Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy.

UNLABELLED: Patients with chronic hepatitis B virus (HBV) infection who develop antiviral resistance lose benefits of therapy and may be predisposed to further resistance. Entecavir (ETV) resistance (ETVr) results from HBV reverse transcriptase substitutions at positions T184, S202, or M250, which emerge in the presence of lamivudine (LVD) resistance substitutions M204I/V +/- L180M. Here, we summarize results from comprehensive resistance monitoring of patients with HBV who were continuously treated with ETV for up to 5 years. Monitoring included genotypic analysis of isolates from all patients at baseline and when HBV DNA was detectable by polymerase chain reaction (> or = 300 copies/mL) from Years 1 through 5. In addition, genotyping was performed on isolates from patients experiencing virologic breakthrough (> or = 1 log(10) rise in HBV DNA). In vitro phenotypic ETV susceptibility was determined for virologic breakthrough isolates, and for HBV containing novel substitutions emerging during treatment. The results over 5 years of therapy showed that in nucleoside-naïve patients, the cumulative probability of genotypic ETVr and genotypic ETVr associated with virologic breakthrough was 1.2% and 0.8%, respectively. In contrast, a reduced barrier to resistance was observed in LVD-refractory patients, as the LVD resistance substitutions, a partial requirement for ETVr, preexist, resulting in a 5-year cumulative probability of genotypic ETVr and genotypic ETVr associated with breakthrough of 51% and 43%, respectively. Importantly, only four patients who achieved < 300 copies/mL HBV DNA subsequently developed ETVr. CONCLUSION: Long-term monitoring showed low rates of resistance in nucleoside-naïve patients during 5 years of ETV therapy, corresponding with potent viral suppression and a high genetic barrier to resistance. These findings support ETV as a primary therapy that enables prolonged treatment with potent viral suppression and minimal resistance.

Early hepatitis B virus DNA reduction in hepatitis B e antigen-positive patients with chronic hepatitis B: A randomized international study of entecavir versus adefovir.

UNLABELLED: This study was undertaken to compare the early antiviral activity and viral kinetic profiles of entecavir (ETV) versus adefovir (ADV) in hepatitis B e antigen positive nucleoside-naïve adults with chronic hepatitis B (CHB). Sixty-nine nucleoside-naïve CHB patients with baseline HBV DNA of 10(8) copies/mL or more were randomized 1:1 to open-label treatment with entecavir 0.5 mg/day or adefovir 10 mg/day for a minimum of 52 weeks. The primary efficacy analysis compared mean reduction in HBV DNA at week 12 adjusted for baseline levels using linear regression. Entecavir was superior to adefovir for mean change from baseline in HBV DNA at week 12 (-6.23 log(10) copies/mL versus -4.42 log(10) copies/mL, respectively; mean difference -1.58 log(10) copies/mL; P < 0.0001). Both drugs demonstrated biphasic viral kinetics, with a first phase of rapid decline lasting 10 days. A significant difference favoring ETV was reached at day 10 (day 10 ETV-ADV difference estimate: -0.66 log(10) copies/mL; 95% CI [-0.30, -0.01]). Early virological response was found to be predictive of subsequent virological response, with those having lower HBV DNA levels at day 10 being more likely to achieve HBV DNA of less than 300 copies/mL at week 48. In addition, there was considerably less variability in the extent of HBV DNA reductions in patients treated with entecavir versus adefovir. Both the mean decrease in serum HBV DNA and the proportion of patients achieving HBV DNA less than 300 copies/mL were greater in entecavir-treated than adefovir-treated patients at weeks 2, 4, 8, 12, 24, and 48. At week 48, one (3%) ETV-treated versus 15 (47%) ADV-treated patients had HBV DNA of 10(5) copies/mL or more. Both antivirals were well tolerated. CONCLUSION: Entecavir therapy resulted in earlier and superior reduction in HBV DNA compared with adefovir in nucleoside-naïve HBeAg-positive patients with CHB.

Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B.

