The FDA’s approval of entecavir was based on clinical trials in which histo-logic, virologic, biochemical, and sero-logic responses were observed after one year of treatment. The study population included nucleoside-naive and lamivu-dine-resistant patients with HBeAg-positive or HBeAg-negative chronic HBV infection with decompensated liver disease.

In terms of co-infection with HBV and HIV, limited data on the safety and efficacy were studied within a small sample population.
Nucleoside-Naive Patients (Studies AI463022 and AI463027) A multinational, randomized double-blind trial was conducted to evaluate the safety and efficacy of nucleoside-naive, HBeAg-positive patients with chronic hepatitis B. Enrollment consisted of 709 patients after 715 patients were randomly assigned to receive either 0.5 mg of once-daily oral entecavir or 100 mg of once-daily oral lamivudine for 52 weeks. At the baseline evaluation, patients had a mean score of 7.8 on the Knodell Necro-inflammatory Scale, a mean HBV-DNA load of 9.66 log10 copies/ml, and a mean serum alanine aminotransferase (ALT) level of 143 units/liter (U/L).

Another multinational, randomized double-blind trial evaluated nucleoside-naive, HBeAg-negative (HBeAb-positive) patients. Enrollment consisted of 638 patients after 648 were randomly selected to receive 0.5 mg of entecavir once daily or 100 mg of oral lamivudine once daily for 52 weeks. At the baseline examination, patients had a mean score of 7.8 on the Knodell Necroinflammatory Scale, a mean serum HBV-DNA load of 7.58 log10 copies/ml, and a mean ALT concentration of 142 U/L.

In both trials, entecavir was considered superior to lamivudine based on the primary endpoint, which was observed at 48 weeks. The primary endpoint was defined as histologic improvements of a reduction of two or more points in Kno-dell Necroinflammatory Scale scores and with no clinical deterioration in Knodell Fibrosis Scale scores.

Secondary endpoints, which included a reduction in viral load and ALT levels, further demonstrated improvements within the entecavir treatment arm. For the HBeAg-positive patients, 72% of those receiving entecavir displayed histologic improvement, compared with 62% of the lamivudine patients at week 48 (P < .05). For the HBeAg-negative patients, 70% of the entecavir patients showed histo-logical improvement, compared with 61% of the lamivudine patients at week 48 (P = .05).
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Undetectable HBV-DNA and normalization of ALT values were documented with statistical significance for both HBeAg-positive and HBeAg-negative patients. Undetectable HBV-DNA levels in HBeAg-positive patients were reported in 67% of those receiving ente-cavir and in 36% of those receiving lamivudine (P = .05); and undetectable HBV-DNA levels in HBeAg-negative patients were reported in 90% of those receiving entecavir and in 72% of those receiving lamivudine (P = .05).

Normalized ALT levels (defined as one times the upper limit of normal or less) were reported in 68% of HBeAg-positive patients receiving entecavir and in 60% of patients receiving lamivudine (P = .05) and in 78% of HBeAg-negative patients receiving entecavir and in 71% of patients taking lamivudine (P = .05).

In summary, both trials found ente-cavir superior to lamivudine in terms of the primary endpoint (histologic improvement) and in secondary endpoints (reductions in viral load and normalization of ALT values) in each treatment arm.

Lamivudine-Resistant Patients (Study AI463026) A multinational, randomized, double-blind trial enrolled 286 (of 293) patients with chronic HBV infection who had not responded to lamivudine. A switch to entecavir provided beneficial results in overall histologic, virologic, and biochemical responses compared with continuous lamivudine therapy. Patients either continued with oral lamivudine 100 mg daily or began a regimen of oral ente-cavir 1 mg daily, after a washout period, for 52 weeks. At 48 weeks, more histo-logic improvements were seen with ente-cavir (55%) than with lamivudine (28%) (P = .01).
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The Knodell Necroinflammatory Scale was used to assess improvement. At 48 weeks, Ishak Fibrosis Scale scores were also significantly improved in the ente-cavir patients (34%) compared with the lamivudine group (16%) (P = .01).

When undetectable HBV-DNA was evaluated, it was determined that patients with fewer than 300 copies/ml were taking entecavir (19%), in contrast to those in the lamivudine group (1%) (P = .0001). The mean change in HBV-DNA was also statistically significant (P = .0001).

The return of liver enzyme values (i.e., ALT) to normal was superior with entecavir (61%) than with lamivudine (15%) (P = .0001).

Overall, entecavir was effective for lamivudine-refractory patients with chronic HBV infection.

Patients with HIV Infection (Study AI463038) This double-blind placebo-controlled trial evaluated patients experiencing a recurrence of HBV infection in addition to being co-infected with HIV. All enrolled patients (n = 68) were receiving HAART, including a standard regimen of lamivu-dine at 300 mg daily.

The patients were randomly assigned to receive entecavir 1 mg orally or placebo for 24 weeks, followed by an open-label phase for an additional 24 weeks, the point at which all patients could receive entecavir. At the start of the study, 99% of the patients were HBeAg-positive.
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The mean baseline serum HBV-DNA level was 9.13 log10 copies/ml, as detected by polymerase chain reaction (PCR) testing. The mean baseline ALT concentration was recorded at 71.5 U/L.

At 24 weeks, undetectable HBV-DNA was reported as 6% in the entecavir patients, in contrast to 0% in the placebo group. The mean change in HBV-DNA, however, did show statistical significance between entecavir (reported as -3.65 copies/ml) and placebo (reported as + 0.11 copies/ml) (P = .001).

Normalized ALT levels occurred at a rate of 34% with entecavir and at a rate of 8% with placebo, although no statistical analysis was reported.

ADVERSE DRUG EVENTS

The most commonly reported adverse drug events (ADEs) associated with ente-cavir were headache, fatigue, dizziness, nausea, insomnia, and somnolence. In clinical trials, the incidence of these ADEs was comparable to those reported in patients using lamivudine (Epivir HBV).

Lactic acidosis and severe hepatomegaly have been reported with nucleo-side analogues such as entecavir. Some patients have also experienced exacerbations of HBV infection, which occurred during entecavir therapy and upon discontinuation of entecavir. tadalis sx

PREGNANCY

Entecavir is classified as a pregnancy category C agent.