Marc Wirden

Polytech Paris-UPMC, Lutetia Parisorum, Île-de-France, France

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Publications (79)389.95 Total impact

  • Journal of Antimicrobial Chemotherapy 09/2014; · 5.34 Impact Factor
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    ABSTRACT: Previous studies on HIV quasispecies have revealed HIV compartmentalization in various tissues within an infected individual. Such HIV variation is a result of a combination of factors including high replication and mutation rates, recombination, and APOBEC3-host selective pressure. To evaluate the differential impact of APOBEC3 editing in HIV-1 compartments, we analyzed the level of G-to-A hypermutation in HIV-1 protease and reverse transcriptase sequences among 30 HAART-treated patients for whom peripheral blood mononuclear cells and body tissues or fluids [cerebral spinal fluid (CSF), rectal tissue, or renal tissue] were collected on the same day. APOBEC3-mediated hypermutation was identified in 36% (11/30) of participants in at least one viral reservoir. HIV hypermutated sequences were often observed in viral sanctuaries (total n = 10; CSF, n = 6; renal tissue, n = 1; rectal tissue n = 3) compared with peripheral blood (total n = 4). Accordingly, APOBEC3 editing generated more G-to-A drug resistance mutations in sanctuaries: three patients' CSF (i.e., G73S in protease; M184I, M230I in reverse transcriptase) and two other patients' rectal tissues (M184I, M230I in reverse transcriptase) while such mutations were absent from paired peripheral blood mononuclear cells. APOBEC3-induced mutations observed in peripheral blood underestimate the overall proportion of hypermutated viruses in anatomical compartments. The resulting mutations may favor escape to antiretrovirals in these compartments in conjunction with a lower penetration of drugs in some sanctuaries. On the other side, because hypermutated sequences often harbor inactivating mutations, our results suggest that accumulation of defective viruses may be more dominant in sanctuaries than in peripheral blood of patients on effective HAART.
    AIDS (London, England) 01/2014; · 4.91 Impact Factor
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    ABSTRACT: Introduction: Selection of resistance mutations on antiretroviral therapy (ART) including darunavir (DRV/r) or atazanavir (ATV/r) has been reported infrequently but mainly in clinical trials where patients were followed very frequently (at least four to five clinical visits and viral load measurements per year). The aim of this study was to evaluate the rate of resistance at failure and mutational patterns emerging in patients receiving DRV/r or ATV/r based-regimen as first line treatment and followed in standard clinical practice with less clinical visits and viral load measurements (median=2 per year). Methods: We studied 1,518 patients starting their first line antiretroviral therapy and followed during at least two years (n=799 TVD+DRV/r, n=70 KVX+DRV/r, n=618 TVD+ATV/r, n=31 KVX+ATV/r). The median viral load at baseline was 76,000 copies/mL and the median CD4 cell count 384 cell/mm(3). Virological failure was defined as two consecutive viral load=50 copies/mL after previous suppression <50 copies/mL, or failure to achieve <50 copies/mL. Predicted susceptibility was determined using the last ANRS algorithm. Results: Among the 1,518 patients, 193 (12.7%) failed during the two years of follow-up. Among patients failing TVD+DRV/r (n=95), the emerging mutations observed were RT M184V (n=8; 8%) and Pro V32I (n=1; 1%). Among patients failing KVX+DRV/r (n=8), the emerging mutations observed were RT M184V (n=3; 37%) and Pro I47V (n=1; 12%). Among patients failing TVD+ATV/r (n=86), the emerging mutations observed were RT M184V (n=9; 10%), Pro N88S (n=2; 2%) and Pro I50L (n=1; 1%). Among patients failing KVX+ATV/r (n=4), the emerging mutations observed were RT M184V (n=2; 50%) and no Pro mutation. Most of patients retained virus predicted to be susceptible to all antiretrovirals (22 virus became resistant to 3TC/FTC and three became resistant to ATV). None of them became resistant to DRV. Conclusions: Among 1,518 patients in routine care who started their first line treatment with DRV/r or ATV/r, very few of them (1.4%) selected resistance mutations at failure with three patients selecting an ATV resistant virus. None of them became resistant to DRV. The less frequent follow-up of patients in routine care compared to clinical trials does not impact the resistance selection rate in patients treated by boosted DRV or ATV based regimen.
