A G Marcelin

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

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Publications (72)349.02 Total impact

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    ABSTRACT: An incomplete Apobec3G/F neutralization by defective HIV-1Vif protein can promote genetic diversification, by inducing G-to-A mutations along HIV-1 genome. The HIV-1 Env V3 loop, critical for co-receptor usage, contains several putative Apobec3G/F target sites. Here, we determined if Apobec3G/F, in presence of Vif-defective HIV-1 virus, can induce G-to-A mutations at V3 positions critical to modulate CXCR4-usage.PBMC and monocyte-derived-macrophages (MDM) from 2 HIV-1 negative donors were infected by CCR5-using 81.A-Vifwt, 81.A-VifE45G-mutant, and 81.A-VifK22E-mutant (known to incompletely/partially neutralize Apobec3G/F). The rate of G-toAs was null or extremely low in 81.A-Vifwt and 81.A-VifE45G infected PBMC from both donors. Conversely, a G-to-As enrichment was detected in 81.A-VifK22E infected PBMC (prevalence ranging from 2.18% at 7dpi to 3.07% at 21dpi in donor #1, and from 10.49% at 7dpi to 8.69% at 21dpi in donor #2). A similar scenario was found in MDM.G-to-As occurred at 8 V3 positions, resulting in amino acid non-synonymous substitutions. Of them, G24E and E25K strongly correlated with phenotypically/genotypically defined CXCR4-using viruses (P-value = 0.04 and 5.5e-7), and increased CXCR4 N-terminus binding affinity for V3 (WT: -40.1Kcal/mol; G24E: -510Kcal/mol; E25K: -522Kcal/mol).The analysis of paired V3 and Vif DNA sequences from 84 HIV-1 infected patients showed that the presence of a Vif-defective virus correlated with a CXCR4-usage in proviral DNA (P-value=0.04). In conclusion, incomplete Apobec3G/F neutralization by single Vif amino acid substitution seeds a CXCR4-using proviral reservoir. This can have implications for the success of CCR5 antagonist-based therapy, as well as for the risk of disease progression. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Antimicrobial Agents and Chemotherapy 06/2015; 59(8):AAC.00137-15. DOI:10.1128/AAC.00137-15 · 4.45 Impact Factor
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    ABSTRACT: Virological failure (VF) in patients on maraviroc-based treatment has been associated with altered HIV tropism and resistance to maraviroc. This multicentre study aimed to characterize VF in patients treated with maraviroc. We analysed 27 patients whose treatment failed between 2008 and 2011. They had been screened for HIV tropism before maraviroc initiation using population-based V3 genotyping. HIV-1 tropism and resistance of R5 viruses to maraviroc at VF and at baseline were determined retrospectively using an ultrasensitive recombinant virus assay (RVA). Viruses from 27 patients given maraviroc on the basis of the R5 genotype were characterized at the time of treatment failure. The RVA indicated that 12 patients harboured CXCR4-using viruses and 15 (56%) had pure R5 viruses at failure. One-third of those harbouring CXCR4-using viruses (4/12) were infected with R5X4/X4 viruses according to the RVA before maraviroc initiation. We analysed the phenotypic resistance to maraviroc of four patients harbouring R5 viruses at failure; two harboured viruses whose maximum percentage inhibition was reduced by 65%-90%, while the other two were infected with susceptible viruses. All patients had effective concentrations of drugs. Half of the maraviroc-treated patients who experienced VF harboured CXCR4-using viruses at failure, one-third of them were detected by a phenotypic method before maraviroc initiation. Phenotypic assessment of R5 virus resistance to CCR5 antagonists at failure could help optimize antiretroviral therapy. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    Journal of Antimicrobial Chemotherapy 02/2015; DOI:10.1093/jac/dkv026 · 5.44 Impact Factor
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    ABSTRACT: Objectives This observational study in antiretroviral treatment-experienced, HIV-1-infected adults explored the efficacy of etravirine plus darunavir/ritonavir (DRV group; n = 999) vs. etravirine plus an alternative boosted protease inhibitor (other PI group; n = 116) using pooled European cohort data.Methods Two international (EuroSIDA; EUResist Network) and five national (France, Italy, Spain, Switzerland and UK) cohorts provided data (collected in 2007–2012). Stratum-adjusted (for confounding factors) Mantel–Haenszel differences in virological responses (viral load < 50 HIV-1 RNA copies/mL) and odds ratios (ORs) with 95% confidence intervals (CIs) were derived.ResultsBaseline characteristics were balanced between groups except for previous use of antiretrovirals (≥ 10: 63% in the DRV group vs. 49% in the other PI group), including previous use of at least three PIs (64% vs. 53%, respectively) and mean number of PI resistance mutations (2.3 vs. 1.9, respectively). Week 24 responses were 73% vs. 75% (observed) and 49% vs. 43% (missing = failure), respectively. Week 48 responses were 75% vs. 73% and 32% vs. 30%, respectively. All 95% CIs around unadjusted and adjusted differences encompassed 0 (difference in responses) or 1 (ORs). While ORs by cohort indicated heterogeneity in response, for pooled data the difference between unadjusted and adjusted for cohort ORs was small.Conclusions These data do not indicate a difference in response between the DRV and other PI groups, although caution should be applied given the small size of the other PI group and the lack of randomization. This suggests that the efficacy and virology results from DUET can be extrapolated to a regimen of etravirine with a boosted PI other than darunavir/ritonavir.
