New Perspectives in the Treatment of HBeAg-positive and HBeAg-negative Chronic Hepatitis B pegylated interferon
Volume 41, Issue 6, Pages 1402-1406
Thomas Berg, M.D.
Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité Campus Virchow-Klinikum, Universitätsmedizin Berlin, Berlin, Germany
Potential conflict of interest: T.B. has received research support from and is a consultant for Hoffmann-La Roche.
Editor(s) for this article:
Hartmut Jaeschke 1, Kevin Mullen 2, Darius Moradpour 3
Available treatments for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B are associated with poor sustained responses. As a result, nucleoside and nucleotide analogues are typically continued indefinitely, a strategy associated with the risk of resistance and unknown long-term safety implications.
We compared the efficacy and safety of peginterferon alfa-2a (180 microg once weekly) plus placebo, peginterferon alfa-2a plus lamivudine (100 mg daily), and lamivudine alone in 177, 179, and 181 patients with HBeAg-negative chronic hepatitis B, respectively. Patients were treated for 48 weeks and followed for an additional 24 weeks.
After 24 weeks of follow-up, the percentage of patients with normalization of alanine aminotransferase levels or hepatitis B virus (HBV) DNA levels below 20,000 copies per milliliter was significantly higher with peginterferon alfa-2a monotherapy (59 percent and 43 percent, respectively) and peginterferon alfa-2a plus lamivudine (60 percent and 44 percent) than with lamivudine monotherapy (44 percent, P=0.004 and P=0.003, respectively; and 29 percent, P=0.007 and P=0.003, respectively). Rates of sustained suppression of HBV DNA to below 400 copies per milliliter were 19 percent with peginterferon alfa-2a monotherapy, 20 percent with combination therapy, and 7 percent with lamivudine alone (P<0.001 for both comparisons with lamivudine alone). Loss of hepatitis B surface antigen occurred in 12 patients in the peginterferon groups, as compared with 0 patients in the group given lamivudine alone. Adverse events, including pyrexia, fatigue, myalgia, and headache, were less frequent with lamivudine monotherapy than with peginterferon alfa-2a monotherapy or combination therapy.
Patients with HBeAg-negative chronic hepatitis B had significantly higher rates of response, sustained for 24 weeks after the cessation of therapy, with peginterferon alfa-2a than with lamivudine. The addition of lamivudine to peginterferon alfa-2a did not improve post-therapy response rates.
Treatment of HBeAg-positive patients with chronic hepatitis B is not effective in most. A combination of immunomodulatory pegylated interferon alfa-2b and antiviral lamivudine might improve the rate of sustained response.
307 HBeAg-positive patients with chronic hepatitis B were assigned combination therapy (100 microg/week pegylated interferon alfa-2b and 100 mg/day lamivudine) or monotherapy (100 microg/week pegylated interferon alfa-2b and placebo) for 52 weeks. During weeks 32-52 the pegylated interferon dose was 50 microg/week in both treatment groups. The analyses were based on the modified intention-to-treat population after exclusion of 24 patients from one centre withdrawn for misconduct, ten who lost HBeAg before the study start, and seven who received no study medication. All included patients were followed up for 26 weeks after treatment.
49 (36%) of 136 patients assigned monotherapy and 46 (35%) of 130 assigned combination therapy had lost HBeAg at the end of follow-up (p=0.91). More of the combination-therapy than of the monotherapy group had cleared HBeAg at the end of treatment (57 [44%] vs 40 [29%]; p=0.01) but relapsed during follow-up. Patterns were similar when response was assessed by suppression of serum hepatitis B virus (HBV) DNA or change in concentrations of alanine aminotransferase. Response rates (HBeAg loss) varied by HBV genotype (p=0.01): A, 42 (47%) patients; B, ten (44%); C, 11 (28%); and D, 26 (25%).
Treatment with pegylated interferon alfa-2b is effective for HBeAg-positive chronic hepatitis B. Combination with lamivudine in the regimen used is not superior to monotherapy. HBV genotype is an important predictor of response to treatment.