    Journal of the International AIDS Society 01/2014; 17(4(Suppl 3)):19744. · 3.94 Impact Factor
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    ABSTRACT: Low-level viraemia during antiretroviral therapy and its accurate measurement have become increasingly relevant. We present an international collaboration of 4,221 paired plasma viral load (pVL) results from four commercial assays, emphasizing data with low pVL.The assays compared were the Abbott RealTime assay and the Roche Amplicor, TaqMan v1 and v2 assays. Correlation between assays was 0.90-0.97. However, at low pVL, correlation fell to 0.45-0.85. Higher inter-assay concordance was observed when detectability was defined as 200-copies/mL versus 50-copies/mL. A pVL of ∼100-125 copies/mL by TaqMan v1/v2 corresponded best to a 50-copies/mL threshold by Amplicor.Correlation and concordance between viral load assays were lower at low pVL. Clear guidelines are needed on the clinical significance of low-level viraemia.
    Journal of clinical microbiology 12/2013; · 4.16 Impact Factor
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    ABSTRACT: In the context of simplification strategies, it is essential to know the feasibility of a switch to a rilpivirine-based therapy. The aim of this study was to describe rilpivirine, tenofovir and emtricitabine resistance in HIV-1-infected patients who experienced virological failure during their previous antiretroviral treatment. The studied population included two groups of patients, all rilpivirine naive, tested for resistance by bulk sequencing from 2008 to 2011: the first group (n = 998) failing a nucleoside reverse transcriptase inhibitor (NRTI) plus boosted protease inhibitor (PI)-based regimen and the second group (n = 3733) failing an NRTI plus non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. In the first group, the frequency of rilpivirine mutations and resistance to rilpivirine (5.1%) was similar to that in antiretroviral-naive HIV-1-infected patients. Among the 1605 patients from the second group with at least one NNRTI mutation in their HIV, the prevalence of viruses 'resistant' or 'possibly resistant' to efavirenz, nevirapine and etravirine was 78%, 79% and 74%, respectively, while 59% were resistant to rilpivirine. Resistance to rilpivirine was significantly more frequent in non-B subtype versus B subtype viruses. Among pretreated patients with viruses with at least one NNRTI mutation (other than for rilpivirine), 22% of sequences were susceptible to the combination rilpivirine/emtricitabine/tenofovir disoproxil fumarate. In patients failing an NRTI plus NNRTI-based regimen, to know the feasibility of a switch to rilpivirine/emtricitabine/tenofovir disoproxil fumarate, reliable resistance information should be available at the time of use of concurrent NNRTI therapy.
    Journal of Antimicrobial Chemotherapy 12/2013; · 5.34 Impact Factor
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    ABSTRACT: The lack of antiretroviral (ARV) backbone activity associated with raltegravir has been proposed as the main explanation for virological relapse observed in patients with undetectable viraemia who are switched from a ritonavir-boosted protease inhibitor (PI) to raltegravir. However ARV activity remains difficult to assess in this context. The aim of our study was to precisely assess the ARV backbone activity in patients with undetectable viraemia who underwent raltegravir switching strategies and to evaluate the efficacy of such switching strategies based on the genotypic sensitivity score (GSS). Patients with a plasma human immunodeficiency virus type 1 (HIV-1) RNA level of <50 copies/mL on a stable two ARV-class regimen were enrolled if they switched one of their ARV drugs to raltegravir 400 mg twice daily. The GSS was calculated using a genotyping test performed on the HIV-1 RNA of the last plasma measurement with a HIV-1 RNA level of >50 copies/mL before the switch and on the results of all previous genotyping tests. The primary endpoint was the proportion of patients with a plasma HIV-1 RNA level of <50 copies/mL at week 24. Fifty-six patients were enrolled in this study. The proportion of patients with a plasma HIV-1 RNA level of <50 copies/mL at week 24 was 92.9 % (range 83.0-97.2 %) in the intent-to-treat analysis and 98.1 % (90.0-99.7 %) in per-protocol analysis. When the backbone was fully active, the proportion was 100.0 % (86.7-100.0 %) at week 24 and week 48 in the per-protocol analysis. We observed a decrease in plasma total cholesterol and triglycerides of -12.7 % (p = 0.005) and -26.5 % (p = 0.001), respectively. Raltegravir switching strategies are effective when the associated backbone is fully active according to the GSS. In the context of undetectable viraemia, where ARV activity remains difficult to assess, the determination of the GSS requires the entire ARV history of the patient and all previous HIV-RNA genotyping test results.
