Medical publications on HBV and HCV Coinfection

Transcription

1 Recent advances of HBV and HCV co-infection 台 中 榮 總 內 科 部 胃 腸 肝 膽 科 呂 宜 達 醫 師

2 Outline Epidemiology of HBV and HCV coinfection Clinical significance of HBV and HCV coinfection Interplay between HBV and HCV in coinfection Treatment HCV dominant coinfection HBV dominant coinfection Conclusions

3 HBV and HCV coinfection Definition: HBsAgantigenemiaand/or HBV viremia plus HCV viremia

4 HBV and HCV co-infection is not uncommon in HBV or HCV endemic area In areas where HBV or HCV is endemic, it is common to encounter patients infected with both viruses South East Asia Mediterranean region Prevalence 10-20% in patients with chronic hepatitis B 2-10% in anti-hcv-positive patients Crespo, et al. Am J Gastroenterol 1994 FattovichG, et al. J Infect Dis 1991 Gaeta GB, et al. J Hepatol2003

5 HBV-HCV HCV coinfection is frequently found in high-risk populations Similar transmission routes 66 Patients (%) Hemodialysis Organ Transplant patients Beta-thalassemia patients Injecting drug users HIV-positive patients Liu Z and HouJ. et al. IntJ Med Sci2006

6 Estimated prevalence rate of HBV-HCV HCV coinfection Worldwide, 350 million people with chronic HBV infection and an estimated 170 million people have chronic HCV infection. HBV-HCV coinfection is prevalent in area where HBV or HCV is endemic. Liu CJet al. HepatolInt2009

7 Clinical significance of HBV and HCV coinfection In most studies, Dually infected patients may have worse clinical outcomes than those with either virus mono-infection

8 Co-infection associated with a higher risk of cirrhosis or HCC Fibrosis score: Prevalence of cirrhosis: HCC: Repeatedly elevated ALT: B+C > C B+C > B B+C > C B+C > B B+C > C B+C > B B+C > B Sagnelli, et al. Infection 2004 Zarski, et al. J Hepatol 1998 Gaeta, et al. J Hepatol 2003 Kirk, et al. Hepatology 2004

9 Patients with HBV/HCV coinfection experience poor long-term outcomes A multicenter Italian (hospital-based cross-sectional) study Patients with HBV/HCV dual infection are at increased risk of cirrhosis compared with those with HBV or HCV monoinfection Patient with cirrhosis (%) 35% 30% 29% 25% 20% 15% 15% 10% Gaeta GB, et al. J Hepatol2003 5% 0% HBV only HBV-HCV

10 Influence and Interaction of HBV and HCV on the Risk of HCC Hospital-based cross-sectional study HCC No. (%) Controls No.(%) Relative Risk (95% C.I.) HBsAg(-) & Anti-HCV(-) 61 (12.5%) 267 (69.5%) 1.00 HBsAg(+)& Anti-HCV(-) 87 (68.0%) 104 (27.1%) 13.96( ) HBsAg(-) & Anti-HCV(+) 13 (10.1%) 8 (2.1%) 27.12( ) HBsAg(+) & Anti-HCV(+) 12(9.4%) 5 (1.3%) ( ) Total 128 (100%) 384 (100%) HBV and HCV have addictive effect on hepatic carcinogenesis Chuang WL, et al. Cancer 1992

11 Long-Term Outcome: Acute HCV Superinfection vs. CHB Alone (Hospital-based case-control study) (Age, Sex, HBeAg match) HCV on HBV HDV on HBV HBV alone Case No LC 20 (31.3%) 12 (18.7%) 11 (17.2%) HCC 6 (9.4%) 2 (3.1%) 3 (4.7%) LC HCV on HBV (P <0.0001) HDV on HBV HCC (P <0.039) HCV on HBV CHB alone HDV on HBV CHB alone Liaw YF, et al. Gastroenterology 2004

12 HBV-HCV HCV co-infected patients are at increased risk of HCC (Community-based cohort study) HCC risk is significantly higher in HBV-HCV co-infected patients than in those with mono-infection (p=0.030 and , respectively) B+C C B NBNC Huang YT, Chen CJ et al. J ClinOncol2011

13 Viral interference Mostly detectable HCV Viremia and low HBV DNA Sometimes high HBV DNA and low HCV RNA Cave: Mostly cross sectional studies Chu et al. J Gastroenterol Hepatol 2008 Crockett et al. Ann Clin Microbol and Antimicrobial 2005

14 Concurrent HBV and HCV coinfection HBV DNA positivity (%) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 54.0% P < % CHB Dual CHB and CHC A makred inhibition of HBV replication by HCV coinfection Sagnelli E, et al. Hepatology 2000

15 Chronic hepatitis B patients with and without HCV co-infection: HCV dominant Dai CY, et al. J. Gastroenterol. Hepatol. 2001

16 A suppressive effect of HCV on HBV viral load (Community-based cohort study) Viral load compared between groups with mono- and dual infection Huang YT, Chen CJ et al. J ClinOncol2011

