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International audience; Comparing survival functions with the log-rank test in the presence of dependent censoring can produce an invalid test result. We extend our previous work on the estimation of the survival function using prognostic variables to adjust for dependent censoring to the comparison of two survival distributions. In these estimators, the weights of a censored individual is redistributed among either a subset of patients in the risk set or all patients in the risk set but giving more weight to patients having smallest distances from the censored subject. The distance is based on two risk scores obtained from two working models, one for the failure time and one for the censoring time. Based on the estimators, we suggest a weighted log-rank test to compare two survival distributions. A simulation study compared performance of our method with the analysis of the observed data without using auxiliary variables and with a recent method based on multiple imputation (KMIB method). With appropriate parameters, the weighted log-rank approach provides sizes of the test comparable to the nominal value but higher powers than the two other methods. The method is illustrated with data from a breast cancer study.

The test of Yang and Prentice, based on the short-term and long-term hazard ratio model for the presence of a regression effect appears to be an attractive one, being able to detect departures from...

International audience; We read with interest the paper, "Improving testing and description of treatment effect in clinical trials with survival outcomes" by Yang [1] and related works published by Yang and Prentice [2, 3]. Alternatives to absence of treatment effect on survival are most commonly framed within the proportional hazards model structure. When broader alternatives of a non-proportional hazards nature are of interest it is known that the high efficiency of the log-rank test can be lost. One test that focuses on this issue is the test of Yang and Prentice [3], based on the short-term and long-term hazard ratio model. The authors argue that the test is able to detect departures from a null hypothesis of no effect against quite broad alternatives. We recall the model on which this test is based and the test itself. Theoretical work and simulations appear to show the test to work well. However, it is important to underline that the test can only be used when the placebo group is clearly defined. Failing to correctly identify which group is the placebo group can have serious consequences and lead to erroneous conclusions. The results may not be interpretable. In situations where we wish to compare Treatment A with Treatment B, neither of which can be considered to correspond unambiguously to the placebo group, our advice would be to avoid this test altogether. We give two examples before concluding that the validity of this test hinges crucially upon a clear and sharp definition of the placebo group.

Summary We consider a comparison of Kaplan–Meier curves from clinical trials in which there may be a delayed treatment effect. Any such delay takes us outside the umbrella of a proportional hazards structure and therefore outside the setting in which the log-rank test would be optimal. The approach of Chauvel and O’Quigley based on Brownian motion approximations enables the construction of powerful tests in situations of non-proportionality and, in particular, a powerful test in the situation of delayed effect. The power of this test is seen to be very close to that of the most powerful test, which, however, is unavailable in practice. We show that the test is unbiased and consistent under general conditions. Under the null, we obtain identical large sample behaviour to the log-rank test so the type 1 error is correctly controlled. Under proportional hazards departures from the null we obtain results that indicate a manageable loss in power compared with the log-rank test. The usual sample size calculations can still provide a useful guide. Support for the theoretical findings are provided by simulations as well as illustrations from three immunotherapy clinical trials.

Background A major challenge to HIV cure strategies is the quantification of persistent reactivation-prone virus in people living with HIV. Objectives To determine whether anti-gp41 antibody levels correlate with viral suppression and HIV-1 DNA levels in patients on ART. Methods Participants with plasma HIV-1 RNA below 50 copies/mL for >12 months were included from three ANRS cohorts (COPANA, MONOI and APROCO). Antibody levels to gp41 were measured by a low-sensitivity enzyme-linked immunoassay. Correlations with patient and virus characteristics, plasma HIV-1 RNA load (standard and ultrasensitive tests) and cell-associated HIV-1 DNA were assessed. Results Median age was 41 years and 77.5% of the 683 participants were men. Median CD4+ T cell count was 582 cells/mm3 and median viral suppression duration was 6.6 years (IQR 2.0-9.5). The overall median anti-gp41 antibody titre was 1.3 (IQR 0.6-1.9); median HIV-1 DNA level was 2.6 (IQR 2.1-3.0) log10 copies/106 leucocytes; and HIV-1 RNA was undetectable in 56% of samples. A lower titre of anti-gp41 antibodies correlated with male gender, longer viral suppression and lower HIV-1 DNA burden. Sustained undetectable HIV-1 RNA was associated with lower anti-gp41 levels [median 1.1 (IQR 0.5-1.6) versus 1.4 (IQR 0.7-1.9), P = 0.009]. Conclusions Anti-gp41 levels decreased with the duration of antiviral suppression on ART. Lower titres were associated with lower HIV-1 DNA levels and longer duration of viral suppression, reflecting minimal antigen stimulation. Anti-gp41 antibody titration may be a useful biomarker reflecting long-term HIV-1 suppression on ART.

