Is Combination Antiviral Therapy Mandatory for Maintenance Therapy in Fully Suppressed Multidrug-Resistant Hepatitis B Patients?

Aim. The efficacy of tenofovir disoproxil fumarate (TDF) monotherapy as maintenance therapy in multidrug-resistant (MDR) hepatitis B virus (HBV) patients after complete virologic suppression (CVS) has not been well evaluated. We evaluated the efficacy of maintenance TDF monotherapy compared with conventional TDF plus entecavir combination therapy after CVS of MDR HBV. Methods. In this single-center retrospective study, patients with MDR HBV who were previously treated with entecavir plus TDF combination therapy and achieved CVS were included. Patients were either maintained on entecavir plus TDF combination therapy or switched to TDF monotherapy after CVS. The primary endpoint was the virologic breakthrough, and secondary outcomes were liver cirrhosis (LC) or hepatocellular carcinoma (HCC) development. To overcome immortal time bias, time-varying Cox proportional hazard regression analysis was performed. Results. A total of 201 patients were included, and 153 patients were maintained on entecavir plus TDF combination therapy (combination group); 48 patients were converted from combination therapy to TDF monotherapy (single group) after CVS. Five patients experienced a virologic breakthrough, one patient in the single group owing to poor transient compliance and four patients in the combination group (P=0.51). One new case of LC developed in the single group; five cases of LC developed in the combination group (P=0.35). No new HCC development occurred in the single group, while seven cases of HCC developments were noted in the combination group. However, these results were not statistically significant (P=0.54). Conclusions. For patients with suppressed HBV DNA, the efficacy of TDF monotherapy as maintenance therapy is comparable to that of entecavir plus TDF combination therapy.

No Resistance to Tenofovir Alafenamide Detected through 96 Weeks of Treatment in Patients with Chronic Hepatitis B Infection

ABSTRACTTenofovir alafenamide (TAF) has shown equivalent efficacy and improved safety profiles for patients with chronic hepatitis B (CHB) compared to tenofovir disoproxil fumarate (TDF). However, limited data are available for its resistance profiles. In two clinical trials, 1,298 hepatitis E antigen-positive and -negative patients with CHB were randomized 2:1 and treated with TAF (n= 866) or TDF (n= 432). Baseline nucleos(t)ide analog resistance substitutions in HBV polymerase/reverse transcriptase (Pol/RT) were assessed using INNO-LiPA Multi-DR v2/v3. Resistance surveillance was conducted for patients with viremia (HBV DNA ≥ 69IU/ml) by HBV Pol/RT sequencing at week 96 or at discontinuation.In vitrophenotypic analysis was performed for patients with conserved site substitutions or virologic breakthrough while adherent to the study drug. At baseline, the majority of patients harbored virus with wild-type Pol/RT (89.2%), with 10.8% harboring resistance associated mutations. A similar percentage of patients in the TAF or TDF groups qualified for sequence analysis through week 96 (TAF, 11.1%; TDF, 10.9%). Of these, a small percentage of patients experienced virologic breakthrough (TAF, 2.8%; TDF, 3.2%) that was often associated with drug nonadherence (TAF, 30%; TDF, 50%). Across treatment groups, 132 patients qualified for sequence analysis through week 96, with nearly half having no sequence changes from baseline (43.2%). Most sequence changes occurred at polymorphic positions, and no isolates showed a reduction in susceptibilityin vitro. After 96 weeks, the proportion of patients achieving virus suppression (HBV DNA < 69 IU/ml) was similar across treatment groups, and no substitutions associated with resistance to TAF or TDF were detected. (These studies have been registered at ClinicalTrials.gov under identifiers NCT01940471 and NCT01940341.)

Clinical Prediction of Failure of Lamivudine Prophylaxis for Hepatitis B Virus-Infected Patients Undergoing Cytotoxic Chemotherapy for Malignancy

ABSTRACTAlthough lamivudine (LAM) prophylaxis is recommended for patients infected with hepatitis B virus (HBV) undergoing chemotherapy for malignant disease, HBV reactivation sometimes occurs during or after LAM administration. The aim of this study was to determine predictors of LAM prophylactic failure in patients with malignancies. Patients with malignancies were routinely screened for serum hepatitis B surface antigen (HBsAg) from June 2002 to August 2008. All consecutive, HBsAg-positive patients received LAM prophylaxis during and after completion of chemotherapy. We assessed risk factors for virologic breakthrough and withdrawal hepatitis. Death without HBV reactivation was regarded as a competing risk event, which was adjusted by Fine and Gray's model. A total of 110 patients were included in this study. They received LAM prophylaxis for a median of 9.2 months. Virologic breakthrough occurred in 15 patients at a median of 10.9 months from the initiation of LAM prophylaxis. Withdrawal hepatitis occurred in 15 patients at a median of 2.4 months after cessation of LAM prophylaxis. Multivariable analysis showed that high baseline HBV DNA titer (≥2,000 IU/ml) (hazard ratio [HR], 9.94;P= 0.0063) and the use of rituximab (HR, 3.19;P= 0.027) were significant predictors of virologic breakthrough and that high baseline HBV DNA titer (HR, 5.90;P= 0.007), liver cirrhosis (HR, 10.4;P= 0.002), and distant metastasis (HR, 5.14;P= 0.008) were independent risk factors for withdrawal hepatitis. Patients with high viremia, liver cirrhosis, rituximab treatment, and distant metastasis are at high risk of prophylactic failure and need antiviral agents with a greater barrier to resistance.