Emergence of a New Circulating B/CRF02/G Recombinant Form Spreading in France

International audienc

Prevalence of HIV-1 drug resistance in treated patients with viral load >50 copies/mL in 2009: a French nationwide study

Background Surveillance of HIV-1 drug resistance in treated patients with plasma viral load (VL) >50 copies/mL. Methods The protease and reverse transcriptase (RT) genes were systematically sequenced in samples from 756 patients with VL >50 copies/mL in 2009. The genotyping results were interpreted for each antiretroviral drug (ARV) by using the ANRS algorithm v21. Weighted analyses were used to derive representative estimates of percentages of patients. Prevalence rates were compared with those obtained in 2004 among patients with VL >1000 copies/mL. Results Sequences were obtained for 506 patients. Sequencing was successful in 45%, 80% and 96% of samples with VL of 51-500, 501-1000 and >1000 copies/mL, respectively. Resistance or possible resistance to at least one ARV was observed in 59% of samples. Overall, 0.9% of samples contained viruses resistant to all drugs belonging to at least three drug classes. All resistance prevalence rates were significantly lower in 2009 than in 2004. Conclusion In France, where 86% of patients were receiving combination antiretroviral therapy in 2009, only 15.0% of patients had a VL >50 copies/mL, suggesting that only 8.9% of treated patients could potentially transmit resistant viruses. Only 0.08% of patients harboured viruses fully resistant to at least three antiretroviral drug classes. Further studies are needed to determine whether resistance continues to decline over tim

Caution is needed in interpreting HIV transmission chains by ultradeep sequencing.

OBJECTIVES: Molecular epidemiology is applied to various aspects of HIV transmission analyses. With ultradeep sequencing (UDS), in-depth characterization of transmission episodes involving minority variants is permitted. We explored HIV-1 epidemiological linkage and evaluated characteristics of transmission dynamics and transmitted drug resistance (TDR) detection through the added value of UDS. DESIGN: HIV pol gene fragments were sequenced by UDS and Sanger sequencing on samples of 70 HIV-1-infected, treatment-naive recently diagnosed MSM. METHODS: Pairwise genetic distances and maximum likelihood phylogenies were computed. Transmission events were identified as clades with branch support at least 70% and intraclade genetic difference less than 4.5%. TDR mutations were recognized from the TDR consensus list. Transmission directionality, directness and inoculum size were inferred from tree topologies. RESULTS: Both datasets concurred in the identification of seven transmission pairs and one cluster of three patients. With UDS, direction of transmission was inferred in four out of eight chains. Evidence for multiple founder viruses was found in two out of eight chains. No transmission of minority-resistant variants was evidenced. TDR mutations prevalence in protease and reverse transcriptase fragments was 4.3% with Sanger sequencing and 18.6% with UDS. CONCLUSION: Although Sanger sequencing and UDS identified the same transmission chains, UDS provided additional information on founder viruses, direction of transmission and levels of TDR. Nevertheless, topology of clusters was not always consistent across gene fragments, calling for a cautious interpretation of the data. Moreover, unobserved intermediary links cannot be excluded. Phylogenetic analysis use as a forensic technique for HIV transmission investigations is risky

Les VIH-1 hyper-résistants (études clonales et impacts thérapeutiques des souches du VIH-1 résistantes aux nouveaux antirétroviraux)

PARIS-BIUP (751062107) / SudocSudocFranceF

Mutations de résistance sur le gène de la transcriptase inverse du VIH-1 (impacts des interruptions thérapeutiques et études d'interactions entre mutations particulières)

Chez les patients infectés par des souches VIH-1 multirésistantes, l interruption totale de traitement peut permettre la réémergence de souches plus sensibles. Cependant, le temps nécessaire peut être très long et délétère, et le retour rapide de la souche multirésistante à la reprise du traitement conduit à l échec en l absence de molécules pleinement actives. D autres contextes d interruptions comme le simple changement de molécule peut avoir également des conséquences négatives. Nous avons également étudié l impact des interactions existant entre les TAMs, la K65R et la L74I/V. Ces interactions peuvent être d ordre purement fonctionnel ou ne concerner que les mécanismes de résistance. Les interactions entre TAMs conduisent à l émergence de deux profils distincts. Ces profils interfèrent eux mêmes avec les mutations en position 74. L émergence de toutes ces mutations dépend d un complexe équilibre entre phénomènes de résistance et capacité réplicative du virus.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Emergence of a New Circulating B/CRF02/G Recombinant Form Spreading in France

International audienc

International Cohort Analysis of the Antiviral Activities of Zidovudine and Tenofovir in the Presence of the K65R Mutation in Reverse Transcriptase▿

