Disclosures Overview of Hepatitis B & C: Current Concepts and Changing paradigms

Transcription

1 Disclosures Overview of Hepatitis B & C: Current Concepts and Changing paradigms Annie Luetkemeyer Division of HIV, ID & Global Medicine UCSF I have received research grant support to UCSF related to HCV from the following: AbbVie Gilead Merck Proteus ACTG (NIH) Overview HCV Selection of patients to treat Changing treatment landscape Life after HCV cure HCC screening HBV New HBV vaccine HBV reactivation New HBV agents Glossary DAA: Directly Acting Agents (i.e. oral HCV drugs) Fibrosis Staging: Metavir F0-F4 HCV Genotype: strain of HCV (1-6), not a drug resistance test SVR: Sustained virologic response: undetectable HCV RNA weeks after stopping treating (SVR12= cure in vast majority) APRI: AST:Platelet ratio, provides estimate of fibrosis FIB-4: Fibrosis estimate that includes age, AST,ALT, Plts 1

2 Your patient 30 yo man, HCV Ab+, establishing care with you PMH: depression Meds: paroxetine, Methadone maintenance x 3 years with intermittent IDU and smoked methamphetamine Social history Prior IDU heroin Alcohol- few beers/day, binge drinks on occasion Sexually active with men (MSM), condoms use inconsistent Reported cases/100,000 population yrs yrs yrs yrs yrs 60+ yrs Year New HCV infections tripled over 5 years, reaching a 15 year high Source: CDC, National Notifiable Diseases Surveillance System (NNDSS) HCV screening guidelines CDC: Baby Boomers and those with risk factors or exposure Resurgence of HCV epidemic in young patients. May be cost effective to offer universal screening CDC HCV Screening guidelines, Barocas CID 2018 HCV Ab+: next steps Confirm viremia with HCV RNA Screen and vaccinate if lack immunity to 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 Fibrosis Assessment : serologic markers (ex: APRI, Fibrotest) and/or imaging Impacts decision to screen for HCC and varices Affects treatment response, choice of therapy, and treatment initiation timeline HCV Genotype: 1-6, determines choice of therapy (for now) 2

3 Case #1 continued HCV RNA: 3 million IU/ml Genotype 1a AST 35/ALT 33 Alb 3.9. INR 1.1 Platelets 210 HIV Ab negative APRI= 0.4 (suggests non-cirrhotic) HAV Immune Hep B S Ab neg, S Ag neg, Core Ab Positive Ultrasound: no evidence of cirrhosis APRI= (AST/AST ULN)/Plts ARS Question Would you offer HCV treatment to this non-cirrhotic patient, with ongoing alcohol use & intermittent substance use? 1) No, I would not treat until evidence of advanced fibrosis or frank cirrhosis as no benefit 2) No, I am worried about reinfection via MSM route 3) Yes, I would pursue treatment now if he is motivated to be treated 4) Yes, but only after he demonstrates 6 months of sobriety from speed and alcohol 5) No, because I can t get access to HCV medications for my patients Whom to treat 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. What about alcohol? Alcohol and HCV are negatively synergistic Data support successful interferon-based HCV treatment in active drinkers Benefit of HCV cure despite continued alcohol in most patients (Russell 2012, Costenin 2013) Successful HCV cure can be a springboard for other positive health changes. Take-home: Counsel regarding alcohol reduction but don t withhold treatment due to alcohol use alone 3

4 Treating Active Injection Drug Users HCV cases averted ACLD- advanced chronic liver dz New HCV cases Liver decompensation Liver transplant Backus AASLD 2017 Ioannou AASLD 2 Cirrhosis Liver cancer Liver related death 96% cure rate in HCV+ methadone clinic attendees, many with active ongoing substance use Jiang AASLD 2017, Dore AIM 2016 Reinfection: IDU & MSM Reinfection: IDU & MSM OASIS Methadone clinic, PILOT STUDY (n=35) ü Substantial ontreatment substance use ü 97% SVR in those who completed ü NO reinfections at one year. Sylvestre AASLD 2017 Dore AASLD 2017 OASIS Methadone clinic, PILOT STUDY (n=35) ü Substantial ontreatement substance use ü 97% SVR in those who completed ü NO reinfections at one year. Sylvestre AASLD 2017 Dore AASLD 2017 TAKE HOME: Reinfections happen but are not a reason to withhold treatment If you aren t seeing reinfections, you aren t treating the high risk populations we have to reach Chaillon AASLD 2017 Chaillon AASLD