--Marcellin P, Lau GK, Bonino F, Farci P, Hadziyannis S, Jin R, et al; Peginterferon Alfa-2a HBeAg-Negative Chronic Hepatitis B Study Group. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004; 351: 1206-1217.
--Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, et al.; HBV 99-01 Study Group; Rotterdam Foundation for Liver Research. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 2005; 365: 123-129.
Success in human immunodeficiency virus drug development in the 1990s revolutionized the treatment of hepatitis B. In addition, lessons learned from the treatment of hepatitis C using conventional interferon-a (IFN-a) or pegylated IFN-a (PEG-IFN-a), yielded superior clinical outcomes in these patients. Thus, treatment options for hepatitis B have expanded from one (IFN-) to four approved medications (IFN-a, lamivudine [LAM], adefovir, and, most recently, PEG-IFN-a2a in Europe, [most recently, FDA approved entecavir for hepatitis B treatment]). Although the short-term efficacy of these drugs for both HBeAg-positive and -negative chronic hepatitis B appears to be comparable, their long-term effect is still limited. Two recent studies have evaluated the efficacy of PEG-IFN-a in combination with LAM in patients with HBeAg-positive and -negative chronic hepatitis B.
The Effect of PEG-IFN-a Monotherapy Versus PEG-IFN-a plus LAM Combination Therapy in Patients With HBeAg-Positive Chronic Hepatitis B
Janssen and colleagues treated patients with HBeAg-positive chronic hepatitis B for 52 weeks with PEG-IFN-a-2b 100 g weekly alone or in combination with a daily dose of 100 mg LAM. Two important notions could be deduced from this study. First, combination therapy was superior to monotherapy when evaluated at the end of treatment. Second, combination therapy failed to be superior when evaluated at the end of follow-up.
In a recent phase III international trial presented by Lau and colleagues at the 2004 American Association for the Study of Liver Diseases Meeting, a 48-week course of PEG-IFN--2a (180 g per week) with or without LAM was compared to LAM monotherapy in HBeAg-positive patients. Similar to the findings of Janssen et al., sustained HBeAg seroconversion at the end of follow-up (week 72) could not be related to the rate of viral suppression observed during or at the end of treatment and was significantly higher in patients treated with PEG-IFN-a-2a alone or in combination with LAM than in patients treated with LAM alone (32% and 27% vs. 19%).
The Effect of PEG-IFN-a Monotherapy Versus PEG-IFN-a Plus LAM Combination Therapy in Patients With HBeAg-Negative Chronic Hepatitis B
The study by Marcellin and colleagues included 537 patients with HBeAg-negative chronic hepatitis B. Forty-eight weeks of PEG-IFN-a-2a alone or in combination with LAM resulted in higher rates of sustained response than did LAM monotherapy. Similar to the studies in HBeAg-positive patients, the more pronounced on-treatment response (week 48) observed with combination therapy or LAM monotherapy did not translate into a superior sustained response when analyzed at the end of follow-up (week 72). Thus, the PEG-IFN-a-2a monotherapy arm induced the highest rates of sustained response, defined as either normalization of alanine aminotransferase (ALT) levels in 59% or as hepatitis B virus (HBV) DNA levels below 20,000 copies/mL in 43%. By the more stringent criterion of HBV DNA levels below 400 copies/mL only 19% achieved a sustained virological response. These data clearly indicate that the addition of LAM to PEG-IFN-a-2a did not enhance sustained response rates and that PEG-IFN-a-2a was superior to LAM. However, the authors pointed out that the more profound HBV DNA suppression induced by the combination regimen was associated with a lower incidence of LAM resistance (presence of YMDD mutants in 1% vs. 18% at the end of therapy). This observation is in agreement with the current view of the development of antiviral drug resistance and confirms data reported in other HBV studies.
