HBV and HCV treatment update

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1 HBV and HCV treatment update HBV Treatment Update 29 Tawesak Tanwandee, MD. Siriraj Hospital, Bangkok, Thailand Hunt CM Hepatology 2 Life Cycle of HBV in the Hepatocyte HBV-Triggered Immune Response Viral polymerase converts pregenomic RA to partially ds DA Infectious HBV virion Partially dsda Cytoplasm Minus strand DA Encapsulated pregenomic mra cccda mra ucleus HBcAg Adapted from Lai CL, et al. J Med Virol. 2;1:7-7. HBsAg Hepatocyte Subviral particles ER HBeAg Precore/core MHC class II CD4+ T cell HBV peptides CD8+ T cell Antigenpresenting cell HBV antigens TF-α Interfer ongamma HBV MHC Down- Infected class I regulations hepatocyte of viral replication CD8+ T cell MHC class I Ganem D, et al. Engl J Med. 24;5: HBV peptides HBsAg HBV DA HBV RA HBV cores Satges of Chronic HBV Infection Immune tolerance HBeAg + (wild) Immune clearance Low replicative phase Reactivation phase HBeAg-/antiHBe+ (PC/CP variants) Favourable outcome following HBeAg seroconversion HBeAg loss HBV-DA cp/ml cp/ml <1 5 cp/ml >1 5 cp/ml HBeAg seroconversion ALT ormal / Mild CH Moderate/severe CH cirrhosis HBeAg+ Chronic hepatitis ormal/mild CH Inactive cirrhosis Inactive-carrier state Moderate/severe CH cirrhosis HBeAg- Chronic hepatitis Disease remission HBsAg loss/seroconversion Prevention of HCC Increased survival Hoofnagle Ann Intern Med 1981; Fattovich Hepatology 198;DiBisceglie Gastroenterology 1987; iederau EJM 199; Chu Gastroenterology 22; van Zonneveld Hepatology 24 1

2 Adjusted Hazard Ratio* for HCC (95% CI) Patients (%) Risk of complications (%) C * * X S P STP-CD AT CD 28 F PRE-CRE REGI(189) Precore/core HBcAg HB e Ag e P25 P21 P1 ALT Chronic HBe - Hepatitis B: ALT pattern untreated patients, 2 months (range 12-) monthly monitoring With flares With flares and Without flares and normalization without normalization 7 pts (44.5%) 59 pts (%) 2 pts (19.5%) months Annual frequency of flares: < nce : 2%, once : 57%, twice : 2% Spontaneous resolution rare only 1/1 in untreated Brunetto MR, J Hepatol, 22 HBeAg seroconversion Inactive HBsAg carrier state HBeAg positive with elevated ALT 8% - 12% per year Spontaneous HBeAg seroconversion 7% - 8% 4% - 2% 1% - 2% 2% - % HBeAg negative chronic hepatitis Lok, Hepatology HBV DA Associated With Increased Risk of HCC and Cirrhosis REVEAL: Long-term follow-up of untreated HBsAg positive individuals in Taiwan Cumulative Incidence of HCC at Year 1 Follow-up [1] ( = 5) < ,- 1, 99,999 Baseline HBV DA (copies/ml) Cumulative Incidence of Cirrhosis at Year 1 Follow-up [2] ( = 582) < - 1, , ,- 1 million 999, Chen CJ, et al. JAMA. 2;295: Iloeje UH, et al. Gastroenterology. 2;1:78-8. Persistently Elevated HBV DA Associated With Increased HCC Risk n = DA at entry: High 1 5 High 1 5 High 1 5 DA at follow-up: Low < 1 4 Mid High HBV DA (copies/ml) *Cox proportional hazards models. Risk is relative to < 1 4 copies/ml at entry/not tested at follow-up. Data adjusted for sex, age, cigarette smoking, and alcohol consumption Chen CJ, et al. JAMA. 2;295:5-7. ALT and Hepatic Complications,2 Chronic Hepatitis B Patients Long-term follow up of 2 HBV-infected patients from Hong Kong Risk of cirrhosis and HCC, relative to ALT <.5 UL Higher when ALT.5-1 UL (P <.1) Highest when ALT > 1-2 UL (P <.1) Yuen MF et al. Gut 25; 54:11 Months of follow-up ALT >1-2 X UL ALT >2 - X UL ALT.5-1 X UL ALT > X UL ALT <.5 X UL 2

