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On-Treatment Quantification of HBsAg in Difficult-to-Treat Patients With Lamivudine Resistance Can Help Identify Those Most Likely to Achieve Sustained Post-Treatment Response to Peginterferon Alfa-2a Rescue Therapy
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Reported by Jules Levin Nov 3 2009, Boston, MA, USA
Hou J,1 Sun J,1 Xie Q,2 Li X,3 Zhang J,4 Wang Y,5 Wang H,6 Lai JY,7 Chen S,8 Jia J,9 Sheng J-F,10 Chan H L-Y,11 Wang J,12 Li M,13 Jiang M,14 Popescu M,15 Sung JYJ11
1Nanfang Hospital, Guangzhou, China; 2Ruijin Hospital, Shanghai, China; 3You'an Hospital, Beijing, China; 4Huashan Hospital, Shanghai, China; 5Xi'nan Hospital, Changqing, China; 6People's Hospital, Beijing, China; 7Princess Margaret Hospital, Hong Kong, China; 8Infectious Disease Hospital, Shandong, China; 9Friendship Hospital, Beijing, China;
10The First Affiliated College of Medicine, Zhejiang University, Zhejiang, China; 11Prince of Wales Hospital, Hong Kong, China; 12Public Health Clinical Center Affiliate to Fudan University, Shanghai, China; 13Tuen Mun Hospital, Hong Kong, China; 14Roche, Shanghai, China; 15F. Hoffmann-La Roche, Basel, Switzerland
Presented at the 60th Annual Meeting of the American Association for the Study of Liver Diseases 30 October - 3 November 2009, Boston, USA
Summary
A finite course of peginterferon alfa-2a is associated with significantly higher rates of HBeAg seroconversion post-treatment than 72 weeks of continuous adefovir therapy in lamivudine-resistant patients
Importantly, a number of peginterferon alfa-2a treated patients achieved HBsAg clearance post-treatment - 16.7% of patients with HBeAg seroconversion - whilst none of the adefovir-treated patients achieved this clinically relevant endpoint. By comparison, 9% (8/87) of HBeAg-positive patients achieving HBeAg seroconversion 6 months post-treatment in the phase 3 study of peginterferon alfa-2a vs lamivudine achieved HBsAg clearance 6 months post-treatment8
The rate of on-treatment HBsAg decline was greater in patients achieving
HBeAg seroconversion 6 months post-treatment than in patients not achieving HBeAg seroconversion
In patients with HBsAg <1500 IU/mL at week 24, rates of HBeAg seroconversion 6 months post-treatment were more than double those in patients with higher HBsAg levels at this time point
Conclusions
We have shown that even hard-to-treat patients with lamivudine resistance can achieve HBeAg seroconversion and HBsAg clearance
- the closest outcome to clinical cure of CHB - with a finite course of peginterferon alfa-2a. As seen in the phase 3 study of peginterferon alfa-2a ± lamivudine vs lamivudine in HBeAg-positive patients,7 on-treatment quantification of HBsAg may help to identify patients most likely to benefit from peginterferon alfa-2a therapy
Background
Nucleos(t)ide analogs have antiviral activity that can effectively suppress replication of the hepatitis B virus. However, for the virus to remain suppressed at the low levels required to prevent disease progression, these agents need to be administered for long periods of time. The prolonged treatment duration required is associated with an increased risk of drug resistance
For example, in patients treated with lamivudine for 4 years, 70% developed resistance to this agent.1-3 Similarly for adefovir, resistance has been reported in 1-3%, 11%, 18% and 28% of patients at years 2, 3, 4 and 5, respectively4
Rescue therapy with other nucleos(t)ide analogs is often limited by the cross-resistance of these agents5,6
Analysis of the phase 3 study comparing peginterferon alfa-2a ± lamivudine with lamivudine alone has demonstrated that patients achieving HBsAg levels <1500 IU/mL during therapy have an increased chance of achieving HBeAg seroconversion post-treatment7
In the current analysis we determined if on-treatment quantification of HBsAg levels, and use of the HBsAg cut-off values used in the phase 3 study, can help to identify the patients with lamivudine-resistant chronic hepatitis B most likely to achieve sustained post-treatment response to peginterferon alfa-2a