Background Successful 2-drug regimens (2DRs) for HIV were made possible by the availability of drugs combining potency and tolerability with a high genetic barrier to resistance. How these deal with resistance development/re-emergence, compared with 3DRs, is thus of paramount importance. Materials and methods A national survey including patients who were either naive or experienced with any 2DR or 3DR but failing integrase strand transfer inhibitor (INSTI)-containing regimens [two consecutive plasma viral load (VL) values >50 copies/mL] was conducted between 2014 and 2019. Genotypic resistance tests were interpreted with the v28 ANRS algorithm. Results Overall, 1104 patients failing any INSTI-containing regimen (2DRs, n = 207; 3DRs, n = 897) were analysed. Five hundred and seventy-seven (52.3%) patients were infected with a B subtype and 527 (47.3%) with non-B subtypes. Overall, 644 (58%) patients showed no known integrase resistance mutations at failure. In multivariate analysis, factors associated with the emergence of at least one integrase mutation were: high VL at failure (OR = 1.24 per 1 log10 copies/mL increase); non-B versus B subtype (OR = 1.75); low genotypic sensitivity score (GSS) (OR = 0.10 for GSS = 2 versus GSS = 0–0.5); and dolutegravir versus raltegravir (OR = 0.46). Although 3DRs versus 2DRs reached statistical significance in univariate analysis (OR = 0.59, P = 0.007), the variable is not retained in the final model. Conclusions This study is one of the largest studies characterizing integrase resistance in patients failing any INSTI-containing 2DR or 3DR in routine clinical care and reveals factors associated with emergence of integrase resistance that should be taken into consideration in clinical management. No difference was evidenced between patients receiving a 2DR or a 3DR.

International audience; No abstract available

International audience; Measuring the magnitude of reduction in HIV‐1 RNA levels accurately is difficult because many patients have a censored reduction due to the limit of detection (LOD) of the virologic assay being employed. The use of censored methods has improved the analysis of such reductions compared with crude methods but implies independent censoring. For HIV‐1 RNA reduction data, the value at which a patient's HIV‐1 RNA reduction becomes censored is mainly determined by the patient's baseline HIV‐1 RNA level. We suggest two possibilities based on modification of the redistribution to the right algorithm to handle the situation of dependence either from a single continuous marker, that is, the baseline HIV‐1 RNA level, or from multiple markers. Two series of simulation, one in the HIV‐1 RNA setting and one in the classical censoring setting, compared performance of the previous methods with our suggestions. Our proposed estimators show good performances when the dependent censoring is due to LOD. Overall, in the classical censoring setting, our suggestions perform as well as other methods including the Inverse Probability of Censoring Weighted and the Kaplan‐Meier imputation with Bootstrap. We applied those estimators to estimate the HIV‐1 RNA reduction at week 8 of 502 patients who received a raltegravir‐containing regimen and to data from the Mayo Clinic trial in primary biliary cirrhosis.

Background Tuberculosis is associated with a risk of immune reconstitution inflammatory syndrome (IRIS) after ART initiation. Methods Data from all patients with newly diagnosed tuberculosis disease and uncontrolled HIV infection from 1997 to 2017 in a French center were retrospectively collected. We evaluated the incidence of tuberculosis-IRIS in patients initiating ART with or without integrase inhibitors (INSTI) Results Fifty-five patients were included: 21 receiving an INSTI regimen and 34 a non-INSTI regimen. Except with regard to ART regimen, the two groups were comparable (median CD4 of 85/mm3). The overall percentage of IRIS was 34% (19/55), with 52% IRIS in INSTI regimen and 23% in non-INSTI regimen respectively (P = 0.04). In a multivariate logistic model, we observed an increased risk of IRIS in the INSTI regimen compared to the non-INSTI, with an OR at 3.33 [95% CI, 1.01–11.1] (P = 0.05) Conclusions ART containing integrase inhibitors could be associated with increased incidence of TB-associated IRIS.

ObjectivesTo evaluate the prevalence and therapeutic relevance of drug resistance among isolates from ART-experienced HIV-1-infected patients over the past two decades in Italy.MethodsDynamics of resistance to one, two and three or more antiretroviral classes were evaluated from 1999–2018. Virological success (VS) after the latest therapy switch was evaluated according to cumulative class resistance and cumulative genotypic susceptibility score (Stanford HIV_DB algorithm).ResultsAmong 13 663 isolates (from 6739 patients), resistance to at least one drug class decreased sharply from 1999 to 2010 (≤2001, 84.6%; 2010, 43.6%; P ConclusionsA dramatic drop of HIV-1 drug resistance at failure has been achieved over the last two decades in Italy; resistance to three or more classes is low but present among currently failing patients. Its management still requires a rational and careful diagnostic and therapeutic approach.

