The M41L, M184V, L210W, and T215Y mutations were associated with a better, although transient, virological outcome in patients treated with efavirenz-based regimens.

Among 470 patients with acquired immune deficiency syndrome and/or human immunodeficiency virus infection (HIV/AIDS) who underwent genotype resistance testing (GRT) after the failure of therapy, 17 (3.6%) harbored the Q151M mutation. The Q151M mutation was associated with younger age, lower CD4(+) lymphocyte count, higher HIV RNA level, and treatment with >2 pre-GRT regimens. By contrast, the Q151M mutation was inversely associated with lamivudine administration. A full reversion of the Q151M mutation was observed in 5 of 5 patients who underwent treatment interruption after GRT. The reversion was followed by a response to salvage therapy in 4 (80%) of 5 patients.

The mutation RT-K65R confers resistance to tenofovir (TDF). Although its prevalence is increasing with the use of this drug, clinical and genotypic correlates of K65R occurrence have yet to be fully identified. Clinical, virological and immunological and genotypic data of patients naïve for TDF who failed HAART regimens and underwent genotypic resistance test (GRT) during 1999-2003 were collected in a database and analyzed retrospectively. Out of 1392 GRT performed for 771 patients, 12 TDF-naïve patients had the K65R mutation with an overall prevalence of 1.6%. Previous AIDS, the use of abacavir, and treatment with efavirenz at GRT were independently associated with a greater risk of expressing K65R, while patients with longer exposure to lamivudine were less likely to present the mutation. Among genotypic correlates, the presence of M184V and NAMs seems to be protective for the emergence of K65R, while a strong positive correlation was found with the Q151M complex mutation. Moreover, the L100I mutation was independently associated with a higher probability of presenting K65R. The selection of mutation K65R in patients failing without TDF is rare. However, exposure to abacavir and/or efavirenz, presence of Q151M and/or L100I, and prior AIDS may favor the selection of this mutation. Conversely, long 3TC exposure, and the presence of M184V or NAMs seem to be protective.

Background Drug-class-wide resistance (DCWR) to anti-retrovirals substantially reduces treatment options. Methods A database of 602 patients failing highly active antiretroviral therapy (HAART) undergoing genotypic resistance test (GRT) was analysed. DCWR was defined according to the International AIDS Society consensus. A multiple logistic regression model was built to define factors significantly associated with DCWR and to assess virological response to salvage regimens. Results NRTI DCWR was observed in 28.5% of 592 NRTI-exposed patients, NNRTI DCWR in 57.7% of 284 NNRTI exposed patients, PI DCWR in 19.9% of 412 PI exposed patients, and three-class resistance in 21.4% of 112 three-class-exposed patients. The prevalence of NRTI and PI DCWR increased significantly by year of exposure to the same class from 8.9% (<1 year) to 35.3% (>4 years) and from 1.2% (<1 year) to 34.8% (>4 years), respectively ( P<0.001, for trend). The risk of developing NRTI and PI DCWR increased by 25% (95% confidence interval [CI]: 1.6%–51.3%) and by 53% (20.5%–94.3%) for each year of treatment, and by 17% (95% CI: 5.6%–29.3%) and by 32% (17.7%–50.3%) for each previous failing NRTI- and PI-containing regimen, respectively. NRTI DCWR due to at least four nucleoside analogues mutations (NAMs) increased by year of NRTI exposure from 8.9% (<1 year) to 32.6% (>4 years; P<0.001, for trend). After adjustment for confounding factors, the probability of achieving plasma viral load <500 copies/ml was significantly reduced in patients with NRTI (OR: 0.750; 95% CI: 0.574–0.979), NNRTI (OR: 0.746; 95% CI: 0.572–0.975), PI (OR: 0.655; 95% CI: 0.456–0.941), three-class (OR: 0.220; 95% CI: 0.082–0.593) resistance. Conclusions The probability of developing NRTI and PI DCWR increased with length of class exposure and with the number of previously failing regimens. By contrast, high levels of NNRTI DCWR were observed within 1 year in NNRTI-failing patients, with a steady prevalence over time. The increase in prevalence with time of NRTI DCWR was due to the accumulation of NAMs. DCWR to NRTIs, NNRTIs, PIs or all the three together was associated with an increased probability of virological failure to subsequent HAART regimens.

Objective To assess on longitudinal data the impact of number of drug-associated mutations at genotype resistance testing (GRT) and history of previous exposure to antiretrovirals on the virological response to genotype-guided antiretroviral therapy. Methods Subjects that failed HAART who underwent GRT between June 1999 and March 2002 were enrolled. GRT was performed by Viroseq-2 with expert advice offered to physicians. Main outcome was reaching undetectable (<80 copies/ml) HIV-1 RNA level after GRT and maintaining undetectable viraemia for at least 6 months. The number of mutations conferring resistance to each class of antiretrovirals was categorized and their effect on virological outcome investigated. Mutations considered in the analysis were those reported by the IAS-USA in 2002. Multivariate analysis was performed by Cox proportional hazard model. Results Four-hundred-and-seventy consecutive subjects were enrolled and followed-up for a median of 14 (IQR 9–19) months after GRT. Sustained undetectable viraemia was reached by 80 of 449 subjects (18%). Using as end-point reaching and maintaining for at least 6 months <400 copies/ml after GRT, 103 out of 447 subjects (23%) reached the outcome. For each single protease inhibitor (PI)-, nucleoside reverse transcriptase inhibitor (NRTI)-and non-nucleoside reverse transcriptase inhibitor (NNRTI)-associated mutation, there was a reduction of, respectively, 11% ( P=0.008), 12% ( P=0.001) and 39% ( P=0.005) in the likelihood of reaching virological outcome. Subjects carrying ≥6 mutations to NRTIs, ≥7 mutations to PIs and ≥2 mutations to NNRTIs were less likely to reach the virological success compared with those carrying 0–1 (NRTI and PI) or 0 (NNRTI) mutations [HR=0.25 (95% CI: 0.10–0.65); HR=0.33 (95% CI: 0.16–0.67); HR=0.33 (95% CI: 0.14–0.77)], respectively. However, at multivariate analysis the probability of reaching a favourable virological outcome in patients with ≥7 mutations to PIs, if naive for NNRTIs [HR=1.74 (0.69–4.36)], and in subjects with ≥2 mutations for NNRTIs if naive for PIs [HR=1.23 (0.22–6.80)], was comparable to those observed in patients with none or one mutation. Conclusions Our data showed a non-linear association between resistance-conferring mutations and virological outcome. GRT-guided therapy still provided remarkable chances of durable virological success even in subjects with ≥7 mutations to PIs and in subjects with ≥2 mutations to NNRTIs, when the subjects did not have a three-class exposure or if GRT showed no evidence of mutations for a drug class. GRT and as-long-as-possible sparing of a drug class could be a convenient strategy for long-term management of drug-failing patients.