BACKGROUND: Entecavir is a potent and selective antiviral agent that has demonstrated efficacy in phase 2 studies in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. METHODS: In this phase 3, double-blind trial, we randomly assigned 648 patients with HBeAg-negative chronic hepatitis B who had not previously been treated with a nucleoside analogue to receive 0.5 mg of entecavir or 100 mg of lamivudine once daily for a minimum of 52 weeks. The primary efficacy end point was histologic improvement (a decrease by at least two points in the Knodell necroinflammatory score, without worsening of fibrosis). RESULTS: Histologic improvement after 48 weeks of treatment occurred in 208 of 296 patients in the entecavir group who had adequate baseline liver-biopsy specimens that could be evaluated (70 percent), as compared with 174 of 287 such patients in the lamivudine group (61 percent, P=0.01). More patients in the entecavir group than in the lamivudine group had undetectable serum hepatitis B virus (HBV) DNA levels according to a polymerase-chain-reaction assay (90 percent vs. 72 percent, P<0.001) and normalization of alanine aminotransferase levels (78 percent vs. 71 percent, P=0.045). The mean reduction in serum HBV DNA levels from baseline to week 48 was greater with entecavir than with lamivudine (5.0 vs. 4.5 log [on a base-10 scale] copies per milliliter, P<0.001). There was no evidence of resistance to entecavir. Safety and adverse-event profiles were similar in the two groups. CONCLUSIONS: Among patients with HBeAg-negative chronic hepatitis B who had not previously been treated with a nucleoside analogue, the rates of histologic improvement, virologic response, and normalization of alanine aminotransferase levels were significantly higher at 48 weeks with entecavir than with lamivudine. The safety profile of the two agents was similar, and there was no evidence of viral resistance to entecavir. (ClinicalTrials.gov number, NCT00035789.).

A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B.

BACKGROUND: Entecavir is a potent and selective guanosine analogue with significant activity against hepatitis B virus (HBV). METHODS: In this phase 3, double-blind trial, we randomly assigned 715 patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B who had not previously received a nucleoside analogue to receive either 0.5 mg of entecavir or 100 mg of lamivudine once daily for a minimum of 52 weeks. The primary efficacy end point was histologic improvement (a decrease by at least two points in the Knodell necroinflammatory score, without worsening of fibrosis) at week 48. Secondary end points included a reduction in the serum HBV DNA level, HBeAg loss and seroconversion, and normalization of the alanine aminotransferase level. RESULTS: Histologic improvement after 48 weeks occurred in 226 of 314 patients in the entecavir group (72 percent) and 195 of 314 patients in the lamivudine group (62 percent, P=0.009). More patients in the entecavir group than in the lamivudine group had undetectable serum HBV DNA levels according to a polymerase-chain-reaction assay (67 percent vs. 36 percent, P<0.001) and normalization of alanine aminotransferase levels (68 percent vs. 60 percent, P=0.02). The mean reduction in serum HBV DNA from baseline to week 48 was greater with entecavir than with lamivudine (6.9 vs. 5.4 log [on a base-10 scale] copies per milliliter, P<0.001). HBeAg seroconversion occurred in 21 percent of entecavir-treated patients and 18 percent of those treated with lamivudine (P=0.33). No viral resistance to entecavir was detected. Safety was similar in the two groups. CONCLUSIONS: Among patients with HBeAg-positive chronic hepatitis B, the rates of histologic, virologic, and biochemical improvement are significantly higher with entecavir than with lamivudine. The safety profile of the two agents is similar, and there is no evidence of viral resistance to entecavir. (ClinicalTrials.gov number, NCT00035633.).

Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures.

OBJECTIVE: To evaluate atazanavir/ritonavir (ATV/RTV) (300/100 mg) once daily, atazanavir/saquinavir (ATV/SQV) (400/1200 mg) once daily, and lopinavir/ritonavir (LPV/RTV) (400/100 mg) twice daily, each with tenofovir (300 mg) once daily and a nucleoside reverse transcriptase inhibitor in treatment-experienced HIV-infected patients. METHODS: Randomized, open-label, 48-week multicenter trial of 358 randomized adult patients who had failed two or more prior HAART regimens with baseline HIV RNA > or = 1000 copies/ml and CD4 cell count > or = 50 x 10(6) cells/l. RESULTS: The primary efficacy endpoint [plasma HIV RNA reduction assessed by time-averaged difference (TAD)] was similar for ATV/RTV and LPV/RTV [TAD 0.13; 97.5% confidence interval, -0.12 to 0.39] at 48 weeks. Mean reductions from baseline for ATV/RTV and LPV/RTV were comparable at 1.93 and 1.87 log10 copies/ml, respectively. Mean CD4 cell count increases were 110 and 121 x 10(6) cells/l for ATV/RTV, and LPV/RTV, respectively. The efficacy of ATV/SQV was lower than LPV/RTV by both these parameters. Declines in total cholesterol and fasting triglycerides were greater with ATV/RTV and ATV/SQV than with LPV/RTV (P < or = 0.005). Lipids in the LPV/RTV arm at week 48 generally increased from baseline. Lipid-lowering agents were used more frequently in the LPV/RTV arm than in the ATV arms (P < 0.05 versus ATV/RTV), as were antidiarrheal agents (P < or = 0.04 versus both ATV treatments). No new or unique safety findings emerged. CONCLUSIONS: ATV boosted with RTV is as effective and well tolerated as LPV/RTV in treatment-experienced patients, with a more favorable impact on serum lipids. Pharmacokinetically enhanced ATV provides a suitable choice for therapy of treatment-experienced HIV-infected patients.