5 California Medi-Cal Guidelines Fibrosis stage 2 or greater Many options: Fibroscan, Fibrosure, APRI/FIB-4, Fibrometer, biopsy) Or, any of the following regardless of extent of fibrosis : HIV Coinfection Diabetes (Type 2) Active injection drug use HCC with life expectancy > 1 yr HBV Coinfection pre/post transplant Other liver disease ( e.g. NASH) MSM with high risk sexual practices ESRD on hemodialysis Women of childbearing age who wish to get pregnant Porphyria cutana tarda Debilitating fatigue Cryoglobulinemia with vasculitis or renal complications HCV Arsenal & Principals of therapy Treatment-Naive Genotype 1a Without Cirrhosis Recommended and alternative regimens listed by evidence level and alphabetically for: Treatment-Naive Genotype 1a Patients Without Cirrhosis RECOMMENDED DURATION RATING Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for patients without baseline NS5A RASs a for elbasvir 12 weeks I, A Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 b 8 weeks I, A mg) Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) 12 weeks I, A Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for patients who are non-black, HIV-uninfected, and whose HCV RNA level is <6 million IU/mL Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) 8 weeks I, B 12 weeks I, A a Includes genotype 1a resistance-associated substitutions at amino acid positions 28, 30, 31, or 93 known to confer antiviral resistance. b This is a 3-tablet coformulation. Please refer to the prescribing information. 5

6 Glecaprevir/Pibrentasvir (G/P) Mavyret Pangenotypic (GT 1-6) 3 pills/once daily 8 weeks for treatment naïve, non-cirrhotic (including HIV), 12 weeks cirrhotics Can be given with CrCl < 30 and in ESRD No need for HCV resistance testing or for ribavirin Activity against some HCV resistant strains Do not use in decompensated liver disease(child-pugh Class B or C) Least expensive! Wholesale acquisition cost (WAC) of 26,400 for 8 weeks. Sofosbuvir/Velpatasvir Epclusa Approved for genotypes pill once a day x 12 weeks for most cases Best for CrCl > 30 (some data to support in renal failure) Generally do not need HCV resistance testing or Ribavirin Can be used in decompensated hepatic disease Side effects: headache, nausea, fatigue All current DAA s generally well tolerated Wholesale price: $74,760 Common Drug Interactions Check drug interactions University of Liverpool HCV drug interactions Statins Acid blockers Avoid altogether with SOF/VEL if possible If necessary, do not exceed 20 mg omeprazole, give 4 hours after SOF/VEL Unlikely to be clinically significant interaction with G/P Compatible with many HIV regimens as well as methadone and buprenorphine Flamm S, et al. World Congress of Gastroenterology at ACG 2017; 2017; Orlando, FL. P1435. #3:SOF/VEL/VOX Vosevi 12 weeks, one pill daily For treatment failures (including NS5a failures)- high cure rate Cannot be used in decompensated liver disease 6

7 High cures rates attainable in previously special populations HIV+ Renal failure including HD Decompensated liver disease Post transplant Active alcohol and substance use Back to our patient Insurance approves G/P x 8 weeks You work with his methadone counselor to coadminister his HCV treatment with methadone Your pharmacist checks in with him every 2 weeks regarding adherence Week 4 lab check: HCV RNA at week 4 is < limit of detection, LFTs have normalized 12 weeks after completing treatment, HCV RNA is undetectable -> Cured! After the cure HCV Ab may remain positive for life Future HCV screening will need to be HCV RNA Counsel about Reinfection Drug use: shared needles, injecting equipment ( works ), straws used for snorting Sexual contact through men having sex with men (MSM): risk highest in HIV+ men but occurs in HIV- If cirrhotic, continue to screen for hepatocellular carcinoma with q 6-12 month imaging EVEN IF markers of cirrhosis regress. HCC Surveillance: U/S +/- AFP every 6 months Ultrasound reasonable screening- do not need to start with CT/MRI Rising incidence over past 20 years Estimated 39,230 cases and 27,170 deaths in 2016 Aging HCV+ population, increasing NAFLD Incidence expected to rise until 2030 High risk groups: Cirrhosis (any cause) Chronic HBV in certain groups. Observational studies in cirrhosis: screening associated with improved survival, detection of early-stage HCC HeimbachJ, AASLD Practice Guidelines,

