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An open label, comparative, multi-center study of peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin in the treatment of patients with chronic hepatitis C/hepatitis B dual infection versus with mono-infected chronic hepatitis C: An interim report
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Reported by Jules Levin
EASL, April 2007, Barcelona, Spain
CJ Liu,1 PJ Chen,1 JH Kao,1 MY Lai,1 CL Chen,1 CH Liu,1 DS Chen,1 ML Yu,2 CY Dai,2 ZY Lin,2 WL Chuang,2 SN Lu,3 JH Wang,3 TH Hu,3 CH Hung,3 CH Chen,3
CM Lee,3 WW Su,4 SS Wu,4 CL Lin,5 LY Liao,5 HT Kuo,6 HT Tung,6 YC Chao,7 SY Tung,8 SS Yang9
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; 8Chang Gung Memorial Hospital, Chiayi, Taiwan; 9Cathay General Hospital, Taiwan
STUDY AIM
To evaluate the efficacy and safety of peginterferon alfa-2a (40kD) (PEGASYS) in combination with ribavirin for the treatment of patients with chronic hepatitis C/ hepatitis B virus (HCV/HBV) co-infection compared to those mono-infected with chronic hepatitis C.
INTRODUCTION
Dual infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) is not uncommon, especially 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 patients.1-3
Patients with dual HBV and HCV infection have more severe liver disease and an increased risk of hepatocellular carcinoma (HCC).4,5 Few data exist on treatment of dual infection. Trials assessing the treatment of dually infected patients with conventional interferon (IFN) monotherapy have been disappointing.6,7 Recent pilot studies using conventional IFN in combination with ribavirin for the treatment of patients with dual chronic hepatitis C and B for 6 months, have shown a sustained HCV clearance rate comparable to that in HCV mono-infected patients.8-10 To date, no clinical trial has assessed the use of peginterferon-based combination therapy in dual HBV and HCV infection.
SUMMARY
A sustained HCV clearance rate of 63% was achieved in the most difficult-to-treat patients with genotype 1 HCV/HBV dual infection, 24 weeks posttreatment.
In HCV genotype non-1 dually infected patients, HCV clearance (83%) was achieved to an extent comparable to that observed in HCV mono-infected
patients (76 and 88% for genotype 1 and non-1 infected patients, respectively).
In general, there was little difference between HCV response rates for genotype 1 and non-1 patients at the end of treatment and 24 weeks post-treatment.
HBV virological response was observed in 51% of the patients with dual chronic hepatitis C and HBeAg-negative chronic hepatitis B.
Rebound of HBV DNA was found in 32% of the dually infected patients whose serum HBV DNA was undetectable pre-treatment.
CONCLUSIONS
Combination therapy using PEGASYS with ribavirin appears to be safe and effective for patients dually infected with HCV and HBV.
Final results will be available at the end of 2007.
METHODS
Eligible patients with active HCV (serum ALT level >1.5 x upper limit of normal and HCV RNA level >105 copies/mL), with (n=161) or without (n=160) co-existence of HBsAg, were consecutively enrolled (Figure 1).
Patients infected with HCV genotype 1 received a 48-week combination therapy with PEGASYS 180 _g weekly plus daily ribavirin 1000-1200 mg (n=207).
Patients with HCV genotype non-1 received a 24-week combination therapy with PEGASYS 180 _g weekly plus daily ribavirin 800 mg (n=114).
The primary efficacy parameter was sustained HCV RNA clearance at 24 weeks
post-treatment. HCV RNA was measured using an in-house real-time PCR assay
with a lower limit of detection of about 100-1,000 copies/mL.
Primary analysis was intention-to-treat (ITT) with a per protocol (PP)
secondary analysis.
Secondary efficacy parameters included ALT normalisation and HBV virological
response (VR) (<1,000 copies/mL) at end of treatment and 24 weeks posttreatment.
HBV DNA was also measured using an in-house real-time PCR assay with a
lower limit of detection of 1,000 copies/mL.
RESULTS
Patient recruitment and enrolment
Patients were recruited from June 2004 and enrolment was completed in February 2006. Here we present interim results updated in February 2007.
The majority of dually infected patients were male (Table1).
Mono-infected HCV genotype non-1 infected patients tended to have a higher proportion of female patients enrolled than the other patients groups.
Intention-to treat (ITT) analysis
ITT analysis included all patients that received at least one dose of study treatment including withdrawals; withdrawn cases with missing data at 24 weeks posttreatment were counted as treatment failure.
Patients numbers for the interim ITT analysis are shown in Table 2.
By the end of February 2007, 26 (8.1%) patients were withdrawn prematurely from the study.
A total of 234 (72.9%) patients completed treatment and follow-up, with the remainder still undergoing therapy.
