Entecavir plus adefovir versus adefovir plus lamivudine in hepatitis B virus e antigen‐positive, lamivudine‐resistant chronic hepatitis B

Abstract

Background and Aim: In areas of the world where tenofovir disoproxil fumarate is not marketed, adefovir (ADV) + lamivudine (LAM) is recommended and widely used for LAM-resistant chronic hepatitis B (CHB). This study hypothesizes that entecavir (ETV) + ADV, where both components are active against LAM-resistant hepatitis B virus (HBV), will provide greater antiviral potency than ADV + LAM where only ADV is active. Methods: Open-label, randomized trial in hepatitis B virus e antigen-positive LAMexperienced CHB patients with LAM resistance treated with ETV 1 mg + ADV 10 mg (n = 138), ADV + LAM 100 mg (n = 137), or ETV (n = 140). Results: At week 48, there was no significant difference in the primary endpoint of HBV-DNA < 50 IU/mL between the treatment groups (25.4% [ETV + ADV] vs 19.7% [ADV + LAM], P = 0.2619; vs 16.4% [ETV], P = 0.1336). However, at week 96, rates of HBV-DNA < 50 IU/mL were significantly greater with ETV + ADV than with ADV + LAM (43.5% vs 28.5%; P = 0.0095). Rates of virologic breakthrough and resistance to ETV or ADV were low through week 96 with both combinations. The delayed benefit of ETV + ADV is likely related to the high baseline viremia in this cohort relating to continued LAM exposure after treatment failure. All three therapies had favorable safety profiles. Conclusions:In patients with LAM-resistant HBV, ETV + ADV demonstrated greater antiviral efficacy than ADV + LAM and comparable safety over 2 years, and may therefore be a preferable treatment option for LAM-resistant CHB, especially in regions where alternative rescue therapies are not available. In highly viremic patients, the benefit of ETV + ADV became apparent after a longer treatment duration.

Prediction of virologic response to tenofovir mono‐rescue therapy for multidrug resistant chronic hepatitis B

“…This occurs because pre‐existing and new‐onset resistant mutations can remain within the same viral genome [Yim et al, ; Villet et al, ; Ahn et al, ]. Before the era of TDF, it was considered that patients with LAM‐R should be treated with a combination regimen such as LAM/LdT/ETV + ADV [Shim et al, ; Ahn et al, ; Park et al, ; Heo et al, ]. However, TDF emergence reversed this concept and showed high efficacy of suppression of LAM‐R.…”

Tenofovir Disoproxil Fumarate Monotherapy is Superior to Entecavir-Adefovir Combination Therapy in Patients with Suboptimal Response to Lamivudine-Adefovir Therapy for Nucleoside-Resistant HBV: A 96-Week Prospective Multicentre Trial

“…Currently, very potent oral antiviral agents can persistently suppress HBV replication, but HBsAg clearance is unlikely to occur despite long-term virological responses [30][31][32]. Biochemical responses and HBeAg loss were similar with previous clinical trials [26,28]. Long-term antiviral therapy is needed to achieve a serological response in treatment-experienced patients with chronic hepatitis B.…”

“…By switching to a high genetic barrier drug, from LAM to ETV, ADV maintains a complementary resistance profile. In the present study, the 96-week long-term efficacy of ETV-ADV combination therapy was more promising than previous trials because of relatively longer study period in patients with suboptimal responses to LAM-ADV rescue therapy or lower baseline HBV DNA levels in patients with LAM-resistant chronic hepatitis B [18,28]. Taken together, long-term ETV-ADV combination therapy is an acceptable alternative salvage therapy for NA-experienced chronic hepatitis B patients, especially with lower HBV DNA levels.…”