Tenofovir disoproxil fumarate in Asian or Pacific Islander chronic hepatitis B patients with high viral load (≥ 9 log10 copies/ml).

BACKGROUND & AIMS: We evaluated the antiviral response of Asian or Pacific Islander (API) patients with chronic hepatitis B (CHB) who had baseline high viral load (HVL), defined as pre-treatment hepatitis B virus (HBV) DNA ≥9 log10 copies/ml, following up to 288 weeks of tenofovir disoproxil fumarate (TDF) treatment. METHODS: A total of 205 HBeAg-negative and HBeAg-positive self-described API patients received 48 weeks of TDF 300 mg (HVL n = 18) or adefovir dipivoxil 10 mg (HVL n = 15) in a blinded fashion, followed by open-label TDF for an additional 240 weeks. The proportions of HVL vs. non-HVL patients with HBV DNA <400 copies/ml were compared. Mean declines in HBV DNA were evaluated in API vs. non-API patients. RESULTS: Throughout the first 72 weeks of treatment, a smaller proportion of HVL API patients reached HBV DNA <400 copies/ml than non-HVL API patients. However, after this timepoint similar proportions of HVL and non-HVL API patients achieved HBV DNA <400 copies/ml (100% vs. 97%, respectively), which was maintained through week 288, where 92% of HVL patients and 99% of non-HVL API patients on treatment had HBV DNA <400 copies/ml. During the 288 weeks of treatment, API patients had similar mean HBV DNA declines as non-API patients, regardless of whether patients were HVL or non-HVL. No API HVL patient had persistent viremia at week 288. No resistance was detected among HVL or non-HVL patients. CONCLUSIONS: API patients with HVL CHB achieve HBV DNA <400 copies/ml with long-term TDF treatment; however, achieving viral suppression may take longer for HVL patients relative to non-HVL API patients.

Seven-year efficacy and safety of treatment with tenofovir disoproxil fumarate for chronic hepatitis B virus infection.

BACKGROUND: Long-term tenofovir disoproxil fumarate (TDF) treatment for chronic hepatitis B (CHB) is associated with sustained viral suppression and regression of fibrosis and cirrhosis at year 5 (240 weeks) and no TDF resistance through 6 years (288 weeks). AIM: We assessed the efficacy, safety, and resistance of TDF for up to 7 years (336 weeks) in HBeAg-positive and HBeAg-negative CHB patients. METHODS: Patients who completed 1 year (48 weeks) of randomized treatment with TDF or adefovir dipivoxil were eligible to receive open-label TDF for a total duration of 8 years (384 weeks). RESULTS: Of 641 patients initially randomized, 585 (91.3 %) entered the open-label phase; 437/585 (74.7 %) remained on study at year 7. For patients on treatment at year 7, 99.3 % maintained viral suppression (HBV DNA < 69 IU/mL), 80.0 % achieved serum alanine aminotransferase normalization, and in HBeAg-positive patients, 84/154 (54.5 %) and 25/154 (11.8 %) achieved HBeAg and HBsAg loss, respectively. One/375 (0.3 %) HBeAg-negative patients achieved HBsAg loss. No resistance to TDF was detected through 7 years. During the open-label phase, grade 3/4 drug-related adverse events were uncommon (1.0 %); ten (1.7 %) patients had elevation of serum creatinine ≥ 0.5 mg/dL above baseline. No significant change in bone mineral density was observed from year 4 to year 7 (week 192 to week 336). CONCLUSIONS: Long-term TDF treatment was associated with sustained virologic, biochemical, and serologic responses, without resistance. TDF treatment was well tolerated, with a low incidence of renal and bone events. These data confirm the safety and efficacy of long-term TDF for CHB.

Efficacy of tenofovir disoproxil fumarate at 240 weeks in patients with chronic hepatitis B with high baseline viral load.

