of bleeding) Discuss risk of decompensation and current barriers to transplantation Back to the Case Physical exam: no physical stigmata cirrhosis Laboratory evaluation Plts 160, AST 45 APRI 0.7 HCV RNA 458,000 IU/ml HCV Genotype 1a HAV total Ab + Hep B S ab+, S ag-, Core ab- Ultrasound: Coarse liver, no clear indication of cirrhosis What should I do, Doc? Do I need to be treated? What are my chances of cure? Benefits of HCV treatment Reduction in fibrosis progression and decompensation 50% cirrhotics will have regression with HCV cure Still are at risk for HCC and should undergo continued screening Decrease in all cause mortality, including nonliver related May impact non-hepatic complications of HCV: Diabetes - Risk of fracture Neurocognitive impairment - Lymphoproliferative Increased risk of CV events disease Renal disease Back to the case: Treat now or wait? Evidence clearly supports treatment in all HCV-infected persons except those with limited life expectancy (less than 12 months) due to non liver related comorbid conditions 4

5 Priority for HCV therapy HIGHEST PRIORTY Advanced Fibrosis (F3) or compensated cirrhosis (F4) Cryoglobulinemia with end organ manifestations Renal complications of HCV infection HIGH PRIORITY Fibrosis (F2) HIV Coinfection HBV Coinfection Other liver disease (e.g. NASH) Debilitating Fatigue Diabetes Porphyria cutanea Tarda HIGH HCV Transmission Risk (includes MSM, IDU) AASLD Position on Treating Patient with HCV : Our Guidance is not intended to be used by payers to deny access to treatment. In no way does this position contradict the evidence evaluated to produce the Guidance and the recommendation made in the Guidance to treat the sickest first, but recognizes need to treat all. HCV Treatment Cost Sofosbuvir: pill, $84,000/12 weeks of therapy Even though many analyses project HCV cure cost effective in the long run, initial costs overwhelming Many plans current restrict access to those with advance fibrosis HCV Arsenal & Principals of therapy 5

6 The HCV Future is here! Assaleh Liver Int 2013: Most HCV patients now curable in 12 weeks or less Majority can receive all-oral therapy without the side effects of injectable interferon Hard to treat patients including cirrhotics, decompensated liver disease and those with prior treatment failure can now be cured Assaleh Liver Int 2013 Protease inhibitors: -PREVIRs eg. simeprevir NS5B Polymerase inhibitors: -BUVIRs : Nucleoside inhibitors: ex. Sofosbuvir Non- Nucleoside inhibitors (NNI): ex. Dasabuvir 6

7 Current DAA combinations NS5b Nucleotide based therapy NS5b Nuke Backbone One drug from 2 nd class SOFOSBUVIR NS5a Protease inhibitor Ribavirin NS5A Inhibitors: -ASVIRs e.g Daclatasvir Ledipasvir Ombitasvir Triple therapy without a NS5b Nuke NS5a NS5b Non-Nuke Protease inhibitor Other approaches Protease inhibitor NS5a Current DAA combinations NS5b Nucleotide based therapy I am confused already NS5b Nuke Backbone One drug from 2 nd class SOFOSBUVIR NS5a Protease inhibitor Triple therapy without a NS5b Nuke Other approaches Ribavirin NS5a NS5b Non-Nuke Protease inhibitor Protease inhibitor NS5a Free downloadable app great patient information 7

8 Genotype 1: Current Standard of Care Sofosbuvir: NS5b nucleotide inhibitor, plus Ledipasvir: NS5a inhibitor Co-formulated as Harvoni : one pill/daily Side Effects: headache, fatigue, nausea Cannot be given at creatinine clearance < 30 ml/min Drug interactions: If taking PPI, must dose at same time, not prior to Harvoni Use lowest dose of statin Ok to coadminister with methadone Avoid with HIV protease inhibitor + tenofovir Sofosbuvir/Ledipasvir Sulkowski IAS 2014 Sofosbuvir/Ledipasvir Sofosbuvir/Ledipasvir Sulkowski IAS 2014 Sulkowski IAS

