- Email: [email protected]
Advances in antiviral therapy for hepatitis
HEPATITIS
Advances in antiviral therapy for hepatitis Marina Berenguer, Teresa L Wright Hepatitis B (HBV) and C (HCV) are major public health problems because of their high prevalence, high rate of chronicity, and the limited efficacy of therapy, in particular for HCV. 1998 was an exciting year in the treatment of chronic HBV infection. New antiviral and HBV-specific immunomodulatory therapies are being evaluated, some of which, such as lamivudine, have an excellent safety profile and potent antiviral efficacy. Advances have also occurred in HCV treatment, which continues to be based on interferon, either alone or with ribavirin. Central to developments in HBV therapy has been the improved knowledge of the HBV lifecycle and lessons learned from the HIV field, where multidrug regimens are standard. Nucleoside analogues, the major agents evaluated in clinical trials for the treatment of chronic HBV infection, have been shown to inhibit viral replication, and improve liver enzymes and histology in infected individuals (figure). After being incorporated into the growing DNA chain, they terminate replication by inhibiting the reverse transcription process. Unfortunately, they are capable only of blocking replication of the intermediates and have limited efficacy at eliminating the source of replication. As a consequence, relapse of infection had been observed after cessation of treatment. Thus, long-term therapy appears essential, although there is concern that prolonged treatment will result in the development of viral resistance with DNA breakthrough. Resistance, which occurs in about 14% of patients treated for 12 months (figure), is associated with mutations in the YMDD locus, the same region of the viral polymerase that has been associated with resistance to lamivudine in the therapy of HIV infection. Synergistic combination regimens with one or more nucleoside/nucleotide analogues and immune stimulants such as interferon or therapeutic vaccines are the best strategy in maximising antivirat activity and in preventing the development of HBV-resistant variants. We should select the most potent synergistic drugs for which development of resistance requires multiple viral mutations; the viral mutations conferring resistance do not overlap; and development of mutations can reinstate sensitivity to a drug to which the virus had been resistant. The decision on the choice of drugs awaits the results of phase III trials on long-term monotherapy with lamivudine and famcicl0vir, and combination therapy with lamivudine and interferon alpha, and phase II trials with adefovir and lobucavir. Recommendations for therapy of chronic HCV have been proposed following the US National Institutes of Health Consensus Conference. Interferon alpha is recommended in patients with elevated serum alanine aminotransferases and liver histology demonstrating active hepatitis, regardless of level of pre-treatment viraemia or infecting genotype. Therapy should be
Lancet 1998; 352: (suppl IV): 15 Department of Veterans Affairs Medical Center, University of California, San Francisco, CA 94121, USA (T L Wright MD)
The Lancet • End of yearreview• Vol 352 • 1998
Lamivudine therapy: a comparison of virall resistance
continued for 3 months, at which time response should be assessed. If a biochemical and/or virological response has been achieved, treatment should be continued for a year. Trials are under way to evaluate new formulations of interferon or combinations of interferon with ribavirin, with encouraging results in interferon-naive patients and in relapsers, with viral clearance achievable in about 40%. Although the goal continues to be the eradication of all detectable viruses, this goal is achieved with current drugs in only a minority of patients. Accordingly, other important and useful goals are being pursued, including: improvement of activity grade and fibrosis stage, which may delay or prevent thedevelopment of cirrhosis, graft failure, and hepatocellular carcinoma; and decrease of viral load and hence risk of infectivity and/or viral recurrence following liver transplantation. Recent identification of the crystalline structure of the HCV NS3 protease promises development of effective inhibitors of this critical viral enzyme. Development of a vaccine in the near future is unlikely, mainly as a result of the quasispecies nature of HCV and the lack of an efficient cell-culture system and suitable animal models. Key references for 1998 Allen MI, Deslauriers M, Andrews CW, et al. Identification and characterization of mutations in hepatitis B virus resistant to lamlvudine. Hepatology 1998; 27: 1670-77. D a v i s GL, Esteban-Mur R, Rustgi V, et al. Interferon alfa-2b alone or in c o m b i n a t i o n with ribavirin for the treatment o f relapse of chronic hepatitis C. N E n g l J M e d 1998; 339:1493-99 International Interferon-~ Hepatocellular C a r c i n o m a Study Group. Effect o f interferon-~ on progression o f cirrhosis to hepatoceHular carcinoma: a retrospective cohort study. Lancet 1998; 351: 1535-39. Lai CL, Chien RN, Leung NWY, et al. A one-year trial of lamivudine for chronic hepatitis B. N E n g l J M e d 1998; 339: 61-68. P o y n a r d T, Marcellin P, Lee S, et al. R a n d o m i s e d trial o f interferon t~2b plus ribavirin for 48 weeks or for 24 weeks versus interferon ~2b plus placebo for 48 weeks for treatment o f chronic infection with hepatitis C virus. Lancet 1998; 352: 1426-32