    Infection 10/2013; · 2.44 Impact Factor
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    ABSTRACT: Several B/CRF02_AG Unique Recombinant Forms (URFs) have previously been identified in France. Here we show that one of them (URF5_B/02/G) is emerging in MSM, a high-risk population where HIV incidence and number of superinfections are increasing. We describe this new Circulating Recombinant Form, CRF56_cpx, estimate the time to its most recent common ancestor, investigate its origins and show that it probably shares common ancestors with strains from the East Mediterranean.
    AIDS (London, England) 09/2013; 27(14):2309-12. · 4.91 Impact Factor
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    ABSTRACT: There are today HIV-infected patients in therapeutic impasses because of highly multidrug-resistant (HMDR) viruses. We studied the distribution of resistance mutations at clonal level, and we analysed the therapeutic strategies used in such cases to achieve undetectable viraemia. The HMDR profile was defined as a genotypic sensitivity score (GSS) ≤1.5 for etravirine and raltegravir with full resistance to darunavir. About 30 clones per gene and per patient were sequenced. Virtual phenotypes were determined. Efficacy of therapeutic strategies was evaluated by follow-up of viral loads, CD4 cell counts and trough concentrations of drugs. Among 1310 patients on treatment and with genotypic resistance testing, 25 (2%) were resistant to darunavir and 11 (0.8%) had an HMDR profile. Five-hundred clones could be analysed for four of them. HMDR profiles were harboured by the great majority of clones and all resistance mutations were located on the same strains for all genes. Despite this and a regimen with a GSS <2.0 in three patients, they achieved a viraemia <20 copies/mL. These results were obtained using different strategies: high doses of drugs; combination of antiretrovirals with full or intermediate susceptibility, such as tipranavir, etravirine or maraviroc; and use of alternative compounds, such as foscarnet or interferon. Patients with HMDR HIV were uncommon, but, in such cases, all resistance mutations were borne on the same majority strains. In this study, tipranavir was the only protease inhibitor with full or intermediate susceptibility. Despite very limited therapeutic options, an undetectable viraemia can be achieved by combining different strategies.
    Journal of Antimicrobial Chemotherapy 07/2013; · 5.34 Impact Factor
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    ABSTRACT: It has been demonstrated for some drugs that the genetic barrier, defined as the number of genetic transitions and/or transversions needed to produce a resistance mutation, can differ between HIV-1 subtypes. We aimed to assess differences in the genetic barrier for the evolution of resistance to the second-generation non-nucleoside reverse transcriptase inhibitors etravirine and rilpivirine in subtypes B and CRF02_AG in antiretroviral-naive patients. An analysis was undertaken of 25 substitutions associated with etravirine and rilpivirine resistance at 12 amino acid positions in 267 nucleotide sequences (136 HIV-1 B and 131 HIV-1 CRF02_AG subtypes) of the reverse transcriptase gene. The majority (7/12) of amino acid positions studied were conserved between the two HIV-1 subtypes, leading to a similar genetic barrier. Different predominant codons between the subtypes were observed in 5/12 positions (90, 98, 179, 181 and 227), with an effect on the calculated genetic barrier only at the V179D and V179F codons (2.5 versus 3.5 for V179D, and 2.5 versus 5 for V179F, respectively, for subtype B versus subtype CRF02_AG). The majority of amino acids involved in etravirine and rilpivirine resistance showed a high degree of conservation of the predominant codon between the B and CRF02_AG subtypes. For rilpivirine, the genetic barrier was the same between the two subtypes. Nevertheless, subtype CRF02_AG showed a higher genetic barrier to acquiring mutations V179D and V179F (mutations associated with resistance to etravirine) compared with subtype B, suggesting that it would be more difficult to produce resistance to etravirine in the CRF02_AG subtype than the B subtype.
