No abstract

Gilead Sciences.

Data are limited on the safety and effectiveness of oral antivirals other than lamivudine and adefovir dipivoxil for treatment of chronic hepatitis B (CHB) in patients with decompensated liver disease. This Phase 2, double-blind study randomized 112 patients with CHB and decompensated liver disease to receive either tenofovir disoproxil fumarate (TDF; n = 45), emtricitabine (FTC)/TDF (fixed-dose combination; n = 45), or entecavir (ETV; n = 22). The primary endpoint was safety; more specifically, tolerability failure (adverse events resulting in permanent treatment discontinuation) and confirmed serum creatinine increase ≥0.5 mg/dL from baseline or confirmed serum phosphorus <2 mg/dL. Patients with insufficient viral suppression (e.g., confirmed HBV DNA ≥400 copies/mL at week 8 or 24) could begin open-label FTC/TDF but were considered failures in this interim week 48 analysis for efficacy endpoints. Tolerability failure was infrequent across arms: 6.7% TDF, 4.4% FTC/TDF, and 9.1% ETV ( P = 0.622) as were confirmed renal parameters meeting threshold 8.9%, 6.7%, and 4.5% ( P = 1.000), respectively. Six patients died (none considered related to study drug) and six received liver transplants (none had HBV recurrence). The adverse event and laboratory profiles were consistent with advanced liver disease and complications, with no unexpected safety signals. At week 48, HBV DNA was <400 copies/mL (69 IU/mL) in 70.5% (TDF), 87.8% (FTC/TDF), and 72.7% (ETV) of patients. Proportions with normal alanine aminotransferase were: 57% (TDF), 76% (FTC/TDF), and 55% (ETV). Hepatitis B e antigen (HBeAg) loss/seroconversion occurred in 21%/21% (TDF), 27%/13% (FTC/TDF), and 0%/0% (ETV). Child-Turcotte-Pugh and Modification for End-stage Liver Disease scores improved in all groups. Conclusion: All treatments were well tolerated in patients with decompensated liver disease due to CHB with improvement in virologic, biochemical, and clinical parameters. (Hepatology 2011.)

BackgroundLong-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).AimWe assessed the efficacy, safety, and resistance of TDF for up to 7 years (336 weeks) in HBeAg-positive and HBeAg-negative CHB patients.MethodsPatients 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).ResultsOf 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).ConclusionsLong-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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10620-014-3486-7) contains supplementary material, which is available to authorized users.

One major challenge in the treatment of chronic hepatitis B is to maintain long-term viral suppression without promoting the selection of drug-resistant mutations. We analyzed data from 347 hepatitis B e antigen-negative and 238 hepatitis B e antigenpositive patients receiving tenofovir disoproxil fumarate (TDF) in an open-label, longterm extension of two phase 3 studies. To date, resistance analyses have been completed for patients receiving up to 288 weeks (6 years) of TDF. Population sequencing of hepatitis B virus (HBV) polymerase/reverse transcriptase (pol/RT) was attempted for all patients at baseline, and any patient who remained viremic (HBV DNA 400 copies/ mL [69 IU/mL]) at week 288 or at the end of treatment with TDF (n 5 52) or emtricitabine (FTC)/TDF (n 5 7). Phenotypic analyses were performed in HepG2 cells using recombinant HBV containing patient pol/RT sequences. Approximately half of the patients on open-label treatment who qualified for genotyping had pol/RT sequence changes compared to baseline (23/52 [44%] on TDF, 4/7 [57%] on FTC/TDF). Most changes were at polymorphic sites and none were associated with TDF resistance. Virologic breakthrough occurred infrequently and was associated with nonadherence to study medication in the majority of cases (12/16, 75%). Per protocol, 57 patients (10%) were eligible to switch to FTC/TDF; the majority had HBV DNA <400 copies/mL at their last study visit regardless of whether they switched to FTC/TDF (n 5 34) or maintained TDF monotherapy (n 5 17). No patient exhibited persistent viremia (HBV DNA never <400 copies/mL) after week 240. Conclusion: TDF monotherapy maintains effective suppression of HBV DNA through 288 weeks of treatment with no evidence of TDF resistance. (HEPATOLOGY 2014;59:434-442) T he treatment goals for chronic hepatitis B (CHB)-infected patients are to improve quality of life and decrease the risk of life-threatening complications by potent and durable suppression of hepatitis B virus (HBV) replication. [1][2][3][4][5] As most patients with CHB will require long-term treatment with nucleos(t)ide analogs, one of the greatest challenges is to maintain effective viral suppression without the selection of resistance mutations. Long-term treatment with first-generation nucleos(t)ide analogs leads to relatively high cumulative resistance rates, 71% after up to 4 years of treatment with lamivudine (LAM), 6 and 29% in hepatitis B e antigen (HBeAg)-negative patients and 20% in HBeAg-positive patients after up to 5 years of treatment with adefovir (ADV). 7,8 Furthermore, 25% of HBeAg-positive patients and 11% of HBeAg-negative patients developed resistance after up to 2 years of treatment with telbivudine.9 Entecavir (ETV) has a markedly lower rate of resistance: 1.2% among treatment-na€ ıve patients treated for up to 5 years.10 However, ETV resistance develops rapidly in patients with prior resistance to LAM: the 5-year cumulative probability of developing ETV resistance is 51% in patients harboring LAM resistance.