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International audience; Objective: The antiviral efficacy of nucleos(t)ide analogues whose main limitation is relapse after discontinuation requires long-term therapy. To overcome the risk of relapse and virological breakthrough during long-term therapy, we performed a phase I/II, open, prospective, multicentre trial using a HBV envelope-expressing DNA vaccine.Design: 70 patients treated effectively with nucleos(t)ide analogues for a median of 3 years (HBV DNA 120 IU/mL) or impossibility of stopping treatment at week 48.Results: Reactivation occurred in 97% of each group after a median 28 days without liver failure but with an HBV DNA

Objectives Interleukin-2 (IL-2) therapy increased CD4 cell counts and delayed antiretroviral therapy (ART) initiation in HIV-infected patients in the Agence Nationale de Recherche sur le SIDA et les Hepatites Virales (ANRS) 119 trial. However, four cases of lymphoma were reported. Epstein−Barr virus (EBV) replication is associated with an increased risk of lymphoma in immunocompromised patients. We assessed whether IL-2 had an impact on EBV replication and the development of lymphoma. Methods A total of 130 ART-naive patients were randomized to receive IL-2 therapy (n = 66) or no treatment (n = 64). Clinical data for patients with lymphomas were reviewed and tumours assessed for evidence of EBV infection and CD25 (the IL-2 receptor) expression. EBV DNA levels were measured in whole blood and plasma in both arms using real-time polymerase chain reaction (PCR), up to 48 weeks after baseline (BL). Results Four lymphomas occurred, a median of 61 weeks [range 40−94 weeks] after randomization at a median CD4 cell count of 396 cells/μL (IQR 234–536 cells/μL). In the IL-2 arm, two patients developed EBV-positive Hodgkin's lymphoma, and one developed EBV-negative Burkitt-type lymphoma. One patient in the control group developed EBV-positive non-Hodgkin's lymphoma. CD25 was negative in all cases. Among the 41 of 55 (control arm) and 44 of 58 (IL-2 arm) patients with detectable EBV DNA in whole blood at both BL and week 48, the median change in EBV DNA between BL and week 48 was +0.04 log10 copies/ml in both arms (P = 0.7). In plasma, EBV was detected at least once in 22 of 52 controls and 21 of 54 IL-2-treated patients (P = 0.8). Conclusions IL-2 therapy had no significant effect on EBV replication over 48 weeks in these ART-naive patients. The occurrence of lymphomas did not seem to be associated with IL-2 therapy.

Objective The aim of the study was to evaluate the predictive value of clinical and molecular risk factors, including peripheral blood mononuclear cell (PBMC) mitochondrial DNA (mtDNA) and mitochondrial RNA (mtRNA), for the development of lactic acidosis (LA) and symptomatic hyperlactataemia (SHL). Methods In a substudy of a large multicentre, randomized trial of three antiretroviral regimens, all containing didanosine (ddI) and stavudine (d4T), in antiretroviral-naive, HIV-1-infected patients, patients with LA/SHL (‘cases’) were compared with those without LA/SHL in a univariate analysis, with significant parameters analysed in a multivariate model. In a molecular substudy, PBMC mtDNA and mtRNA from cases and matched controls at baseline and time of event were examined. Results In 911 subjects followed for a median of 192 weeks, 24 cases were identified (14 SHL and 10 LA). In univariate analysis, cases were more likely to be female (P=0.05) and to have a high body mass index (BMI) (P=0.02). In multivariate analyses, only BMI remained an independent predictor of the development of LA/SHL (P=0.03). Between cases and controls there was no significant difference in mtDNA copy number at baseline (389 vs. 411 copies/cell, respectively; P=0.60) or at time of event (329 vs. 474 copies/cell, respectively; P=0.21), in the change in mtDNA copy number from baseline to event (−65 vs. +113 copies/cell, respectively; P=0.12), in mtRNA expression at baseline or time of event, or in the change in mtRNA expression from baseline to event. Conclusion The development of LA/SHL was associated with increased BMI, but PBMC mtDNA and mtRNA did not predict LA/SHL. This demonstrates the ineffectiveness of routine measurement of PBMC mtDNA in patients on ddI and d4T as a means of predicting development of LA/SHL.