    Journal of Antimicrobial Chemotherapy 07/2013; · 5.34 Impact Factor
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    ABSTRACT: OBJECTIVES: The HIV reverse transcriptase (RT) mutation K65R confers resistance to nucleos(t)ide reverse transcriptase inhibitors (NRTIs). Here, analysing a large database, we report the selection of another rare K65E mutation in patients failing on NRTI-containing regimens. METHODS: Clinical and virological characteristics of patients harbouring the K65E mutation were analysed using a large RT sequence database from treatment-experienced individuals. Structural analysis of the K65E RT mutant complex was performed by means of docking simulations. The replication capacity was assessed using viruses harbouring the K65E mutation introduced by site-directed mutagenesis (SDM) in pNL 4-3. RESULTS: Overall, in 23 530 sequences from patients failing on antiretroviral therapy, the prevalence of substitutions at position K65 in RT was 2.4%. In addition to K65R (n = 395) and K65N (n = 9), another mutation, K65E, was found in 15 patients. In 11 out of 15 cases, tenofovir, abacavir, didanosine or stavudine were present at the time of K65E selection. The molecular recognition of RT containing K65E supports evidence for the role of this mutation in resistance to tenofovir. The SDM pNL4-3 K65E variant harboured a very low replicative capacity (5% versus wild-type). CONCLUSIONS: We investigated the role of a novel rare NRTI mutation located at position Lys65 of RT (K65E), found in drug-experienced patients failing on NRTIs. The low frequency of this mutation is probably related to the high impairment of replicative capacity induced by this mutation. This study should have significant clinical implications, as these findings warn clinicians that other minor substitutions at Lys65 (such as K65E) play a role in NRTI resistance.
    Journal of Antimicrobial Chemotherapy 06/2013; · 5.34 Impact Factor
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    ABSTRACT: 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 time.
    Journal of Antimicrobial Chemotherapy 02/2013; · 5.34 Impact Factor
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    ABSTRACT: OBJECTIVES: The prevalence of rilpivirine, emtricitabine and tenofovir resistance-associated mutations (RAMs), described in vitro and in vivo, was determined in antiretroviral-naive patients. PATIENTS AND METHODS: From 2008 to 2011, 1729 treatment-naive patients were tested for resistance by bulk sequencing. We studied the primary rilpivirine RAMs (K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, H221Y, F227C and M230I/L) and other potential rilpivirine-associated mutations (V90I, L100I, K101T, E138S, V179D/I, Y188L, V189I, G190A/E/S and M230V). We also studied the M184V/I and K65R mutations for emtricitabine and tenofovir, respectively. RESULTS: Among 1729 sequences, half of patients had B-subtype viruses and the other half non-B (with 26.7% CRF02, n = 461). Primary rilpivirine RAMs were infrequent (4.6%, n = 79) and the most prevalent were E138A (3%, n = 52), E138K, (0.3%, n = 5), H221Y (0.3%, n = 5), E138G (0.2%, n = 4) and Y181C (0.2%, n = 4). The frequency of the primary rilpivirine RAMs was similar between B and non-B subtypes. The other potential rilpivirine-associated mutations that were most prevalent were V179I (8.4%, n = 145), V90I (3.8%, n = 65) and V189I (2.3%, n = 40). The common V179I, V189I and V90I polymorphisms have not been associated with virological failure in Phase 3 clinical studies. By the ANRS algorithm, 4.9% (n = 84) of samples were resistant to rilpivirine, 3.7% (n = 32) of B-subtype viruses versus 6% (n = 52) of non-B-subtype viruses (P = 0.02, χ(2) test). The prevalence of K65R and M184I/V was 0.06% (1/1729) and 1% (18/1729), respectively. The prevalence of K103N was 2% (35/1729). CONCLUSIONS: The prevalence of rilpivirine, emtricitabine and tenofovir resistance mutations was very low in antiretroviral-naive patients. The prevalence of resistance to rilpivirine (4.9%, n = 84) was not statistically different from the prevalence of efavirenz and nevirapine resistance in our population.
