The suboptimal outcomes of current hepatitis B therapies have prompted the notion of their use in combination to achieve a synergistic effect and decreased mutagenicity (2
). Furthermore, it has been suggested that the enhanced efficacy of the combination will allow for the dose reduction of its components, thus decreasing the risk of potential adverse effects (2
). In our study, we explored this notion in the subset of HBeAg-positive patients. Our study is the first to examine the combination of interferon and lamivudine for chronic hepatitis B treatment, pooling data from all pertinent randomized-controlled trials into meta-analysis. This analysis will aid in achieving evidence-based conclusions on the matter, resolving the controversy in its regard and directing future investigational efforts.
In our analysis, we found pegylated interferon monotherapy to be of comparable efficacy to its combination with lamivudine, providing similar rates of sustained virological and biochemical responses, and HBeAg clearance and seroconversion (P
=0.66, 0.94, 0.26 and 0.34 respectively). Furthermore, while the pegylated interferon trials predominantly involved treatment-naïve patients, analysis of previously treated patients within one of those studies yielded similar outcomes (24
). In contrast, the addition of lamivudine to conventional interferon resulted in superior sustained virological, biochemical and seroconversion rates (P
=0.007, 0.01 and 0.09 respectively), similarly observed with sequential and concurrent administration (20
). A similar trend was observed with HBeAg clearance rates, although the sample size was insufficient to detect this effect (P
=0.09). As with pegylated interferon, treatment-naïve patients comprised the majority of the studied population and to a greater extent. Nonetheless, a controlled, nonrandomized trial of previously treated patients reported similar outcomes (25
). These outcomes are corroborated by those of our histological analysis (P
<0.001 and P
=0.70 for histological improvement in the CON and PEG groups respectively) and by those of others (26
). Importantly, our analysis provides an explanation to the discordance between the combinations' effectiveness with conventional and not with pegylated interferon, with lamivudine-induced mutagenicity suppressed with the former, while not with the latter (P
=0.12, and 0.05 respectively).
Accordingly, two possible regimens emerged from our analysis: pegylated interferon monotherapy, and conventional interferon and lamivudine combination therapy. A comparison between the two found them to be of comparable efficacy (P
>0.05), with the exception of virological response (P
<0.001). That said, it is the authors opinion that this combinations' favourable virological response should not prompt its use as the regimen of choice, as a greater portion of treatment-naïve and thus easier to treat patients, comprised the CON as compared with the PEG group, with three CON group studies exclusively examining this patient population (16
). Our hypothesis is further supported by the superior virological outcomes of conventional as compared with pegylated interferon monotherapy (P
<0.0001), which is in conflict with current knowledge (27
), and is easily explained by this hypothesis. Accordingly, we suggest that in comparable populations, pegylated interferon monotherapy is likely to be similarly or more efficacious than lamivudine and conventional interferon combination therapy. More so, the thrice-weekly injection therapy required with conventional interferon poses a risk of low-patient compliance rates (1
), with the risk further exacerbated by the addition of a second agent. The weekly administration of pegylated interferon monotherapy is likely to alleviate this concern, while carrying similar economic costs (29
). Consequently, we conclude that pegylated interferon monotherapy is likely to be the treatment of choice for HBeAg-positive chronic hepatitis B, with this conclusion being supported by others (27
). That said, when conventional interferon therapy is considered, particularly in highly compliant patients, its combination with lamivudine should be entertained.
Similarly, studies examining the HBeAg-negative hepatitis B population did not find the addition of lamivudine to pegylated (30
), or conventional (31
), interferon to be advantageous. In addition, while the superiority of the combination over lamivudine monotherapy was suggested in previous studies, this effect is likely to represent interferon's greater inherent efficacy as compared with lamivudine, rather than the enhanced properties of the combination, as demonstrated in those very studies (22
Our study contains several limitations. Firstly, our use of intention to treat analysis, the methodological heterogeneity of the included studies, and the heterogeneity of their treatment and follow-up protocols, may have introduced some inaccuracies in our analysis. Notably, while the PEG group comprised large, carefully planned, well-executed studies, the CON group involved smaller, lower quality ones, thus weakening our conclusions in its regard. Secondly, the absence of adequate controls precluded the authors from studying the subsets of treatment-naïve and previously treated populations. Those concerns, however, were alleviated by the low patient lost for follow-up rates, the lack of statistically significant heterogeneity across studies, the beneficial effects of the combination with conventional interferon across the measured indicators and the agreement between our conclusions and those of other studies.
While the focus of our study was lamivudine and interferon combination therapy, a plethora of other combinations have been explored as well. Among those studied were combinations of interferon and various antiviral agents (32
), interleukin-12 (34
) and prednisone (35
). All yielded disappointing results. Additionally, studies investigating various antiviral combinations resulted in conflicting outcomes (36
). Those results indicate the need for further study, as the goal of a safe and efficacious therapy is yet to be attained.