Primary Care for Hepatitis B and C:

Transcription

1 Primary Care for Hepatitis B and C: Clinical Tools for Efficient Management Estimated 17 Million Persons With HCV Infection Worldwide 3-4 million newly infected each yr worldwide Advances in Internal Medicine May and June 211 Rena K. Fo, M.D. Associate Professor of Clinical Medicine and Medical Editor, National VA Hepatitis C Website Prevalence of infection > 1% 2.5% to 1.% 1.% to 2.5% NA * * World Health Organization 28. Available at: * HCV Outcomes in Net 2 Years 16% Decompensated liver disease 81% HCC 18% Liver related death Natural History and potential clinical outcomes in HCV 15% Spontaneously resolve No chronic infection Ab+, RNA - Acute HCV infection 85% Chronic HCV Variable natural h Ab+, RNA + Variable degrees of liver disease 2% Cirrhosis Asymptomatic fibrosis Stable or progressive 1-2% Hepatocellular Carcinoma 1-4% per year in US 2% Decompensate in first 5 yrs Clinical ss cirrhosis? Liver transplant Davis, G, Liver Transpl 23; 9(4): Page 1 As of 6/21/211 8:7 AM

2 Potential determinants of disease progression Alcohol Steatosis Male se HBV coinfection Age at infection HIV, Immunosuppression Hepatocyte Host genetic Determinants * HCV RNA viral load HCV Genotype Mode of acquisition Ethnicity Duration ALT elevation Interpretation of HCV Diagnostic Tests HCV Ab HCV RNA Interpretation Positive Positive Acute or chronic HCV Positive Negative Spontaneous resolution of HCV; successful treatment of HCV; Acute phase with low level viremia Negative Positive Early acute HCV; Chronic HCV with immunocompromised state and false negative Ab; false positive RNA Negative Negative No HCV infection Initial Evaluation of Patient with HCV History risk factors, family, social, seual, occupational, alcohol and drug history, estimate duration of infection Physical Signs of liver disease, splenomegaly Initial laboratories RNA, Genotype, HIV Ab, HBsAg, HBsAb, HBcAb, HAVAb CBC, platelet, INR, Albumin, AST, ALT, Alkphos, Bili, TSH, Fasting glucose, Creatinine, Lipids Consider biopsy if considering treatment or patient desires prognostic information Consider ultrasound if biopsy not planned to look for any evidence of cirrhosis or portal hypertension Counseling BMI, alcohol, seual, household transmission Vaccination for HBV and HAV if not immune Refer to GI-Liver if motivated for treatment or decompensated or co-infected HIV or HBV Understanding HCV RNA Testing: Do Not Routinely Follow the HCV Viral Load!!! HCV RNA mandatory to make Chronic HCV diagnosis But, Quantitative RNA (Viral Load) Does not correlate with degree of fibrosis Does not predict progression of disease Does not change significantly over time Necessary for treatment before, during, after Pre-treatment viral load predictive of success Change in RNA reflects response But if not on HCV treatment, no role for viral load Will not change management Confuses patients about state of their HCV disease Page 2 As of 6/21/211 8:7 AM

3 Hepatitis C Genotype The Non-Significance of ALT in Hepatitis C 1/3 have normal ALT ¼ have ALT >2 upper limit normal Remainder are slightly elevated Poor correlation between level and histology Does not predict response to treatment ALT normalization does not correlate with histological changes from therapy Blatt, J Viral Hep, 2. Antiviral Treatment of HCV Aim of treatment Slow or halt progression to cirrhosis Reduce progression to decompensation Reduce risk of liver related deaths Reduce risk of hepatocellular carcinoma 1 Regimen only since 21 Pegylated interferon and ribavirin Genotype 1 = 48 weeks, Genotype 2,3 = 24 weeks New Drugs for HCV May 211 Protease inhibitors - Telaprevir, Boceprevir Boceprevir FDA approved May 13, sannouncements/ucm25539.htm Telaprevir FDA approved May 23, orpatientadvocates/ucm htm Page 3 As of 6/21/211 8:7 AM