3 ALT - new (-) strand DA synthesis dadadg 5 Cap (A)n - Translocation pgra Translocation new (-) strand DA synthesis dadadg 5 Cap (A)n pgra ormal Aminotransferase Levels and Risk of Mortality from Liver Diseases > < Kim HC et al. BMJ 24; 28: Korea Medical Insurance Corporation 94,5 men; 47,522 women 5-59 yrs old. Risk ratio (95% CI) 59. Relative risk for liver mortality compared with AST and ALT <2 IU/l Elevated ormal HCC risk score developed from REVEAL database Poster presentation Digestive Disease Week, Washington DC, May 19-24, 27 Chen C-J, et al. Hepatol Int 28;2:A (Abstract FP15), and oral presentation at APASL 28. Risk Factor Adjustment Score HBeAg HBV DA, copies/ml HBV genotype egative < egative ~< 1 1 egative 1~< 14 B or B+C egative 1~< 14 C 4 egative 14~< 15 B or B+C egative 14~< 15 C 7 egative 1 B or B+C 4 egative 1 C 7 Positive B or B+C Positive C Risk Factor Adjustment Scores Family history Alcohol Serum ALT Gender Age of HCC intake (U/L) Female 4 o o <15 Male Yes 2 Yes Therapeutic endpoints over time IF- : (i) 2 5 -A Synthetase: RaseL (ii) PKR (iii) MxA Loss of HBeAg Loss of HBV DA Anti-HBe+ Improved histology Anti-HBs+ Improved Loss of survival HBsAg Attachment and Penetration Golgi complex Release Reentry Re-entry uncoating DA repair envelope proteins S, M, L transport to cell nucleus CCC DA ucleus pregenomic RA core proteins LA PRTEI MIICHRMSME HBV RA transcripts HBV polymerase protein TIME HBV DA Replication Gordien et al (21) J Virol 75:284 ucleoside/nucleotide analogues (a) Purine analogues Inhibition of Reverse Transcription: ucleos(t)ide Analogues H H S H 2 H Entecavir (cyclopentane group) H 2 H H 2 C H H LdT H P H Adefovir (b) Pyrimidine analogues(l-nucleosides) H H 2 F S H 2 H Emtricitabine H P Tenofovir H H F C H H Clevudine H Attachment and Penetration ucleos(t)ide Analogues eg. LMV, ADV, ETV Golgi complex Release Chain Termination Re-entry uncoating DA repair envelope proteins S, M, L transport to cell nucleus CCC DA ucleus pregenomic RA core proteins HBV DA SYTHESIS MIICHRMSME HBV RA transcripts HBV polymerase protein LA PRTEI Delaney et al (21) Antiviral Chem Chemother. 12:1-5

4 % patients %patients %patients Log 1 Decrease HBV DA at 1 Year %patients %patients HBV DA Reduction With ral Agents in Chronic Hepatitis B* Initial Evaluation of HBsAg+ Patient ADV [1] 1 mg -.5 ADV [2] mg L-FMAU [] LAM [4] *Data from individual reports, not direct comparisons (different populations, baseline values, HBV DA assays). TDF [5] LdT [4] ETV [] 1. Hepsera [package insert]. 2. Marcellin P, et al. Engl J Med. 2;48: Yoo BC, et al. AASLD 25. Abstract Tyzeka [package insert]. 5. Heathcote E, et al. AASLD 27. Abstract LB.. Baraclude [package insert]. -.9 History and PE Investigations Assess risk factors Liver disease activity (coinfection) Serologic and virologic Alcohol use markers Family history of HBV Screening for HCC and HCC (AFP and ultrasound q m) Physical findings of cirrhosis Categorization of Disease HBeAg-Positive Patients: Treatment Response in Chronic Hepatitis B HBeAg positive or negative Replication high or low (HBV DA) 2,-2, IU/mL ALT elevated or normal Liver histology Drug Treatment Duration HBeAg-Positive Patients HBeAg Seroconversion at Yr 1, % HBV DA egative at Yr 1,* % ff-treatment Durability of HBeAg Seroconversion, % HBsAg Loss LAM 1 yr < 1 ADV 1 yr ETV 1 yr PegIF 1 yr ~ 9 Telbivudine 1 yr 2 8 Tenofovir 1 yr 21 7 A A *: hybridization assay; adefovir, entecavir, and peginterferon: PCR assay. 24 weeks posttreatment. Dienstag JL, et al. Engl J Med. 1999;41: Marcellin P, et al. Engl J Med. 24;51: Lau GK, et al. Engl J Med. 25;52: Baraclude [package insert]. Tyzeka [package insert]. Lai CL, et al. AASLD 2. Abstract 91. Lau GK, et al. EASL 2. Abstract 5., Heathcote EJ, et al. AASLD 27. Abstract LB. HBeAg seroconversion during continued treatment HBeAg-egative Patients: Treatment Response in Chronic Hepatitis B LAM ADV ETV LdT TDF 9 Entecavir 1 21 Adefovir 12 LAM ADV ETV LdT TDF Telbivudine Drug Treatment Duration HBeAg-egative Patients HBV DA egative at Yr 1,* % ff-treatment Durability of HBV DA egativity, % LAM Indefinite -7 < 1 ADV Indefinite 51 5 ETV Indefinite 9 A PegIF 1 yr 19 Telbivudine Indefinite 88 A Tenofovir Indefinite 9 A Year * Biopsies at wk Year *: hybridization assay; adefovir, entecavir, and peginterferon: PCR assay. 24 weeks posttreatment. Hadziyannis SJ, et al. Engl J Med. 2;48:8-87. Marcellin P, et al. Engl J Med. 24;51: Baraclude [package insert]. Tyzeka [package insert]. Lok AS, et al. Hepatology. 2;2: Hadziyannis SJ, et al. Hepatology. 2;2: , Marcellin P, et al. AASLD 27. Abstract LB2. 4

