Once a decision is made that a patient with HBV infection needs therapy, two major groups of antiviral therapies are currently utilised.
These are interferon therapy (interferon alpha or ‘pegylated’ interferon alpha) or an oral nucleoside or nucleotide agent such as lamivudine, adefovir and entecavir.
There is a substantial number of new nucleosides in development, including tenofovir, emtricitabine, telbuvidine, clevudine, valtorcitabine and others.
The patterns of response observed with nucleotides are broadly similar although these agents have different structures, inhibit different phases of hepatitis B replication and have variable
mechanisms of action. Their pharmacokinetics, inhibitory capacity, onset of action, resistance patterns and rates of HBeAg seroconversion vary during the first year of treatment.
Interferon alpha
The main advantages of interferon alpha (or ‘alfa’) over nucleoside analogues are the theoretical absence of resistance and the possibility of a finite treatment course (48 weeks). Interferon alpha may have additional immunomodulatory properties. Also, pre-treatment factors predictive of response to interferon alpha therapy have been partially defined.
Pegylated forms of interferon alpha with improved pharmacokinetic profiles and more convenient once-weekly administration are now licenced. Studies in HBeAg-positive and anti-HBe positive patients indicate that the addition of lamivudine to PEG IFN alpha2a does not improve seroconversion rates when compared to PEG IFN alpha2a alone.
Treatment rates, however, have not translated into higher rates of seroconversion. In anti-HBe positive patients, relapse rates remain high after stopping 48 weeks of peg interferon treatment. Interferon must be used with caution in patients with decompensated cirrhosis. This drug, which has to be injected, causes more side effects than nucleoside analogues and requires a high level of monitoring. Treatment stopping points at present have been only tentatively defined.
Nucleoside analogues
Overall, nucleoside analogues represent the primary therapeutic choice for all variants of HBV infection, including wild-type and precore/core mutation variants. The goal of therapy is achieved with the currently approved agents in this category.
Lamivudine – This is a relatively inexpensive drug with few side effects, even in patients with advanced disease. It appears effective in those who have failed interferon alpha therapy (HBeAg-negative patients, for example) and in improving decompensated disease. The major disadvantage of lamivudine is the high rate of resistance seen in both HBeAg positive and anti-HBe positive patients. Resistance has typically been managed by sequential treatment with adefovir or entecavir but the advantage of the strategy compared to more recent combination therapy is questionable. Elimination of the drug occurs mainly by renal clearance and dosages need to be adapted to creatinine clearance. The other clinical concerns during lamivudine therapy are withdrawal or initiating hepatitis flares.
Adefovir – The efficacy of adefovir has been assessed in patients with HBeAg positive and negative disease and other settings. In HBeAg positive patients seroconversion rates at one year are low but can increment with time. However, analysis of the data to date within a subset of patients in which a variable proportion (particularly HBeAg positive patients with higher BMI) revealed slower and poor primary responses. Patients with a slower decrement in HBV DNA
have been observed to have relatively high rates of resistance.
Adefovir pharmacokinetics are substantially altered in patients with marked and severe renal impairment.
It is important to identify patients for whom adefovir monotherapy may not suffice. It remains an important drug for the treatment of lamivudine-resistant hepatitis B but both therapies should be
continued in patients failing lamivudine.
Entecavir – Early studies suggest that entecavir, which inhibits all three activities of the HBV polymerase/reverse-transcriptase, is a potent inhibitor of hepatitis B virus replication. Despite this, studies indicate that although the mean change from baseline was almost 7 log in HBeAg positive patients, HBeAg seroconversion occurred in just 21 per cent of entecavir-treated patients after one year of treatment. Genotypic resistance has been reported in naive patients, but is rare. Dose adjustments are required in cases of renal impairment.
The cumulative human risk will require surveillance until entecavir’s long-term efficacy and complex resistance profile become better known.
Phase 2 studies of telbuvidine have been completed. Results are promising but, as with other agents, call into question the scope and potential shortcomings of single agents for therapy of patients with high levels of HBV replication. The combination of telbuvidine plus lamivudine does not look favourable. Patients with levels of virus of > 104 copies/ml after six months are at higher risk of resistance.
Similarly, phase 3 placebo-controlled trials of 24 week treatment with clevudine are completed. No emergence of resistance mutations has been observed among patients, although in vitro studies suggest that there may be cross-resistance with lamivudine-resistant HBV mutants.
Therapy can theoretically involve a finite course of therapy, continuous long-term therapy (or indefinite suppressive therapy) and, for many patients, a treatment course that cannot be defined at the start and which will be dependent upon the initial response.
There are, therefore, major uncertainties in predicting whether a monotherapy will suffice or whether combination therapies are more beneficial. Thus several treatment options exist for individual patients.