Optimized combination therapies with adefovir dipivoxil (ADV) and lamivudine telbivudine or entecavir may be effective for chronic hepatitis B patients with a suboptimal response to ADV monotherapy

摘要

Objective: To identify high risk factors in chronic hepatitis B (CHB) patients for suboptimal response to adefovir dipivoxil (ADV) monotherapy, and to assess the efficacy of optimized therapy combining ADV with lamivudine (LAM), telbivudine (LdT), or entecavir (ETV) in patients with a suboptimal response to ADV alone. Methods: Suboptimal response to ADV monotherapy was defined as having a decline in serum hepatitis B virus (HBV) DNA level of more than 1 log compared to baseline, but with viremia still detectable (HBV DNA ≥ 100 IU/mL), after 48 weeks of therapy. All patients who received ADV monotherapy in our clinic were analyzed retrospectively. Both univariate and multivariate logistic regression models were applied for risk factor analysis. Patients who showed suboptimal response completed at least 12 months of optimized combination therapy consisting of ADV plus LAM, ADV plus LdT, ADV plus ETV, or continuous ADV monotherapy. The primary outcome measurement was complete viral suppression, indicated by a reduction of HBV DNA to undetectable levels (CVS, with HBV DNA < 100 IU/mL). Secondary outcome measures were HBeAg seroconversion for HBeAg-positive patients, HBsAg loss, alanine aminotransferase (ALT) normalization and virological breakthrough rates. Results: Of 521 patients who received ADV monotherapy, 170 showed a suboptimal response. These were grouped for continued therapy as follows: 34 in group A (continuous ADV monotherapy), 55 in group B (ADV plus LAM), 38 in group C (ADV plus LdT), and 43 in group D (ADV plus ETV). Using a logistic model, five conditions were identified as high risk factors for suboptimal response: presence of the tyrosine-methionine-aspartate-aspartate (YMDD) HBV DNA polymerase mutation; being HBeAg positive; having a high baseline level of HBV DNA; having a primary virological non-response to ADV; and [initial virological response] to ADV. After 48 weeks of ADV monotherapy, there were no withdrawn patients who had experienced side effects. The median HBV DNA levels were (4.4±1.3) log, (4.6±1.3) log, (4.7±1.4) log, and (4.5±1.5) log in groups A, B, C, D, respectively (F = 0.228, P = 0.876). After 48-weeks of continued ADV monotherapy or optimized combination therapy, the CVS rates were 23.5% (8/34), 60% (33/55), 52.6% (20/38), and 58.1% (25/43), respectively (χ² = 12.952, P = 0.005). The median HBV DNA declines were (0.5±1.7) log, (2.0±1.3) log, (1.8±1.6) log, and (1.8±1.5) log, respectively (F = 6.775, P < 0.001). Virologic breakthrough rates were 26.5% (9/34), 7.3% (4/55), 10.5% (4/38), and 9.3% (4/43), respectively (χ² = 8.057, P = 0.045). Conclusion: Optimized combination therapies consisting of ADV plus LAM, LdT, or ETV may be reasonable choices for hepatitis B patients with a suboptimal response to ADV monotherapy.