Studies 102 and 103 have compared Viread ( Tenofovir disoproxil ) to Hepsera ( Adefovir dipivoxil ) among patients with HBeAg-negative chronic hepatitis B and patients with HBeAg-positive hepatitis B, respectively.
Results from both studies show that patients with chronic hepatitis B who received Viread for 48 weeks experienced superior efficacy results compared to those who received Hepsera, as shown by the significantly higher percentage of Viread patients in each trial achieving the primary efficacy endpoint. Forty-eight week data show that Viread was well-tolerated by patients in both studies.

Study 102

Study 102 is a multi-center, randomized, double-blind Phase III clinical trial evaluating the efficacy, safety and tolerability of Viread compared to Hepsera among patients with HBeAg-negative presumed pre-core mutant chronic hepatitis B. Study participants were either new to HBV therapy ( treatment-naïve ), or had previous experience with Lamivudine ( Epivir ) ( treatment-experienced ). Three hundred and seventy-five patients were randomized in a 2:1 ratio to receive either Viread ( 300 mg once daily; n=250 ) or Hepsera ( 10 mg once daily; n=125 ) for 48-weeks.

The primary efficacy endpoint was the proportion of patients at week 48 with a complete response as defined by serum HBV DNA levels below 400 copies/mL and histologic improvement characterized by at least a two point reduction in the Knodell necroinflammatory score ( a measure of necro-inflammation - an inflammatory process in the liver including or leading to death of liver cells ) with no concurrent worsening of fibrosis. Baseline characteristics were similar among patients in both study arms. At baseline, mean HBV RNA levels were 6.86 log(10) c/mL in the Viread group and 6.98 log(10) c/mL in the Hepsera group.

At week 48, 71 percent of patients in the Viread arm had a complete response compared to 49 percent in the Hepsera arm ( p less than 0.001, intent-to-treat analysis where missing equals failure ). Ninety-three percent of Viread patients compared to 63 percent of Hepsera patients achieved a reduction in HBV DNA levels to below 400 copies/mL ( p less than 0.001 ). Normal alanine aminotransferases ( ALT, a measure of liver damage ) was observed in 77 percent of patients in both arms of the study at week 48.

Patients in the Viread arm experienced a comparable treatment response regardless of treatment history. Among treatment-experienced patients, 93 percent of Viread patients achieved a reduction in HBV DNA levels to below 400 copies/mL.

Viread and Hepsera were generally well tolerated. The incidence of grade 2-4 adverse events observed in both arms was similar. Adverse events leading to study discontinuation included bladder neoplasm, cervix carcinoma, feeling hot, anorexia and fatigue in the Viread arm and myopathy and liposarcoma in the Hepsera arm. The incidence of ALT flares was low and similar in both arms ( 1.2 vs. 0.8 percent for Viread and Hepsera, respectively ). No Viread patient experienced a confirmed 0.5 mg increase in serum creatinine or creatinine clearance of less than 50 ml/min.

All Viread patients with HBV DNA of more than 400 copies/mL at week 48 or with confirmed viral breakthrough before week 48 were evaluated with genotypic analysis of the virus, and none had developed mutations associated with resistance to Viread.

Study 103

Study 103 is a multi-center, randomized, double-blind Phase III clinical trial that evaluates the efficacy, safety and tolerability of Viread compared to Hepsera among treatment-naive patients with HBeAg-positive chronic hepatitis B. Two hundred and sixty-six patients were randomized in a 2:1 ratio to receive either Viread ( 300 mg once daily; n=176 ) or Hepsera ( 10 mg once daily; n=90 ).

Similar to Study 102, the primary efficacy endpoint was the proportion of patients at week 48 with a complete response as defined by serum HBV DNA levels below 400 copies/mL and histologic improvement characterized by at least a two point reduction in the Knodell necroinflammatory score with no concurrent worsening of fibrosis. Baseline characteristics were similar among patients in both study arms. At baseline, mean HBV RNA levels were 8.64 log(10) c/mL in the Viread group and 8.88 log(10) c/mL in the Hepsera group.

At 48 weeks, 67 percent of patients in the Viread arm had a complete response compared to 12 percent in the Hepsera arm ( p less than 0.001 ). In addition, 76 percent of Viread patients compared to 13 percent of Hepsera patients achieved a reduction in HBV DNA levels to below 400 copies/mL ( p less than 0.001 ). Normal ALT was observed in 69 percent of Viread patients compared to 54 percent of patients treated with Hepsera ( p=0.018 ).

Among patients for whom seroconversion data are available at 48 weeks, 21 percent of Viread patients ( n=158 ) "e" antigen seroconverted by week 48, compared to 18 percent of Hepsera patients ( n=82; p greater than 0.05 ).
Seroconversion is defined as both the disappearance of the hepatitis B "e" antigen ( HBe-antigen negative ), a marker of HBV replication, and the appearance of antibodies specific for this antigen ( HBe-antibody positive ).
In addition, three percent of Viread patients ( n=153 ) compared to zero percent of Hepsera patients ( n=80; p=0.018 ) experienced "s" antigen ( HbsAg ) loss, which can indicate that a patient has cleared chronic hepatitis B infection.

As with Study 102, Viread and Hepsera were generally well tolerated. The incidence of grade 2-4 adverse events observed in both arms were similar. Early transient Grade 3 or 4 ALT flares were more frequent in the Viread group, with 11 percent of Viread patients compared to 4 percent of Hepsera patients experiencing flares greater than five times the upper limit of normal and two times baseline values. ALT flares were associated with a strong decline in HBV DNA typically observed in the first eight weeks of therapy.

Renal profile and drug resistance findings in study 103 were the same as those observed in study 102, with no Viread patient experiencing a confirmed 0.5 mg increase in serum creatinine or creatinine clearance of less than 50 mL/min and no patient developing mutations associated with Viread resistance.

Source: Gilead, 2007

XagenaMedicine2007



Link: Xapedia - Medical Encyclopedia