Hepatitis C. Update on Management. Hepatitis C Virus Infection Burden of Disease in United States

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1 Hepatitis C Update on Management Norah Terrault, MD, MPH University of California San Francisco Hawaii, 2010 Hepatitis C Virus Infection Burden of Disease in United States New infections (cases)/year ,000 (42,000) ,000 (6,500) Deaths from acute liver failure Persons ever infected (1.8%) Persons with chronic infection Adjusted estimate Rare 3.9 million ( )* 2.7 million ( )* 4 million Chronic liver disease = HCV-related 40% - 60% Deaths from chronic disease/year 8,000-10,000. Source: CDC Prevalence of HCV Infection Predicted Future Prevalence of HCV in the United States 4.0% 3.0% 2.0% Total Infected HCC Cirrhosis 1.0% 0.0% Deaths due to HCV * Year Armstrong et al, Hepatology, 2000

2 Case History #1 A High-risk Needlestick 28yo intern during his first night on call was inserting an intravenous catheter when he stuck his finger with a needle that had just been removed from the patient s vein. The wound bled. The source patient: HIV RNA 6000 copies/ml, CD4 50, on HAART HCV RNA 3 million copies/ml HBV negative. Case History #1 Needlestick Continues The doctor s 2 week post-needlestick blood sample was HCV RNA positive, at 920,000 IU/mL, ALT 48 IU/mL. At 4 weeks: At 8 weeks: HCV RNA 48 million IU/ml ALT 144 IU/mL T Bili 0.8 g/dl HCV RNA 3.7 million IU/ml ALT 1807 IU/mL T Bili 1.7 mg/dl Case History #1 What should be done next? A. Tell him up to 45% of HCV infections resolve and to come back in a year to find out B. Repeat tests again because these results are likely false positive HCV RNA results C. Treat with peg-interferon D. Continue to follow and if HCV RNA persists for 6 months, treat with peginterferon and ribavirin E. Keep him out of work so he doesn t infect a patient

3 Acute HCV Infection HCV RNA Positive by day 12 avg ALT Anti-HCV (EIA) HCV RNA No Symptoms ALT Weeks post-exposure 100,000,000 10,000,000 1,000, ,000 10,000 1, HCV RNA Treatment of Acute Hepatitis C 34 with Acute Hepatitis 41% asymptomatic, 9% jaundice Mean age 39 yrs 10/34 needlestick injury N=4 Resolved Spontaneously 8 wks observation Early Intervention Late Intervention Delay X 12 mos IFN 6 MU daily X 4 wks Relapse or persistent viremia IFN 6 MU TIW X 20 wks Nomura H,, Hepatology 2004;39: Treatment of Acute Hepatitis C Response after 4 wks Response after 24 wks Early Treatment N=15 Delayed Treatment N=15 P Value 13 (87%) 6 (40%) (100%) 8 (53%) The majority of patients need only 4 wks treatment if treatment is given early --> favored strategy Nomura H,, Hepatology 2004;39:1213-9

4 Treatment of Acute HCV Due to high rate of chronicity following exposure, patient with acute HCV should be considered for therapy Excellent results with interferon monotherapy (80-100% end of treatment and SVR) Pegylated interferon monotherapy probably treatment of choice Consider use of ribavirin addition on case by case basis only No definitive recommendation for duration of therapy but consider 6 months of therapy Jaeckel NEJM 2001, Nomura Hepatology, 2004, Strader Hepatology 2004 Natural History of Chronic HCV Infection Exposure (Acute Phase) Resolved 15-45% Stable Poynard T, Lancet : Mathurin P, Hepatology : Benhamou J, Hepatology :1054 Freeman, Hepatology % Chronic 75-95% No prophylaxis available Consider antivirals if seroconvert and viremic 5%-25% over years Cirrhosis 3%/yr HCC 5%/yr decomp Liver Decompensation Hepatoma Fibrosis Progression is not Linear Hazard Rate Transition Rates to Cirrhosis ALD HCV HBV PBC Age Risk of fibrosis higher once fibrosis present A steep acceleration is seen at ~50 years in patients with HCV Poynard, J Hepatol 2003

