[Show abstract][Hide abstract] ABSTRACT: on behalf of the FHDH ANRS CO4 (French Hospital Database on HIV, Agence Nationale de Recherches sur le Sida, cohort 4) Abstract Introduction: We compared the effectiveness of tenofovir/emtricitabine (TDF/FTC) combined with either lopinavir/r (LPV/r) or another recommended third drug in the 2010 French guidelines in antiretroviral-nave patients starting combination antiretroviral therapy in 2004Á2008 in the French Hospital Database on HIV. Methods: The outcomes were stop or switch of the third component, viral load (VL) B500 copies/ml, an increase of at least 100 CD4 cells/mm 3 , AIDS-defining event and non-AIDS-defining hospitalization or death. Propensity scores were estimated by logistic regression based on the clinical centre and other confounders. In each clinical centre, each patient initiating LPV/r was matched with a patient initiating another third drug (efavirenz or atazanavir/r) and having a close propensity score. Cox's proportional hazards models were then used, with treatment as covariate. Time was right-censored at four years. Results: 1269 patients started LPV/r plus TDF/FTC, and 890 could be matched to 890 patients receiving another third drug. Baseline characteristics were well balanced between these two groups. LPV/r was associated with a higher risk of third drug stop (hazard ratio (HR): 1.69; 95% confidence interval (CI), 1.42Á2.00) and with less rapid viral suppression (HR: 0.83; 95% CI, 0.72Á 0.95). There was no difference in the time required for a CD4 cell increment of at least 100/mm 3 , or to the occurrence of an AIDS-defining event. Non-AIDS-defining hospitalizations or deaths were more frequent with LPV/r (HR: 1.79; 95% CI, 1.33Á2.39). Conclusions: For first-line therapy, in this observational setting, TDF/FTC plus LPV/r were less durable than TDF/FTC plus another recommended third drug, led to a less rapid viral suppression and were associated with a higher risk of non-AIDS morbidity.
Journal of the International AIDS Society 09/2014; · 4.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The distribution and evolution of X4/R5 viral tropism during HIV-2 infection remains unknown. HIV-2 tropism was assessed in 83 antiretroviral-experienced patients with virological failure. Tropism was predicted as X4 in 58% of patients and was associated with a CD4 cell count of less than 100 cells/μl, and with a higher number of drug resistance mutations. This high prevalence of X4 virus might compromise the use of CCR5 inhibitors, currently mostly considered in HIV-2 salvage therapy of highly pretreated patients.
AIDS (London, England) 09/2014; 28(14):2160-2162. · 6.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To describe the virological and pharmacological outcomes of three different recommended once-daily first-line regimens in a cross-sectional analysis within an observational cohort using ultra-sensitive HIV quantification.
Journal of Antimicrobial Chemotherapy 06/2014; · 5.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess the virological response, genotypic resistance profiles, and antiretroviral plasma concentrations in HIV-2 antiretroviral-treated (antiretroviral therapy, ART) patients in Côte d'Ivoire.
A cross-sectional survey was conducted among HIV-2 patients receiving ART. Plasma HIV-2 viral load was performed using the ANRS assay. Protease and reverse transcriptase sequencing was performed using in-house methods and antiretroviral plasma concentrations were assessed using ultra performance liquid chromatography combined with tandem mass spectrometry.
One hundred forty five HIV-2-treated patients were enrolled with a median CD4 cell count of 360/μl (interquartile range, IQR = 215-528). Median duration of ART was 4 years (IQR = 2-7) and 74% of patients displayed viral load less than 50 copies/ml. Median plasma HIV-2 RNA among patients with viral load more than 50 copies/ml was 3016 copies/ml (IQR = 436-5156). Most patients (84%) received a lopinavir/ritonavir-based regimen. HIV-2 resistance mutations to nucleoside reverse transcriptase inhibitors and protease inhibitors were detected in 21 of 25 (84%) and 20 of 29 (69%) samples, respectively. The most prevalent nucleoside reverse transcriptase inhibitor resistance mutations were M184I/V (90%), Q151M (24%), and S215F/Y (24%). The most prevalent protease inhibitor resistance mutations were V47A (60%) and I54M (30%). Median CD4 cell counts were 434/μl (292-573) and 204/μl (122-281) in patients with viral load less than 50 copies/ml and those exhibiting virological failure (P < 0.0001), respectively. The proportions of patients with adequate antiretroviral plasma concentrations were 81 and 93% in patients displaying virological failure and in those with viral load less than 50 copies/ml, respectively (P = 0.046), suggesting good treatment adherence.