slvl5
Advances in antiviral therapy for hepatitis Marina Berenguer, Teresa L Wright Hepatitis B (HBV) and C (HCV) are major public health problems because of their high prevalence, high rate of chronicity, and the limited efficacy of therapy, in particular for HCV. 1998 was an exciting year in the treatment of chronic HBV infection. New antiviral and HBV-specific immunomodulatory therapies are being evaluated, some of which, such as lamivudine, have an excellent safety profile and potent antiviral efficacy. Advances have also occurred in HCV treatment, which continues to be based on interferon, either alone or with ribavirin. Central to developments in HBV therapy has been the improved knowledge of the HBV lifecycle and lessons learned from the HIV field, where multidrug regimens are standard. Nucleoside analogues, the major agents evaluated in clinical trials for the treatment of chronic HBV infection, have been shown to inhibit viral replication, and improve liver enzymes and histology in infected individuals (figure). After being incorporated into the growing DNA chain, they terminate replication by inhibiting the reverse transcription process. Unfortunately, they are capable only of blocking replication of the intermediates and have limited efficacy at eliminating the source of replication. As a consequence, relapse of infection had been observed after cessation of treatment. Thus, long-term therapy appears essential, although there is concern that prolonged treatment will result in the development of viral resistance with DNA breakthrough. Resistance, which occurs in about 14% of patients treated for 12 months (figure), is associated with mutations in the YMDD locus, the same region of the viral polymerase that has been associated with resistance to lamivudine in the therapy of HIV infection. Synergistic combination regimens with one or more nucleoside/nucleotide analogues and immune stimulants such as interferon or therapeutic vaccines are the best strategy in maximising antivirat activity and in preventing the development of HBV-resistant variants. We should select the most potent synergistic drugs for which development of resistance requires multiple viral mutations; the viral mutations conferring resistance do not overlap; and development of mutations can reinstate sensitivity to a drug to which the virus had been resistant. The decision on the choice of drugs awaits the results of phase III trials on long-term monotherapy with lamivudine and famcicl0vir, and combination therapy with lamivudine and interferon alpha, and phase II trials with adefovir and lobucavir. Recommendations for therapy of chronic HCV have been proposed following the US National Institutes of Health Consensus Conference. Interferon alpha is recommended in patients with elevated serum alanine aminotransferases and liver histology demonstrating active hepatitis, regardless of level of pre-treatment viraemia or infecting genotype. Therapy should be
Lancet 1998; 352: (suppl IV): 15 Department of Veterans Affairs Medical Center, University of California, San Francisco, CA 94121, USA (T L Wright MD)
The Lancet • End of yearreview• Vol 352 • 1998
Lamivudine therapy: a comparison of virall resistance
continued for 3 months, at which time response should be assessed. If a biochemical and/or virological response has been achieved, treatment should be continued for a year. Trials are under way to evaluate new formulations of interferon or combinations of interferon with ribavirin, with encouraging results in interferon-naive patients and in relapsers, with viral clearance achievable in about 40%. Although the goal continues to be the eradication of all detectable viruses, this goal is achieved with current drugs in only a minority of patients. Accordingly, other important and useful goals are being pursued, including: improvement of activity grade and fibrosis stage, which may delay or prevent thedevelopment of cirrhosis, graft failure, and hepatocellular carcinoma; and decrease of viral load and hence risk of infectivity and/or viral recurrence following liver transplantation. Recent identification of the crystalline structure of the HCV NS3 protease promises development of effective inhibitors of this critical viral enzyme. Development of a vaccine in the near future is unlikely, mainly as a result of the quasispecies nature of HCV and the lack of an efficient cell-culture system and suitable animal models. Key references for 1998 Allen MI, Deslauriers M, Andrews CW, et al. Identification and characterization of mutations in hepatitis B virus resistant to lamlvudine. Hepatology 1998; 27: 1670-77. D a v i s GL, Esteban-Mur R, Rustgi V, et al. Interferon alfa-2b alone or in c o m b i n a t i o n with ribavirin for the treatment o f relapse of chronic hepatitis C. N E n g l J M e d 1998; 339:1493-99 International Interferon-~ Hepatocellular C a r c i n o m a Study Group. Effect o f interferon-~ on progression o f cirrhosis to hepatoceHular carcinoma: a retrospective cohort study. Lancet 1998; 351: 1535-39. Lai CL, Chien RN, Leung NWY, et al. A one-year trial of lamivudine for chronic hepatitis B. N E n g l J M e d 1998; 339: 61-68. P o y n a r d T, Marcellin P, Lee S, et al. R a n d o m i s e d trial o f interferon t~2b plus ribavirin for 48 weeks or for 24 weeks versus interferon ~2b plus placebo for 48 weeks for treatment o f chronic infection with hepatitis C virus. Lancet 1998; 352: 1426-32
slvl5