icon-    folder.gif   Conference Reports for NATAP  
 
  EASL
43rd Annual Meeting of the European Association For The Study Of The Liver
Milan, Italy
April 23-27, 2008
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An open-label, comparative, multicentre study of peginterferon alfa-2a (40KD) plus ribavirin in the treatment of patients chronically infected with HCV/HBV or HCV alone
 
 
  Reported by Jules Levn
43rd EASL, April 2008 Milan, Italy
 
C-J Liu1, W-L Chuang2, C-M Lee3, S-S Wu4, L-Y Liao5, H-T Kuo6, Y-C Chao7, C-L Chen1, P-J Chen1, D-S Chen1 1National Taiwan University College of Medicine and National Taiwan University Hospital, Taiwan; 2Kaohsiung Medical University Hospital, Taiwan; 3Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 4Changhua Christian Hospital, Taiwan; 5Ren-Ai Branch, Taipei City Hospital, Taiwan; 6Chi-Mei Medical Center, Taiwan; 7Tri-Service General Hospital, Taiwan
 
BACKGROUND
There is an urgent unmet need for efficacious therapy for patients co-infected with hepatitis B virus (HBV) and hepatitis C virus (HCV)
 
HBV/HCV co-infection is common in areas with a high endemic level of both infections, with a prevalence of around 7-11% in patients with chronic HBV infection and 2-10% of chronic hepatitis C patients1-3
 
Co-infected patients have more severe liver disease and an increased risk of hepatocellular carcinoma than mono-infected patients4,5
 
Few data exist on treatment of HBV/HCV co-infection. Trials assessing the treatment of co-infected patients with conventional interferon (IFN) monotherapy at conventional doses have been disappointing6,7
 
IFN + ribavirin (RBV) for 24 weeks in patients with HCV/HBV co-infection demonstrated an HCV sustained viral response (SVR) comparable to that observed in HCV mono-infected patients8-10
 
We hypothesised that when treating with peginterferon alfa-2a (PEGASYS) + RBV (COPEGUS), there will be no difference between the SVR for HCV mono-infected and HBV/HCV co-infected patients
 
Here we present the results of a large multicentre study with PEGASYS + COPEGUS in mono- and co-infected patients in Taiwan
 
AUTHOR SUMMARY
In difficult to treat HBV/HCV genotype 1 co-infected patients, 48 weeks' treatment with PEGASYS + COPEGUS achieved an HCV SVR in 72% of patients
 
In HBV/HCV genotype 2/3 co-infected patients, 83% of patients achieved an SVR after 24 weeks of treatment
- These results are comparable to that observed in HCV mono-infected patients where 77% of genotype 1 and 84% of genotype 2/3 infected patients achieved an SVR
 
HBV virologic response was obtained in 56% of patients with HBV/HCV co-infection
 
Importantly, HBsAg clearance - an important indicator of treatment success - was observed in 11% of HBV/HCV co-infected patients, 84% of which had undetectable HBV DNA at end of treatment
 
36% of HBV/HCV co-infected patients with undetectable serum HBV DNA pre-treatment experienced rebound of HBV DNA (from Jules: use of oral antiviral such as tenofovir or entecavir would suppress HBV DNA).
 
AUTHOR CONCLUSION
Combination therapy with PEGASYS and COPEGUS appears to be safe and effective to HBV/HCV co-infected patients with active chronic hepatitis C. The impact of the combination therapy on HBsAg clearance during longer-term observation remains to be determined.
 
OBJECTIVE
To evaluate the efficacy and safety of peginterferon alfa-2a (40KD) (PEGASYS) in combination with ribavirin (COPEGUS) for the treatment of patients co infected with HCV/HBV compared with those monoinfected with HCV
 
METHODS
· Eligible patients with active HCV (serum ALT level ≥1.5 x upper limit of normal and HCV RNA level ≥1000 copies/mL), with (n=161) or without (n=160) detectable HBsAg, were consecutively enrolled (Figure 1)
· Patients with HCV genotype 1 received 48 weeks of combination therapy with PEGASYS 180 ug weekly plus daily COPEGUS 1000-1200 mg (n=207)
· Patients with HCV genotype 2/3 received 24 weeks of combination therapy with PEGASYS 180 ug weekly plus daily COPEGUS 800 mg (n=114)
· The primary efficacy parameter was sustained HCV RNA clearance (<25 IU/mL) 24 weeks off-treatment (SVR). HCV RNA was measured using a commercial real-time PCR assay with a lower limit of detection of 25 IU/mL (Cobas Taqman HCV Test v2.0)
· Secondary endpoints were HBV viral response (<1000 copies/mL), ALT normalisation and HBsAg clearance at end of treatment and 24 weeks off treatment. HBV DNA was also measured using an in-house realtime PCR assay with a lower limit of detection of 1000 copies/mL
 