4 Pegylated alfa-2a + RBV IDEAL Study: PegIFN alfa-2a vs PegIFN alfa-2b in Treatment-Naive GT1 HCV Pts SVR (per cent) 57% PEG (18ug) + RBV 1/12mg Overall Genotype 1 Genotype non-1 (2-6) 76% 46% 45% 37% IFN (3mU) + RBV 1/12mg 61% Fried, NEJM, 22 Patients (%) Intent-to-treat analysis 4 38 SVR McHutchison JG, et al. N Engl J Med. 29;361: PegIFN alfa-2b 1.5 µg/kg/wk + RBV 8-14 mg/day PegIFN alfa-2b 1. µg/kg/wk + RBV 8-14 mg/day PegIFN alfa-2a 18 µg/wk + RBV 1-12 mg/day Patterns of Response to Treatment HCV RNA level IFN TREATMENT Nonresponder Sustained responder Months Relapser Effect of HCV Treatment on HCV RNA Sustained Virological Response (SVR) Virus is not replicating, completely suppressed Response persists 6 months after treatment is stopped Qualitative HCV RNA undetectable is definitive assay SVR rates - Pegylated Interferon + Ribavirin Genotype 1: 42-46% Genotype 2,3: 76-82% Long Term Data 99% still remain RNA undetectable 5 yrs after treatment 1. Manns MP, et al. Lancet. 21;358: Fried MW, et al. N Engl J Med. 22;347: Gianni E, et al. Aliment Pharmacol Ther. 21 Feb 15;31(4):52-8 Page 4 As of 6/21/211 8:7 AM

5 SVR SVR Associated With Improved Clinical Outcomes Durable Leads to improved histology Leads to clinical benefits Decreases decompensation Prevents de novo esophageal varices Decreases risk of hepatocellular carcinoma Decreases mortality Bruno S, et al. Hepatology. 21;51: Veldt BJ, et al. Ann Intern Med. 27;147: Maylin S, et al. Gastroenterology. 28;135: Contraindications to HCV Treatment Major uncontrolled depressive illness Pregnancy or unwilling to comply with contraception Autoimmune condition which may be eacerbated by interferon Solid organ transplant Severe concurrent medical condition such as uncontrolled HTN, CHF, CAD, COPD, DM Severe untreated thyroid disease Ghany MG et al, Hepatology 29;49:1335 Which Patients Should Be Treated? Consider every patient for treatment, including: HIV-HCV infected patients Cirrhotic patients Normal ALT High HCV RNA viral load Boceprevir and Telaprevir both approved in May 211 Boceprevir Phase III trials SPRINT-2: naive Genotype 1 (GT1) patients RESPOND-2: nonresponder GT1 patients (partial responders and relapsers) Telaprevir Phase III trials ADVANCE: naive GT1 patients ILLUMINATE: response-guided therapy in naive GT1 paitents REALIZE: nonresponder GT1 patients (null responders, partial responders, relapsers) Poorard, et al NEJM, March 31, 211, 364: ; Bacon et al, NEJM, March 31, 21;. Jacobson IM, et al. AASLD 21. Abstract 211;. Foster GR, et al. APASL 211. Abstract 1529 Page 5 As of 6/21/211 8:7 AM