Background Integrase strand transfer inhibitors (INSTIs) are recommended by international guidelines as first-line therapy in antiretroviral-naive and -experienced HIV-1-infected patients. Objectives This study aimed at evaluating the prevalence at failure of INSTI-resistant variants and the impact of baseline minority resistant variants (MiRVs) on the virological response to an INSTI-based regimen. Methods Samples at failure of 134 patients failing a raltegravir-containing (n = 65), an elvitegravir-containing (n = 20) or a dolutegravir-containing (n = 49) regimen were sequenced by Sanger sequencing and ultra-deep sequencing (UDS). Baseline samples of patients with virological failure (VF) (n = 34) and of those with virological success (VS) (n = 31) under INSTI treatment were sequenced by UDS. Data were analysed using the SmartGene platform, and resistance was interpreted according to the ANRS algorithm version 27. Results At failure, the prevalence of at least one INSTI-resistant variant was 39.6% by Sanger sequencing and 57.5% by UDS, changing the interpretation of resistance in 17/134 (13%) patients. Among 53 patients harbouring at least one resistance mutation detected by both techniques, the most dominant INSTI resistance mutations were N155H (45%), Q148H/K/R (23%), T97A (19%) and Y143C (11%). There was no difference in prevalence of baseline MiRVs between patients with VF and those with VS. MiRVs found at baseline in patients with VF were not detected at failure either in majority or minority mutations. Conclusions UDS is more sensitive than Sanger sequencing at detecting INSTI MiRVs at treatment failure. The presence of MiRVs at failure could be important to the decision to switch to other INSTIs. However, there was no association between the presence of baseline MiRVs and the response to INSTI-based therapies in our study.

One aspect of an analysis of survival data based on the proportional hazards model that has been receiving increasing attention is that of the predictive ability or explained variation of the model. A number of contending measures have been suggested, including one measure, R2 (β), which has been proposed given its several desirable properties, including its capacity to accommodate time-dependent covariates, a major feature of the model and one that gives rise to great generality. A thorough study of the properties of available measures, including the aforementioned measure, has been carried out recently. In that work, the authors used bootstrap techniques, particularly complex in the setting of censored data, in order to obtain estimates of precision. The motivation of this work is to provide analytical expressions of precision, in particular confidence interval estimates for R2 (β). We use Taylor series approximations with and without local linearizing transforms. We also consider a very simple expression based on the Fisher's transformation. This latter approach has two great advantages. It is very easy and quick to calculate, and secondly, it can be obtained for any of the methods given in the recent review. A large simulation study is carried out to investigate the properties of the different methods. Finally, three well-known datasets in breast cancer, lymphoma and lung cancer research are given as illustrations. Copyright © 2017 John Wiley & Sons, Ltd.

International audience; Objectives: To describe integrase strand transfer inhibitor (INSTI) resistance profiles and factors associated with resistance in antiretroviral-naive and -experienced patients failing an INSTI-based regimen in clinical practice.Methods: Data were collected from patients failing an INSTI-containing regimen in a multicentre French study between 2014 and 2017. Failure was defined as two consecutive plasma viral loads (VL) >50 copies/mL. Reverse transcriptase, protease and integrase coding regions were sequenced at baseline and failure. INSTI resistance-associated mutations (RAMs) included in the Agence Nationale de Recherches sur le SIDA genotypic algorithm were investigated.Results: Among the 674 patients, 359 were failing on raltegravir, 154 on elvitegravir and 161 on dolutegravir therapy. Overall, 90% were experienced patients and 389 (58%) patients showed no INSTI RAMs at failure. The strongest factors associated with emergence of at least one INSTI mutation were high VL at failure (OR = 1.2 per 1 log10 copies/mL increase) and low genotypic sensitivity score (GSS) (OR = 0.08 for GSS ≥3 versus GSS = 0-0.5). Patients failing dolutegravir also had significantly fewer INSTI RAMs at failure than patients failing raltegravir (OR = 0.57, P = 0.02) or elvitegravir (OR = 0.45, P = 0.005). Among the 68 patients failing a first-line regimen, 11/41 (27%) patients on raltegravir, 7/18 (39%) on elvitegravir and 0/9 on dolutegravir had viruses with emergent INSTI RAMs at failure.Conclusions: These results confirmed the robustness of dolutegravir regarding resistance selection in integrase in the case of virological failure in routine clinical care.