Could we conclude from these data that a 48-week course of PEG-IFN- monotherapy can be taken as the new first-line standard for treating patients with HBeAg-positive as well as HBeAg-negative chronic hepatitis B?
Comparing the Short- and Long-Term Efficacy of (PEG)-IFN- Versus LAM
When one examines the long-term effects of (PEG)-IFN-a and LAM or adefovir, there is good evidence that the nucleos(t)ide analogs show increasing response rates with time that might be even somewhat superior to interferon-based regimens, especially if one considers that these drugs are given for more than just 48 weeks. Long-term treatment using LAM or adefovir can induce HBeAg seroconversion rates of up to 50% after 3 to 5 years.[8-10] Furthermore, there is now convincing evidence that HBeAg seroconversion and clinical remission are generally durable provided treatment will be continued for 6 to 12 months beyond seroconversion. Similar data were recently published in HBeAg-negative disease. Thus, LAM given to HBeAg-negative patients for 2 years yielded similar rates of long-term remission (50%) when compared to 1 year of IFN-a monotherapy.
The Problem of Defining Endpoints in the Treatment of HBeAg-Positive and -Negative Chronic Hepatitis B
In HBeAg-positive patients seroconversion from HBeAg to anti-HBe can be used to assess therapy response and has been found to be a reliable surrogate marker for the prognosis of chronic HBV infection. In contrast, the endpoint of therapy in patients with HBeAg-negative disease is more difficult to assess, and HBV DNA suppression and ALT normalization are the only practical measures of response to therapy. However, normal ALT levels and suppression of HBV DNA below 20,000 copies/mL do not guarantee a sustained remission. Considering the fluctuating course of HBeAg-negative chronic hepatitis B, 24 weeks may not be a very reliable timepoint at which to measure sustained response. Moreover, it is well known that maintenance of both undetectable HBV DNA and normal ALT activity declines progressively the longer patients are followed after treatment.
If one considers HBsAg loss or seroconversion to anti-HBs as the ultimate goal of therapy, the finding in the Marcellin study that only 12 patients treated with PEG-IFN-a (and none of the patients treated with LAM alone) lost HBsAg by the end of the 24 weeks of follow-up clearly illustrates how far one still has to go to achieve this idealistic goal.
By means of a novel technique for quantifying covalently closed circular DNA (cccDNA) in liver biopsy specimens, Werle-Lapostolle and colleagues showed for the first time that the cccDNA pool can be reduced significantly by adefovir treatment and that HBsAg quantification in serum is a representative surrogate marker for the intrahepatic cccDNA pool. HBsAg seroconversion was recently demonstrated in about 2% of HBeAg-positive and HBeAg-negative patients after a median duration of adefovir treatment of 44 to 49 weeks. However, at present, suppression of HBV DNA levels remains the major goal and can be taken as the most reliable indicator for controlling disease progression. Thus, prospective trials of LAM in patients with either HBeAg-positive or -negative chronic hepatitis B proved that viral suppression had an important impact on outcome of chronic liver disease by reducing the rate of decompensation and hepatocellular carcinoma (HCC) development. Unfortunately, hepatic decompensation occurred especially among patients with YMDD mutations, limiting the benefit of LAM. Indeed, induction of drug resistance during nucleoside therapy remains a major risk, especially for those patients who already suffer from advanced hepatic fibrosis. Since incomplete suppression of HBV DNA must be considered as the principal cause for the emergence of YMDD mutations, the search for new modalities of long-term antiviral therapy promoting HBeAg seroconversion and stable sustained response is imperative.