6 Both Protease Inhibitors Improve Results for HCV Genotype 1 Infection SVR Rates With BOC and TPV in GT1 Treatment-Naive and -Eperienced Pts SVR improved with telaprevir + PEG-IFN/ RBV compared to PEG-IFN/RBV Treatment naïve patients: SVR 61-69% vs 41-46% Prior non-responders / relapsers: SVR 51-53% vs 14% SVR improved with boceprevir + PEG-IFN/RBV compared to PEG-IFN/RBV Treatment naïve patients: SVR 63-66% vs 38% Prior partial responders / relapsers : SVR 52-75% vs. 7-29% SVR (%) Current Standard of Care [1-2] Treatment-Naive Pts [3-4] Treatment- Eperienced SVR (%) SOC + Protease Inhibitors (Approval Anticipated in 211) [1-2] [3-4] Treatment-Naive Pts Treatment- Eperienced Poorard, et al NEJM, March 31, 211, 364: ; Bacon et al, NEJM, March 31, 21;. Jacobson IM, et al. AASLD 21. Abstract 211;. Foster GR, et al. APASL 211. Abstract Poordad F, et al. AASLD 21. Abstract LB Jacobson IM, et al. AASLD 21. Abstract Bacon BR, et al. AASLD 21. Abstract Foster GR, et al. APASL 211. Abstract SPRINT-2: Overall SVR Rates ADVANCE: Overall SVR and Relapse Rates SVR (%) Wk PR + Response- Guided BOC/PR P <.1 for both treatment arms vs control n/n = 233/ / / Wk PR + 44-Wk BOC/PR Wk PR Patients (%) P <.1 for both treatment arms vs control n = SVR 8-wk TVR/PR + 16/4-wk PR (n = 364) 12-wk TVR/PR + 12/36-wk PR (n = 363) 48-wk PR (n = 361) n = Relapse Poorard, et al NEJM, March 31, 211, 364: Jacobson IM, et al. AASLD 21. Abstract 211. Page 6 As of 6/21/211 8:7 AM

7 SVR (%) ILLUMINATE: Overall SVR Rates 72 n/n = 388/54 149/162 14/16 Overall Sherman KE, et al. AASLD 21. Abstract LB wk therapy Patients With ervr wk therapy How Will We Use Protease Inhibitors for HCV? Initial paradigm to be approved will be addition of DAA to pegifn/rbv Will substantially improve therapeutic possibilities for many GT1 patients However, challenging patient scenarios will remain, including Previous null responders and other patients with adverse prognostic factors: is the improvement in SVR rate with telaprevir or boceprevir good enough? Patients who cannot tolerate pegifn, RBV, and/or the adverse events associated with telaprevir or boceprevir Patients who cannot adhere to comple regimens for 6-12 mos; risk of resistance with suboptimal adherence Others: Patients with end-stage renal disease, HCV/HIV coinfection, transplants IDEAL Trial: SVR Rates According to IL28B SNP rs SVR Rates by host IL28B genotype 1 Caucasians African Americans 8 SVR (%) n = 186 n = 559 n = 392 TT CT CC Ge D, et al. Nature. 29;461: Ge et al, Nature, 29 Page 7 As of 6/21/211 8:7 AM

8 Multivariate Analysis of Baseline Predictors of SVR (Genotype 1 HCV) ITT analysis of patients from IDEAL study who consented to genetic testing, regardless of adherence level (n = 164) plus 67 patients from another trial Predictor Adjusted Odds Ratio (95% CI) P Value rs CC 5.2 ( ) <.1 HCV RNA level 6, IU/mL 3.1 ( ) <.1 White vs black 2.8 (2.-4.) <.1 Hispanic vs black 2.1 ( ).41 METAVIR F-F2 2.7 (1.8-4.) <.1 Fasting blood sugar < 5.6 mmol/l 1.7 ( ) <.1 Hepatitis B Virus Thompson AJ, et al. Gastroenterology. 21;139: Hepatitis B Clinical Terminology Chronic hepatitis B Chronic inflammatory disease of the liver due to persistent infection from HBV; subdivide eag(+) or (-) Inactive HBsAg carrier state Persistent HBV w/o significant ongoing inflammation Resolved hepatitis B Previous HBV without further virologic, biochemical, histological infection or disease Reactivation of hepatitis B Reappearance of active disease in person known to have inactive or resolved HBV HBeAg clearance; e Antigen seroconversion Loss of HBeAg and detection anti-hbe in person previously HBeAg (+) Natural Course of Chronic HBV Page 8 As of 6/21/211 8:7 AM