5 (%) Comparison of antivirals in HBeAg(-): Undetectable HBV DA * <4 copies/ml(1) Adefovir <1 copies/ml (2,) Entecavir < copies/ml4, > Duration of therapy (Years) Telbivudine < copies/ml *Collation of currently available data not from head-to-head studies 1. Hadziyannis S, et al. Hepatology 2;2: Hadziyannis S, et al. EJM 25; 52: Hadziyannis S, et al. Hepatology 25; 42 (suppl 1):754A (Abstract LB14). 4. Lai C-L et al. EJM 2;54: ; 5. Shouval D, et al. EASL 2, Vienna, Austria, ral abstract 45. Lai CL, AASLD 2 82 HBeAg+ CHB 1 9 % of patients Improvement in Histology after 48 weeks Therapy ot head-to-head studies 59 5 placebo peg LAM ADV ETV Ldt TDF Improvement in Histology after 48 weeks Therapy Algorithm for the management of HBeAgpositive patients with CHB infection HBeAg- CHB 1 9 % of patients ot head-to-head studies placebo peg LAM ADV ETV Ldt TDF HBV DA <2, IU* ALT normal* o treatment Monitor ALT, HBeAg, HBV DA, every mo HBeAg positive HBV DA 2, IU *1 IU = 5. copies/ml Treatment Guideline APASL 28, IH 28 EASL 29 Algorithm for the management of HBeAg-positive patients with CHB infection HBeAg positive Algorithm for the management of HBeAg-positive patients with CHB infection HBeAg positive HBV DA <2, IU* ALT normal HBV DA 2, IU HBV DA <2, IU* ALT normal HBV DA 2, IU o treatment Monitor ALT, HBeAg, HBV DA, every 12 mo *1 IU = 5. copies/ml ALT normal ALT 1-2 x UL ALT > 2 x UL ALT > 5xUL o treatment Monitor ALT, HBeAg, HBV DA, every 1- mo Consider biopsy, if age >4 years Treat if significant disease Treatment Guideline APASL 28, IH 28 EASL 29 Rx if persistent (~ months) or has concerns for hepatic decompensation Interferon- based therapy, entecavir, telbivudine, lamivudine, adefovir, (tenofovir)* are all first-line options *1 IU = 5. copies/ml ALT normal ALT 1-2 x UL ALT > 2 x UL ALT > 5xUL * EASL ans IH Rx indicated If HBV-DA < 2x1 IU/ml, may choose to observe closely for months for seroconversion if no concerns for hepatic decompensation Interferon- based therapy; entecavir, telbivudine, (tenofovir)* or lamivudine recommended, particularly if there is concern for hepatic decompensation Liaw YF, Hepatol Int 28 5