We observed adequate drug plasma concentrations and virological suppression in a high proportion of HIV-2-infected patients. However, in cases of virological failure, the limited HIV-2 therapeutic arsenal and cross-resistance dramatically reduced treatment options.
AIDS (London, England) 02/2014; · 6.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: The prognostic value of pre-existing minority resistant variants (MVs) to predict the risk of virological failure (VF) to first-line NNRTI-containing ART remains to be elucidated. METHODS: This was a retrospective case-control study nested within 6 observational European cohorts. HIV-1-infected adults with no pre-existing NNRTI resistance by bulk sequencing who started 1st line ART including nevirapine (NVP) or efavirenz (EFV) and had 1mL pre-ART plasma with VL≥10000 copies/mL available for testing were included. Cases experienced VF to first-line ART, defined as 2 consecutive VL>200 copies/mL after >6 months of initial ART regimen; controls were subjects from the same cohort with a VL≤200 copies/mL at a matched time since ART initiation. 454 sequencing of RT was centralised in a single laboratory and analysed in parallel in 2 different laboratories using the AVA software (v2.7), blinded for clinical outcomes and the other lab results. Presence of MVs was defined as detection of ≥1 IAS-USA (March 2013) mutations in 1-25% of each subject’s HIV-1 population. Standard logistic regression was used to estimate odds ratios (OR) of VF according to MV detection. Multivariable estimates were adjusted for HIV subtype, calendar year of starting NNRTI (baseline), time from sample to baseline, baseline VL, NNRTI started, NRTI backbone started and cohort. RESULTS: 368 subjects (81 VF and 287 controls) with median (IQR) CD4 254 cells/mm3 (167-358) and viral load 4.91 (4.55-5.31) were included. 83% started EFV. Main NRTI backbones were ZDV/3TC (44%), TDF/FTC (21%) and ABC/3TC (10%). Main HIV subtypes were: 79% B, 6% C, 3% A, CRF01_AE or G. Identical MVs were detected in the 2 labs. 17.3% cases and 7.3% controls had MVs (p=0.009). Most prevalent MVs were M184I (3%), V108I (2.5%) and V75I (1%). Detection of ≥1 MVs vs. no MVs was associated with the risk of VF (OR: 2.49, 95% CI: 1.12, 5.55, p=0.03); a trend was observed for ≥1 vs. no NRTI MVs (OR: 2.29, 95% CI: 0.87, 6.03, p=0.09); ≥1 vs. no NNRTI MVs (OR: 2.14, 95% CI: 0.61, 7.50, p=0.23). CONCLUSION: Pre-existing MVs in reverse transcriptase more than double the risk of virological failure to first-line NNRTI-based ART.
[Show abstract][Hide abstract] ABSTRACT: In this study, we assessed phenotypic susceptibility to dolutegravir and raltegravir in a large variety of HIV-1 'non-B' subtypes (n = 72) issued from integrase inhibitor (INI)-naive clinical isolates. All samples were susceptible to both dolutegravir and raltegravir with median IC50 values of 1.22 nmol/l and 1.53 nmol/l, respectively; similar to what was observed for B subtype. Thus, despite the high prevalence of polymorphic substitutions in integrase in 'non-B' clinical isolates, phenotypic susceptibility to dolutegravir remained unchanged.
AIDS (London, England) 08/2013; · 6.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Here we summarize the discussions and conclusions from an expert workshop held in October 2012 to consider the implications of HIV drug resistance in the context of scale-up of access to antiretroviral therapy and prophylaxis in resource-limited settings. Topics considered during the workshop included the implications of drug resistance for the selection of first-line regimens and sequencing of treatments, optimal surveillance strategies and prevention of mother-to-child transmission.
[Show abstract][Hide abstract] ABSTRACT: Recent data from studies on treatment as prevention (TasP) and preexposure prophylaxis (PrEP) show that antiretroviral drugs can be used in prevention, as well as in treatment. The movement from first-generation antiretroviral therapy (ART) coformulations based on thymidine analogues to second-generation ART coformulations based on tenofovir may coincide with future prevention strategies that also use tenofovir/emtricitabine, raising concerns regarding drug resistance. In published studies, failure of prophylaxis was associated with poor adherence and low plasma drug levels. Although rates of drug resistance in cases of failed prevention was low, regular human immunodeficiency virus (HIV) testing was undertaken in these clinical trials. Although legitimate concerns exist about ART adherence and drug resistance associated with PrEP and TasP in real-world settings, efforts to curb the continuing HIV epidemic through use of these novel prevention strategies should move forward because the development and approval of newer drugs reserved for prevention might take many more years. Efforts must be made to monitor ART adherence and to intervene through counseling and other means in order to optimize adherence and retention in care, whenever necessary. Finally, further research involving the generalized epidemic is needed to determine when suboptimal drug use may occur and when regular testing and monitoring of the long-term consequences of ART use may not be routine.