Results
Lamivudine-resistant patients can achieve HBeAg seroconversion and HBsAg clearance with peginterferon alfa-2a
The rate of post-treatment HBeAg seroconversion achieved with peginterferon alfa-2a was significantly higher than that achieved at the end of the 72-week treatment with adefovir (P=0.045)
Of the 18 peginterferon alfa-2a-treated patients who achieved HBeAg seroconversion, three (16.7%) also achieved HBsAg seroconversion (Figure 1)
Figure 1. Peginterferon alfa-2a-treated lamivudine-resistant patient with HBeAg seroconversion achieve high rates of HBsAg clearance
On-treatment HBsAg decline in lamivudine-resistant patients
HBsAg levels in peginterferon alfa-2a-treated patients had decreased from baseline by 0.75 log10 IU/mL at week 24 and by 0.92 log10 IU/mL at week 48. These declines were significantly (P<0.001 for both comparisons) greater than those achieved by adefovir-treated patients (0.31 log10 IU/mL and 0.35 log10, respectively)
Association of on-treatment HBsAg decline with post-treatment response to peginterferon alfa-2a
A total of 18 (11.6%) peginterferon alfa-2a-treated patients achieved HBeAg seroconversion 6 months post-treatment (compared with 3.8% of adefovir-treated patients; P=0.045)
HBsAg decline was more pronounced in patients achieving HBeAg seroconversion 6 months post-treatment (responders) than in patients without HBeAg seroconversion 6 months post-treatment (non-responders) (Figure 2)
Figure 2. On-treatment decline in HBsAg from baseline is greater
in responders to peginterferon alfa-2a than in non-responders
At week 24 of therapy, 30.3% (47/155) peginterferon alfa-2a-treated patients had HBsAg levels <1500 IU/mL
The rate of HBeAg seroconversion 6 months post-treatment in patients with HBsAg <1500 IU/mL at week 24 was more than double that in patients with HBsAg ≥1500 IU/mL at week 24 (Figure 3)
Figure 3. Low levels of HBsAg at week 24 are associated with increased rates of HBeAg seroconversion 6 months post-treatment
Safety
No unexpected adverse events were reported in either treatment group Rates of serious adverse events were 7.8% in the peginterferon alfa-2a group and 2.1% in the adefovir group; however, all serious adverse events had been resolved at the end of the study
Despite discontinuation of lamivudine, only 1% of each group experienced a serious hepatobiliary disorder (abnormal hepatic function/hepatitis in peginterferon alfa-2a-treated patients and choleastatic jaundince in adefovir-treated patients)
References
1. Liaw YF. The current management of HBV drug resistance. J Clin Virol.
2005; 34 (suppl 1):S143-6
2. Liaw YF. Impact of YMDD mutations during lamivudine therapy in
patients with chronic hepatitis B. Antivir Chem Chemother 2001; 21 (suppl 1):67-71
3. Kwon SY et al. Rapid re-emergence of YMDD mutation of hepatitis B
virus with hepatic decompensation after lamivudine retreatment. World J Gastroenterol 2008; 14:4416-4419
4. Leemans WF et al. Future prospectives for the management of chronic hepatitis B. World J Gastroenterol 2007; 13:2554-2567
5. Lada O et al. In vitro susceptibility of lamivudine-resistant hepatitis B virus to adefovir and tenofovir. Antivir Ther 2004; 9:353-363
6. Yang H et al. Cross-resistance testing of next-generation nucleoside and nucleotide analogues against lamivudine-resistant HBV. Antiv Ther 2005; 10:625-633
7. Lau GKK et al. On-treatment monitoring of HBsAg levels to predict response to peginterferon alfa-2a in patients with HBeAg-positive chronic hepatitis B. J Hepatol 2009; 50 (suppl 1):S333
8. Lau GKK et al. Peginterferon alfa-2a, lamivudine and the combination for HBeAg-positive chronic hepatitis B. New Engl J Med 2005; 352:2682-2695
Disclosure information:
Editorial support for the development of this poster was provided by Elements
Communications and funded by F. Hoffmann-La Roche, Basel, Switzerland
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