Background Children with HIV will be on antiretroviral therapy (ART) longer than adults, and therefore the durability of first-line ART and timing of switch to second-line are key questions. We assess the long-term outcome of protease inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) first-line ART and viral load switch criteria in children. Methods In a randomised open-label factorial trial, we compared effectiveness of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor versus two NRTIs plus an NNRTI and of switch to second-line ART at a viral load of 1000 copies per mL versus 30,000 copies per mL in previously untreated children infected with HIV from Europe and North and South America. Random assignment was by computer-generated sequentially numbered lists stratified by age, region, and by exposure to perinatal ART. Primary outcome was change in viral load between baseline and 4 years. Analysis was by intention to treat, which we defined as all patients that started treatment. This study is registered with ISRCTN, number ISRCTN73318385. Findings Between Sept 25, 2002, and Sept 7, 2005, 266 children (median age 6.5 years; IQR 2.8-12.9) were randomly assigned treatment regimens: 66 to receive protease inhibitor and switch to second-line at 1000 copies per mL (PI-low), 65 protease inhibitor and switch at 30,000 copies per mL (PI-higher), 68 NNRTI and switch at 1000 copies per mL (NNRTI-low), and 67 NNRTI and switch at 30,000 copies per mL (NNRTI-higher). Median follow-up was 5.0 years (IQR 4.2-6.0) and 188 (71%) children were on first-line ART at trial end. At 4 years, mean reductions in viral load were -3.16 log(10) copies per mL for protease inhibitors versus -3.31 log(10) copies per mL for NNRTIs (difference -0.15 log(10) copies per mL, 95% CI -0.41 to 0.11; p=0.26), and -3.26 log(10) copies per mL for switching at the low versus -3.20 log(10) copies per mL for switching at the higher threshold (difference 0.06 log(10) copies per mL, 95% CI -0.20 to 0.32; p=0.56). Protease inhibitor resistance was uncommon and there was no increase in NRTI resistance in the PI-higher compared with the PI-low group. NNRTI resistance was selected early, and about 10% more children accumulated NRTI mutations in the NNRTI-higher than the NNRTI-low group. Nine children had new CDC stage-C events and 60 had grade 3/4 adverse events; both were balanced across randomised groups. Interpretation Good long-term outcomes were achieved with all treatments strategies. Delayed switching of protease-inhibitor-based ART might be reasonable where future drug options are limited, because the risk of selecting for NRTI and protease-inhibitor resistance is low. Funding Paediatric European Network for Treatment of AIDS (PENTA) and Pediatric AIDS Clinical Trials Group (PACTG/IMPAACT).

The rights and well-being of children involved in clinical research in Europe should be assured by the respect of ethical considerations and legal rules. Specific provisions are included in the Directive 2001/20/EC (CT-Dir) aimed at providing a homogeneous ethical and legal context to perform clinical trials in Europe. The TEDDY Network of Excellence carried out a “Survey on the ethical and legal frameworks existing in Europe for paediatric clinical trials” to examine the measures enforced by Member States to implement the CT-Dir and other relevant ethical norms. The results showed that many differences exist in the protection of children enrolled in clinical trials. Such differences are especially due to a non-coordinated implementation of the Directive’s Article 4 and a lack of public awareness on ethical issues in this field. The recently approved ‘Ethical considerations for clinical trials on medicinal products conducted with the paediatric population’ should speed up the implementation of an ‘ad hoc set of ethical rules’ and increase the level of minors’ protection. Nevertheless, in lack of ‘binding rules’, a coordination at European level is still needed. Public initiatives aiming at promoting in-depth debates have to be supported in order to encourage this process of coordination.