9 SOF/LED in Cirrhosis Sofosbuvir/Ledispasvir Indications ION-1Treatment Naïve Cirrhotics: 12 weeks 94% cure w/o RBV No benefit to 24 weeks No clear benefit of RBV ION-2Treatment Experienced Cirrhotics 86% SVR ( 19/22) with 12 weeks 100% SVR (22/22) with 24 weeks No clear benefit of RBV Genotype 1 Patient Cirrhotic? Duration Treatment naïve, HCV RNA < 6 million Treatment Naïve, HCV> 6 million Treatment Naïve Non-cirrhotic Non-cirrhotic Cirrhotic 8 weeks 12 weeks Treatment Experienced Non-cirrhotic Treatment Experienced Cirrhotic 24 weeks Sulkowski IAS 2014, IDSA 2014 SOF/LED in Decompensated Cirrhotics SOLAR: 12 weeks SOF/LED/RBV in CPT-B & C SOF/LED to retreat Cirrhotics SIRIUS : cirrhotics with prior PEG/RBV and PEG/RBV/PI failure (no sosfosbuvir or NS5a failures) Flamm AASLD #239 Bouliere AASLD 2014 Abstract # LB-6 9

10 Genotype 2: Sofosbuvir/Ribavirin Cirrhotic? Duration Non Genotype 1 Treatment naïve Non-cirrhotic & Cirrhotic 12 weeks Treatment Experienced Non-Cirrhotic 12 weeks Treatment-Experienced Cirrhotic 16 weeks Ledipasvir not active in Genotype 2 Genotype 3: Sofosbuvir/Ribavirin Treatment naïve Cirrhotic? Non-cirrhotic & Cirrhotic Duration 24 weeks GT3: Limitations of SOF/RBV Treatment Experienced Non-Cirrhotic 24 weeks Treatment-Experienced Cirrhotic 24 weeks CONSIDER SOF/PEG/RBV Better treatment options coming for Genotype 3 Pan-genotype NS5a (GS-5816) Merck Pangenotypic Combination (PI+NS5a) Sofosbuvir + Ribavirin Sofosbuvir + PEG/RBV (treatment naïve) Zeuzem 2014 NEJM VALENCE, Lawitz 2014 NEJM LONESTAR 10

11 In the DAA era, does HIV matter? Yes & No YES: HIV-HCV coinfection negatively impacts HCV disease progression & patient outcomes Elevated risk of fibrosis progression Increased liver related morbidity and all cause mortality Increased risk of nonhepatic complications Increased hepatoxicity with antiretroviral therapy In the DAA era, does HIV matter? NO: DAA-based therapy equally effective in HIV-infected and uninfected ION-1: HIV uninfected patients, 12 weeks sofosbuvir/ledipasvir ION-4: HIV-infected patients, 12 weeks sofosbuvir/ledipasvir 98% Kirk AIM 2013;158(9):658 Sulkowski IAS 2014, Osinusi AASLD 2014 #84 Monitoring on and after treatment Reinfection: Achilles heel of Cure HCV Genotype Fibrosis Staging Before therapy x x 4 weeks Every 4 weeks End of therapy 12 weeks after therapy completed HCV RNA x x x x CBC* x x x LFTS/Renal x x x *More Frequent CBC monitoring if Ribavirin-containing regimen Cirrhotic patients need continued HCC surveillance after cure Hill AASLD 2014 Abstract 44 11

12 Conclusions Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning. Winston Churchill We finally have to tools to cure HCV in the majority of HCV patients This is the beginning: Future regimens will be even shorter (and hopefully cheaper) and address remaining gaps (such as treatment in ESRD and Genotype 3) While we need to prioritize treatment of those with most advanced disease, all benefit from HCV cure In order realize the tremendous potential of HCV DAAs, we will need large cadre of HCV treaters, including primary care based Thank you!! Resources References AASLD/IDSA HCV Guidelines: University of Liverpool HCV Drug interaction database: Patient education resource HCV Advocate: 1. Yehia, B.R., et al., The treatment cascade for chronic hepatitis C virus infection in the United States: a systematic review and meta-analysis. PLoS One, (7): p. e Smith, B.D., et al., Recommendations for the identification of chronic hepatitis C virus infection among persons born during MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control, (RR-4): p Asselah, T. and P. Marcellin, Interferon free therapy with direct acting antivirals for HCV. Liver international : official journal of the International Association for the Study of the Liver, Suppl 1: p Ditah, I., et al., The changing epidemiology of hepatitis C virus infection in the United States: National Health and Nutrition Examination Survey 2001 through Journal of Hepatology, (4): p

13 References 1. Yehia, B.R., et al., The treatment cascade for chronic hepatitis C virus infection in the United States: a systematic review and meta-analysis. PLoS One, (7): p. e Smith, B.D., et al., Recommendations for the identification of chronic hepatitis C virus infection among persons born during MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control, (RR-4): p Asselah, T. and P. Marcellin, Interferon free therapy with direct acting antivirals for HCV. Liver international : official journal of the International Association for the Study of the Liver, Suppl 1: p Ditah, I., et al., The changing epidemiology of hepatitis C virus infection in the United States: National Health and Nutrition Examination Survey 2001 through Journal of Hepatology, (4): p