5 Risk Factors for Progressive Fibrosis and Cirrhosis Persistently elevated ALT levels Longer duration of infection Male sex Age >40 years at time of infection HIV coinfection or immunocompromised state Alcohol excess (>50 gm/day) Cannabis use daily Steatosis (obesity, metabolic syndrome) Poynard T, Lancet : Mathurin P, Hepatology : Benhamou J, Hepatology : Ishida J, Clin Gastroenterol Hepatol 2008;6:69-75 Modifying Lifestyle Factors to Reduce the Risk of Cirrhosis Alcohol intake Heavy (>2 drinks/d women, >4 drinks/d men) associated with higher risk of cirrhosis Abstinence recommended Metabolic syndrome and hepatic steatosis Advanced fibrosis twice as prevalent in patients with hepatic steatosis Insulin resistance and diabetes associated with highr risk of cirrhosis Strive for ideal BMI and treatment of MS comorbities Cannabis use Daily use associated with 3-6 fold higher risk of cirrhosis than non-users Abstinence recommended Factors Not Influencing Fibrosis Progression ALT HCV Viral load Mode of transmission Genotype NIH Consensus Development Conference Statement Poynard et al. Lancet. 1997;349:

6 Initial Management of Patients With Chronic HCV Infection Reduce risk of transmission to others Sexual contacts, children, household members Lifestyle changes to prevent disease progression Reduction or abstinence from alcohol and cannabis Optimization of weight, lipids, insulin resistance Avoidance of herbal remedies and over-thecounter medications Vaccination: HAV, HBV if applicable If cirrhosis present refer to hepatologist Importance of Determining Stage of Fibrosis Detection of cirrhosis leads to initiation of specific surveillance procedures HCC, varices Fibrosis stage used to guide timing of antiviral therapy Fibrosis stage is important determinant of response to antiviral therapy Liver Biopsy is Gold Standard for Assessment of Fibrosis F0: No fibrosis F1: Fibrous expansion of some portal areas F2: Fibrous expansion of most portal areas with occasional portal to portal bridging F3: Fibrous expansion of portal areas with marked bridging (portal to portal and portal to central) F4: Cirrhosis, probable or defined Courtesy of Gregory Everson, MD.

7 Case #2 58 yo Hispanic male recently diagnosed with HCV Blood transfusion in 1960 No alcohol consumption Examination: BMI 30, otherwise normal US: echogenic liver, spleen 14.5 cm Labs: HCV RNA 1.3 million IU/mL ALT 77 U/L, AST 130 U/L. Platelets: 130,000 Negative/normal: Bilirubin, Albumin, AFP Negative HBsAg, HIV There are several deatures to suggest a diagnosis of cirrhosis. These include all of the following EXCEPT A. Liver echogenecity B. Mild splenomegaly C. AST > ALT in absence of alcohol use D. Low platelet count Assessment of Stage of Disease Liver biopsy is considered gold standard Clinical Clues to Presence of Cirrhosis Low platelet count (<140K) AST>ALT (in absence of alcohol use) Abdominal imaging: nodular liver, splenomegaly Abnormal indices of liver synthetic function: low albumin, elevated PT and elevated bilirubin Non-invasive tests of fibrosis are available (or will be soon) Serum fibrosis tests Hepatic elastrography