Hopefully, the application of other nucleos(t)ide analogs, such as tenofovir, entecavir, or telbivudine, which have been shown to inhibit HBV replication more profoundly than adefovir or LAM, may herald a new phase of antiviral therapy and is likely to have implications for cccDNA clearance and of the development of drug resistance.[22-24]
Role of HBV Genotypes
HBV genotypes can considerably influence treatment response. Thus, in accordance with earlier retrospective studies, a significant difference in the response rate depending on the genotype was found in the study by Janssen et al., where genotype A was found to be an independent prognostic factor for sustained HBeAg loss. Therefore, HBeAg-positive patients infected with HBV genotype A (and B) and high ALT levels but low viral load will profit from (PEG)-IFN-a-based monotherapy, which offers the highest chance of achieving sustained seroconversion with a finite course of therapy. However, it should be pointed out that a higher disease activity as defined by markedly elevated ALT levels influenced treatment response to nucleos(t)ides in the same way as shown for (PEG)-IFN-a-based regimens.
Both of these large-scale studies open up new perspectives and questions to be addressed in future clinical trials. For example, one could try do develop stopping rules for a treatment regimen that lacks effectiveness. Thus, could we predict HBeAg seroconversion by the viral kinetics under treatment? This concept was taken up in a separate analysis of the data from the Janssen et al. study showing that during PEG-IFN--2b monotherapy HBeAg loss was associated with a marked reduction in viral load within the first 24 weeks in 90% of the patients. In contrast, only 6% of the patients with stable viremia during treatment (defined as less than 1 log decline of HBV DNA) achieved HBeAg elimination (H. L. A. Janssen, personal communication, January 2005). Thus, decisions regarding treatment duration and termination should become more flexible in the future based on the individual therapeutic response.
To summarize the salient points that can be deduced from these two studies, there is no doubt that PEG-IFN-a-based therapy can induce the highest rates of remission after 1 year of treatment. However, it is not yet definitively proven whether PEG-IFN-a is superior to conventional IFN-a. Arguments in favor of the use of PEG-IFN-a are its better tolerability and convenient administration. LAM is superior to PEG-IFN-a in achieving HBV DNA suppression on treatment. Combination therapy reduces the emergence of LAM resistance but is not superior to PEG-IFN- monotherapy when response rates are evaluated at the end of follow-up. The assessment of sustained response in HBeAg-negative chronic hepatitis B is difficult and may have to be redefined. In contrast to (PEG)-IFN-a, sustained response to nucleos(t)ide analogs is delayed but becomes evident after 2 to 3 years of treatment. Thus, nucleos(t)ide analogs may be as efficient as (PEG)-IFN-a when one compares response rates after longer durations of treatment.
1 Lok ASF. Hepatitis B: progress in the last decade. Semin Liver Dis 2003; 23: 1-4. Links
2 Cooksley WG, Piratvisuth T, Lee SD, Mahachai V, Chao YC, Tanwandee T, et al. Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepat 2003; 10: 298-305. Links
3 Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 2005; 365: 123-129. Links
4 Marcellin P, Lau GK, Bonino F, Farci P, Hadziyannis S, Jin R, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004; 351: 1206-1217. Links
5 Lau GKK, Piratvisuth T, Luo KX, Marcellin P, Thongasawat S, Cooksley G, et al. Peginterferon alfa-2a (40KD) (Pegasys) monotherapy and in combination with lamivudine is more effective than lamivudine monotherapy in HBeAg-positive chronic hepatitis B: results from a large, multinational study. HEPATOLOGY 2004; 40(Suppl 1): 171A. Links
