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  The 21st Conference of the Asian Pacific Association for the Study of the Liver
APASL Feb 17-20, 2011
Bangkok, Thailand
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Response rates with shorter duration and lower doses of peginterferon alfa-2a are inferior to those with 180 μg for 48 weeks
  Reported by Jules Levin
Presented at The 21st Conference of the Asian Pacific Association for the Study of the Liver (APASL 2011), 17-20 February 2011, Bangkok, Thailand
Q Xie,1 J Sung,2 T Tanwandee,3 KH Han,4 C Wat,5 C-W Hsu,6 J Jia7 1Department of Infectious Diseases, Ruijin Hospital, Shanghai, China; 2Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong; 3Department of Microbiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; 4Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea; 5Roche Products Ltd, Welwyn Garden City, UK; 6Liver Research Unit, Chang Gung Memorial Hospital and Chang Gung University College of Medicine Taipei, Taiwan; 7Beijing Friendship Hospital, Capital Medical University, Beijing, China
The NEPTUNE study confirms that compared with lower doses and shorter durations, the licensed dose (180 μg/week) and duration (48 weeks) of PEG-IFN alfa-2a is the most efficacious and beneficial treatment regimen for CHB patients
Rate of HBeAg seroconversion 6 months post-treatment was higher in the 180 μg/48-week arm than in the other treatment arms (36.2% compared with 14.1-25.8% in the other treatment arms). The 90 μg/week dose was inferior to the 180 μg/week dose and 24 weeks of treatment were inferior to 48 weeks of treatment for the primary efficacy endpoint
Response to peginterferon alfa-2 therapy is known to increase post-treatment.1 In the NEPTUNE study, HBeAg seroconversion increased in the 24-week arms between 6 months and 12 months post-treatment (week 72 time point). However, they did not reach the levels achieved with the licensed regimen (180 μg/48 weeks) 6 months post-treatment (the 12-month post-treatment time point had not been reached for the 48-week arms)
Rates of response were consistently higher in the 180 μg/48-week arm for secondary endpoints
High rates of response were achieved in the 180/48-week arm in patients infected with genotype B or genotype C (42.2% and 38.8%, respectively, for HBeAg seroconversion) and a similar trend was observed for all secondary efficacy parameters
Peginterferon alfa-2a (40 kDa; PEG-IFN alfa-2a; PEGASYS) has proven efficacy in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB)1 and is recommended as a first-line therapy for CHB by all international treatment guidelines2-4
Although the licensed dose and duration of PEG-IFN alfa 2a is 180 μg/week for 48 weeks in all countries, there is currently a lack of consensus on the most appropriate dose and duration, which is reflected in varying recommendations in international guidelines2-4
The lack of consensus may result from varying interpretations of the results from the phase 25 and the phase 31 studies of PEG-IFN alfa-2a in HBeAg-positive patients. In the phase 2 study (N=194), patients received PEG-IFN alfa-2a (90, 180 or 270 μg/week) or conventional interferon for 24 weeks.5 Rates of sustained immune control (HBeAg seroconversion 6 months post-treatment) were similar in all three PEG-IFN alfa-2a groups (32%) and significantly higher than in the interferon group (25%). In the phase 3 study, patients (N=271) received a finite 48-week course of PEG-IFN alfa-2a (180 μg/week) and 32% of patients achieved HBeAg seroconversion 6 months post-treatment1
As neither the phase 2 study nor the phase 3 study was designed to identify both the most appropriate dose and duration of PEG-IFN alfa-2a in HBeAg-positive patients and cross-study comparisons are not appropriate, a single study comparing different treatment regimens was required. The NEPTUNE study was designed to establish the most appropriate PEG-IFN alfa-2a treatment regimen for HBeAg-positive patients
The aim of the NEPTUNE study was to compare the efficacy and safety of PEG-IFN alfa-2a given for either 24 or 48 weeks and at doses of either 90 μg/week or 180 μg/week
This was a phase 4, double-blind, randomized, multicenter trial with a 2 x 2 factorial design (Figure 1). HBeAg-positive patients were randomized (1:1:1:1) to PEG-IFN alfa-2a (90 μg/week or 180 μg/week for 24 or 48 weeks) by subcutaneous injection once weekly. Patients were stratified by baseline alanine aminotransferase (ALT) levels: > upper limit of normal (ULN) - 2 x ULN; 2-5 x ULN; 5-10 x ULN and viral genotype (A, B, D or C plus other genotypes)
Figure 1. NEPTUNE Study: a 2 x 2 factorial design non-inferiority study in HBeAg-positive patients