UNLABELLED: We evaluated the antiviral response of patients with chronic hepatitis B (CHB) who had baseline high viral load (HVL), defined as having hepatitis B virus (HBV) DNA ≥ 9 log10 copies/mL, after 240 weeks of tenofovir disoproxil fumarate (TDF) treatment. A total of 641 hepatitis B e antigen (HBeAg)-negative and HBeAg-positive patients (129 with HVL) received 48 weeks of TDF 300 mg (HVL n = 82) or adefovir dipivoxil (ADV) 10 mg (HVL n = 47), followed by open-label TDF for an additional 192 weeks. Patients with confirmed HBV DNA ≥ 400 copies/mL on or after week 72 had the option of adding emtricitabine (FTC). By week 240, 98.3% of HVL and 99.2% of non-HVL patients on treatment achieved HBV DNA <400 copies/mL. Both groups had similar rates of histologic regression between baseline and week 240. Patients with HVL generally took longer to achieve HBV DNA <400 copies/mL than non-HVL patients, but by week 96, the percentages of patients with HBV DNA <400 copies/mL were similar in both groups. Among HVL patients, time to achieving HBV DNA <400 copies/mL was shorter among those initially receiving TDF, compared to ADV. No patient with baseline HVL had persistent viremia at week 240 or amino acid substitutions associated with TDF resistance. CONCLUSION: CHB patients with HVL can achieve HBV DNA negativity with long-term TDF treatment, although time to HBV DNA <400 copies/mL may be longer, relative to patients with non-HVL.

Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B.

BACKGROUND & AIMS: Tenofovir disoproxil fumarate (TDF), a nucleotide analogue and potent inhibitor of hepatitis B virus (HBV) polymerase, showed superior efficacy to adefovir dipivoxil in treatment of chronic hepatitis B through 48 weeks. We evaluated long-term efficacy and safety of TDF monotherapy in patients with chronic hepatitis B who were positive or negative for hepatitis B e antigen (HBeAg(+) or HBeAg(-)). METHODS: After 48 weeks of double-blind comparison of TDF to adefovir dipivoxil, patients who underwent liver biopsy were eligible to continue the study on open-label TDF for 7 additional years; data presented were collected up to 3 years (week 144) from 85% of participants. Primary efficacy end points at week 144 included levels of HBV DNA and alanine aminotransferase, development of resistance mutations, and presence of HBeAg or hepatitis B surface antigen (HBsAg). RESULTS: At week 144, 87% of HBeAg(-) and 72% of HBeAg(+) patients treated with TDF had levels of HBV DNA <400 copies/mL. Among patients who had previously received adefovir dipivoxil and then received TDF, 88% of the HBeAg(-) and 71% of the HBeAg(+) patients had levels of HBV DNA <400 copies/mL; overall, 81% and 74%, respectively, maintained normalized levels of alanine aminotransferase and 34% had lost HBeAg. Amino acid substitutions in HBV DNA polymerase that are associated with resistance to tenofovir were not detected in any patient. Cumulatively, 8% of HBeAg(+) patients lost HBsAg. TDF maintained a favorable safety profile for up to 3 years. CONCLUSIONS: TDF was safe and effective in the long-term management of HBeAg(+) and HBeAg(-) patients with chronic hepatitis B.

Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.

BACKGROUND: Tenofovir disoproxil fumarate (DF) is a nucleotide analogue and a potent inhibitor of human immunodeficiency virus type 1 reverse transcriptase and hepatitis B virus (HBV) polymerase. METHODS: In two double-blind, phase 3 studies, we randomly assigned patients with hepatitis B e antigen (HBeAg)-negative or HBeAg-positive chronic HBV infection to receive tenofovir DF or adefovir dipivoxil (ratio, 2:1) once daily for 48 weeks. The primary efficacy end point was a plasma HBV DNA level of less than 400 copies per milliliter (69 IU per milliliter) and histologic improvement (i.e., a reduction in the Knodell necroinflammation score of 2 or more points without worsening fibrosis) at week 48. Secondary end points included viral suppression (i.e., an HBV DNA level of <400 copies per milliliter), histologic improvement, serologic response, normalization of alanine aminotransferase levels, and development of resistance mutations. RESULTS: At week 48, in both studies, a significantly higher proportion of patients receiving tenofovir DF than of those receiving adefovir dipivoxil had reached the primary end point (P<0.001). Viral suppression occurred in more HBeAg-negative patients receiving tenofovir DF than patients receiving adefovir dipivoxil (93% vs. 63%, P<0.001) and in more HBeAg-positive patients receiving tenofovir DF than patients receiving adefovir dipivoxil (76% vs. 13%, P<0.001). Significantly more HBeAg-positive patients treated with tenofovir DF than those treated with adefovir dipivoxil had normalized alanine aminotransferase levels (68% vs. 54%, P=0.03) and loss of hepatitis B surface antigen (3% vs. 0%, P=0.02). At week 48, amino acid substitutions within HBV DNA polymerase associated with phenotypic resistance to tenofovir DF or other drugs to treat HBV infection had not developed in any of the patients. Tenofovir DF produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not. The safety profile was similar for the two treatments in both studies. CONCLUSIONS: Among patients with chronic HBV infection, tenofovir DF at a daily dose of 300 mg had superior antiviral efficacy with a similar safety profile as compared with adefovir dipivoxil at a daily dose of 10 mg through week 48. (ClinicalTrials.gov numbers, NCT00116805 and NCT00117676.)