    Journal of Antimicrobial Chemotherapy 01/2013; · 5.34 Impact Factor
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    ABSTRACT: To treat human immunodeficiency virus (HIV)-infected patients, international guidelines recommend the combination of two nucleos(t)ide reverse transcriptase inhibitors [N(t)RTIs] and a third agent [non-NRTI (NNRTI), boosted protease inhibitor (r/PI) or integrase inhibitor (INI)] for initial treatment. The objective of this study was to compare the selection of resistance to antiretrovirals (ARVs) for regimens containing or lacking N(t)RTIs in patients experiencing their first virological failure. Eligible patients had a first virological failure, defined as the occurrence of two consecutive HIV plasma viral loads ≥50 copies/mL. Genotypic resistance testing was performed at the time of virological failure (on the second sample with detectable viral load ≥50 copies/mL) in patients failing regimens of N(t)RTIs + r/PI or NNRTI or INI, r/PI + NNRTI or INI, and INI + NNRTI. Among 434 virological failures analysed, resistance testing results were available in 416 cases (95.9%). Higher rates of drug resistance were observed in patients receiving N(t)RTI-sparing regimens. When the combination of N(t)RTIs + r/PI was used, PIs protect themselves and the associated N(t)RTIs from the selection of resistance; however, this was not observed with the NNRTI + r/PI combination. The same phenomenon was observed for raltegravir: when used in combination with N(t)RTIs, INI resistance mutations were less frequently selected compared with its use in combination with PIs or NNRTIs. In conclusion, regimens of the ARV classes combined impact the frequency of resistance development. Lower resistance is observed for N(t)RTI-based regimens, with more therapeutic options for subsequent regimens after failure.
    Journal of Global Antimicrobial Resistance. 01/2013;
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    ABSTRACT: OBJECTIVES: The genotypic method is reliable enough for the determination of tropism and largely preferred in Europe. However, careful interpretation is essential when assessing HIV genotypic resistance during treatment interruption (TI) due to the possible disappearance of resistant strains. The results of HIV genotypic tropism testing in such a context remain unknown. METHODS: First, we studied changes in tropism in patients included in a structured TI assay: the Reverse study. Second, we investigated the unexpected tropism switches from X4 to R5 recorded in our routine database. RESULTS: Tropism determination was possible in 21 patients of the Reverse study, 9 of whom had an X4 virus (43%) at baseline. Two patients displayed a change of tropism during TI, both switching from X4 to R5. Regarding the database investigation, 7 of the 222 patients with at least two plasma tropism determinations recorded in the database displayed a switch from X4 to R5. TI due to non-compliance at the time of the tropism change was reported for five of these seven patients. CONCLUSIONS: We have shown that the redistribution of the HIV population caused by TI could potentially result in X4 viruses becoming undetected and inappropriate prescription of a CCR5 receptor antagonist. Therefore, genotypic tropism results should be interpreted with caution in such a context.
    Journal of Antimicrobial Chemotherapy 09/2012; · 5.34 Impact Factor
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    ABSTRACT: BACKGROUND: The combination of raltegravir (RAL) and etravirine (ETR) represents a novel antiretroviral treatment option in patients with toxicity or long-term exposure to standard therapies including protease inhibitors (PI) and nucleoside reverse transcriptase inhibitors (NRTI). The objective of this study was to evaluate the capacity of dual RAL/ETR therapy to maintain virological suppression in HIV-1 patients under effective antiretroviral therapy (ART). METHODS: Using the Nadis database we retrospectively identified all patients in our centre who were switched from different ART regimens to ETR 200 mg twice daily plus RAL 400 mg twice daily prior to February 2010, having a suppressed HIV-1 plasma viral load (pVL<200 copies/ml) at the moment of switch. Patients already on RAL or ETR at baseline were not excluded from the study. Treatment failure was defined as two consecutive pVL>50 copies/ml or discontinuation of RAL/ETR for any reason. RESULTS: A total of 18 patients were included. Median baseline characteristics were: age 48 years (IQR 45-56), duration of ART 14 years (IQR 13-16), duration of viral suppression 6 years (IQR 5-9), duration of NRTI exposure 11 years (IQR 8-14) and PI exposure 6 years (IQR 3-9). In intent-to-treat analysis, the efficacy at 6 months of follow-up was 94.4% (n=17/18, 95% CI 74.2, 99%) and 83.3% (n=15/18, 95% CI 60.7, 94.1%) at 12 months. In per-protocol analysis, the efficacy at 12 months was 100% (n=15/15, 95% CI 80.6, 100%). No tolerability-related treatment discontinuation was recorded. CONCLUSIONS: This study, although on a limited number of patients, suggests that raltegravir plus etravirine represents a potential option of NRTI/PI-sparing strategy, deserving further investigation in randomized studies.