OBJECTIVES: Efavirenz and nevirapine failure is associated with a rapid selection of resistance-associated mutations (RAMs), which may impact on etravirine or rilpivirine susceptibility. However, RAMs for rilpivirine and etravirine cannot be reported on previous resistance genotypes because these specific RAMs were not analyzed at that time. Therefore, our objective was to determine, in virologically suppressed HIV-1-infected individuals, the presence of RAMs to rilpivirine, etravirine and the combination of tenofovir/emtricitabine/rilpivirine in HIV-1 DNA from individuals previously exposed to efavirenz and/or nevirapine. METHODS: The studied population included 169 treatment-experienced individuals enrolled in the ANRS 138-EASIER trial who previously failed on and/or were intolerant to efavirenz and/or nevirapine and who had plasma HIV-1 RNA

BACKGROUND The end-stage LIVER disease and RALtegravir-Agence Nationale de Recherche sur le Sida et les hepatites (LIVERAL-ANRS) 148 study aimed to evaluate the safety, efficacy, and pharmacokinetic parameters of raltegravir (RAL) in human immunodeficiency virus (HIV)-infected patients with end-stage liver disease (ESLD) (substudy 1) and to assess the lack of pharmacokinetic interaction between RAL and the immunosuppressive regimen introduced after liver transplant (substudy 2). METHODS All patients received 400 mg RAL twice daily plus 2 nucleoside reverse transcriptase inhibitors. Liver function and immunovirological parameters were monitored throughout the study. Serial blood samples were drawn to explore RAL pharmacokinetics. Plasma concentrations of protein unbound, total RAL, and RAL glucuronide were determined by liquid chromatography-tandem mass spectrometry. RESULTS Ten patients with ESLD were analyzed in substudy 1. Despite an increased RAL exposure, RAL was well tolerated in all patients and no patient had to stop RAL therapy because of adverse events. Four patients were analyzed in substudy 2. No pharmacokinetic interaction was observed between cyclosporine, mycophenolic acid, and RAL. RAL tolerability was excellent; there were no episodes of acute rejection or opportunistic infection. HIV-RNA levels remained controlled and CD4 cell counts remained stable in all patients throughout the study. CONCLUSIONS The results of the substudy 1 support RAL administration to patients with ESLD. Substudy 2 assesses the safety, tolerability, and efficacy of RAL therapy in HIV-infected patients after liver transplant. RAL might be recommended as a suitable antiretroviral therapy in HIV-infected patients undergoing liver transplant.

SummaryTo determine whether viral load rebounds during HAART impact on CD4+ T cell recovery and immune reconstitution, we studied a prospective cohort of 355 antiretroviral naive patients enrolled to be randomized in a trial of three strategies of induction/maintenance HAART. The extent of immune reconstitution in blood through 72 weeks of antiretroviral treatment was evaluated. Lymphocyte subset markers (CD4, CD8, CD45RA, CD62L, CD16, CD19), activation markers (HLA-DR, CD38, CD25) were performed by cytometry analysis. Our results showed that plasma HIV-1 RNA was suppressed to below 500 copies per ml through week 72 in 240 patients (group 1) while the remaining 115 patients experienced at least one viral rebound (group 2). At baseline, CD4 cell count was higher and HIV-1 RNA was lower in group 1 than in group 2. Over 72 weeks, mean increase in CD4+ T cell count was 0·32 cell/mm3/day in group 1 and only 0·14 cell/mm3/day in group 2 (P

Interleukin-2 (IL-2) therapy increased CD4 cell counts and delayed antiretroviral therapy (ART) initiation in HIV-infected patients in the Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS) 119 trial. However, four cases of lymphoma were reported. Epstein-Barr virus (EBV) replication is associated with an increased risk of lymphoma in immunocompromised patients. We assessed whether IL-2 had an impact on EBV replication and the development of lymphoma.A total of 130 ART-naïve patients were randomized to receive IL-2 therapy (n = 66) or no treatment (n = 64). Clinical data for patients with lymphomas were reviewed and tumours assessed for evidence of EBV infection and CD25 (the IL-2 receptor) expression. EBV DNA levels were measured in whole blood and plasma in both arms using real-time polymerase chain reaction (PCR), up to 48 weeks after baseline (BL).Four lymphomas occurred, a median of 61 weeks [range 40-94 weeks] after randomization at a median CD4 cell count of 396 cells/μL (IQR 234-536 cells/μL). In the IL-2 arm, two patients developed EBV-positive Hodgkin's lymphoma, and one developed EBV-negative Burkitt-type lymphoma. One patient in the control group developed EBV-positive non-Hodgkin's lymphoma. CD25 was negative in all cases. Among the 41 of 55 (control arm) and 44 of 58 (IL-2 arm) patients with detectable EBV DNA in whole blood at both BL and week 48, the median change in EBV DNA between BL and week 48 was +0.04 log10 copies/ml in both arms (P = 0.7). In plasma, EBV was detected at least once in 22 of 52 controls and 21 of 54 IL-2-treated patients (P = 0.8).IL-2 therapy had no significant effect on EBV replication over 48 weeks in these ART-naïve patients. The occurrence of lymphomas did not seem to be associated with IL-2 therapy.

