Commentary: combination therapy with two nucleos(t)ide analogues in chronic hepatitis B


The study of Ghany et al.[1] takes us on an interesting journey back to the previous decade. Treatment of chronic hepatitis B (CHB) with adefovir dipivoxil (ADV) commenced in 2003, and it was hoped that this drug would achieve long term HBV suppression without resistance.[2, 3] However, with prolonged treatment increasing resistance rates were reported, reaching up to 30% after 5 years of therapy.[4]

As ADV and lamivudine (LAM) have different resistance profiles, the efficacy of their combination started to be evaluated around 2005 in several subsets of CHB patients. However with the exception of studies of ADV addition in patients with LAM resistant HBV infection[5, 6] most of the research interest in CHB treatment was concentrated on monotherapy with the newer compounds, first entecavir, and then tenofovir,[7] currently representing the first line antiviral therapies for CHB.[8, 9]

The extended study of Ghany et al.[1] comes with a long delay to support the superiority of extended combination therapy with ADV and LAM vs. ADV alone in treatment-naïve patients, who were either HBeAg-positive or -negative. It is a small study, lacking a LAM monotherapy arm but has the advantage of a long duration of follow-up and inclusion of histological responses and histochemical evaluation of HBsAg and HBcAg in the liver. However, the inclusion in both arms of several LAM experienced patients, with 70% of them LAM resistant, dilutes the findings in those who were treatment naïve. On the other hand the conclusion that extended combination therapy with LAM and ADV is more effective than ADV alone is not a questionable one.

Despite these findings, in view of the overall potency, safety, and the excellent resistance profile of the new first-line antivirals, the results of this study remain of little, if any, clinical relevance.


Declaration of personal interests: Member of advisory boards for Gilead, Novartis and Pfizer. Declaration of funding interests: None.