The Journal of Infectious Diseases 06/2013; 207 Suppl 2:S101-6. · 5.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We reported the first transmitted drug resistance survey study in HIV-2-infected patients living in France. The prevalence of transmitted drug resistance was 5.0% (CI95 = 0.1-9.9%) with mutations detected only in protease, not in reverse transcriptase. In this series, 10% of patients displayed X4/Dual-Mixed viruses. These findings classified the rate of transmitted drug resistance in HIV-2 French Cohort as low prevalence.
AIDS (London, England) 04/2013; · 6.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of our study was to assess a possible association between plasma inflammatory biomarkers (CRP, IL-6, soluble CD14) and the extent of fibrosis or cirrhosis using a FibroScan® in HIV/HCV co-infected patients.
This cross-sectional study assessed 60 HIV/HCV co-infected patients who had paired plasma samples and FibroScan® values available. All included patients were controlled for HIV infection (HIV-1 RNA <50 copies/mL) and had detectable HCV RNA levels. Levels of three biomarkers were measured in all samples using commercial ELISA kits. Multivariate logistic regression models identified factors associated with the METAVIR stages of fibrosis (F0-F2 vs. F3-F4).
In univariate logistic regression analyses, in addition to sCD14 (odds ratio [OR] = 3.23, 95% confidence interval [95%CI] = 1.30-7.97, P = 0.01), aspartate aminotransferase (AST), alanine aminotransferase, platelet counts, and CD4 cell counts were associated with the stage of liver fibrosis and, thus, were introduced into the model. However, only AST (OR = 1.06, 95%CI = 1.02-1.10, P = 0.0009) was independently associated with F3-F4 stage liver fibrosis.
In our study of HIV/HCV co-infected patients, sCD14 plasma level, a biomarker of monocyte activation, was not independently associated with the F3-F4 stage of liver fibrosis. We hypothesize that the higher levels of inflammation markers observed in HIV/HCV co-infected patients, compared to HCV mono-infected patients, prevent this association being observed within this population.
PLoS ONE 03/2013; 8(3):e59205. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Considering HIV-2 phenotypic data; experience from HIV-1 and from the follow-up of HIV-2-infected patients, a panel of European experts voted on a rule set for interpretation of mutations in HIV-2 protease, reverse transcriptase and integrase and an automated tool for HIV-2 drug resistance analyses freely available on the internet (http://www.hiv-grade.de).
[Show abstract][Hide abstract] ABSTRACT: To describe the prevalence of the L76V protease inhibitors resistance-associated mutation (PI-RAM) in relation with patients' characteristics and protease genotypic background in HIV-1 B- and "non-B"-infected patients.
Frequency of the L76V mutation between 1998 and 2010 was surveyed in the laboratory database of 3 clinical centers. Major PI-RAMs were identified according to the IAS-USA list. Fisher's and Wilcoxon tests were used to compare variables.
Among the overall 29,643 sequences analyzed, the prevalence of L76V was 1.50%, while was 5.42% in PI-resistant viruses. Since 2008 the prevalence of L76V was higher in "non-B"-infected than in B-infected patients each year. Median time since diagnosis of HIV-1 infection and median time under antiretroviral-based regimen were both shorter in "non-B"- than in B-infected patients (8 vs 11 years, P<0.0001; and 7 vs 8 years, P = 0.004). In addition, "non-B"-infected patients had been pre-exposed to a lower number of PI (2 vs 3, P = 0.016). The L76V was also associated with a lower number of major PI-RAMs in "non-B" vs B samples (3 vs 4, P = 0.0001), and thus it was more frequent found as single major PI-RAM in "non-B" vs B subtype (10% vs 2%, P = 0.014).
We showed an impact of viral subtype on the selection of the L76V major PI-RAM with a higher prevalence in "non-B" subtypes observed since 2008. In addition, in "non-B"-infected patients this mutation appeared more rapidly and was associated with less PI-RAM.