BACKGROUND: The restricted mean survival time (RMST) measures have not been used as primary measure of efficacy in HIV/AIDS clinical trials. In this work, we aim to compare analysis based on the difference in RMST (Δ-RMST) measure and two other treatment-effect measures in a recent HIV equivalence trial, and investigate the performance and characteristics of Δ-RMST-based analysis in a simulation study. SETTING AND METHODS: We reanalyzed a recent HIV equivalence trial (ACTG A5257 trial) with hazard ratio (HR) and Δ-RMST, and then compared the results with the original analysis based on risk difference estimated by Kaplan-Meier curves (RD(KM)). In a simulation study, we investigated the performance and operating characteristics of Δ-RMST-based analysis in the setting of non-proportional hazards ratio. RESULTS: In the ACTG A5257 trial, analyses based on Δ-RMST globally led to similar conclusions as the published finding based on RD(KM). In contrast, analyses based on HR provided some discordant equivalence conclusions compared both with the initial analyses based on RD(KM) and the Δ-RMST. Results of simulation study indicate that the violation of the proportional hazards assumption has an impact on Δ-RMST based analysis regarding the probability of declaring equivalence. CONCLUSION: Though the RMST based analysis is an alternative measure of efficacy in HIV/AIDS clinical trials such an analysis can be strongly impacted by departures from the proportional hazards assumption.

Objectives We used the D:A:D risk score for chronic kidney disease (CKD) for patients starting antiretroviral therapy (ART) in the recent years, and investigated whether specific regimens enhanced the risk of CKD in the different risk groups. Design Retrospective analysis of a prospectively collected cohort of French HIV-infected patients. Methods Patients who started their first ART after January the 1st, 2004 with a baseline estimated glomerular filtration rate (eGFR) greater than 60 ml/min per 1.73 m were analyzed. CKD was defined by confirmed eGFR less than 60 ml/min per 1.73 m. Incidence of CKD was estimated by Kaplan-Meier method, and Poisson regression models were used to quantify the relationship between CKD, exposure to the initial ART regimens and the D:A:D score. Results We included 6301 patients representing 21 936 person-years of follow-up (PYFU), median eGFR at baseline was 101 ml/min per 1.73 m (inter-quartile range 86; 118) and CKD incidence 9.6/1000 PYFU. Five years probabilities of CKD were 0.65, 4.6 and 15.9% in the low, medium and high-risk groups, respectively. In patients treated with a boosted protease inhibitor, incidences rates were 7.1/1000 and 9.0/1000 PYFU in the absence or presence of tenofovir, respectively, and markedly increased with increasing risk score. In the low-risk group the treatment choice had no impact on CKD incidence. Conclusion When choosing the ideal first antiretroviral regimen for one given patient, clinicians should rely on the D:A:D score and avoid some drugs in high-risk patients, whereas in low-risk patients classic regimens may be safely prescribed, with an economic benefit due to soon available generic formulations.

International audience; Objectives: The aim of this study was to investigate the use of three treatment-effect measures in the analysis of randomized trials using a time-to-event endpoint and assess their influence on the results. Study Design and Setting: A recent equivalence trial showed discordant results with the use of different measures. Different hypotheses may explain such discordant results including a mistaken hypothesized distribution of time to failure and an overestimation of failure rates in the protocol. In a simulation study, we investigate different situations in comparing analyses based hazard ratio (HR), risk difference estimated by KaplaneMeier curves, and difference in restricted mean survival time. We also compared these three analyses on genuine data from a recent equivalence trial. Results: In the equivalence trial, two analyses would have concluded equivalence, whereas the original analysis based on HR estimate did not declare equivalence. Results of our simulation study indicate little to moderate differences between the three analyses when the true distribution of time to failure is different to the hypothesized distribution. The main discordant results are found when failure rates have been overestimated or underestimated regardless of the distribution. Conclusion: With the distributions investigated, differences between analyses based on different measures are much more driven by mistaken hypothesized failure rates than by the shape of the distribution of time to failure.

Using 3 randomized Protease inhibitor (PI) monotherapy studies: Kalesolo, Dream and Monoi, we performed a pooled-analysis. Our objective was to determine in PI monotherapy and standard tritherapy: 1) distribution of ultrasensitive viral load (USVL) at week 96 (W96); 2) factors associated with virological failure (VF) at W96 and 3) factors associated with USVL1 copy at W96.VF was defined as 2 consecutive measurements of Human Immunodeficiency Virus Type 1 RNA viral load50 copies/mL and analysed in Intention-To-Treat. A logistic model was used to investigate which variables were predictive of a VF and Fisher test to investigate differences in USVL at W96.Among 609 patients, 73% were male with median age of 44.4 years (IQR 39.8-52.1), baseline CD4/CD8 ratio was 0.8 (IQR 0.6-1.10), baseline CD4 was 564.5/mm3 (IQR 422-707) and 59% presented a baseline USVL1 copy/mL. At W96, the proportion of USVL1 copy/mL was significantly different between PI monotherapy and standard tritherapy in pooled-analysis (65% versus 74%; p=0.04). Overall, baseline USVL1copy/mL, tritherapy and to be a female were associated with USVL1 copy/mL at W96 (p0.0001, p=0.049 and p=0.006). In PI monotherapy receiving DRV/r was associated with USVL1 copy/mL at W96 (p=0.003). Factors associated to virological succes at W96 were higher baseline CD4 (p=0.034) and baseline USVL1 copy/mL (p=0.0005).Pooled-analysis of 3 PI monotherapy trials showed better efficacy of tritherapy in terms of USVL at W96. Furthermore regarding USVL at W96, to receive LPV/r seems to be more deleterious than DRV/r. Baseline USVL impacts VF at W96 more specifically in tritherapy arm.NCT00421551, NCT00946595, and NCT00140751.

