Emergence of lamivudine-resistant hepatitis B virus during combination antiretroviral therapy that includes lamivudine for patients co-infected with HIV and hepatitis B virus in China: a 2-year pilot cohort study

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• 作者：Dr Yang Han ; PhD^a ; ^&dagger ; ; ^{hanyang_pumch@126.com" class="auth_mail" title="E-mail the corresponding author} ; Lijun Gu ; PhD^b ; ^&dagger ; ; Ting Zhu ; BSc^a ; Prof Taisheng Li ; MD^a ; Xiaojing Song ; BSc^a ; Ying Huang ; MSc^c ; Feifei Yang ; MSc^c ; Shuo Guan ; MSc^c ; Jing Xie ; PhD^a ; Prof Takaomi Ishida ; PhD^b
• 刊名：The Lancet
• 出版年：2015
• 出版时间：October 2015
• 年：2015
• 卷：386
• 期：supp_S1
• 页码：S32
• 全文大小：61 K

文摘

In China, more than 10% of individuals infected with HIV are carriers of hepatitis B virus (HBV). Patients infected with HIV-1 are usually given combination antiretroviral therapy that includes lamivudine (ART-3TC) as a reverse-transcriptase inhibitor. Previous studies from some developed counties showed that, in ART-3TC, 3TC-resistant HBV progressively emerges at a rate of 15–20% per year in patients co-infected with HIV-1 and HBV. We investigated the occurrence of 3TC-resistant HBV during ART-3TC for double infections and tested the use of tenofovir disoproxil fumarate (TDF) as an additional reverse-transcriptase inhibitor (ART-3TC/TDF) in a 2-year cohort study in China.

Methods

172 plasma samples from 43 Chinese patients co-infected with HIV-1 and HBV (from 134 cases positive for HBsAg) were examined for the prevalence of 3TC-resistant HBV by direct sequencing of PCR products covering the HBV reverse transcriptase gene. The patients were randomised (7:1), using a randomised number table, to receive either ART-3TC or ART-3TC/TDF (because ART-3TC/TDF was not a standard first-line treatment in China at that time). HIV-1 RNA and HBV DNA loads were detected at baseline, 12 weeks, 48 weeks, and 96 weeks from plasma samples. All samples were tested for HIV and HBV drug resistance against 3TC. The efficacy of viral suppression and incidence of drug-resistance mutation were compared between the two groups. This study was approved by the ethics committee at Peking Union Medical College Hospital, Beijing, China, and registered at ClinicalTrials.gov (identifiers NCT00618176 and NCT00872417). Patients were enrolled in Chinese cohort studies (National Key Technologies R&D Program for the tenth and 11th Five-year Plans).

Findings

Median HIV-1 RNA loads of the ART-3TC group and the ART-3TC/TDF group significantly decreased from 26 205 copies/mL (IQR 917; p<0·0001) to fewer than 20 copies/mL (<20; p=0·0278) and from 58 972 copies/mL (3395; p<0·0001) to fewer than 20 copies/mL (<20; p=0·0207), respectively, after 96 weeks of treatment. Median HBV DNA loads also significantly decreased from 3·4 × 10⁶ IU/mL (IQR <20; p<0·0001) to less than 20 IU/mL (<20; p<0·0001) in the ART-3TC group and from 2·7×10⁵ IU/mL (399; p<0·;0001) to less than 20 IU/mL (<20; p=0·0152) in the ART-3TC/TDF group after 96 weeks of treatment. Although median HIV-1 viral load did not differ significantly (p>0·05) between the two groups after 96 weeks, the rate of HIV-1 RNA decline in the ART-3TC/TDF group was slightly lower than that in the ART-3TC group (RNA load range <20–905 copies/mL vs <20–4932 copies/mL at 12 weeks, <20–157 copies/mL vs <20–398 copies/mL at 48 weeks). ART-3TC/TDF had a higher efficacy than ART-3TC in controlling amounts of HBV. At 96 weeks, the median HBV DNA load was less than 20 IU/mL (IQR <20–1·2 × 10⁸) in the ART-3TC group, suggesting that some patients had rebound or uncontrolled HBV DNA loads, but no such case was reported in the ART-3TC/TDF group, the median HBV DNA load of which was <20 IU/mL (<20; p=0<0119). Ten (23%) of 43 patients, all from the ART-3TC group, had HBV breakthrough after 96 weeks of treatment, and eight of these patients were resistant to ART-3TC (60% tr204 mutation and 80% rt180 mutation; appendix).

Interpretation

Although both regimens were able to control replication of HIV and HBV during the 2-year treatment, our findings showed that, in China, ART-3TC is likely to lead to the emergence of 3TC-resistant HBV, lending support to the benefit of the inclusion of TDF for patients co-infected with HIV-1 and HBV.