8 Diagnostic Limitations of Liver Biopsy Invasive procedure Major complications = 0.5% Contraindicated in some patients Cost and inconvenience Does not easily lend itself to repeat testing Significant sampling and observer error Cirrhosis is missed in 10% 20% of cases Staging reliant on: Length of biopsy Number of biopsies performed Type of biopsy needle used Etiology of liver disease Non-Invasive Tests of Fibrosis Blood tests Fibrotest APRI ELF Forns FIBROSpect Fibrometer Hepascore FIB-4 (coinfected patients) Liver Imaging Transient elastrography MR spectoscopy Diffuse-weighted MRI Sterling, Hepatol. 2006; 43(6): Halfon, Am J Gastro. 2006;101: Wai, Hepatol. 2003;38: Forns, Hepatol. 2002;36: Patel, J Hepatol. 2004;41: Rosenberg, Gastroenterol. 2004;127; Zaman, Am J Med. 2007;120:e9-12. Lewin, Hepatol. 2007;46: Adams, Clin Chem ; Cales, Hepatol., 2005;42: Correlation between FibroTest and Liver Biopsy Stage FT > 0.80 Spec 97% PPV 92% Indeterminate 54% FT 0.20 Sens 92% NPV 87% Imbert-Bismut. Lancet 2001;357: n=134 F2-F4 fibrosis: 45%

9 Serum Fibrosis Markers Simple, inexpensive, widely available Bivariate classification (cut-points) High NPV (>90%) exclude cirrhosis or significant fibrosis but inadequate PPV Potentially avoids biopsy in ~35% of patients Unable to reliably differentiate intermediate fibrosis stages Insensitive to change/ treatment effects in longitudinal studies Limited data on factors affecting performance of assays, e.g., renal function, high IgG levels, presence of steatosis Liver Elastrography Dedicated electronic system Personal computer Ultrasonic and lowfrequency signals Vibrator Probe Transducer Non-invasive <5 min. scan time 10 measurements 2 to 6 cm deep Cylinder 1 x 4 cm 2.5 to 75 kpa Liver stiffness correlates with fibrosis Non-Invasive Markers Abdominal Imaging Liver Elastography High accuracy in exclusion of F3 (bridging fibrosis or cirrhosis) Technical problems preventing determination in 5-10% Diffuse-weighted MRI (and other versions) Similar performance to liver elastography Useful in obese and others failing elastrography

10 Future Testing Algorithms to Identify Advanced Fibrosis Serum fibrosis markers Elastography Tests Agree Tests Disagree F0-F1 F2-4 F4 Liver Biopsy Treatment Optional Follow with repeat testing annually Treatment Treatment HCC Surveillance EGD for varices Castera L, et al. Gastroenterology HCV Therapeutic Goals HCV Treatment Eradicate Viral Disease Reduce burden of disease in population Slow/Prevent Progression to Cirrhosis Reduce deaths due to HCV-related liver complications 1 2 SVR = 13.5% 1 Ascites, GI bleeding, encephalopathy 2 Surveillance with US every 6 mos

11 All persons with chronic HCV should be considered for treatment NIH Consensus Statement, 2002 Minimum Requirements HCV RNA-positive by PCR Compensated liver disease Liver enzymes normal or abnormal No contraindications to use of interferon or ribavirin Liver biopsy not required but useful in assessing disease severity and determining urgency of initiating antiviral therapy Case #3 58 yo Hispanc male recently diagnosed with HCV Examination: BMI 30, otherwise normal No medications and no other comorbidities US: echogenic liver, spleen normal Labs: HCV RNA 1.3 million IU/mL, genotype 1a ALT 77 U/L, AST 130 U/L. Platelets: 260,000 Negative/normal: Bilirubin, Albumin, AFP Negative HBsAg, HIV Liver biopsy shows stage 2 (scale of 4) fibrosis What do you recommend regarding treatment? A. Treat now with peg-ifn and weightbased ribavirin B. Treat now with peg-ifn and flatdosed ribavirin (800 mg daily) C. Weight loss with goal of BMI 25, then treat with peg-ifn and ribavirin D. Defer treatment, await new drugs