A K65R mutation in HIV-1 reverse transcriptase can occur with the failure of tenofovir-, didanosine-, abacavir-, and, in some cases, stavudine-containing regimens and leads to reduced phenotypic susceptibility to these drugs and hypersusceptibility to zidovudine, but its clinical impact is poorly described. We identified isolates with the K65R mutation within the Stanford Resistance Database and a French cohort for which subsequent treatment and virological response data were available. The partial genotypic susceptibility score (pGSS) was defined as the genotypic susceptibility score (GSS) excluding the salvage regimen's nucleoside reverse transcriptase inhibitor (NRTI) component. A three-part virologic response variable was defined (e.g., complete virologic response, partial virologic response, and no virologic response). Univariate, multivariate, and bootstrap analyses evaluated factors associated with the virologic response, focusing on the contributions of zidovudine and tenofovir. Seventy-one of 130 patients (55%) achieved a complete virologic response (defined as an HIV RNA level of <200 copies/ml). In univariate analyses, pGSS and zidovudine use in the salvage regimen were predictors of the virologic response. In a multivariate analysis, pGSS and zidovudine and tenofovir use were associated with the virologic response. Bootstrap analyses showed similar reductions in HIV RNA levels with zidovudine or tenofovir use (0.5 to 0.9 log10). In the presence of K65R, zidovudine and tenofovir are associated with similar reductions in HIV RNA levels. Given its tolerability, tenofovir may be the preferred agent over zidovudine even in the presence of the K65R mutation

M184V/I does not impact the efficacy of abacavir/lamivudine/dolutegravir use as switch therapy in virologically suppressed patients

International audienceBackground: M184V/I NRTI resistance mutations can be selected by either lamivudine/emtricitabine or abacavir. There are controversies about the use of abacavir/lamivudine/dolutegravir combinations in HIV-1-infected treatment-experienced patients with a fully suppressed HIV viral load (VL) and harbouring M184V/I.Objectives: We assessed the efficacy of abacavir/lamivudine/dolutegravir when used in HIV-infected pretreated patients with an undetectable VL who previously harboured M184V/I as a unique NRTI resistance mutation in a genotypic resistance test and had no resistance to integrase inhibitors.Patients and methods: A total of 154 patients with a fully suppressed HIV-1 plasma VL (<50 copies/mL) treated with tenofovir disoproxil fumarate/emtricitabine/boosted PI or abacavir/lamivudine/boosted PI who switched to an abacavir/lamivudine/dolutegravir regimen and had M184V/I as a unique NRTI resistance mutation in their therapeutic history were retrospectively analysed up to 12 months after the switch to abacavir/lamivudine/dolutegravir. Assessment of residual viraemia was performed at Months 1, 3, 6 and 12. Plasma VL with undetectable HIV-1 RNA corresponded to an absence of residual viraemia.Results: During the 12 months of follow-up, three patients had a blip of VL (53, 62 and 106 copies/mL) at Month 3 followed by a subsequent VL <50 copies/mL. No patient harboured a virological failure during the follow-up. Moreover, there was no change in residual viraemia during the follow-up.Conclusions: M184V/I as a unique NRTI resistance mutation, regardless of possible selection by regimens containing lamivudine/emtricitabine or abacavir, does not affect the virological response of well-controlled patients who switched to abacavir/lamivudine/dolutegravir for at least 12 months

Clinically Relevant Genotype Interpretation of Resistance to Didanosine

We analyzed the didanosine (ddI) arm of the randomized, placebo-controlled Jaguar trial in order to define a genotypic score for ddI associated with virologic response. In this arm, 111 patients experiencing virologic failure received ddI in addition to their current combination therapy for 4 weeks. The impact of mutations in the reverse transcriptase gene on the virologic response to ddI was studied in univariate analysis. Genotypic score was constructed using step-by-step analyses first including only mutations associated to poorer virologic response (scored as +1), while secondarily, mutations associated to a better response (scored as −1) were also eligible. Eight mutations were associated with a reduced response to ddI, M41L, D67N, T69D, L74V, V118I, L210W, T215Y/F, and K219Q/E, and two mutations were associated with a better response, K70R and M184V/I. The best prediction of the virologic response to ddI was obtained with a composite score comprising mutations added and subtracted (set II, M41L + T69D + L74V+ T215Y/F + K219Q/E − K70R − M184V/I; P = 4.5 × 10(−9)) and by comparing that to only mutations added (set I, M41L + T69D + L74V + L210W + T215Y/F + K219Q/E; P = 1.2 × 10(−7)). Patients had a human immunodeficiency virus RNA reduction of 1.24, 0.84, 0.61, 0.40, and 0.07 log(10) copies/ml when they were ranked as having a genotypic score II of −2, −1, or 0 or 1 and 2 mutations or more, respectively. In conclusion, we developed and validated a genotypic score, taking into account mutations negatively and positively impacting the virologic response to ddI