OBJECTIVES To compare nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-sparing regimens with tenofovir alafenamide (TAF)-based combinations in HIV-1-infected adults, we performed a network meta-analysis (NMA) to provide estimates of relative efficacy for these two regimens. METHODS A systematic literature review (SLR) was performed to identify phase 3/4 randomized controlled clinical trials evaluating the efficacy of commonly used combination antiretroviral therapy (cART) including an NRTI backbone or that of commonly used NRTI-sparing regimens. A Bayesian random-effect model was used to compare virological suppression rates at 48 weeks for NRTI-sparing regimens and elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF). RESULTS Twenty-three studies in treatment-naive patients identified by the SLR were included in the NMA, including four studies assessing NRTI-sparing regimens. In treatment-naive patients, the probability of achieving virological suppression at 48 weeks was between 40% and 60% higher with E/C/F/TAF than with NRTI-sparing strategies. The credible interval vs. darunavir/ritonavir (DVR/r) + raltegravir (RAL) and LPV/r monotherapy did not include 1. In the subgroup of naive patients with viral load

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. RESULTS Baseline 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.

It is often assumed, but has not been consistently observed, that some characteristics of reproductive history are specifically related to breast cancer of pre- or postmenopausal onset. To determine whether inconsistent reports may be due to differences in definition of menopause, we computed the relative odds (RO) of breast cancer for nulliparity, age at first live birth, family history of breast cancer and prior history of benign breast disease, separately in pre- and postmenopausal women, using seven different definitions of menopause. Results show that (i) relative odds of breast cancer and their confidence intervals may vary according to definitions of menopause; (ii) age-based definitions of menopause are associated with moderate differential misclassification bias between cases and controls; (iii) nulliparity, late age at first birth and family history of breast cancer seem to be specific risk factors for pre- but not postmenopausal breast cancer when cutoff for menopausal status is 10 years or more after last menses; and (iv) when information on menstrual history is not available, 50 years of age may be the best proxy for all menses-based definitions of menopause. We conclude that inconsistent findings on the effect of menopausal status in the association of breast cancer with some reproductive factors are partly due to statistical imprecision and differential misclassification bias associated with different age-based or menses-based definitions of menopause. Researchers should either test whether their conclusions hold using several definitions of menopause or give a biological rationale for the choice of a given definition of menopause.

International audience; Background: HIV therapy reduces the CSF HIV RNA viral load (VL) and prevents disorders related to HIV encephalitis. However, these brain disorders may persist in some cases. A large population of antiretroviral-treated patients who had a VL > 1.7 log10 copies/mL in CSF with detectable or undetectable VL in plasma associated with cognitive impairment was studied, in order to characterize discriminatory factors of these two patient populations.Methods: Blood and CSF samples were collected at the time of neurological disorders for 227 patients in 22 centres in France and 1 centre in Switzerland. Genotypic HIV resistance tests were performed on CSF. The genotypic susceptibility score was calculated according to the last Agence Nationale de Recherche sur le Sida et les hépatites virales Action Coordonnée 11 (ANRS AC11) genotype interpretation algorithm.Results: Among the 227 studied patients with VL > 1.7 log10 copies/mL in CSF, 195 had VL detectable in plasma [median (IQR) HIV RNA was 3.7 (2.7–4.7) log10 copies/mL] and 32 had discordant VL in plasma (VL 1.7 log10 copies/mL. Resistance to antiretrovirals was observed in CSF for the two groups of patients.Conclusions: Fourteen percent of this population of patients with cognitive impairment and detectable VL in CSF had well controlled VL in plasma. Thus, it is important to explore CSF HIV (VL and genotype) even if the HIV VL is controlled in plasma because HIV resistance may be observed.

