Lamivudine-interferon combination therapy for chronic hepatitis B: further support but no conclusive evidence
Authors: Solko Walle Schalm
Journal: Journal of Hepatology (2001)

There is a larger need for effective therapy in chronic hepatitis B than currently perceived within and outside the subspecialty of Hepatology. While the epidemic of chronic hepatitis C is being highlighted, the current and future burden of hepatitis B is assumed to be diminishing rapidly due to the widespread introduction of an effective vaccine since more than a decade. However, in my personal view, the epidemiology of hepatitis B and C are rather similar. For both diseases the incidence has fallen significantly in developed countries due to universal screening of blood and introduction of clean and disposable needles within and outside medicine; for hepatitis B additional measures like screening of pregnant women and recommendations of safe sex have been introduced generally. Despite the low incidence of new hepatitis infections the prevalence is changing less clearly due to the decades-long duration of the disease and immigration from countries with high prevalence of chronic hepatitis. For both viruses a cohort with chronic disease is moving through our time. In contrast to chronic hepatitis C spontaneous regression of active disease occurs regularly in chronic hepatitis B in association with HBeAg seroconversion; however, immune escape with re-emergence of HBeAg-negative disease is being recognized increasingly. Liver transplantation for chronic viral hepatitis is being performed with similar frequency (10–20%) for hepatitis B and hepatitis C in many European units during the last 5 years. Therefore, the need for effective therapy of chronic hepatitis B can be said to be of similar importance to that of chronic hepatitis C. Despite the availability of two approved drugs for chronic hepatitis B, there is no proof that treatment alters the natural history of the disease [1Fattovich G, Giustina G, Realdi G, Corrocher R, Schalm SW. Long-term outcome of hepatitis B e antigen-positive patients with compensated cirrhosis treated with interferon-alpha. Hepatology 1997;26:1338–1342.Google Scholar, 2Bortolotti F. Jara P. Barbera C. Gregorio G.V. Vegnente A. Zancan L. et al.Long term effect on alpha interferon in children with chronic hepatitis B.Gut. 2000; 46: 715-718Crossref PubMed Scopus (119) Google Scholar]. Although response to antiviral therapy [3Niederau C. Heintges T. Lange S. Goldmann G. Niederau C.M. Mohr L. Haussinger D. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B.N Engl J Med. 1996; 334: 1422-1427Crossref PubMed Scopus (805) Google Scholar, 4Villeneuve J.P. Condreay L.D. Willems B. Layrergues G.P. Fenyves D. Bilodeau M. et al.Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B.Hepatology. 2000; 31: 207-210Crossref PubMed Scopus (418) Google Scholar] improves survival, the frequency of response is low; therefore the effect of therapy is not detectable in an intention-to-treat analysis. The often-quoted HBeAg seroconversion rate of 33% after 16 weeks of interferon-alpha was obtained in selected patient cohorts with marked disease activity at baseline. Recent large studies [[5]Schalm S.W. Heathcote J. Cianciara J. Farrell G. Sherman M. Willems B. et al.Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial.Gut. 2000; 46: 562-568Crossref PubMed Scopus (513) Google Scholar] showed response percentages of 20% and subsequent analysis revealed a strong correlation between baseline serum ALT and HBeAg seroconversion rate: 5–10% for serum ALT <2× elevated, 20% for baseline ALT of 2–5× the upper limit of normal, and 30–40% for ALT >5× elevated. Responses to interferon and lamivudine therapy are rather similar, but the durability of the response obtained with lamivudine might be less than customary for interferon [[6]VanNunen A.B. Hansen B.E. Suh D.J. Löhr H.F. Chemello L. Fontaine H. et al.Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B: relation to type of therapy and pretreatment serum HBV DNA and ALT.J Hepatol. 2001; 34: 155Google Scholar]. In summary, in the last decade therapeutic efficacy in hepatitis B appears to be stable in contrast to the increasing therapeutic successes in two other chronic viral diseases HIV and HCV. Clearly, for the individual with chronic hepatitis B and active disease there is still an unfulfilled need for effective therapy. It is logical to assess whether combination therapy of interferon and lamivudine can increase the therapeutic benefit, especially since the two drugs appear to complement each other in antiviral and immunomodulatory activities. The first pilot studies showed no pharmacological interaction [[7]Johnson M.A. Jenkins J.M. Bye C. A study of the pharmacokinetic interaction between lamivudine and alpha interferon.Eur J Clin Pharmacol. 2000; 56: 289-292Crossref PubMed Scopus (5) Google Scholar], good tolerability (similar to interferon monotherapy), but also no striking efficacy in non-responders to interferon [[8]Mutimer D. Naoumov N. Honkoop P. Marinos G. Ahmed M. de Man R.A. et al.Combination alpha-interferon and lamivudine therapy for alpha-interferon resistant chronic hepatitis B infection: results of a pilot study.J Hepatol. 