17 Impact of HBV on HCV replication Detectable serum HCV RNA: In 41%~65% anti-hcv + and HBsAg+ In 90%~98 % anti-hcv + HCV RNA level lower in HBV DNA positive than in HBV DNA negative patients Wang, et al. J Gastroenterol 1999 Mathurin, et al. J Viral Hepatol 2000 Sagnelli, et al Hepatology 2000 Jardi, et al. Hepatolology 2001 Chu, et al. Scand J Gastroenterol 2004 Zarski, et al. J Hepatol1998

18 Concurrent HBV and HCV dual infection HCV RNA positivity (%) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 90.7% CHC P < % Dual CHC and CHB A significantly lower rate of HCV viremia among patients with chronic HBV and HCV dual infection Sagnelli E, et al. Hepatology 2000

19 Acute HBV Superinfection in Patients with Chronic Hepatitis C: HBV dominant HCV RNA positivity (%) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Sagnelli E, et al. Hepatology % CHC P < % CHC with acute HBV infection A marked inhibition of the HCV genome by HBV acute replication

20 Impact of HBV on HCV Impact of HBV on spontaneous HCV clearance Objective: factors associated with HCV clearance Study population: 203 spontaneously HCV-recovered subjects (HCV Ab+/RNA-) 293 chronically HCV-infected patients (HCV Ab+/RNA+) HIV co-infection negatively associated with HCV clearance (OR 0.37; ) HBV co-infection positively associated with HCV clearance (OR 5.0; ) Piasecki, et al. Hepatolology 2004

21 Concurrent HBV and HCV dual infection A much higher rate of spontaneous HCV clearance among HBV/HCV dually infected patients Dai CY, et al. GUT 2007

22 HBsAg-seropositivity seropositivity is associated with spontaneous HCV clearance A cohort of 106 patients of intravenous drug injection Exposure to HBV infection does not ensure spontaneous HCV clearance Van den Berg CH, el al. PLoSONE2011

23 Mini-summary Active HCV infection suppress HBV infection HBV could enhance spontaneous HCV clearance There exists in vivo reciprocal virus interaction between HBV and HCV infection Shih CM, et al Journal of Virology 1993 Schuttler Christian G, et al. J Hepatol 2002

24 Treatment of HBV/HCV coinfection All HCV RNA positive About 80-90% HCV dominant (HBeAg negative, low HBV DNA level) About 10-20% HBV dominant (HBeAgpositive, high HBV DNA level), usually in young children or teenager Practical goals for treatment Eradicate HCV Control HBV (ideally to eradicate)

25 Treatment of HBV/HCV coinfection: needed urgently, which virus is the target? 60% % 50% 48% 40% 30% 20% 10% 23% 14.5% 14.5% 0% Active HCV/Inactive HBV Active HCV/Active HBV Inactive HCV/Active HBV Inactive HCV/Inactive HBV Raimondo G et al. Hepatology 2006

26 Proposed strategies for the treatment of HBV/HCV hepatitis Possible regimens: Treat HCV as a priority by Peg-IFN/RBV Treat HBV as a priority by NUC and/or Peg-IFN Treat both: Combined Peg-IFN/RBV/NUC

27 Current treatment guidelines for HBV and HCV coinfection The dominant virus in HBV-HCV co-infected patients should be determined before treatment 1 HBV DNA levels are often low or undetectable and HCV is usually responsible for the activity of chronic hepatitis in most patients 2,3 HBV-HCV co-infected patients may be selected for antiviral treatment by the same criteria as those patients with HCV monoinfection McCaughanGW, et al. JGH CraxiA, et al. J Hepatol MarcellinP, et al. J Hepatol2009

28 Achieving an SVR may be considered equivalent to a cure for CHC

29 PEGSYS + ribavirin in patients with HCV/HBV or HCV alone study design (n=161) (n=160) (n=97) (n=64) (n=110) (n=50) Liu et al, Gastroenterology 2009

30 Similar SVR rates in HBV-HCV HCV co-infected compared with HCV monoinfected Asian patients HCV SVR(%) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% PEGASYS 180 μg/wk + RBV mg/d for 48 weeks 72% Liu CJ, et al. Gastroenterology % PEGASYS 180 μg/wk + RBV 800 mg/d for 24 weeks 77% 84% N= HCV GT1 HCV GT2/3 HCV GT1 HCV GT2/3 HBV-HCV co-infection HCV mono-infection ITT population

31 HBV viral load (low or intermediate level) does not affect HCV SVR Active HBV (intermediate level) Inactive HBV (low level)hbv DNA HBVDNA 10 4 ~10 5 copies/ml <10 4 copies/ml Case No. 40 (25%) 121 (75%) SVR 77.5% 76.9% Liu CJ, et al, Gastroenterology 2009

32 HCV SVR is durable in HBV-HCV HCV co-infected pts Median 4.6-year (range 1-5 years ) post-treatment follow-up Reappearance of HCV RNA in 6 pts(5 relapse, 1 re-infection) HCV SVR(%) 100% PEGASYS 180 μg/wk + RBV mg/d for 48 weeks 94% PEGASYS 180 μg/wk + RBV 800 mg/d for 24 weeks 100% 100% 98% 80% 60% 40% 20% 0% N= 78/83 55/55 86/86 39/40 HCV GT1 HCV GT2/3 HCV GT1 HCV GT2/3 HBV-HCV co-infection HCV mono-infection Yu ML, Hepatology 2013 (Epub)

