Positive and Negative drug Selection Pressures on the N348I Connection Domain Mutation: New Insights from in vivo Data-猫眼课题宝

N348I 连接域突变的正向和负向药物选择压力：来自体内数据的新见解

DOI：

发表时间：

2010

期刊：

Antiviral Therapy

影响因子：

1.2

通讯作者：

中科院分区：

医学4区

文献类型：

作者：

H. Price;D. Asboe;A. Pozniak;B. Gazzard;E. Fearnhill;D. Pillay;D. Dunn

Background There is conflicting evidence on specific reverse transcriptase inhibitors to which the N348I mutation in the connection domain of HIV type-1 reverse transcriptase confers resistance. Here, we examined associations between the emergence of N348I and anti-retroviral history in a large clinical database. Methods We analysed 5,353 resistance tests (that were sequenced beyond codon 348) among 2,266 antiretroviral-experienced patients. Associations between N348I and individual antiretroviral drug exposure were estimated using a matched case-control approach. Cases were defined as the first resistance test where N348I was detected; for each case, the 10 closest (in calendar time) N348N tests were selected as controls. Odds ratios (ORs) adjusted for effects of all other drugs were estimated by conditional logistic regression. Results N348I was detected in 198 (8.7%) cases. Drugs that were statistically significantly positively associated with N348I were efavirenz (OR 1.55, 95% confidence interval [CI] 1.08–2.23; P=0.017) and nevirapine (OR 2.06, 95% CI 1.49–2.85; P<0.001). Tenofovir disoproxil fumarate (TDF) was significantly negatively associated (OR 0.27, 95% CI 0.15–0.48; P<0.001) with N348I. Similar findings were observed when the analysis was repeated to include only those tests within 2 years of the resistance test. Effects for zidovudine and stavudine were evident only in an additional analysis, which considered exposure to both drugs jointly within 2 years prior to the resistance test: exposure to zidovudine alone (OR 4.61, 95% CI 1.83–11.61; P<0.001) and exposure to stavudine alone (OR 3.39, 95% CI 1.32–8.71; P=0.011). Conclusions This is the first clinical evidence to suggest that efavirenz might select for N348I in addition to nevirapine, that stavudine might select for N348I in addition to zidovudine and that TDF might protect against the mutation.