PLoS ONE 01/2013; 8(1):e54381. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: In the ANRS 139 TRIO trial, the use of 3 new active drugs (raltegravir, etravirine, and darunavir/ritonavir), resulted in a potent and sustained inhibition of viral replication in multidrug-resistant treatment-experienced patients. The aim of this virological sub-study of the ANRS 139 TRIO trial was to assess: (i) the evolution of HIV-1 DNA over the first year; and (ii) the association between baseline HIV-1 DNA and virological outcome. METHODS: Among the 103 HIV-1-infected patients included in the ANRS-139 TRIO trial, HIV-1 DNA specimens were available for 92, 84, 88, and 83 patients at Week (W)0, W12, W24, and W48, respectively. Quantification of total HIV-1 DNA was performed by using the commercial kit "Generic HIV DNA Cell" (Biocentric, Bandol, France). RESULTS: Baseline median HIV-1 DNA of patients displaying virological success (n = 61), viral blip (n = 20), and virological failure (n = 11) were 2.34 log(10) copies/10(6) PBMC (IQR = 2.15-2.66), 2.42 (IQR = 2.12-2.48), and 2.68 (IQR = 2.46-2.83), respectively. Although not statistically significant, patients exhibiting virological success or viral blip had a tendency to display lower baseline HIV-1 DNA than patients experiencing virological failure (P = 0.06). Median decrease of HIV-1 DNA between baseline and W48 was -0.13 log(10) copies/10(6) PBMC (IQR = -0.34 to +0.10), mainly explained by the evolution from W0 to W4. No more changes were observed in the W4-W48 period. CONCLUSIONS: In highly-experienced multidrug-resistant patients, HIV-1 DNA slightly decreased during the first month and then remained stable during the first year of highly potent antiretroviral regimen. In this population, baseline HIV-1 DNA might help to better predict the virological response and to tailor clinical therapeutic management as more aggressive therapeutic choices in patients with higher baseline HIV-1 DNA.
PLoS ONE 01/2013; 8(1):e53621. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Various items are complicating the treatment of HIV-2 infected patients. Compared to HIV-1 there is much less treatment experience, no evidence from randomized control trials, a reduced number of effective drugs and no broadly available test for viral load monitoring. In case of treatment failure there is only limited guidance and presently no easy accessible tool for nucleic acid sequence interpretation available. To solve this problem, we initiated an expert workshop to address some of these problems. A panel of experts from four different European countries voted on a rule set for interpretation of mutations in the HIV-2 protease, reverse transcriptase and integrase. Rules were proposed by each member and were then modified during discussion by considering data gained from HIV-1 and accumulated experience of the follow up of HIV-2-infected patients. Based on the HIV-GRADE internet-tool an online tool was developed to make the rule set easily accessible and usable. Rules were laid down for the interpretation of HIV-2 drug resistance to NRTIs, PIs and INIs (integrase inhibitors). Due to natural resistance of HIV-2, usage of NNRTIs and T-20 was not recommended as part of an antiretroviral regimen for HIV-2. These rules were then translated in a machine interpretable format (algorithm specification interface, ASI) and the HIV-GRADE tool was extended for usage of HIV-2 sequences. Further consensus sequences were generated from the reference sequence data set provided by Los Alamos National Laboratories. In contrast to HIV-1, mutations were compared to a group specific consensus sequence (Group A or Group B) and not to a consensus sequence from the most predominant HIV-2 Group A. This change was necessary due to significant differences between the various HIV-2 strains. We developed a rule set and an automated tool for HIV-2 drug resistance analyses. This tool and the rules will be freely available on the internet. Access to the pre-publication versions can be granted by each of the group members. To keep the algorithm rules up-to-date it will be actualized on a yearly basis.
Journal of the International AIDS Society 11/2012; 15(6):18180. · 4.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this study assessing HIV-2 tropism among 43 paired plasma/PBMC specimens, the concordance between proviral DNA and plasma RNA genotypic tropism prediction was 74%. All the discordances were attributable to the prediction of R5 in RNA and X4/Dual-Mixed in DNA. HIV-2 genotypic tropism test based on proviral DNA is a suitable tool for tropism determination in HIV-2-infected patients with low or undetectable viral load.
AIDS (London, England) 10/2012; · 6.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In October 2009 the French National Authority for Health recommended that HIV testing be proposed at least once to all persons aged 15 to 70 years in all healthcare settings. We examined whether routine HIV screening with a rapid test in emergency departments (EDs) was feasible without dedicated staff, and whether newly diagnosed persons could be linked to care.
This one-year study started in December 2009 in 6 EDs in the Paris area, using the INSTI™ test. Eligible individuals were persons 18 to 70 years old who did not present for a vital emergency, for blood or sexual HIV exposure, or for HIV screening. Written informed consent was required.
