Eight RCTs were included for review (n=1,209). Six studies were of patients treated with conventional interferon (n=566) and two studies were of patients treated with PEGylated interferon (n=643). Five scored 3 on the Jadad and three scored 2. None of the studies was blinded.
Overall combination therapy was associated with greater rates of virological response (odds ratio 2.8, 95% CI: 1.7 to 4.3, p<.001), biochemical response (odds ratio 1.9, 95% CI: 1.5 to 2.5, p<0.001), sustained HBeAg clearance (odds ratio 2.1, 95% CI: 1.3 to 3.4, p=0.003) and sustained seroconversion (odds ratio 1.8, 95% CI: 1.3 to 2.6, p<0.001) compared to lamivudine monotherapy.
When the different forms of combination therapy were considered separately, conventional interferon combination therapy (six studies, n=566) also showed greater rates of virological response (odds ratio 4.5, 95% CI:2.2 to 9.4, p<0.001), biochemical response (odds ratio 2.1, 95%CI:1.3 to 3.2, p=0.002), sustained HBeAg clearance (odds ratio 2.6, 95% CI:1.3 to 5.2, p=0.008) and sustained seroconversion (odds ratio 2.6, 95% CI:1.4 to 4.8, p=0.001) compared to lamivudine monotherapy.
PEGylated interferon combination therapy (two studies, n=643) was associated with significantly greater rates of virological response (odds ratio 2.0, 95% CI:2.2 to 9.4, p=0.02), biochemical response (odds ratio 1.8, 95% CI: 1.3 to 2.6, p<0.001) and sustained seroconversion (odds ratio 1.6, 95%CI: 1.1 to 2.3, p=0.03), but not sustained HBeAg clearance compared to lamivudine monotherapy. There was no evidence of statistical heterogeneity for any outcomes.
There were no differences between patients treated with combination therapy and those treated with monotherapy in rates of histological improvement or worsening. YMDD mutation emergence was greater in patients given monotherapy when compared to combination therapy patients overall (odds ratio 0.4, 95% CI: 0.2 to 0.9 p=.03) and when compared to patients treated with PEGylated interferon (odds ratio 0.2, 95% CI:0.06 to 0.7, p=.009), but not when compared to patients treated with conventional interferon.
Higher rates of adverse events occurred in patients treated with combination therapy overall (odds ratio 2.8, 95% CI:1.1 to 6.9 p=0.03) and in patients treated with PEGylated interferon combination therapy (odds ratio 6.8, 95% CI: 1.8 to 26.1, p=0.005), but not in patients treated with conventional interferon combination therapy when compared to patients treated with monotherapy. There was one incident of liver-related mortality in a patient treated with PEGylated interferon combination therapy.