International audience; Objective : The importance of an early reduction of HIV-1 RNA as a marker for positive longer term outcome is still under debate. We investigate whether antiretroviral-experienced patients receiving raltegravir plus etravirine have a higher early reduction of HIV-1 RNA compared with patients receiving raltegravir. Design: An observational study of treatment-experienced patients. Methods: The objective is investigated in 349 patients included in a raltegravir resistance study. The early outcome is defined as a reduction of HIV-1 RNA at week 8. The crude method that consists to define all measurements below the limit of quantification to be equal to the limit of quantification provides biased estimates. Such a reduction is censored by the limit of quantification and is subject to selection bias in observational studies. Results: Crude method showed a significant higher reduction in HIV-1 RNA reduction in patients receiving raltegravir plus etravirine compared with patients receiving raltegravir (mean reduction of 2.1 versus 1.8 log 10 copies/ml). However, survival methods adjusted for both censoring, due to the limit of quantification, and confounding factors lead to a non-significant difference between the two treatment groups (mean reduction of 2.8 versus 2.7 log 10 copies/ml).. Conclusion: Taking into account censoring and confounding factors, our study did not demonstrate a higher early reduction of HIV-1 RNA in patients receiving raltegravir with versus without etravirine.

Due to the differences between bioavailability of efavirenz (EFV) and tenofovir (TDF), the single-tablet regimen of EFV/emtricitabine (FTC)/TDF is not approved as initial antiretroviral therapy (ART) in Europe by the European Medical Agency. To compare clinical, immunological, and virological outcomes between co-formulated TDF/FTC+EFV and the co-formulated EFV/FTC/TDF single-tablet regimen in patients infected with HIV-1 naive to ART, the data of patients (n = 231) who initiated either TDF/FTC+EFV (n = 155) or EFV/FTC/TDF (n = 76) between January 1, 2007 and June 1, 2010 were analyzed. Changes from baseline to week 48 (TDF/FTC+EFV vs. EFV/FTC/TDF) in HIV plasma load (− 3.25 log vs. −3.32 log) and CD4+ T cell count (+180 vs. +138 cells/mm3) were similar in the two groups. Treatment discontinuation was recorded in 50 (22%) patients (40 on TDF/FTC+EFV and 10 on EFV/FTC/TDF, P = 0.03) but time to discontinuation did not differ between the two groups. Only patients on TDF/FTC+EFV discontinued treatment because of neurological symptoms. Virological failure occurred in 11 (4.7%) patients (seven on TDF/FTC+EFV and four on EFV/FTC/TDF, P = 0.75) with new resistance-associated mutations in five among the six with successful resistance genotype tests. Only baseline resistance-associated mutations was a risk factor for virological failure (P = 0.0146). These data show comparable outcomes between TDF/FTC+EFV or EFV/FTC/TDF used in patients infected with HIV-1 and not treated previously, consistent with a low rate of virological failure in the absence of pretreatment resistance. This would suggest that the European Medical Agency should approve co-formulated EFV/FTC/TDF single-tablet regimen for patients naive to ART. J. Med. Virol. 87:187–191, 2015. © 2014 Wiley Periodicals, Inc.

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.

The relevance of low-level HIV DNA in patients who have undergone prolonged therapy is not well understood. The objective of this study was to determine factors that influence the establishment of low-level HIV DNA in long-term treated patients (excluding treatment since acute infection).This was a cross-sectional study involving 243 patients receiving highly active antiretroviral therapy (HAART) for ≥6 months (median: 9 years of treatment) with plasma HIV RNA50 copies/mL at the study timepoint, for whom total DNA measurements were performed. Patients treated since early acute infection or receiving cancer chemotherapeutic/immunosuppressive agents were excluded from the study.Overall, the median HIV DNA was 372 copies/10(6) peripheral blood mononuclear cells (PBMCs). Forty-seven patients had levels of HIV DNA below the limit of detection and 58 patients had low-level HIV DNA (100 copies/10(6) PBMCs). In multivariate analysis, a low total HIV DNA in HAART-treated patients was clearly associated with a low HIV RNA pre-therapeutic viral load (P0.0001), regardless of the cut-off used.These results may be helpful to identify candidates for future trials aiming at a functional cure of HIV infection, since low total HIV DNA levels will most likely be a prerequisite of successful immunological control of HIV replication.

Since the introduction of zidovudine, a nucleoside analogue reverse transcriptase inhibitor, there has been continuous improvement in the efficacy of antiretroviral treatments. Briefly, antiretroviral therapy moved from the era of zidovudine monotherapy to a combination of two analogues of the reverse transcriptase and then to triple-drug therapy with the introduction of protease inhibitors in 1996. The efficacy of triple-drug combinations was further consolidated with the introduction of the non-nucleoside analogue reverse transcriptase inhibitor. Beyond 1996, the impressive improvement in efficacy has implied that death and clinical endpoints could not be reasonably used as primary efficacy endpoints. Recent studies used plasma viral load as surrogate endpoints to evaluate efficacy of antiretroviral combinations. Progress in antiretroviral efficacy has also led to a move from superiority to noninferiority design. Methodological issues in noninferiority design have been already criticized, but recent trials provide a good opportunity for discussing some key features of that design. Recent studies are used to illustrate some inconsistencies in the choice of response rates, power and noninferiority margin. It appears that HIV noninferiority trials are overpowered by assuming lower success rates than those observed, enrolling a large number of patients and choosing a large margin. Consequently, failure to demonstrate noninferiority is uncommon. Novel designs or endpoints should be introduced emphasizing the expected benefits in terms of toxicity, adherence, resistance or costs.