12 HCV Treatment: The Reality Not all patients are candidates for treatment with current drugs Current antiviral therapy has variable efficacy in different patient populations Side effects are frequent and adherence to full dose therapy significantly affects response rates Treatment is Selective Treatment Recommendations for Chronic Hepatitis C Genotype 1 Genotype 2/3 Peg-IFN Dose (weekly) PEG-IFN α-2b 1.5 µg/kg Peg-IFN α-2a 180 µg PEG-IFN α-2b 1.5 µg/kg Peg-IFN α-2a 180 µg Ribavirin Dose per day (divided dose) Based on weight mg (peg-ifn α-2b) Fixed dose 800 mg mg (peg-ifn α-2a) Duration 48 weeks 24 weeks Anti-HCV Therapy Main Contraindications IFN Significant depression Autoimmune conditions Cardiac failure or arrhythmias Low WBC, platelet count Uncontrolled seizures Pregnancy Ribavirin Hemolytic anemia or comorbidities that would be exacerbated by anemia Renal failure (Cr>2.0) Wanting to conceive

13 Increasing Efficacy of HCV Antiviral Therapy % Patients with SVR 60% 40% 20% 13-19% 38-45% 55-56% 0% IFN α 48 wks IFN α-2b + RBV PEG-IFN + RBV McHutchison JG. Semin Liver Dis. 1999; Manns M, Lancet 2001; Fried M, N Engl J Med 2002 Genotype is Major Determinant of Response to Treatment % 70-85% 75-80% % SVR % 50-60% 40-50% Genotype Manns M, Lancet 2001, Fried M, N Engl J Med 2002 Zeuzem S et al. Hepatology 2004; Kamal Sm Hepatology 2008 SVR Rates in Specific HCV Subpopulations with Genotype 1 Factor HIV Coinfection Genotype 1 African American Race SVR Rate (range) 14-29% 19-28% Advanced fibrosis 18-24% References Chung R et al., N Engl J Med 2004; Carrat F. et al. JAMA, 2004; Torriani et al. N Engl J Med Jeffers, Hepatology 2004 Muir, N Engl J Med 2004; Conjeevaram Gastroenterology 2007 Marotta, PoWER study, AASLD 2008

14 Treatment Considerations Individualize the Decision Risk of complications in absence of complications Stage of fibrosis predicts future complication risk Likelihood of achieving viral eradication HCV genotype is primary determinant Response during treatment important Presence of contraindications Not all patients can safely take interferon and ribavirin Patient motivation (likelihood of high compliance) Adherence to full treatment doses and duration strongly influences efficacy Patterns of Virological Response Baseline Treatment Nonresponder HCV RNA HCV RNA Undetectable Detection limit Time Relapser Sustained virologic responder (SVR) 6 months Baseline Predictors of Virologic Response HCV Viral Factors Genotype Viral Load Host Factors Age Race Gender Overweight/Obesity Insulin Resistance HIV Coinfection IL28B polymorphism Disease Related Bridging fibrosis or cirrhosis Normal ALT levels Lindsay KL. Hepatology 2002;36:S114-S120, Reddy KR. Hepatology 1999;30: ; Harrison SA Clin Gastroenterol Hepatol. 2005;3:S92-S96, Romero-Gomez, M. Gastroenterology 2005;128: , Chung RT N Engl J Med. 2004;351:

15 Maximizing Chances of Achieving SVR Modify any pre-treatment factors that can influence response Anticipate and aggressively manage side effects to insure adherence Complete treatment at prescribed doses Consider adjusting treatment duration depending upon when HCV RNA becomes undetectable Patterns of Virologic Response 2-log decline HCV RNA Level RVR cevr pevr Partial EVR = HCV RNA > 2-log drop at wk 12 and negative wk Weeks on Treatment Use of viral kinetics to define on-treatment predictors of response Adapted from Slide courtesy of Donald M Jensen, MD, 2005 Utility of Viral Kinetics Rapid loss of HCV RNA (RVR) predicts high rate of SVR = 80-90% Very encouraging for patients May be able to shorten treatment in select patients Failure to achieve a 2-log VL decline by week 12 is highly predictive of non-response STOP treatment Delayed loss of HCV RNA predicts low rate of SVR = (slow responders) Consider prolonging treatment to reduce relapse