33 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Virological response* to HBV: in paitents with detectable HBV DNA pre-treatment HBV VR*(%) 68 patients with HBV-HCV co-infection had detectable HBV DNA at baseline End-of-treatment 63% Liu CJ, et al, Gastroenterology % 6m post-treatment 58% 53% HCV GT1 HCV GT2/3 HCV GT1 HCV GT2/3 * HBV DNA <1,000 copies/ml at end of therapy or post-treatment

34 HBsAg clearance 6 months post-treatment treatment Total HCV GT 1 HCV GT 2/3 P EOT 19/161 (11.8%) 14/97 5/64 (11.8%) (14.4%) (7.8%) EOFU 18/161 (11.2%) 12/97 (12.4%) 6/64 (9.4%) Seroconversionto anti-hbs noted in 8 (44.4%) of the 18 cases at EOFU Liu CJ, et al, Gastroenterology 2009

35 Low pre-treatment HBsAg titer is associated with clearance of HBsAg 6 months post-treatment treatment Liu CJ, et al, Gastroenterology 2009

36 Baseline HBsAg level predicts HBsAg clearance 6 months post-treatment treatment By using ROC curve, 20 IU/mL was the best cut-off of serum HBsAglevel at baseline for predicting HBsAg clearance 6 months post-treatment Accuracy Sensitivity Specificity PPV NPV 91.2% 85.7% 84% 41.4% 97.8% The HBsAgclearance rate among the 30 patients with baseline serum HBsAg<20 IU/mL (40%, n=12)was significantly greater than among the 90 patients with baseline serum HBsAg >20 IU/mL (2.2%, n=2; P <0.05) Yu ML et al. J Infect Dis 2010

37 Around 30% of cumulative rate of sustained HBsAg seroclearance during 5Y F/U 48-wk PegIFN/RBV 24-wk PegIFN/RBV Yu ML, Hepatology2013 (Epub)

38 19 German ptswith chronic HBV/HCV coinfection (HBsAg and HCV RNA positive) 10 HCV GT1; 9 HCV GT 2/3 Baseline HBV DNA negative in 13 (68%) Peg-IFN alfa-2b and ribavirin for 48 weeks PotthoffA, et al. J Hepatol2008

39 HCV SVR rates in HBV-HCV HCV co-infected patients * GT2: n=4; GT3: n=5 PotthoffA, et al. J Hepatol2008

40 Reactivation of HBV? Releasing the enemy within

41 HBV reappearance in patients with undetectable serum HBV DNA pre-treatment Post-treatment HBV reappearance: 28/77 (36.4%) No significant hepatitis flare Dual Hepatitis C and B HCV GT1 HCV GT 2/3 HBV DNA Number (%) Baseline EOT EOFU (68.1%) 17 (56.7%) + 5 (10.6%) 7 (23.3%) + 6 (12.8%) 5 (16.7%) (8.5%) 1 (3.3%) HBV reappearance: increase of serum HBV DNA to >1,000 copies/ml post-treatment Liu CJ, et al, Gastroenterology 2009

42 German experience Potthoffet al. J Hepatol2008 HBV reappearance rate: 4/19 (21%)

43 Mini-Summary (1) HCV SVR in dually infected patients is the same as in HCV mono-infected patients SVR is also durable (~97%) HBV co-infection does not influence HCV SVR Active HBV Inactive HBV

44 Mini-Summary (2) HBV virological response was obtained in 53~58% of patients with dual HBVHCV infection Importantly, HBsAgclearance was observed in ~10% of dually infected patients at end of treatment and increased to about ~30% during 4.6-year follow-up However, about 33%of dually infected patients experienced reappearance of HBV DNA, but without significant hepatitis flare

45 Optimal treatment for HBV dominant dual infection? Further clinical trials are needed!

46 Combined IFN plus Lamivudine treatment in patients with HBeAg+ve, dual HBV and HCV chronic infection HCV SVR, EOT/EOFU HBV DNA negative, EOT/EOFU HBsAg loss HBeAg loss/ Anti-Hbe conversion 50%/50% 37.5%/12.5% 0% 37.5%/20% Marroneet al. J Hepatol2004

47 Conclusions HCV/HBV coinfection is prevalent in some parts of South- East Asia HBV endemic countries High risk populations include IDUs and HIV patients High risk of LC and HCC compared to either virus monoinfection HCV/HBV dually infected patients with HCV dominance should be treated with the same regimen as monoinfected HCV patients Comparable HCV SVR rates and HCV SVR durability in HCV/HBV dually infected patients as observed among those with HCV monoinfection Peg-IFN/RBV therapy may also result in an HBV virologic response Clearance of HBsAgis possible in a significant proportion of patients, especially in those with low baseline HBsAg level