Background We tested whether pre-HAART viraemia affects the achievement and maintenance of virological success in HIV-1-infected patients starting modern first-line therapies. Methods A total of 1,430 patients starting their first HAART (genotype-tailored) in 2008 (median; IQR: 2006–2009) were grouped according to levels of pre-HAART viraemia (≤30,000, 30,001–100,000, 100,001–300,000, 300,001–500,000 and >500,000 copies/ml). The impact of pre-therapy viraemia on the time to virological success (viraemia ≤50 copies/ml) and on the time to virological rebound (first of two consecutive viraemia values >50 copies/ml after virological success) were evaluated by Kaplan–Meier curves and Cox regression analyses. Results Median pre-HAART viraemia was 5.1 log10 copies/ml (IQR 4.5–5.5), and 53% of patients had viraemia >100,000 copies/ml. By week 48, the prevalence of patients reaching virological success was >90% in all pre-HAART viraemia ranges, with the only exception of range >500,000 copies/ml (virological success =83%; P500,000 copies/ml showed the lowest hazard of virological undetectability after adjusting for age, gender, pre-HAART CD4+ T-cell count, transmitted drug resistance, calendar year and third drug administered (adjusted hazard ratio [95% CI]: 0.27 [0.21, 0.35]; P500,000 copies/ml was also associated with higher probability of virological rebound compared with patients belonging to lower viraemia strata at weeks 4, 12 and 24 ( P=0.050). Conclusions At the time of modern HAART, and even though an average >90% of virological success, high pre-HAART viraemia remains an independent factor associated with delayed and decreased virological success. Patients starting HAART with >500,000 copies/ml represent a significant population that may deserve special attention.

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.

OBJECTIVE To address the ability of a 24-week Maraviroc (MVC) intensification of a stable antiretroviral therapy (cART) to significantly increase the CD4 cell count slope. METHODS Patients were eligible if they had CD4

One aspect of an analysis of survival data based on the proportional hazards model that has been receiving increasing attention is that of the predictive ability or explained variation of the model. A number of contending measures have been suggested, including one measure, R

International audience; Objectives In the context of a rilpivirine/emtricitabine/tenofovir disoproxil fumarate switch in HIV-1-infected patients with at least 1 year of virological success, we determined whether proviral DNA is an alternative to plasma HIV RNA for resistance genotyping.Methods Resistance-associated mutations (RAMs) in DNA after at least 1 year of virological success [viral load (VL) 50 copies/mL). Kappa's coefficient was used to measure agreement between the DNA and RNA genotypes.Results In patients without VF (n = 130) and with VF (n = 114), RNA and DNA showed resistance to at least one drug of the rilpivirine/emtricitabine/tenofovir disoproxil fumarate combination in 8% and 9% and in 60% and 45%, respectively. For rilpivirine RAMs, correlation between RNA and DNA was higher in patients without VF than in patients with VF (kappa = 0.60 versus 0.19, P = 0.026). Overall, the prevalence of RAMs was lower in DNA than in RNA.Conclusions Incomplete information provided by the DNA genotypic test is more notable in patients with VF, suggesting that all resistance mutations associated with prior VF have not been archived in the proviral DNA or decreased to a level below the threshold of detection. In the case where no historical plasma genotypic test is available, DNA testing might be useful to rule out switching to rilpivirine/emtricitabine/tenofovir disoproxil fumarate.

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSION 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.

OBJECTIVES To analyse the emergence of resistant viruses in patients failing darunavir monotherapy, including minority species, and to investigate the impact of baseline reverse transcriptase (RT), protease (PR) and gag resistance mutations on virological failure (VF) occurrence. METHODS Nine of the 225 HIV-1-infected patients enrolled in the MONOI trial (darunavir/ritonavir monotherapy or darunavir/ritonavir + two nucleoside reverse transcriptase inhibitors in a switch strategy) experienced VF, defined as two plasma HIV-1 viral loads >400 copies/mL at least 2 weeks apart. Among these nine patients with VF, five were in the darunavir/ritonavir monotherapy arm and four were in the darunavir/ritonavir triple therapy arm. Bulk sequences of the PR, RT and gag genes at baseline (on DNA) and at the time of VF (on RNA) were determined for all patients with two viral loads >50 copies/mL at least 2 weeks apart (n = 47). PR and gag gene clonal analysis was performed on plasma samples of the nine patients with VF. RESULTS There was no association between mutations in RT, PR and gag genes in DNA and VF occurrence. None of the patients demonstrated selection of darunavir resistance mutations among the 47 patients with a viral load >50 copies/mL at least 2 weeks apart. The virus of one of the nine patients with VF presented minority variants with darunavir resistance mutations at positions 32, 47 and 50. Clonal analysis of the gag region for the nine patients with VF did not show any selection of minority variants. CONCLUSIONS In patients with failure on darunavir/ritonavir monotherapy we did not find any selection of darunavir resistance mutations using standard genotype testing. However, the virus of one patient among nine failures presented minority variants plus darunavir resistance mutations.