    HIV Medicine 02/2015; 16(5). DOI:10.1111/hiv.12218 · 3.45 Impact Factor
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    ABSTRACT: There are few data on the clinical and virological factors associated with maraviroc (MVC) virological response (VR) in clinical practice. This study aimed to identify factors associated with VR to MVC-containing regimens in 104 treatment-experienced but CCR5 inhibitor-naive HIV-1 patients. VR was defined at Month 3 (M3) as HIV-1 RNA viral load (VL) <50 copies/mL. The impact on VR of age, sex, baseline tropism, HIV subtype (B vs non-B), nadir CD4 cell count and CD4 cell count, baseline VL, genotypic susceptibility score of treatment, once or twice daily treatment, presence of raltegravir in optimized background therapy and MVC concentrations was investigated. Median baseline VL was 3.3 log10 copies/mL (range 1.7-6.0 log10 copies/mL) and CD4 cell count was 299 cells/mm3 (range 7-841 cells/mm3). At M3, 53.8% of patients were responders. In univariate analysis, a better efficacy of MVC-containing regimen was associated with a high CD4 cell count (p=0.0069) and there was a trend for low baseline VL, high nadir CD4 cell count and HIV subtype (B versus non B). Only low baseline VL remained significantly associated with better VR in the multivariate analysis. This study demonstrated a VR of an optimized antiretroviral treatment including MVC in clinical practice similar to that observed in clinical trials. The factors associated with VR were higher baseline CD4 cell count in univariate analysis and lower baseline VL in multivariate analysis.
    AIDS Research and Human Retroviruses 11/2014; 31(5). DOI:10.1089/AID.2014.0223 · 2.46 Impact Factor
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    ABSTRACT: Objectives In resource-limited settings, few data are available on virological failure after long-term first-line antiretroviral therapy. This study characterized the genotypic resistance patterns at the time of failure after at least 36 months of a first-line regimen in Mali, West Africa.