6 Algorithm for the management of HBeAg-nagative patients with CHB infection Algorithm for the management of HBeAg-nagative patients with CHB infection HBeAg negative HBeAg negative HBV DA <2, IU* ALT normal* HBV DA 2, IU HBV DA <2, IU* ALT normal HBV DA 2, IU o treatment Monitor ALT, HBeAg, HBV DA, every mo *1 IU = 5. copies/ml Treatment Guideline APASL 28, IH 28 EASL 29 o treatment ALT normal ALT 1-2 x UL ALT > 2 x UL Monitor ALT, HBeAg, HBV DA, every 12 mo o treatment Consider biopsy, if age >4 years Treat if significant disease Monitor ALT, HBeAg, HBV DA, every 1- mo *1 IU = 5. copies/ml * EASL ans IH Liaw YF, Hepatol Int 28 Treatment if persistent (- months) or has concerns of hepatic decompensation IF based-therapy, entecavir, (tenofovir)* adefovir, telbivudine, lamivudine, Long-term oral antiviral treatment usually required Algorithm for the management of CHB infection with liver cirrhosis. Recommendation Compensated HBV-DA<2x1 IU/ml (< 1 4 cp/ml) ALT, HBeAg or HBV-DA q months HCC surveillance AFP and ultrasonography q -months Liver cirrhosis Decompensated HBV-DA>2x1 IU/ml (> 1 4 cp/ml) Yes ETV TV Ldt LAM Hepatitis flare o IF based ETV TV ADV Ldt LAM Conventional supportive treatment Antiviral therapy Consider transplant ETV TV Ldt LAM ADV How to monitor- on treatment During therapy, ALT, HBeAg and/or HBV-DA should be monitored at least every months (I). Renal function should be monitored if adefovir, tenofovir is used (I). During IF therapy, monitoring of adverse effects is mandatory (I). Treatment Guideline APASL 28, IH 28 EASL 29 Recommendation When to stop When to stop Recommendation Duration of Therapy Conventional IF 4 months for HBeAg-positive patients (II) and at least a year for HBeAg-negative patients (I). PegIF At least month for HBeAg-positive patients (II) and 12 months for HBeAg-negative patients (I). Treatment Guideline APASL 28, IH 28 EASL 29 For oral antiviral agents: In HBeAg-positive patients Stop Rx when HBeAg seroconversion with undetectable HBV-DA has been documented on 2 separate occasions at least months apart (II) In HBeAg-negative patients ot clear how long this treatment should be continued Discontinuation can be considered if undetectable HBV- DA has been documented on three separate occasions months apart. (II). Treatment Guideline APASL 28, IH 28 EASL 29

7 Undetectable HBV DA (%) ALT (U/L) HBV DA log copies/ml Stopping therapy in HBeAg-ve patients is associated with high relapse rate *Hybridisation Assay Post-Treatment wk 24 or 48 n Treatment wk 48/52 45% 4% 27% 5% 51% 15% 11% 8% IF* Peg-IF# LAM# ADV# #PCR assay Marcellin, EJM 25 Lai, AASLD 25 Hadziyannis, EJM 25 Liaw, Gastro 2 liveri, Am J Gastro 1999 Resistance Rates of ucleoside Analogues % Adefovir aïve e Adefovir YMDDm Entecavir YMDDm Entecavir aïve Telbivudine e+ Telbivudine e- 2.7 Year 1 Year 2 Year Year 4 Year 5 HBV Resistance Mutations Dynamics of Resistance Emergence () I(G) Terminal protein II(F) Spacer Pol/RT RaseH GVGLSPFLLA YMDD 845 a.a. A B C D E LAM resistance rtl8v/i rtv17l rtm24v/i/s ADV resistance rtl18m rta181t/v rt2t rtl2v? ETV resistance rtl18m rtm24v/i rtt184s/a/i/l rts22g/c LdT resistance rtl8v/i rtl18m rtm24i TDF resistance rta194t rtm24v rtl18m Allen MI, et al. Hepatology. 1998;27: Qi X, et al. J Hepatol. 24;4(suppl 1):2-21. Tenney D, et al. Antimicrob Agents Chemother. 24;48: Tyzeka [package insert]. Lai CL, et al. Gastroenterology. 25;129: Schildgen, et al. Engl J Med. 2;54: Locarnini S. 2 IDRW. Abstract P2. rtm25i/v Rise in serum transaminase s Codon 18 L L 12 L/M 18 M 24 M M M 42 Months M Codon 24 M M M M M/V M/V V V Codon 27 V V V V V V V V Worsening of liver disease Si Ahmed et al. Hepatology. 2;2: ; Zoulim Antivir Chem Chemother 21;12: ; Yuen et al Hepatology 21; 4: ; Locarnini et al Antiviral Therapy 24;9: % with 15 disease progression 1 5 Time to disease progression by YMDD mutant status Placebo (n=215) YMDDm (n=29) (49%) Wild Type (n=221) Placebo YMDDm Time after randomisation (months) WT 21 % 1% 5% Ways to Prevent HBV Resistance Treat only indicated When treat with oral agents Maximize antiviral activity select most potent drug Maximize genetic barriers to resistance avoid sequential monotherapy choose drugs requiring multiple resistance mutations choose drugs where patient is naïve Increase pharmacologic barriers patient compliance Prior drug experience 7