8 HCC Surveillance: HCV 3. Should we screen in HCV+ pts with F3 fibrosis? Yes! Essential to adequately stage fibrosis prior to HCV tx Nearly 50% of pts with F3 fibrosis on pre-treatment Fibroscan ( 9.5 kpa) will have post-svr Fibroscan <9.5 kpa Fibroscan and other non-invasive fibrosis surrogates have not been validated in post-svr pts Limited evidence comparing post-svr biopsy with Fibroscan shows you will underestimate fibrosis stage if you rely on post- SVR results 5 UCSF pts with F3 fibrosis on post-svr biopsy: 3 (60%) had post-svr Fibroscan <9.5; 1 of these developed HCC post-svr (Price et al, unpublished data) DON T stop HCC screening on basis of improvement in fibrosis if initially F3 HCC Surveillance: Chronic HBV Surveillance recommended HBV Population Group Threshold incidence for efficacy of surveillance Incidence of HCC Cirrhosis %/yr 3-8%/yr Family h/o HCC 0.2%/yr Incidence higher than without family history Asian male >40 years 0.2%/yr %/yr Asian female >50 years 0.2%/yr %/yr African/North American Blacks 0.2%/yr Occurs at earlier age Benefit uncertain Males <40, Females <50 0.2%/yr <0.2%/yr BruixJ, AASLD Practice Guidelines, HCC Surveillance: Chronic HBV 1. How should we approach HCC screening in patients with HIV/HBV? What about Caucasian pts? Surveillance recommended HBV Population Group Cirrhosis Family h/o HCC Asian male >40 years Asian female >50 years African/North American Blacks Benefit uncertain Males <40, Females <50 BruixJ, AASLD Practice Guidelines, HCC Surveillance: Chronic HBV 1. How should we approach HCC screening in patients with HIV/HBV? What about Caucasian pts? Surveillance recommended HBV Population Group Cirrhosis Family h/o HCC Asian male >40 years Asian female >50 years African/North American Blacks Benefit uncertain Males <40, Females <50 If no cirrhosis and chronic inactive HBV (long-term normal ALT, low HBV DNA) the incidence of HCC is probably too low to make surveillance worthwhile However additional risk factors have to be taken into account including older age, persistence of viral replication, coinfection with HCV or HIV, or presence of other liver disease Caucasian pts with active HBV are likely at risk for HCC and should be screened BruixJ, AASLD Practice Guidelines,

9 HCC Surveillance: Chronic HBV 1. How should we approach HCC screening in patients with HIV/HBV? What about Caucasian pts? Surveillance recommended HBV Population Group Cirrhosis Family h/o HCC Asian male >40 years Asian female >50 years African/North American Blacks Benefit uncertain Males <40, Females <50 If no cirrhosis and chronic inactive HBV (long-term normal ALT, low HBV DNA) the incidence of HCC is probably too low to make surveillance worthwhile However additional risk factors have to be taken into account including older age, persistence of viral replication, coinfection with HCV or HIV, or presence of other liver disease Caucasian pts with active HBV are likely at risk for HCC and should be screened BruixJ, AASLD Practice Guidelines, New HBV vaccine HEPLISAV: HBV vaccine with an adjuvant to improve response, given at week 0 & 4 Medical Letter, Issue 1539, 1/18 Who needs this? FDA Approved for 18 yrs old More injection site reactions Wholesale price: vs for Standard HBV vaccines May be good option for older and/or more immunosuppressed patients Those in a hurry or at risk for non-completion: 2 doses, completed in a month (compared to standard 3 dose, 6 month series)? Use in prior non-responders? HBV reactivation 9