    Antiviral therapy 09/2012; · 3.07 Impact Factor
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    ABSTRACT: To investigate the best conditions of raltegravir use to avoid the selection of resistance mutations in the three main genetic pathways: 148, 155 and 143. A total of 161 patients failing on raltegravir with two consecutive HIV-1 viral loads >20 copies/mL were studied. Ten parameters [HIV-1 RNA and CD4 at baseline and failure, genotypic sensitivity score (GSS) of treatment associated with raltegravir, protease inhibitors used, time spent on raltegravir, subtype, sex and age] were tested in univariate and multivariate logistic regression analyses and compared with the emergence of resistance mutations to raltegravir at failure. Phenotypic susceptibility to raltegravir was studied in 16 patients without the main resistance mutations to raltegravir at failure. At raltegravir failure, 46/161 patients (28.6%) had integrase resistance mutations, whereas 115/161 (71.4%) had no resistance mutations. High HIV-1 viral load level at failure (OR = 2.81, 95% CI 1.8-4.6, P < 0.001) and low GSS of treatment associated with raltegravir (OR = 11.6, 95% CI 4.5-36.4, P < 0.001) were independently associated with the selection of raltegravir mutations. The percentages of patients with integrase resistance mutations were 7.7% (6/78) versus 48.1% (40/83) when viral load is ≤200 or >200 copies/mL and 47.5% (39/82) versus 8.9% (7/79) when GSS is <2 or ≥2. Among patients without main resistance mutations, two patients showed raltegravir phenotypic resistance, one naturally with F121Y at baseline and the other acquiring G118R at failure. Our results show that to avoid the selection of raltegravir resistance mutations, patients have to be treated with at least two active drugs in combination with raltegravir and to maintain a viral load ≤200 copies/mL.
    Journal of Antimicrobial Chemotherapy 07/2012; 67(10):2494-500. · 5.34 Impact Factor
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    ABSTRACT: Recent clinical trials with rilpivirine combined with emtricitabine and tenofovir revealed that patients failing treatment, frequently, harbored viruses encoding resistance-associated mutations in the HIV-1 reverse transcriptase at position E138K and M184I. We show here that APOBEC3 proteins play a role in the emergence of these drug resistance mutations. We used a Vif mutant that has suboptimal activity against APOBEC3 to assess the in-vitro frequency of APOBEC3-induced resistance mutations in reverse transcriptase. To assess the degree of in-vivo G-to-A viral hypermutation, a large amount of data of HIV-1 RT proviral sequences from peripheral blood mononuclear cells (PBMCs) recovered from infected patients under HAART was analyzed. In-vitro replication experiments in cell lines with and without APOBEC3 expression suggest that APOBEC3-driven mutagenesis contributes to the generation of both M184I and E138K within HIV proviral repository in the absence of drug exposure. Additionally, analysis of 601 patients PBMCs sequences revealed that the copresence of mutations E138K and M184I were never detected in nonhypermutated sequences, whereas these mutations were found at a high frequency (24%) in the context of APOBEC3 editing and in the absence of exposure to etravirine-rilpivirine. We demonstrate using in-vitro experiments and analyzing patients PBMCs sequences that M184I and E138K resistance-associated mutations may pre-exist in proviral reservoir at a high frequency prior to drug exposure, as a result of APOBEC3 editing. Thus, incomplete neutralization of one or more APOBEC3 proteins may favor viral escape to rilpivirine-emtricitabine.
    AIDS (London, England) 06/2012; 26(13):1619-24. · 4.91 Impact Factor
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    ABSTRACT: Foscarnet (FOS) is a pyrophosphate analogue that inhibits both cytomegalovirus (CMV) and human immunodeficiency virus (HIV) replication. We describe herein the emergence of CMV resistance to FOS in a 54-year-old man receiving FOS salvage therapy because of multidrug-resistant HIV-1 infection. Oral valganciclovir (VGCV) treatment allowed subsequently the improvement of FOS-resistant CMV infection.
    Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 03/2012; 54(2):194-6. · 3.12 Impact Factor
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    ABSTRACT: To compare the frequency of the selection of the M184V/I resistance mutation in HIV-infected patients who experienced virological failure while receiving emtricitabine (FTC) or lamivudine (3TC), administered with tenofovir disoproxil fumarate (TDF) and either efavirenz (EFV) or a ritonavir-boosted protease inhibitor (PI; lopinavir or atazanavir). Patient data held at two clinical centres in France were analysed retrospectively. Eligible patients had experienced virological suppression (plasma HIV RNA <200 copies/mL) for ≥ 6 months before experiencing their first virological failure (at least two measurements of plasma HIV RNA ≥ 200 copies/mL). Of the 880 patients eligible for the study, 278 patients had experienced virological failure while receiving FTC + TDF + ritonavir-boosted PI, 257 while receiving FTC + TDF + EFV, 178 while receiving 3TC + TDF + EFV and 167 while receiving 3TC + TDF + ritonavir-boosted PI. Proportions of patients harbouring the M184V/I mutation were 24% (n = 62) for those who received FTC + TDF + EFV versus 51% (n = 91) for 3TC + TDF + EFV (P < 0.0001; Fisher's exact test); proportions were 11% (n = 30) for FTC + TDF + ritonavir-boosted PI versus 22% (n = 37) for 3TC + TDF + ritonavir-boosted PI (P = 0.002; Fisher's exact test). The use of lamivudine versus emtricitabine (P = 0.001), non-nucleoside reverse transcriptase inhibitors versus ritonavir-boosted PIs (P = 0.01) and the level of viral load at the time of virological failure (P = 0.01) were associated with selection of the M184V/I mutation (logistic regression analysis). Emtricitabine and lamivudine showed differing resistance profiles when administered in combination with tenofovir disproxil fumarate and either efavirenz or a ritonavir-boosted PI. The prevalence of the M184V/I resistance mutation was significantly lower in patients who received emtricitabine and tenofovir disoproxil fumarate than in those who received lamivudine and tenofovir disoproxil fumarate.
    Journal of Antimicrobial Chemotherapy 02/2012; 67(6):1475-8. · 5.34 Impact Factor
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    ABSTRACT: A higher proportion of intermittent viremia (to have a HIV-1 RNA viral load>50 copies/mL not confirmed) was reported in the boosted protease inhibitor monotherapy arm in some studies including MONOI trial, and that could have an impact on the replenishment of the HIV-1 DNA reservoirs. The HIV-1 DNA level is an interesting marker which reflects the size of cellular HIV reservoir. Our objectives were to study the impact of 96 weeks of Darunavir/ritonavir monotherapy versus a triple standard combination on the HIV-1 blood reservoir and factors associated with HIV-1 plasma DNA at baseline in MONOI trial sub-study. This sub-study is focused on 160 patients (79 patients in monotherapy arm and 81 in tritherapy arm) for whom blood cells were available both at baseline and at week 96 (W96). Baseline HIV-1 plasma DNA was associated with CD4 nadir, pre therapeutic HIV-1 RNA viral load and baseline HIV-1 RNA measured by ultrasensitive assay. A similar median delta HIV-DNA was observed between D0 and W96 in both arms; 0.35 log copies/10(6) leucocytes in monotherapy arm versus 0.51 log copies/10(6) leucocytes in tritherapy arm. Despite a higher proportion of intermittent viremia in monotherapy arm, a similar evolution of cellular HIV-1 DNA level was observed between mono and triple therapy arm. ClinicalTrials. gov NCT00421551.
    PLoS ONE 01/2012; 7(7):e41390. · 3.53 Impact Factor

Publication Stats

1k Citations
389.95 Total Impact Points

Institutions

  • 2008–2013
    • Polytech Paris-UPMC
      Lutetia Parisorum, Île-de-France, France
    • Ecole normale supérieure de Cachan
      Cachon, Île-de-France, France
  • 2006–2013
    • Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix")
      • • Service des Maladies Infectieuses et Tropicales
      • • Service de Virologie
      Lutetia Parisorum, Île-de-France, France
  • 2005–2013
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • Hôpital Bichat - Claude-Bernard (Hôpitaux Universitaires Paris Nord Val de Seine)
      Lutetia Parisorum, Île-de-France, France
  • 2004–2013
    • Pierre and Marie Curie University - Paris 6
      Lutetia Parisorum, Île-de-France, France
    • Centre Hospitalier Universitaire de Bordeaux
      Burdeos, Aquitaine, France
  • 2001–2010
    • Hôpitaux Universitaires La Pitié salpêtrière - Charles Foix
      Lutetia Parisorum, Île-de-France, France
  • 2009
    • Université René Descartes - Paris 5
      • Faculté de Médecine
      Lutetia Parisorum, Île-de-France, France
    • Paris Diderot University
      Lutetia Parisorum, Île-de-France, France