16 Extended Treatment Duration in Chronic Hepatitis C Genotype 1 Infected Slow Responders Prospective, randomized, multinational, multicenter study 1427 patients given peg-ifn 1,5 ug/kg/wk and RBV mg daily Responses in Slow Responders At week 24, 11% (N=159) identified as slow responders Buti M, et al. Presented at EASL Abstract #141. Genotype 1 Treatment Algorithm Peg-IFN (180 ug or 1.5 ug/kg) weekly + weight-based RBV (~13 mg/kg) WK 4 RVR No RVR 24 wks if low baseline VL and fibrosis score WK12 Complete EVR HCV RNA <50 IU/ml Partial EVR 2-log Decline 48 wks 48 wks 72 wks No EVR Stop Proposed Genotype 2/3 Treatment Algorithm Peg-IFN (180 ug or 1.5 ug/kg) weekly + RBV 800 mg/d (consider 13.5 mg/kg dose if other unfavorable factors at baseline?) WK 4 RVR No RVR If LVL and no cirrhosis Consider treatment wks Treat for 24 wks WK12? Complete EVR HCV RNA <50 IU/ml Partial EVR 2-log Decline 48 wks? 48 weeks or longer? No EVR Stop?

17 . HCV Treatment Summary Peg-IFN plus ribavirin is current treatment of choice for patients with chronic HCV Overall ~55% will achieve viral clearance but many patients groups have response rates <50% Need to individualize decision to treat Many patient groups at higher risk of complications with treatment, e.g. dialysis, cirrhotics Need specific expertise to execute treatment safely Treatment efficacy depends on adherence On-treatment responses dictate treatment duration New HCV Drug Targets Neutralizing antibodies. Virus Binding and receptor mediated endocytosis B1 Receptors Entry Inhibitors. CD81 Receptors Liver cell Glycosylation inhibitors. Transport and release Cell membrane Vesicle Core of the virus released RNA uncoating Nucleus Nucleocapside assembly Oligonucleotides and sirna Cyclophillin B inhibitors.. Translation and RNA replication polyprotein processing New Targets Lifecycle Step.. Protease inhibitors Polymerase inhibitors RNA synthesis Boceprevir + PegIFN + RBV in Genotype 1 Treatment Naïve Chronic HCV ITT analysis % of Patients With Undetectable HCV RNA 37% 4 wk Lead-In No Lead-In Virologic breakthrough = Persistent 2 log10 increase in HCV RNA from nadir and 50,000 IU/mL HCV RNA level Kwo P. et al AASLD Abstract LB16

18 Telaprevir Plus Peg-IFN ± RBV SVR and Relapse Rates (ITT) Genotype 1 Treatment Naïve Chronic HCV % of Patients With Undetectable HCV RNA Control T12/P12 T12/PR12 T12/PR24 1 patient each in T12/PR12 & T12/PR24 relapsed between wks 36 and 48, respectively * ** % SVR Relapse *P=0.08 T12/PR12 vs control **P=0.01 T12/PR24 vs control Hezode C, N Engl J Med New STAT-C Regimens Summary Cure rates will be higher than with peg-ifn + RBV Most drugs focused on genotype 1, but new targets likely to be effective across genotypes RBV will remain in regimen for the foreseeable future -> Adds to efficacy and reduces rates of resistance Adding third drug = more adverse events Still have high fatality rate for drugs in phase 1/2 Drug resistance is major barrier Rapid viral clearance will be critical Polymerase inhibitors have higher genetic barrier to resistance than protease inhibitors to date Combinations drugs with different targets desirable Future HCV Therapy STAT-C Near Future + Ribavirin Peg-Interferon + 24 vs 48 weeks duration Next Phase STAT-C + STAT-C

19 HCV Treatment Final Issue Treat Now or Await New Drugs? Treat now: Genotype 2, 3, 5 (high likelihood of response) Genotype 4 and 6 (unknown response) Those with advanced fibrosis (due to risk of liver complications in absence of treatment ) Await new drugs: Genotype 1 with mild to moderate fibrosis Other messages to patients: Treatment side effects increased not decreased Unclear is treatment duration will be shortened