Among 183 957 eligible persons, 11 401 were offered HIV testing (6.2%), of whom 7936 accepted (69.6%) and 7215 (90.9%) were tested (overall screening rate 3.9%); 1857 non eligible persons were also tested. Fifty-five new diagnoses of HIV infection were confirmed by Western blot (0.61% (95% CI 0.46-0.79). There was one false-positive rapid test result. Among the newly diagnosed persons, 48 (87%) were linked to care, of whom 36 were not lost to follow-up at month 6 (75%); median CD4 cell count was 241/mm(3) (IQR: 52-423/mm(3)).
Screening rates were similar to those reported in opt-in studies with no dedicated staff. The rate of new diagnoses was similar to that observed in free anonymous test centres in the Paris area, and well above the prevalence (0.1%) at which testing has been shown to be cost-effective.
PLoS ONE 10/2012; 7(10):e46437. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE:: This study investigated the impact on virological outcome of the gag cleavage sites (CS) and the protease-coding region (PR) mutations in protease inhibitor (PI)-naïve and PI-experienced patients infected with HIV-2 receiving lopinavir-containing regimen. METHODS:: Baseline gag and PR were sequenced in 46 HIV-2 group-A-infected patients receiving lopinavir. Virological response (VR) was defined as plasma viral load (VL) <100 copies/mL at month 3. Associations between VR and frequencies of mutations in gag (MA/CA, CA/p2, p2/NC, NC/p1, p1/p6) and gag-pol (NC/p6) CS and PR, with respect to the HIV-2ROD strain, were tested using Fisher's exact test. RESULTS:: VR occurred in 14/17 (82%) PI-naïve and 17/29 (59%) PI-experienced patients. Virological failure (VF) was associated with higher baseline VL (median: 6 765 vs. 1 098 copies/mL, P = 0.02). More PR mutations were observed in PI-experienced compared to PI-naïve patients (median: 8 vs. 5, P = 0.003). In PI-naïve patients, T435A (NC/p6), V447 M (p1/p6), and Y14H (PR) were associated with VF (P = 0.011, P = 0.033, P = 0.022, respectively). T435A and V447 M were associated with Y14H (P = 0.018, P = 0.039, respectively). In PI-experienced patients, D427E (NC/p1) was associated with VR (P = 0.014). A430 V (NC/p1) and I82F (PR) were associated with VF (P = 0.046, P = 0.050, respectively). Mutations at position 430 were associated with a higher number of mutations in PR (median: 10 vs. 7, P = 0.008). CONCLUSIONS:: We have demonstrated, for the first time, an association between gag, gag-pol CS and PR mutations, with distinct profiles between PI-naïve and PI-experienced patients. These mutations might impact the virological outcome of HIV-2-infected patients receiving lopinavir-containing regimen.
AIDS (London, England) 09/2012; · 6.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. Human immunodeficiency virus type 2 (HIV-2) infection is characterized by a slower progression than HIV type 1. It is not known whether markers of inflammation such as high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), and soluble CD14 (sCD14) may predict disease progression among HIV-2 patients. Methods. We performed longitudinal retrospective analysis using 384 samples from 71 patients included in the HIV-2 French cohort ANRS CO5 and followed for a median of 8 years. Baseline was the time of the first available measurement. Disease progression was defined by the occurrence of death, Centers for Disease Control and Prevention B/C stage HIV-related event, drop in CD4 <350 cells/µL, and HIV-2 RNA detection. Cox regression models and mixed models were used for statistical analyses. Results. At baseline, 75% of patients were asymptomatic, 34% were treated; 30% had detectable HIV-2 RNA load, and median CD4 cell count was 415/µL. The 3 biomarkers were positively related to each other. In adjusted analyses, sCD14 was the main factor explaining variation of hsCRP and IL-6 (P < .001). Lower CD4, older age, and advanced clinical stage were associated with higher sCD14. The biomarkers were correlated with HIV-2 RNA in unadjusted analyses only. Patients with baseline levels above either the median values (hsCRP = 1.38 mg/L; IL-6 = 1.97 pg/mL) or the highest quartile (sCD14 = 1.74 µg/mL) had a higher risk of disease progression (all P < .003). After adjustment for CD4 count, only sCD14 remained significantly associated with disease progression (hazard ratio, 3.59; P = .004). Conclusions. In this cohort of HIV-2-infected patients, sCD14 represents a better predictive biomarker of disease progression than hsCRP or IL-6, independent of CD4.