9 Typical HBV DNA, IU/mL Immune Tolerance > 2, and often > Immune Active/ HBeAg Positive CHB Nonreplicative (Inactive Carrier) HBeAg- Negative CHB 2, < HBeAg Positive Positive Negative Negative ALT Histology Treatment candidate? Phases of Chronic HBV Infection Normal Liver biopsy typically normal or minimal findings Elevated or fluctuating Active inflammation on liver biopsy Normal HBsAg may become undetectable Elevated or fluctuating Active inflammation on liver biopsy No Yes No Yes Lok AS, et al. Hepatology. 29;5: ;5: A model of the natural history of chronic viral hepatitis Hepatocellular carcinoma Chronic hepatitis Cirrhosis Death Decompensated cirrhosis Inactive disease Reactivation Factors Associated with Progression of HBV-related Liver Disease Older age (longer duration infection) HBV genotype C High levels HBV DNA Alcohol Coinfection with HCV, HDV or HIV Carcinogens (aflatoin) Smoking Correlates of Severe Liver Disease Outcomes in HBV Patients Retrospective, longitudinal cohort study of the Kaiser Permanente Medical Care Program of Northern California Viral Hepatitis Registry Parameter Adjusted Risk Ratios for Chronic HBV Outcomes HCC Decompensated Cirrhosis Younger than 5 yrs of age Male Non-Asian race.65* 1.47* Diagnosed alcohol abuse Diabetes 1.9* 2.67 *Nonsignificant correlations. Manos MM, et al. AASLD 21. Abstract 175. Page 9 As of 6/21/211 8:7 AM

10 Groups Who Should be HBV Screened Born in areas of high prevalence including immigrants and adopted children Household and seual contacts of HBsAg + persons US born persons whose parents were born in regions of high HBV endemicity Ever injected drugs Multiple seual partners Men who have se with men Inmates of correctional facilities Chronically elevated ALT or AST HCV or HIV infected, or persons needing immunosuppressive therapy Renal dialysis All pregnant women Lok, AASLD Guidelines, Hepatology, 29 CHB Prevalence Among Asian-Americans in San Francisco From Prevalence of chronic HBV infection among 3163 Asian American adults: 8.9% Among chronically infected individuals, 65.4% were unaware of their serostatus Among individuals without evidence of chronic infection, 44.8% showed no evidence of protective antibodies and, therefore, were at risk for future infection Lin SY, et al. Hepatology. 27;46: Initial Evaluation of Patient with HBsAg+ in Primary Care Hepatitis B Serologic Markers Acute hepatitis B Recovery from acute hepatitis B Chronic HBeAg + disease Chronic HBeAg disease Successful vaccination HBsAg (may clear) Anti-HBs Anti-HBc IgM Anti-HBc HBeAg Anti-HBe (in some cases) Lok AS, McMahon BJ. Hepatology. 29;5: DNA (PCR if required) (may be only marker during window period) Page 1 As of 6/21/211 8:7 AM

11 Reasons for Isolated HBcAb + 1. May be an indicator of chronic HBV infection where sag has decreased to undetectable levels but DNA is detectable. Seen in high prevalence regions and HIV +, HCV+ 2. May be a marker of immunity after recovery from prior infection 3. May be a false positive test result 4. May be the only marker of infection during the window phase of acute hepatitis B; these persons should test positive for anti-hbc IgM. 8 genotypes of HBV Labeled A-H HBV Genotypes Geographical variation, all genotypes seen in U.S. A = 35%, B= 22%, C= 31% Genotypes may be a factor in progression of liver disease and response to interferon t The Impact of Viral Load (DNA) in Hepatitis B Viral load significant factor in natural history of liver disease prolonged immune destruction of antigenpresenting liver cells results in cirrhosis prolonged low-level viremia may influence progression Viral load impacts risk of HCC direct viral effect with replication and / or random integration can cause HCC Cumulative Incidence of Liver Cirrhosis for Five HBV DNA Categories (n=3,774) Cumulative Incidence of Liver Cirrhosis < P value for log-rank test, <.1. Year of Follow-up Chen CJ, JAMA. 26;295:65-73 Page 11 As of 6/21/211 8:7 AM

