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Infection with the hepatitis B virus (HBV) remains a major cause of morbidity and mortality worldwide. Although safe and effective vaccines have been in use for nearly two decades and have begun to have measurable impact, their full effect will take decades to be evident. Effective therapies against hepatitis B were first introduced in the mid-1980s when it became apparent that prolonged therapy with alpha interferon resulted in clearance of active HBV infection in 30-40% of treated patients compared with only 10-12% of controls. 1 However, the use of interferon is associated with frequent and sometimes severe side effects which may limit its use.
The development of second generation nucleoside analogues represented the next major step in the control of hepatitis B and lamivudine is now commonly used in the treatment of this chronic viral infection. 2 Unfortunately, it appears that many individuals require prolonged therapy for 12 months or more with lamivudine for control of HBV infection and this prolonged use of a single nucleoside analogue is associated with development of viral resistance in about 15% of patients per year. 3 The basis for becoming resistant to lamivudine is mutations within the YMDD amino acid domain of the HBV DNA polymerase. Although this viral resistance is usually only associated with mild reactivation of hepatitis, the resulting liver disease may occasionally be very severe.
COMBINATION THERAPY: HISTORICAL PERSPECTIVE
Several antiviral and immunomodulatory agents have been tested in combination as therapy for chronic hepatitis B. Some of these combinations included alpha and gamma interferon, alpha interferon and acyclovir, prednisone and interferon, and so on. Some appeared to offer marginal benefit but others had no benefit and even appeared to have additive toxicity. 4 However, these early studies illustrated many of the pitfalls to be encountered later in subsequent studies of two or more drugs in combination for the treatment of chronic hepatitis B. Firstly, each drug should ideally be proven to have therapeutic benefit when used individually. This tenet was somewhat undermined in the case of chronic hepatitis C where ribavirin was found to clearly add significantly to the antiviral effect of alpha interferon but had little effect by itself. The timing of combination therapy is also problematic. Should both drugs be used simultaneously or...