RESULTS
 
Patient characteristics

· Patient characteristics are listed in Table 1:
- Dually infected patients were negative for HBeAg
- Except in the mono-infected HCV genotype 2/3 arm, the majority of patients were male
- The mean age was 50 years but patients in the mono-infected HCV genotype 1 arm were significantly younger
- Generally, HCV RNA load was higher in genotype 1 patients than in genotype 2/3 patients
- HBV DNA level was higher in genotype 2/3 patients
 

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HCV response
 
HCV genotype 2/3 infected patients had a slightly better sustained response than genotype 1 patients in both HBV/HCV co-infected and HCV mono-infected patients (Figure 2)
 
HCV clearance rates were comparable at the end of treatment (88% vs 92%) and 24 weeks off-treatment (83% vs 84%) for HBV/HCV co-infected and HCV mono-infected patients with genotype 2/3 infection, respectively
 
The majority of HCV genotype 1 infected patients with HBV/HCV co-infection achieved an SVR (72%) after 24 weeks of treatment-free follow-up and an even higher rate of HCV clearance was achieved in HCV mono-infected patients (77%)
 
A logistic regression analysis of factors associated with achieving SVR indicates that the most significant factors are baseline HCV RNA levels and extent of liver disease (Table 2)
 

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HBV response
 
Virological

 
After excluding patients who withdrew, we had 145 cases with serial serum HBV DNA samples available for analysis. Of these, 68 (47%) had HBV DNA >1000 copies/mL pre-treatment
- HBV virologic response (reduction of HBV DNA to <1000 copies/mL) was obtained in 47 patients (69%) at the end of treatment and in 38 (56%) at the end of follow up (Figure 3)
 
Of the 77 patients with undetectable (<1000 copies/mL) serum HBV DNA pre-treatment, rebound (increase of HBV DNA to >1000 copies/mL) occurred in 28 (36%); 15/47 (31%) with genotype 1 and 13/30 (43%) with genotype 2/3.
 
Median HBV DNA levels at end of treatment and end of follow-up in patients with detectable HBV DNA prior to treatment are given in Table 3
 
Stratifying the rebound patients by presence or absence of HCV SVR, we found that the rebound rate was 37% in patients with HCV SVR and 27% in patients without HCV SVR. This difference was not significant
 
No rebound was associated with an elevation of serum ALT >200 IU/mL, and most of these patients had achieved an HCV SVR
 
Figure 3: Viral response* (VR) at end of treatment (EoT) and 24 weeks after end of treatment (EoFU) in patients with detectable serum HBV DNA pre-treatment
 
* HBV virologic response, serum HBV DNA reached <1000 copies/mL at end of treatment or 24 weeks post-treatment in those with detectable serum HBV DNA pre-treatment
 

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HBsAg clearance
 
11% of HBV/HCV co-infected patients cleared HBsAg at the end of treatment-free follow-up (Table 4, Figure 6)
 
Baseline factors predisposing to HBsAg clearance were low HCV RNA levels, HBV genotype and low baseline HBsAg levels
 
Of the 85 co-infected patients with undetectable HBV prior to treatment, 12 (14%) cleared HBsAg
 
Of the 19 patients who cleared HBsAg, 16 (84%) had HBV DNA suppressed to undetectable levels at the end of treatment
 

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Biochemical response (ITT)
 
HCV mono-infected patients had a slightly higher ALT normalisation rate than HBV/HCV co-infected patients at the end of treatment and 24 weeks post treatment (ITT analysis)
 
The majority (62%) of HCV genotype 1 infected patients with HBV/HCV co infection achieved a biochemical response at 24-weeks post-treatment: for non-1 GT 67% achieved normalization 24-weeks post-treatment; for monoinfection percents were a little higher: 70% for GT-1 and 78% for GT-2.
 
Safety
 
Patient withdrawals
--21 patients withdrew from treatment during the study (Table 5)
-- The three most common reasons for withdrawal were non-compliance, skin lesions and general malaise
 

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REFERENCES
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3. Liu CJ, et al. Natural course and treatment of dual hepatitis B virus and hepatitis C virus infections. J Formos Med Assoc 2005;104(11):783-91.
4. Sagnelli E, et al. Virologic and clinical expressions of reciprocal inhibitory effect of hepatitis B, C, and delta viruses in patients with chronic hepatitis. Hepatology 2000;32(5):1106-10.
5. Benvegnu L, et al. Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis. A prospective study. Cancer 1994;74(9):2442-8.
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