Virologic breakthrough in a patient with chronic hepatitis B by combination treatment with tenofovir disoproxil fumarate and entecavir

Abstract

Tenofovir disoproxil fumarate (TDF) is widely used to treat hepatitis B virus (HBV) patients in the USA and Europe. No confirmed report of resistance selection during treatment with TDF in treatment-naïve and nucleoside/nucleotide analog-treated chronic hepatitis B patients has yet been reported. Here, we report for the first time a patient with chronic hepatitis B and cirrhosis who emerged with virologic breakthrough during combination therapy with TDF and entecavir (ETV), against ETV-resistant virus. A 51-year-old Japanese woman with hepatitis B e-antigen (HBeAg), whose genotype was C, received ETV monotherapy continuously followed by TDF and ETV combination therapy, because her HBV DNA levels had been >3.5 log copies/mL. At the start of combination therapy, amino acid substitutions of the reverse transcriptase (rt) gene, rtL180M, rtT184I/M, and rtM204V, were detected. After this, serum HBV DNA decreased to less than 2.1 log copies/mL and remained at this level until 31 months of combination therapy, when it again began to increase. Amino acid substitutions of rtL180M, rtS202G, and rtM204V emerged and were associated with an increase in serum HBV DNA at virologic breakthrough. Long-term therapy with TDF against the ETV-resistant virus has the potential to induce virologic breakthrough and resistance, and careful follow-up should be carried out.

Efficacy and Safety of Tenofovir Disoproxil Treatment for Chronic Hepatitis B Patients with Genotypic Resistance to Other Nucleoside Analogues

“…However, Suzuki et al . [ 29 ] recently reported the occurrence of virological breakthrough during the long-term follow-up period after TDF plus ETV treatment of patients, suggesting that TDF rescue therapy for drug-resistant patients still need to be closely followed up. The study results, by detecting gene loci, did not show the loci that decreased TDF susceptibility.…”

Successful Management of a Patient with Multiple Nucleos(t)ide Analogue-Resistant Hepatitis B Virus and Diffuse Large B Cell Lymphoma Using Tenofovir Disoproxil Fumarate: A Case Report

“…However, there is one report of an HIV-and HBVcoinfected patient in whom tenofovir disoproxil fumarate resistance was acquired through the combination of rtL180M and rtM204V, which together confer lamivudine resistance and rtA194T mutations 26) . Suzuki et al 27) also reported a tenofovir-multiple drug resistant strain in a long-term user of NUCs. Our case suggested that it may be important to add tenofovir disoproxil fumarate to entecavir for the patients with multiple drug resistant HBV strain.…”

Current and future directions for treating hepatitis B virus infection

“…Apart from interferon, with the use of NUCs such as entecavir and tenofovir, it is always possible for resistant mutants to emerge [97][98][99][100][101] . Suzuki et al [101] reported that 51-year-old Japanese women with chronic hepatitis B and cirrhosis have virological breakthrough during combination therapy with tenofovir and entecavir against entecavir-resistant virus.…”

“…Suzuki et al [101] reported that 51-year-old Japanese women with chronic hepatitis B and cirrhosis have virological breakthrough during combination therapy with tenofovir and entecavir against entecavir-resistant virus. Even long-term therapy with tenofovir against the entecavir-resistant virus has the potential to induce virological breakthrough and resistance.…”