10 HBV Viral Life Cycle HBsAg pos Slide 37 Slide 38 Viral Life Cycle- latent or recovered HBV Immune system considers this recovered BUT cccdna is template for viral replication Nucleus Entry ER Repair Recycling Budding cccdna Plus strand synthesis Minus strand synthesis S, C, P,e synthesis Reverse transcriptase P protein pregenomic RNA Nucleus ER cccdna HBsAg neg Anti-HBs Anti-HBc Transcription Host RNA pol Translation RNA packaging (encapsidation) Risk of HBV reactivation Notably: High dose steroids, rituximab, TNF-alpha blockers, chemotherapy Bessone WJG 2016 HBV reactivation with DAA FDA warning about risk of HBV reactivation during HCV treatment : 24 cases none on HBV active treatment before HCV treatment Transaminitis on therapy weeks 4-8 of HCV treatment 2 died, 1 transplant, 3 decompensated Transaminitis mistakenly attributed to DAA initially (8) Baseline HBV serologies: HBV DNA detectable: 7 HBsAg(+), DNA (-): 4 HBsAg(-), DNA (-): 3 HBV serologies unknown:

11 HBV reactivation Mechanism with HCV treatment-? Viral interference HCV can have known suppressive effect on HBV in dually infected patients Check HBV serologies before HCV treatment or immunosuppressive therapy(hbsab, sag, core Ab) Consider adding HBV Core Ab (+) to the problem list so not overlooked by other providers Entecavir or Tenofovir preferred over lamivudine for those at higher risk CJ Chu Journal of Gastroenterology and Hepatology 23 (2008) DiBisceglie Hepatology 2015 HBV: What is on the horizon? Virus life cycle (antivirals) Host immune response (immunomodulators) Mechanism Entry inhibitors Polymerase inhibitors Myrcludex Drug TAF, CMX-157, AGX-1009, Besifovir, Lagociclovir Capsid blockers GLS-4, NVR Release inhibitors cccdna cleavage (gene editing) Transcription inhibitors (RNA interference) Innate immunity Adaptive immunity Rep-2139, Rep-2165 CRISPR/Cas9, TALENS, ZFNs ARC-520, ARC-521 GS-9620, Birinapant Therapeutic vaccines (GS- 4774), Engineered T cells Soriano V, Expert Opin Investig Drugs,

12 Resources AASLD HBV treatment guidelines: tisb2009.pdf EASL HBV management guidelines: AASLD/IDSA HCV Guidelines: University of Liverpool HCV Drug interaction database: Patient education resources Than Thank you! HB core Ab HBsAb HBsAg Interpretation Action NEG POS NEG Vaccinated, Immune No Action NEG NEG NEG Not HBV infected Vaccinate for HBV Backup slides POS NEG POS Active HBV infection Check HBV DNA Treat HBV according to guidelines (US) Consider treatment even if low/undetectable HBV DNA (EASL) Monitor transaminases (q 4 weeks) POS NEG NEG Possible occult infection Check DNA Consider treatment if DNA+ (EASL) Vaccinate (if DNA negative) POS POS NEG Immune recovery Monitor transaminases on therapy Consider HBV reactivation if 12

13 HBV infection: Dynamic & Lifelong Latent HBV (S Ag negative, core Ab+) HBV infection: Dynamic & Lifelong Latent HBV (S Ag negative, core Ab+) HIGH DNA Normal AST/ALT S Ag+ HBV infection: Dynamic & Lifelong Latent HBV (S Ag negative, core Ab+) HBV infection: Dynamic & Lifelong Latent HBV (S Ag negative, core Ab+) HIGH DNA Elevated AST/ALT S Ag + Low/no DNA Normal AST/ALT S Ag+ 13

14 HBV infection: Dynamic & Lifelong Indications for HBV treatment Latent HBV (S Ag negative, core Ab+) DNA (-) Normal AST/ALT Treat Compensated cirrhotics HBV DNA threshold HBV DNA > 2000 IU Decompensated cirrhotics Immune Active (E Ag Positive or Negative) Any detectable DNA HBV DNA > 2000 IU, AST > 2x ULN (DNA threshold varies by guideline) EASL Guidelines 2012, AASLD Guidelines