1998; 28: 923-929Abstract Full Text PDF PubMed Scopus (104) Google Scholar]. Two large randomized controlled trials in 226 and 238 predominantly Caucasian patients with HBeAg positive chronic hepatitis B have been carried out subsequently. In the study in 238 interferon non-responders the HBeAg seroconversion rate for placebo, lamivudine and combination therapy was between 12 and 18% without a statistical significant difference (Schiff ER, personal communication). However, in the study in 226 previously untreated patients [[5]Schalm S.W. Heathcote J. Cianciara J. Farrell G. Sherman M. Willems B. et al.Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial.Gut. 2000; 46: 562-568Crossref PubMed Scopus (513) Google Scholar] the HBeAg seroconversion rate for combination therapy was 29% and for the two monotherapies 19 and 20%, respectively. The difference between the response with combination and those with monotherapy was not significant in the intention-to-treat analysis, but in the 180 patients who adhered to the study protocol the rate of response with combination therapy (36%) was significantly higher than the response with lamivudine (19%) or interferon (22%). The authors concluded that the potential benefit of combining lamivudine with interferon should be investigated further in studies with different regimens of combination therapy. In this issue of the Journal, Barbaro et al. [[9]Barbaro G. Zechini F. Pellicelli A.M. Francavilla R. Scotto G. Bacca D. et al.Long-term efficacy of interferon alpha-2b and lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B. An Italian multicenter, randomized trial.J Hepatol. 2001; 35: 406-411Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar] report the results of a new large randomized controlled trial comparing 24 weeks of interferon combination therapy with 52 weeks of lamivudine monotherapy in 151 patients with HBeAg positive chronic hepatitis B; 20 patients were non-responders to a previous course of interferon therapy. Strong elements in the trial design are the longer duration of combination therapy (24 weeks), the assessment at the end of therapy (24 or 52 weeks) and at the end of follow-up (48 weeks later). The study was completed by 94–96% of the patients, indicating also an excellent tolerance of combination therapy. HBeAg seroconversion with undetectable levels of serum HBVDNA by the Abbott solution-hybridization test was observed in 35% at the end of treatment for the combination therapy versus 19% for lamivudine monotherapy. Relapse of detectable HBeAg and HBVDNA was observed in 7% for combination therapy and 21% for lamivudine therapy. The sustained HBeAg seroconversion rate of 33% for combination therapy was – on an intention to treat basis – significantly different from 15% for lamivudine monotherapy. These results from an independent trial strongly support the concept of combining lamivudine and interferon for the treatment of HBeAg positive chronic hepatitis B. However the trial also reports findings which contrast with earlier observations. With combination therapy the HBeAg seroconversion rate in non-responders to a previous course of interferon was similar or even better than those in previously untreated patients; with lamivudine therapy the ALT normalization rate of 27% and the histological improvement in Knodell score also of 27% were remarkably low in view of the results in other large studies [5Schalm S.W. Heathcote J. Cianciara J. Farrell G. Sherman M. Willems B. et al.Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial.Gut. 2000; 46: 562-568Crossref PubMed Scopus (513) Google Scholar, 10Lai C.L. Chien R.N. Leung N.W. Chang T.T. Guan R. Tai D.I. et al.A one-year trial of lamivudine for chronic hepatitis B.N Engl J Med. 1998; 339: 61-68Crossref PubMed Scopus (1791) Google Scholar]. The incidence of genotypic mutations in the YMDD locus was 13% after 6 months of combination therapy and 16% after 52 weeks of lamivudine in contrast to 0% with combination therapy and 31% in lamivudine recipients in a previous large trial (5). Discrepant results in different trials are part of modern medicine. It usually calls for another trial and finally a meta-analysis of the various trials will be performed. In the case of lamivudine-interferon combination therapy another large trial comparing 52 weeks of combination therapy with 52 weeks of interferon using the new pegylated form is under way in more than 200 patients. Another approach would be the collection of the individual patient data of the four completed trials into one large database and independent analysis by a clinical investigator and a biostatistician. Consistent results of therapeutic studies appear the stepping stone to further improvement in therapeutic regimens as has been the case in chronic hepatitis C and HIV. The morbidity and mortality of chronic hepatitis B are so important that investigators in academic centers and industry should work together in order to improve the consistency of analysis for therapeutic studies and thereby the treatment of chronic hepatitis B.