No detectable resistance to tenofovir in patients with Adefovir- and Entecavir-resistant chronic hepatitis B after 240 weeks of treatment with tenofovir disoproxil fumarate monotherapy

초록

Background and aims: A major challenge in the treatment of chronic hepatitis B (CHB) patients is to maintain long-term viral suppression without emerging the drug-resistant mutations. Monotherapy with tenofovir disoproxil fumarate (TDF) is efficacious in patients with lamivudine-, entecavir- (ETV), or adefovir (ADV) resistant hepatitis B virus. Method: We conducted two multicenter, randomized, open-label trials (IN-US-174-0202 and IN-US-174-0205) designed to compare the efficacy and safety of TDF monotherapy with that of TDF + ETV combination therapy in multiple-drug CHB patients with multiple drug failure and persistent viremia. Patients were randomized 1:1 to receive TDF monotherapy or TDF + ETV combination therapy for 48 weeks, and then to maintain TDF monotherapy or to switch to TDF monotherapy. One study enrolled patients with ETV-resistance without ADV-resistance (n = 90), and the other patients with ADV-resistance (n = 102). Resistance mutations were determined by restriction fragment mass polymorphism analyses and direct sequencing of the pol/RT. Resistance profile was surveilled for patients who experienced virologic breakthrough (VB: increases in HBV DNA levels ≥ 1 log10 IU/ml from nadir on two consecutive tests) or persistent viremia (HBV DNA > 60 IU/ml) at Week 240 or discontinuation. Results: Over the 240-week treatment period, 94 patients with ADV-resistance and 82 patients with ETV-resistance completed up to 240 weeks of TDF monotherapy. Three (3.3%) patients in the ETV-resistance group and 4 (3.9%) patients in the ADV-resistance group experienced VB ( p > 0.99). All of which were associated with decreased adherence to study medication (less than 80%) and were transient requiring no treatment modification. During VB, some of the baseline resistance mutations, but no additional substitutions, were detected in pol/RT region of HBV in the patients. Among the 12 patients who discontinued the study, none had VB at drop-out, but 2 had HBV DNA > 60 IU/ml at the last time point of treatment, where no additional substitutions were detected in pol/RT gene compared to baseline. At week 240, 1 and 8 patients in the ETV-resistance and ADV-resistance groups, respectively, had HBV DNA levels > 60 IU/ml ( p = 0.04). Among them, 2 patients in the ADV-resistance group had at least one detectable HBV resistance mutation at week 240, all of which were present at baseline. No patients developed additional substitutions in pol/RT compared to baseline. Conclusion: TDF monotherapy maintains effective suppression of HBV DNA through 240 weeks of treatment with no evidence of additional resistance mutations in patients with ADV- and ETV-resistant CHB.