    Journal of Antimicrobial Chemotherapy 05/2014; 69(9). DOI:10.1093/jac/dku153 · 5.44 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; 69(4). DOI:10.1093/jac/dkt463 · 5.44 Impact Factor
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    ABSTRACT: Objectives: As recommended by the French ANRS programme for the surveillance of HIV-1 resistance, we estimated the prevalence of transmitted drug resistance-associated mutations (RAMs) in antiretroviral-naive, chronically HIV-1-infected patients. Methods: RAMswere sought in samples from661 newly diagnosed HIV-1-infected patients in 2010/11 at 36 HIVclinical care centres.Weighted analyses were used to derive representative estimates of the percentage of patients with RAMs. Results: At patient inclusion, the prevalence of viruswith protease (PR) or reverse transcriptase (RT) RAMswas 9.0%(95% CI 6.8%-11.2%). No integrase RAMs were observed. The prevalences of protease inhibitor, nucleoside RT inhibitor and non-nucleoside RT inhibitor RAMs were 1.8%, 6.2% and 2.4%, respectively. Resistance to one, two and three classes of antiretroviral agent was observed in 7.9%, 0.9% and 0.2% of patients, respectively. The frequency of RAMs was higher in patients infected with B compared with non-B subtype virus (11.9% versus 5.1%, P=0.003). Baseline characteristics (gender, age, country of transmission, CD4 cell count and viral load)were not associated with the prevalence of transmitted RAMs. However, men having sex with men (MSM)were more frequently infected with resistant virus than were other transmission groups (12.5%versus5.8%,P=0.003).Compared with the 2006/07 survey, the over all prevalence of resistance remained stable. However, a significant decrease in the frequency of virus with PRRAMs was observed in 2010/11 compared with the 2006/07 survey (1.8%versus 5.0%, P=0.003). Conclusions: In France in 2010/11, the global prevalence of transmitted drug-resistant variants was 9.0%, and the prevalence was stable compared with the 2006/07 survey. MSM and B subtype-infected patients are the groupswith a higher prevalence of drug resistance. © The Author 2013. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
    Journal of Antimicrobial Chemotherapy 11/2013; 68(11):2626-2631. DOI:10.1093/jac/dkt238 · 5.44 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; 42(2). DOI:10.1007/s15010-013-0542-8 · 2.86 Impact Factor
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    JAIDS Journal of Acquired Immune Deficiency Syndromes 08/2013; 63(5):e159-63. DOI:10.1097/QAI.0b013e31829b2c4b · 4.39 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; 68(11). DOI:10.1093/jac/dkt251 · 5.44 Impact Factor
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    ABSTRACT: Background. The induction of neutralizing antibodies against conserved regions of the HIV-1 envelope protein is a major goal of vaccine strategies. We previously identified 3S, a critical conserved motif of gp41 that induces the NKp44&emsp14;L ligand of an activating NK receptor. In vivo, anti-3S antibodies protect against the NK-cell mediated CD4 depletion that occurs without efficient viral neutralization. Methods. Specific substitutions within the 3S peptide motif were prepared by directed mutagenesis. Virus production was monitored by measuring the p24 production. Neutralization assays were performed with immune-purified antibodies from immunized mice and a cohort of HIV-infected patients. Expression of NKp44&emsp14;L on CD4+ T cells and degranulation assay on activating NK cells were both performed by flow cytometer. Results. Here, we show that specific substitutions in the 3S motif reduce viral infection without affecting gp41 production, while decreasing both its capacity to induce NKp44&emsp14;L expression on CD4+ T cells and its sensitivity to autologous NK cells. Generation of antibodies in mice against the W614 specific position in the 3S motif elicited a capacity to neutralize cross-clade viruses, notable in its magnitude, breadth and durability. Antibodies against this 3S variant were also detected in sera from some HIV-1 infected patients, demonstrated both neutralization activity and protection against CD4 depletion. Conclusions. These findings suggest that a specific substitution in a 3S-based immunogen might allow the generation of specific antibodies, providing a foundation for a rational vaccine that combine a capacity to neutralize HIV-1 and to protect CD4+ T cells.
    Clinical Infectious Diseases 05/2013; · 9.42 Impact Factor
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    ABSTRACT: Human herpes virus 8 (HHV-8) is an oncogenic gamma-herpes virus first described in 1994 in Kaposi sarcoma (KS) lesions. HHV-8 is involved in the pathophysiologic features of multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL), both rare B-cell lymphoproliferative diseases. HHV-8-related tumours occur almost exclusively in immunocompromised patients, most with HIV infection. Combined antiretroviral therapies have reduced the incidence of KS but not MCD and PEL. HHV-8-related diseases frequently exhibit pulmonary involvement, which may indicate the disease. KS in the lung is often asymptomatic but may require specific therapy. It mostly shows cutaneous or mucosal involvement. Patients with typical MCD present fever and lymphadenopathy associated with interstitial lung disease without opportunistic infection. Specific treatment may be urgent. PEL provokes a febrile, lymphocytic-exudative pleural effusion, without pleural mass on CT scan. Rapid diagnosis prevents unnecessary exams and leads to specific, rapid treatment. Therapy is complex, combining antiretroviral therapy and chemotherapy.