8 Patients still at risk ADV Added to LAM in LAM-Resistant Patients Virological Response by Resistance Definition log HBV-DA at baseline virologic breakthrough -8 log HBV-DA at baseline >8 log HBV DA at baseline p< Month s (Lampertico et al., Hepatology 25;42: ) Clinical breakthrou gh Recommendations for Managing Drug Resistance Resistance Rescue Therapy Add-on adefovir therapy is indicated (I) Switching to entecavir (1 mg/day) is an option (I). Adefovir Telbivudine *ff label. Recommendation Add-on or switching to lamivudine, telbivudine, or entecavir (III). Add-on adefovir therapy is indicated (IV). Switching to IF-based therapy is an option (III) Treatment Guideline APASL 28, IH 28 EASL 29 What should be the primary treatment? Long-term Benefits Antiviral potency Durability of response Contraindications Ease of administration Duration of Rx Costs of Rx & monitoring Patient and provider preference Long-term Risks HCV Treatment update 29 Side effects Drug resistance HCV 2-2 wks Factors That May Influence the utcome of Hepatitis C Resolved All abnormal ALT 1/ jaundice > 8% chronic 2/ 1/ All abnormal pathology Abnormal ALT normal ALT cirrhosis 2-% in 1-2 yr Host Virus Sex (male) Viral load Age (>4) HCV genotype Race Quasispecies Genetics Immune response Duration of Infection Environment Alcohol or drugs HBV coinfection HIV coinfection Steatosis, ASH Iron HCC %/yr Alberti A, et al. J Hepatol. 1999;1(suppl 1):

9 AASLD Recommendation 1. As part of a comprehensive health evaluation, all persons should be screened for behaviors that place them at high risk for HCV infection. (Class I, level B) 2. Persons who are at risk should be tested for the presence of HCV infection (Class I, level B) HCV screening recommended IVDU even only once Pt. with high risk HIV infection Hemophilia received factor prior to 1987 Hemodialysis Unexplained abnormal ALT Recipients of transfusions or organ Tx before July 1992 Children born to HCV-infected mothers Health care worker after a needle stick or mucosal exposure to HCV-positive blood Current sexual partners of HCV-infected persons* Although the prevalence of infection is low, a negative test can reassure AASLD Recommendation Measures to Avoid Transmission. Persons infected with HCV should be counseled on how to avoid HCV transmission to others (Class I, level C) HCV-infected persons should be counseled to avoid sharing toothbrushes and dental or shaving equipment Stop using illicit drugs HCV-infected persons should be advised to not donate blood, body organs, other tissue or semen HCV-infected persons should be counseled that the risk of sexual transmission is low, and that the infection itself is not a reason to change sexual practices ( i.e. those in long-term relationships need not start using barrier precautions and others should always practice safer sex) AASLD Recommendation 4. Patients suspected of having acute or chronic HCV infection should first be tested for anti-hcv (Class I, Level B.) 5. HCV RA testing should be performed in: a) Patients with a positive anti-hcv test (Class I, Level B) b) Patients for whom antiviral treatment is being considered, using a sensitive quantitative assay (Class I, Level A) c) Patients with unexplained liver disease whose anti-hcv test is negative and who are immunocompromised or suspected of having acute HCV infection (Class I, Level B).. HCV genotyping should be performed in all HCV-infected persons prior to interferon-based treatment in order to plan for the dose and duration of therapy and to estimate the likelihood of response (Class I, Level A) Sensitivity and Positive Predictive Value of Anti-HCV EIA Wk. Before test positive Sensitivity Positive Predictive Value Low Prevalence High Prevalence EIA EIA EIA n.d. Anti HCV s/co >.8 is usually true positive Gretch D, Hepatology,