Table 2. Patient numbers for interim analysis
HCV RNA ranged from 5.6 to 7.3 log in HBV/HCV dual infected, and 4 log in non-1 genotype HCV monoinfected and 7.4 log in HCV genotype 1 monoinfected. Median HBV DNA was 1.27 to 1.33 x 10 to the 4th.
HCV response
HCV genotype non-1 infected patients had a slightly better sustained response than genotype 1 patients in both HCV and HBV dually infected and HCV monoinfected patients (Figure 2).
HCV clearance rates were comparable at the end of treatment (88% vs 92%) and 24 weeks post-treatment (83% vs 88%) for dually infected and HCV monoinfected patients with non-1 genotype infection, respectively.
The majority of HCV genotype 1 infected patients with dual HCV/HBV infection achieved a sustained response (63%) after 24 weeks of treatment-free follow-up
and an even higher rate of HCV clearance was achieved in HCV mono-infected patients (76%).
A per protocol analysis, including data for all patients completing 12 weeks of treatment, showed comparable end-of-treatment and sustained responses except for patients with genotype 1 HCV/HBV dual infection (Figure 3).
Figure 2. HCV RNA clearance at the end of treatment and at 24 weeks
post-treatment ITT
* ITT (intention-to-treat) analysis of patients receiving at least one dose of study
treatment including withdrawals; withdrawn cases without HCV RNA testing at
24 weeks post-treatment are counted as treatment failure
Figure 3. HCV RNA clearance at the end of treatment and at 24 weeks
post-treatment PP
* PP (Per protocol) anaysis of patients completing at least 12 weeks of treatment
HBV response
In 84 dually infected patients with available data for analysis, 43 (51.2%) had detectable serum HBV DNA pre-treatment.
Of the 43 patients with detectable serum HBV DNA at baseline, HBV virological response (VR) was obtained in 24 patients (55.8%) at the end of treatment and in 22 (51.2%) at the end of follow-up (Table 3).
None of the dually infected patients lost HBsAg at the end of treatment-free follow-up.
Of the 41 patients with undetectable serum HBV DNA at baseline, rebound of HBV DNA was observed in 13 patients (31.7%), including 5 (12.2%) and 11 (26.8%) at the end of treatment and follow-up, respectively. Twelve of the 13 patients achieved HCV SVR; none was associated with an elevation of serum ALT >200 IU/L (Table 4).
Biochemical response
HCV mono-infected patients had a slightly better ALT normalisation rate than HCV and HBV dually infected patients at the end of treatment and post-treatment
follow-up by ITT and PP analyses (Figures 4 and 5).
The majority of HCV genotype 1-infected patients with dual HCV/HBV infection achieved a biochemical response (59%) after 24 weeks of treatment-free follow-up and an even higher rate of HCV clearance was achieved in HCV mono-infected patients (69%).
Patient withdrawals
Causes of the 26 withdrawals from the study are shown in Table 5.
The two most common reasons for withdrawal (2.5% of patient population) were non-compliance and skin lesions.
REFERENCES
1. Liu Z, Hou J. Hepatitis B virus (HBV) and hepatitis C virus (HCV) dual infection. Int J Med Sci 2006;3(2):57-62.
2. Chen DS, Kuo GC, Sung JL, et al. Hepatitis C virus infection in an area hyperendemic for hepatitis B and chronic liver disease: the Taiwan experience. J Infect Dis 1990;162:817-22.
3. Liu CJ, Liou JM, Chen DS, Chen PJ. 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, Coppola N, Scolastico C, 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, Fattovich G, Noventa F, 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.
6. Sagnelli E, Coppola N, Scolastico C, et al. Isolated anti-HBc in chronic hepatitis C predicts a poor response to interferon treatment. J Med Virol 2001;65(4):681-7.
7. Khattab E, Chemin I, Vuillermoz I, et al. Analysis of HCV co-infection with occult hepatitis B virus in patients undergoing IFN therapy. J Clin Virol 2005;33(2):150-7.
8. Chuang WL, Dai CY, Chang WY, et al. Viral interaction and responses in chronic hepatitis C and B coinfected patients with interferon-alpha plus ribavirin combination therapy. Antivir Ther
2005;10(1):125-33.
9. Liu CJ, Chen PJ, Lai MY, et al. Ribavirin and interferon is effective for hepatitis C virus clearance in hepatitis B and C dually infected patients. Hepatology 2003;37:568-76.
10. Hung CH, Lee CM, Lu SN, et al. Combination therapy with interferon-alpha and ribavirin in patients with dual hepatitis B and hepatitis C virus infection. J Gastroenterol Hepatol 2005;20(5):727-32.
Diclosure INFORMATION
This research was partly funded by Roche, Basel, Switzerland
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