    European Respiratory Journal 02/2013; DOI:10.1183/09031936.00154212 · 7.13 Impact Factor
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    ABSTRACT: There is evidence that HIV-1 evolution under maraviroc (MVC) pressure can lead to the selection of either X4-tropic variants and/or R5-tropic, MVC-resistant isolates. However, the viral dynamics of HIV-1 variants in patients with virological failure (VF) on MVC-containing regimens remain poorly studied. Here, we investigated the V3 loop evolution of HIV-1 on MVC in relation to coreceptor usage and the nature of HIV-1 quasispecies before MVC therapy using bulk population sequences and ultradeep sequencing. The majority of patients had no detectable minority X4 variant at baseline. The evolution of tropism was followed up until VF and showed three possibilities for viral evolution in these patients: emergence of preexisting X4 variants, de novo selection of R5 variants presenting V3 loop mutations, or replication of R5 variants without selection of known mutations.
    Antimicrobial Agents and Chemotherapy 02/2013; 57(2). DOI:10.1128/AAC.02159-12 · 4.45 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.
    01/2013; 2(2). DOI:10.1016/j.jgar.2013.12.001
  • Journal of Antimicrobial Chemotherapy 11/2012; 68(4). DOI:10.1093/jac/dks474 · 5.44 Impact Factor
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    ABSTRACT: The aims of the study were to assess the risk of HHV8 transmission resulting from organ transplantation, and related morbidity in liver, heart and kidney transplant recipients. Donor and recipient serologies were screened between January 1, 2004 and January 1, 2005 using HHV8 indirect immunofluorescence latent assay (latent IFA) and indirect immunofluorescent lytic assay (lytic IFA). Recipients negative for latent IFA with a donor positive for at least one test were sequentially monitored for HHV8 viremia and underwent serological tests over a period of 2 years. The results showed that among 2354 donors, HHV8 seroprevalence was 9.9% (lytic IFA) and 4.4% (latent IFA). A total of 454 organ recipients (281 renal, 116 liver and 57 heart) were monitored over a 2-year period. Seroconversion was observed in 12 patients (cumulative incidence 28%) whose donor had positive latent IFA and in 36 patients (cumulative incidence 29%) whose donors were positive only for lytic IFA, without differences across types of transplants. Positive HHV8 viremia was detected in only 4 out of 89 liver transplant recipients during follow-up and not in recipients of other types of transplant. Two liver transplant recipients and one kidney transplant recipient developed KS. In conclusion, although HHV8 transmission is a frequent event after organ transplantation, HHV8-related morbidity is rather rare but can be life threatening. Donor screening is advisable for monitoring HHV8 seronegative liver transplant recipients.
    American Journal of Transplantation 10/2012; 13(1). DOI:10.1111/j.1600-6143.2012.04290.x · 6.19 Impact Factor
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    ABSTRACT: Background: Etravirine (ETR) is recommended as twice-daily dosing in pretreated patients. There are no data regarding the use of ETR once daily in HIV-experienced patients with prior resistance to first-generation non-nucleoside reverse transcripase inhibitors (NNRTIs).Objectives: To evaluate the capacity of once-daily ETR to maintain suppressed viremia over 48 weeks after switching from ETR twice daily in NNRTI-experienced patients.Methods: In this pilot open-label study, patients with plasma viral load (pVL) <50 copies/mL on a stable ETR 200 mg bid regimen were enrolled to switch to ETR 400 mg qd and followed up over 48 weeks. The primary endpoint was the proportion of patients with pVL <50 copies/mL at week 24. Secondary endpoints included the rate of pVL< 50 copies/mL at week 48, ETR pharmacokinetic parameters, and tolerability and resistance profile.Results: Twenty-four patients were included. They had extensive antiretroviral treatment for a median of 14 years (range, 1-19). All except for 2 had prior resistance to NNRTIs. Seven patients discontinued ETR once daily prior to week 48 for virological failure (3), protocol deviation (3), and side effects (1). At week 24, 95% of patients maintained pVL< 50 copies/mL (95% CI, 78.4-99.7) and 85% at week 48 (95%CI, 65.6-95.8). Two of the 3 patients with virological failure had ETR resistance mutations prior to initiation. The median ETR Ctrough level remained stable after switching from twice daily 515 ng/mL (340-758) to once daily 422 ng/mL (264-655).Conclusion: These results suggest that ETR is effective as a once-daily regimen in patients with prior NNRTI experience when HIV is sensitive to ETR. The stability of Ctrough concentrations on a once-daily regimen confirms the once-daily profile of the drug in experienced patients.