The primary efficacy parameter was HBeAg seroconversion 6 months post-treatment. Secondary endpoints included HBeAg loss, HBsAg seroconversion, HBsAg clearance, ALT normalization, HBV DNA <2,000 IU/mL and HBV DNA <20,000 IU/mL and a triple endpoint of HBeAg seroconversion, ALT normalization and HBV DNA <20,000 IU/mL. All secondary endpoints were assessed 6 months post-treatment. As rates of response to PEG-IFN alfa-2a are known to increase post-treatment, HBeAg seroconversion was also assessed at week 72 (6 months post-treatment for the 48-week arms and 12 months post-treatment for the 24-week arms)
Statistical Analysis
The null hypotheses were that 24 weeks is inferior to 48 weeks and 90 μg/week is inferior to 180 μg/week. The primary test statistic was the odds ratio (OR) with a non inferiority margin pre-specified as 1.88. OR 48/24 or 180/90 was significant if the upper 95% confidence interval (CI) was <1.88 at the significance level of 0.025; the null hypothesis would be rejected
Highest rates of HBeAg seroconversion 6 months post-treatment were achieved in the 180 μg/48-week arm (36.2%; Figure 2), which is the licensed dose and duration for PEG-IFN alfa-2a
At week 72, response rates in the 24-week arm (12 months post-treatment) had increased to 18.3% in the 90 ug/24 week-arm and 27.1% in the 180 ug/24-week arm, but did not reach the levels achieved in the 180 ug/48-week arm 6 months post-treatment
To test the null hypotheses, the duration groups and dose groups were pooled. For both comparisons, the null hypotheses were retained: the upper 95% CI was >1.88 and the p values for non inferiority were not significant. This demonstrates that 90 μg/week is inferior to 180 μg/week and that 24 weeks of therapy are inferior to 48 weeks of therapy
Figure 2. Highest rates of HBeAg seroconversion in the 180 μg/48-week arm. A. Response rates in the four treatment arms; B. Non-inferiority analyses of 90 μg/week versus 180 μg/week and 24 weeks versus 48 weeks



Highest rates of all secondary endpoint parameters were achieve in the 180 ug/48-week arm (Table 1). In total, three patients in each of the 48-week treatment arms achieved HBsAg clearance compared with only one patient in the 90 μg/24-week arm and no patients in the 180 μg/24-week arm


In the majority of cases where hypothesis testing was conducted for secondary endpoints, 90 μg/week was inferior to 180 μg/week and 24 weeks of therapy were inferior to 48 weeks of therapy (Table 2). For ALT normalization, the null hypothesis of inferiority of 90 μg/week compared with 180 μg/week showed borderline non-inferiority


Genotype Subanalysis
A small number of patients were infected with genotype A (N=22) or genotype D (N=38). Rates of HBeAg seroconversion in the 90 μg/24-week, 180 μg/24-week, 90 μg/48-week and 180 μg/48-week arms were 0%, 12.5%, 33.3% and 25.0%, respectively, in genotype A-infected patients and 9.1%, 33.3%, 18.2% and 0%, respectively, in genotype D-infected patients. As a result of the small numbers of patients infected with genotypes A and D, comparisons between treatment arms are not appropriate
The majority of patients included in the analysis were infected with either genotype B (N=186; 34.2%) or genotype C (N=281, 51.7%)
The highest response rates for the primary and secondary efficacy endpoints were achieved in the 180 μg/48-week arm for both genotype B- and genotype C-infected patients (Figure 3). Rates of HBeAg seroconversion 6 months post treatment were similar in genotypes B and C
Figure 3. High rates of response were achieved in the 180 μg/48-week arm in patients infected with genotype B or genotype C Genotype B


Genotype C


1. Lau GK et al. Peginterferon alfa-2a, lamivudine and the combination for HBeAg positive chronic hepatitis B. N Engl J Med 2005;352:2682-2695
v 2. European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B. J Hepatol 2009;50:227-242
3. Liaw YF et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int 2008;2:263-283
4. Lok A, McMahon B. Chronic hepatitis B: update 2009. http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice %20Guidelines/Chronic_Hep_B_Update_2009%208_24_2009.pdf
5. Cooksley WGE et al. Peginterferon alfa-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepatitis 2003;10:298-305
Disclosure information: Editorial support for the development of this poster was funded by F. Hoffmann-La Roche, Basel, Switzerland