6 Chan HL, Leung NW, Hui AY, Wong VW, Liew CT, Chim AM, et al. A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone. Ann Intern Med 2005; 142: 240-250. Links
7 Richman D. The impact of drug resistance on the effectiveness of chemotherapy for chronic hepatitis B. HEPATOLOGY 2000; 32: 866-867. Links
8 Liaw YF. Results of lamivudine trials in Asia. J Hepatol 2003; 39:(Suppl 1): S111-S115. Links
9 Leung NW, Lai CL, Chang TT, Guan R, Lee CM, Ng KY, et al. Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy. HEPATOLOGY 2003; 33: 1527-1532. Links
10 Marcellin P, Chang TT, Lim S, Sievert W, Tong M, Arterburn S, et al. Long-term efficacy and safety of adefovir (ADV) 10 mg in HBeAg+ chronic hepatitis B (CHB) patients: increasing serologic, virologic and biochemical response over time. HEPATOLOGY 2004; 40(Suppl 1): 655A. Links
11 Dienstag JL, Cianciara J, Karayalcin S, Kowdley KV, Willems B, Plisek S, et al. Durability of serologic response after lamivudine treatment of chronic hepatitis B. HEPATOLOGY 2003; 37: 748-755. Links
12 Chang TT, Shiffman M, Tong M, Marcellin P, Liaw Y-F, Luengrojanakul P, et al. Durability of HBeAg seroconversion after adefovir dipivoxil treatment for chronic hepatitis B. J Hepatol 2004; 40(Suppl 1): 126A. Links
13 Fung SK, Wong F, Hussain M, Lok AS. Sustained response after a 2-year course of lamivudine treatment of hepatitis B e antigen-negative chronic hepatitis B. J Viral Hepat 2004; 11: 432-438. Links
14 Keefe EB, Dietrich DT, Han S-HB, Jacobson IM, Martin P, Schiff ER, Tobias H et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States. Clin Gastroenterol Hepatol 2004; 2: 87-106. Links
15 Chu CJ, Hussain M, Lok ASF. Quantitative serum HBV DNA levels during different stages of chronic hepatitis B infection. HEPATOLOGY 2002; 36: 1408-1415. Links
16 Manesis EK, Hadziyannis SJ. Interferon alpha treatment and retreatment of hepatitis B e antigen-negative chronic hepatitis B. Gastroenterology 2001; 121: 101-109. Links
17 Werle-Lapostolle B, Bowden S, Locarnini S, Wursthorn K, Petersen J, Lau G, et al. Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology 2004; 126: 1750-1758. Links
18 Shiffman M, Marcellin P, Jeffers L, Gordon S, Peters M, Rizzetto M, et al. HBsAg seroconversion in adefovir dipivoxil (ADV) treated chronic hepatitis B patients. J Hepatol 2004; 40(Suppl 1): 17A. Links
19 Mommeja-Marin H, Mondou E, Blum MR, Rousseau F. Serum HBV DNA as a marker of efficacy during therapy for chronic HBV infection: analysis and review of the literature. HEPATOLOGY 2002; 37: 1309-1319. Links
20 Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004; 351: 1521-1531. Links
21 Di Marco V, Marzano A, Lampertico P, Andreone P, Santantonio T, Almasio PL, et al. Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine. HEPATOLOGY 2004; 40: 883-891. Links
22 Chang TT, Gish R, de Man R, Gadano A, Sollano J, Han KH, et al. Entecavir is superior to lamivudine for the treatment of HBeAg(+) chronic hepatitis B: results of phase III study ETV-022 in nucleoside naive patients. HEPATOLOGY 2004; 40(Suppl 1): 192A. Links
23 Lai CL, Lim SG, Brown NA, Zouh XJ, Lloyd DM, Lee YM, et al. A dose-finding study of once-daily oral telbivudine in HBeAg positive patients with chronic hepatitis B virus infection. HEPATOLOGY 2004; 40: 719-726. Links
24 van Bömmel F, Wünsche T, Mauss S, Reinke P, Bergk A, Schürmann D, et al. Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. HEPATOLOGY 2004; 40: 1421-1425. Links
25 Fung SK, Lok ASF. Hepatitis B virus genotypes: do they play a role in the outcome of HBV infection. HEPATOLOGY 2004: 40: 790-792. Links
26 Perrillo RP, Lai CL, Liaw YF, Dienstag JL, Schiff ER, Schalm SW, et al. Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B. HEPATOLOGY 2002; 36: 186-194.
27 Janssen HLA, Gerken G, Carreno V, Marcellin P, Naoumov NV, Craxi A, et al. Interferon alfa for chronic hepatitis B infection: increased efficacy of prolonged treatment. HEPATOLOGY 1999; 30: 238-243.