    HIV Clinical Trials 09/2012; 13(5):284-8. DOI:10.1310/hct1305-284 · 2.14 Impact Factor
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    ABSTRACT: Precise characterization of viruses present in reservoirs in long-term pretreated patients will be a major issue to consider in the context of viral eradication. We assessed the frequency of defective viruses present in cellular reservoirs. Peripheral blood mononuclear cells (PBMCs) and rectal biopsy samples were compared between five patients on successful long-term highly active antiretroviral therapy (HAART) (>7 years without blips) and five untreated patients. Molecular cloning and sequencing of the reverse transcriptase region were used to detect the presence of and quantify in-frame stop codons in HIV quasi-species. The relationship between the size of the reservoir and the frequency of defective genomes was assessed. Defective genomes were systematically detected in all patients on long-term HAART in both compartments (PBMCs and rectal tissues), with a higher level of defective genomes per sample compared with PBMCs of untreated patients. A high level of defective genomes was correlated with a small size of HIV proviral DNA. Regarding the nucleotide context, guanine (G) to adenine (A) substitution at tryptophan positions was responsible for the appearance of 89% of all in-frame stop codons in the context of G-to-A hypermutation, likely reflecting APOBEC3 footprints on the viral genome. We propose a scenario whereby defective genomes accumulate during HAART treatment, eventually reaching a viral extinction threshold. In the context of viral eradication, measurement of the relative amounts of defective and non-defective viruses (by molecular cloning and ultradeep sequencing) should be used as a new criterion for eradicating HIV.
    Journal of Antimicrobial Chemotherapy 06/2012; 67(10):2323-6. DOI:10.1093/jac/dks219 · 5.44 Impact Factor
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    ABSTRACT: Background. Many statistical models have been tested to predict phenotypic or virological response from genotypic data. A statistical framework called Super Learner has been introduced either to compare different methods/learners (discrete Super Learner) or to combine them in a Super Learner prediction method. Methods. The Jaguar trial is used to apply the Super Learner framework. The Jaguar study is an "add-on" trial comparing the efficacy of adding didanosine to an on-going failing regimen. Our aim was also to investigate the impact on the use of different cross-validation strategies and different loss functions. Four different repartitions between training set and validations set were tested through two loss functions. Six statistical methods were compared. We assess performance by evaluating R(2) values and accuracy by calculating the rates of patients being correctly classified. Results. Our results indicated that the more recent Super Learner methodology of building a new predictor based on a weighted combination of different methods/learners provided good performance. A simple linear model provided similar results to those of this new predictor. Slight discrepancy arises between the two loss functions investigated, and slight difference arises also between results based on cross-validated risks and results from full dataset. The Super Learner methodology and linear model provided around 80% of patients correctly classified. The difference between the lower and higher rates is around 10 percent. The number of mutations retained in different learners also varys from one to 41. Conclusions. The more recent Super Learner methodology combining the prediction of many learners provided good performance on our small dataset.
    AIDS research and treatment 04/2012; 2012:478467. DOI:10.1155/2012/478467
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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. DOI:10.1093/jac/dks047 · 5.44 Impact Factor

Publication Stats

950 Citations
349.02 Total Impact Points

Institutions

  • 2011–2015
    • Polytech Paris-UPMC
      Lutetia Parisorum, Île-de-France, France
    • Université Paris 13 Nord
      Île-de-France, France
  • 2012–2013
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • ANRS - Agence Nationale de Recherche sur le Sida et les hépatites virales
      Lutetia Parisorum, Île-de-France, France
  • 2005–2013
    • Pierre and Marie Curie University - Paris 6
      Lutetia Parisorum, Île-de-France, France
  • 1999–2013
    • Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix")
      • Service de Virologie
      Lutetia Parisorum, Île-de-France, France
  • 2010
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2000–2010
    • Hôpitaux Universitaires La Pitié salpêtrière - Charles Foix
      Lutetia Parisorum, Île-de-France, France
  • 2004
    • Hôpital Bichat - Claude-Bernard (Hôpitaux Universitaires Paris Nord Val de Seine)
      Lutetia Parisorum, Île-de-France, France
  • 2002
    • Chelsea and Westminster Hospital NHS Foundation Trust
      Londinium, England, United Kingdom