A double-blind placebo-controlled study of emtricitabine in chronic hepatitis B.

BACKGROUND: Emtricitabine is a nucleoside analogue approved for treatment of human immunodeficiency virus 1 with clinical activity against hepatitis B virus (HBV). METHODS: To compare the safety and efficacy of emtricitabine with placebo in patients with HBV, we conducted a randomized (2:1), double-blind study at 34 sites in North America, Asia, and Europe that enrolled adults between November 2000 and July 2002 who had chronic HBV infection but had never been exposed to nucleoside or nucleotide treatment. Each patient received either 200 mg of emtricitabine (n=167) or placebo (n=81) once daily for 48 weeks and underwent a pretreatment and end-of-treatment liver biopsy. Histologic improvement was defined as a 2-point reduction in Knodell necroinflammatory score with no worsening in fibrosis. RESULTS: At the end of treatment, 103 (62%) of 167 patients receiving active treatment had improved liver histologic findings vs 20 (25%) of 81 receiving placebo (P<.001), with significance demonstrated in subgroups positive (P<.001) and negative (P=.002) for hepatitis Be (HBe) antigen. Serum HBV DNA readings showed less than 400 copies/mL in 91 (54%) of 167 patients in the emtricitabine group vs 2 (2%) of 81 in the placebo group (P<.001); alanine aminotransferase levels were normal in 65% (109/167) vs 25% (20/81), respectively (P<.001). At week 48, 20 (13%) of 159 patients in the emtricitabine group with HBV DNA measured at the end of treatment had detectable virus with resistance mutations (95% confidence interval, 8%-18%). The rate of seroconversion to anti-HBe (12%) and HBe antigen loss were not different between arms. The safety profile of emtricitabine during treatment was similar to that of placebo. Posttreatment exacerbation of HBV infection developed in 23% of emtricitabine-treated patients. CONCLUSION: In patients with chronic HBV, both positive and negative for HBe antigen, 48 weeks of emtricitabine treatment resulted in significant histologic, virologic, and biochemical improvement.

Randomized, double-blind study of emtricitabine (FTC) plus clevudine versus FTC alone in treatment of chronic hepatitis B.

Emtricitabine (FTC) is approved for the treatment of human immunodeficiency virus. FTC and clevudine (CLV) have activity against hepatitis B virus (HBV). This report summarizes the results of a double-blind, multicenter study of patients with chronic hepatitis B who had completed a phase 3 study of FTC and were randomized 1:1 to 200 mg FTC once daily (QD) plus 10 mg CLV QD or 200 mg FTC QD plus placebo for 24 weeks with 24 weeks of follow-up. One hundred sixty-three patients were treated (82 with FTC plus CLV [FTC+CLV] and 81 with FTC); 72% were men, 53% were Asian, 47% were Caucasian, and 52% were hepatitis B e antigen positive, and the median baseline HBV DNA level was 6 log(10) copies/ml. After 24 weeks of treatment, 74% (FTC+CLV) versus 65% (FTC alone) had serum HBV DNA levels of <4,700 copies/ml (P = 0.114) (Digene HBV Hybrid Capture II assay). Twenty-four weeks posttreatment, the mean change in serum HBV DNA levels from baseline was -1.25 log(10) copies/ml (FTC+CLV), 40% had undetectable viremia (versus 23% for FTC alone), and 63% had normal alanine aminotransferase levels (versus 42% for FTC alone) (P < or = 0.025 for all endpoints). The safety profile was similar between arms during treatment, with less posttreatment exacerbation of hepatitis B in the combination arm. In summary, after 24 weeks of treatment, no significant difference between arms was observed, but there was a significantly greater virologic and biochemical response 24 weeks posttreatment in the FTC+CLV arm.