10 IU/mL) Interpretation of HCV Assays Anti-HCV HCV RA Interpretation Positive Positive Acute or chronic HCV depending on the clinical context. Positive egative Resolution of HCV; Acute HCV during period of low-level viremia, false positive egative Positive Early acute HCV infection; chronic HCV in setting of immunosuppressed state; false positive HCV RA test. AASLD Recommendation 7. A liver biopsy should be considered in patients with chronic hepatitis C infection if the patient and health care provider wish information regarding fibrosis stage for prognostic purposes or to make a decision regarding treatment (Class IIa, Level B) 8. Currently available noninvasive tests may be useful in defining the presence or absence of advanced fibrosis in persons with chronic hepatitis C infection, but should not replace the liver biopsy in routine clinical practice (Class IIb, Level C). egative egative Absence of HCV infection. Persons therapy is accepted Age 18 years or older and HCV RA positive in serum and Liver biopsy showing chronic hepatitis with significant fibrosis (bridging fibrosis or higher) and Compensated liver disease (total serum bilirubin <1.5 g/dl; IR 1.5; serum albumin >.4, platelet count > 75, mm and no evidence of hepatic decompensation (hepatic encephalopathy or ascites) and Acceptable hematological and biochemical indices (Hemoglobin >1 g/dl for men and 12 g/dl for women; neutrophil count >15 /mm and serum creatinine <1.5 mg/dl and Willing to be treated and to adhere to treatment requirements and o contraindications Persons for whom therapy is currently contraindicated Major uncontrolled depressive illness Solid organ transplant (renal, heart or lung) Autoimmune hepatitis or other autoimmune condition known to be exacerbated by peginterferon and ribavirin Untreated thyroid disease Pregnant or unwilling to comply with adequate contraception Severe concurrent medical disease such as sever hypertension, heart failure, signicficant coronary heart disease, poorly controlled diabetes, chronic obstructive pulmonary disease Age less than 2 years Known hypersensitivity to drugs used to treat HCV Definitions of early virological response Treatment of Chronic Hepatitis C: Breakthrough and Relapse Response Definition RVR* HCV RA negative (<5 IU/mL) at week 4 EVR** Complete EVR (cevr) Partial EVR (pevr) o RVR but HCV RA negative (<5 IU/mL) at week 12 o RVR and HCV RA positive at week 12, but 2 log 1 drop from baseline on-evr <2 log 1 drop from baseline at week 12 * RVR = rapid virological response ** EVR = early virological response HCV RA (log PegIF/RBV ull response Partial response Breakthrough Relapse 2 log decline 2 Limit of detection 1 SVR Weeks 1

11 Result of HCV Treatment Sustained Virological Response Factors Associated With SVR % 4% 2% % PEG-IF alfa-2b PEG-IF alfa-2a Manns et al., Lancet 21 Fried et al., EJM 22 % 5% 54% 47% 47% 45% n = 55 n = 514 n = 511 n = 444 n = 45 4% % 1/1.2 g RBV.8 g RBV n = 224 2% % IF + RBV,5 PEG-IF + RBV 1,5 PEG-IF + RBV IF + RBV PEG-IF + P PEG-IF + RBV Pretreatment or fixed Genotype HCV RA level Histology Race HIV coinfection Steatosis Body weight Adherence Dynamic factors Rapid virologic response (HCV RA negative at Wk 4) Early virologic response Partial (HCV RA decline of > 2 logs at Wk 12) Complete (HCV RA negative at Wk 12) PegIF/ RBV 8mg/d 24 weeks Anti-HCV + HCV viral load and genotype HCV genotype 2, HCV genotype 1(4-) Treat 24 wk Liver Biopsy >A2F2 PegIF/RBV 8-14 mg/d HCV RA at end of treatment and 24 wk post treatment (SVR)* Wk 12 HCV RA >2log drop Wk 24 HCV RA* Continue to wk 48 + Mild histology Follow up <2log drop Stop Delay clearance week should continue for 72 AASLD Recommendation General Management Issues 4. All persons with chronic HCV infection who lack antibodies to hepatitis A and B should be offered vaccination against these two viral infections (Class IIa, Level C). 5. Persons with chronic HCV infection should be advised to abstain from alcohol consumption (Class IIb, Level C).. o recommendation can be made for the use of herbal products. (Class III, level C). Test with sensitive test with limit <5 IU HCV RA at wk 48 (ETR)* and wk 72 (SVR)* 11