Human herpesvirus-6 and -7 (HHV-6 and HHV-7) may lead to pathological manifestations in renal transplant recipients. The aim of this study was to investigate beta-herpesvirus infections in 50 adult kidney transplant recipients after transplantation to examine the effect, interactions, and pathogenic consequences of infection and the effect of immunosuppressive regimens and Human cytomegalovirus (HCMV) prophylaxis with VACV. Beta-herpesviruses loads in the blood of 50 adult kidney transplant recipients over a 6-month period after transplantation and 198 blood donors were determined using polymerase chain reaction. The rate of HHV-6 detection in peripheral mononuclear cells (PBMCs) was higher in patients with end-stage renal disease and during the post-transplantation follow-up than in healthy subjects (33% and 68% vs. 12%, respectively). The detection rate of HHV-7 in PBMCs was similar between patients, both before grafting and during the follow-up for transplant recipients (69% and 88%, respectively), and healthy subjects (78%), and correlated with the number of lymphocytes. HCMV in plasma was detected only in patients during the post-transplant period (24%). VACV prophylaxis had no negative effect on the replication of HHV-6 or HHV-7, and univariate analyses demonstrated associations between HHV-6 infection and acute graft rejection [Odds ratio (OR) = 2.94, 95% confidence interval (CI), 1.05–8.2, P = 0.04], and between HHV-7 infection and cholestasis [OR = 2.61 (95% CI, 1.08–6.3), P = 0.03]. Immunosuppressive regimens had no effect on beta-herpesviruses infections. This study revealed the differing behavior of HCMV, HHV-6, and HHV-7 in kidney transplant recipients, and confirmed the association of HHV-6 with graft rejection. J. Med. Virol. 84:450–456, 2012. © 2011 Wiley Periodicals, Inc.

Summary Background and objectives The main aim of this study was determining the risk factors of chronic kidney disease (CKD) in HIV-1-infected patients. Design, setting, participants, & measurements Patients were followed from seven large HIV reference centers in France that maintain prospective databases on HIV-1-infected patients. The main outcome was the time to CKD defined as two consecutive measures of estimated GFR ≤60 ml/min per 1.73 m2 over ≥3 months. A Cox9s model with delayed entry was used to search predictive factors of time to CKD. Results From 1993 to 2006, 349 out of 7378 patients were found to have CKD. Of these, 166 had hypertension, 33 had diabetes, and 26 were antiretroviral therapy–naive. Occurrence of acute kidney injury (hazard ratio [HR] = 2.40) and hypertension (HR = 2.39) were strongly associated with an increased risk of CKD. Patients with a durable level of CD4 count >200 cells/mm3 had a lower risk of CKD (HR = 0.63). Recent exposure to indinavir (HR = 2.03), totenofovir (HR = 1.55), and abacavir (HR = 1.37) were associated with an increased risk of CKD. Past exposure to tenofovir was also associated with an increased risk of CKD (HR = 2.23), and a trend toward significance was observed for past exposure to indinavir (HR = 1.28). Conclusions CKD was not rare in HIV-infected patients and occurs preferentially in HIV-infected patients exposed to certain ARVs, specifically abacavir, indinavir and tenofovir. This requires closer monitoring of renal function in patients exposed to one of these drugs.

The aim of this cross-sectional study was to determine which antiretroviral drugs (ARVs) are associated with changes in the characteristics of semen and the impact of these ARVs according to their score penetration into the male genital compartment. Data from 144 men infected with HIV-1 enrolled in an Assisted Reproductive Technology program were analyzed retrospectively. A seminal penetration score of ARV was based on the available literature. The nonparametric Kruskal-Wallis test and chi-square test were used. There was no difference on sperm parameters between NRTI, NNRTI, or PI regimen. In patients receiving NRTIs or PIs no differences were observed between antiretrovirals of these classes. However, in patients receiving NNRTIs, nevirapine (n = 22) was associated with a higher percentage of progressively motile spermatozoa (P < 0.0001) versus efavirenz (n = 38) as well as vitality (P = 0.0004). No relationship was observed between semen quality and the penetration score. NRTIs and PIs were not associated with any semen changes. Nevirapine was associated with a better quality of semen versus efavirenz. It would be of interest to validate, improve and test our penetration score in a prospective study.