12 Cumulative Incidence of Decompensated Cirrhosis (N=3774) The REVEAL Study: Serum HBV DNA Level and Risk of HCC Cumulative Incidence of Decompensated Liver Cirrhosis Baseline HBV DNA Level P value for log rank test <.1. Year of Follow-up Yang HI, et al. N Engl J Med. 22;347: Long-term (mean follow-up: 11.4 yrs) cohort study to determine risk of cirrhosis and HCC among untreated HBsAg+ individuals in Taiwan Multivariable-Adjusted HR < 3 All participants (N = 3653) HBeAg negative (n = 388) ,- 99,999 1,- 999,999 HBV DNA (copies/ml) million Chen CJ, et al. JAMA. 26;295: Meaning of HBeAg positivity HBeAg is a protein from the precore region of virus HBeAg spontaneously seroconverts to anti-hbe in 2 settings: 1. Acute infection, prior to conversion of HBsAg to HBsAb 2. Or, may occur up to decades after infection in those with chronic HBV Loss of HBeAg usually coincides with drop in DNA level and remission of liver disease Some continue to have active liver disease and high level DNA after HBeAg loss (precore mutants) New Understanding of HBeAg-negative disease May represent the late phase in the natural history of chronic HBV More common in childhood > adult infections HBeAg (-) variants have mutations in core promotor and / or pre-core region of genome Still high level of viral replication occurs HBeAg (-) can still develop cirrhosis or HCC Responds to antiviral medications but high relapse rate after discontinuation Page 12 As of 6/21/211 8:7 AM

13 Annual Rates of Disease Progression in Hepatitis B Infection From Highest to Lowest Risk of Progression to Cirrhosis and Complications HBeAg (+) chronic hep B HBeAg (-) chronic hep B 5% 1-2% Cirrhosis All HbsAg (+) 3% 2%.4% Decompensation HCC 1. Highest risk = Chronic HBV with consistently elevated enzymes and high level HBV DNA 2. Net highest risk = Inactive chronic HBV but with flares of reactivation and enzyme elevation 3. Lowest risk = Inactive chronic HBV with persistently normal liver enzymes and low level DNA HCC Surveillance Is Recommended for: Hepatitis B Asian males 4 years of age or older Asian females 5 years of age or older All cirrhotic hepatitis B patients Family history of HCC Africans older than 2 years of age Hepatitis C All cirrhotic hepatitis C patients Brui J, et al. Hepatology. 25;42: Updated in 21 online: Guidelines/HCCUpdate21.pdf Measurements of HBV Treatment Effect 1. Reduction of HBV DNA level to undetectable level 2. HBeAg seroconversion 3. Normalization of ALT Page 13 As of 6/21/211 8:7 AM

14 HBV Treatment Landscape Undetectable* HBV DNA After 1 Yr of Treatment Peginterferon alfa-2a Lamivudine Entecavir Tenofovir Interferon alfa-2b Adefovir Telbivudine Undetectable* HBV DNA (%) Not head-to-head trials; different patient populations and trial designs HBeAg Positive 6 67 LAM ADV LdT ETV TDF *By PCR-based assay (LLD ~ 5 IU/mL) ecept for some LAM studies Peg- IFN LAM ADV HBeAg Negative LdT ETV TDF 63 Peg- IFN Lok AS, et al. Hepatology. 27;45: Lok AS, et al. Hepatology. 29;5: Comparison of Hepatitis B and C Similar Tests, Different Meaning Hep B Antibody Vaccinated (sab) Eposed (sab + cab) ALT Indicates active disease, strong predictor of treatment response Viral load Predictor of cirrhosis and HCC Genotype Weak predictor of treatment response Hep C Eposed (HCV Ab) Does not determine active disease, not predictor of treatment response No correlation w/ cirrhosis or HCC Strong predictor of treatment response Chronic HBsAg positive HCV RNA positive Resolved sag (-) sab (+) cab (+) Ab (+) qualitative RNA (-) Page 14 As of 6/21/211 8:7 AM