Introduction Treatment options for children with HIV-1 are limited. We aimed to compare activity and safety of three dualnucleoside analogue reverse-transcriptase inhibitor (NRTI) regimens with or without a protease inhibitor in previously untreated children with HIV-1. Methods In our multicentre trial, we randomly assigned 36 children to zidovudine and lamivudine, 45 to zidovudine and abacavir, and 47 to lamivudine and abacavir. Children who were symptomfree (n=55) were also randomly assigned to receive nelfinavir or placebo. Children with more advanced disease received open-label nelfinavir (73). Primary endpoints were change in plasma HIV-1 RNA at 24 and 48 weeks for the NRTI comparison and occurrence of serious adverse events for both randomised comparisons. Analyses were by intention to treat. Findings Children had a median CD4 percentage of 22% (IQR 15–29) and a mean HIV-1 RNA concentration of 5·0 log copies/mL (SD 0·8). One child was lost to follow-up and one died of sepsis. At 48 weeks, in the zidovudine/lamivudine, zidovudine/abacavir, and lamivudine/abacavir groups, mean HIV-1 RNA had decreased by 1·71, 2·19, and 2·63 log copies/mL, respectively (estimated in absence of nelfinavir) (p=0·02 after adjustment for baseline factors). One child had a hypersensitivity reaction to abacavir; and three with possible reactions stopped abacavir. There were 24 serious adverse events—six in the symptom-free children (all on nelfinavir), but none were attributed to nelfinavir. Interpretation Regimens containing abacavir were more effective than zidovudine/lamivudine. Such regimens could be combined with protease inhibitors and non-nucleoside reverse transcriptase inhibitors for safe and effective treatment of previously untreated children with HIV-1.

Objectives Heavily treatment-experienced patients with good virological control could be at risk of virological failure on switching to a new regimen if pre-existing drug resistance is not taken into account. We examined whether genotyping based on cellular HIV-1 DNA during controlled viraemia identifies resistance mutations detected in plasma HIV-1 RNA during treatment with previous antiretroviral regimens. Patients and methods All 169 patients enrolled in the Agence Nationale de Recherche sur le SIDA (ANRS) 138-intEgrase inhibitor MK_0518 to Avoid Subcutaneous Injections of EnfuviRtide (EASIER) trial had already received three antiretroviral drug classes [nucleoside reverse transcriptase inhibitor (NRTI), nonnucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI)] and had plasma HIV-1 RNA

Heavily treatment-experienced patients with good virological control could be at risk of virological failure on switching to a new regimen if pre-existing drug resistance is not taken into account. We examined whether genotyping based on cellular HIV-1 DNA during controlled viraemia identifies resistance mutations detected in plasma HIV-1 RNA during treatment with previous antiretroviral regimens.All 169 patients enrolled in the Agence Nationale de Recherche sur le SIDA (ANRS) 138-intEgrase inhibitor MK_0518 to Avoid Subcutaneous Injections of EnfuviRtide (EASIER) trial had already received three antiretroviral drug classes [nucleoside reverse transcriptase inhibitor (NRTI), nonnucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI)] and had plasma HIV-1 RNA400 copies/ml at baseline. The results of previous resistance genotyping of plasma HIV-1 RNA in individual patients were compared with those of resistance genotyping of whole-blood HIV-1 DNA at randomization.A median of 4 plasma RNA genotypes were available for the 169 patients. The median numbers of resistance mutations in HIV-1 RNA and DNA were, respectively, 5 and 4 for NRTIs, 2 and 1 for NNRTIs, and 10 and 8 for PIs. The difference was significant for all three drug classes (P=0.001). Resistance to at least one antiretroviral drug was detected exclusively in HIV-1 RNA or in DNA in 63% and 13% of patients for NRTI, 47% and 1% of patients for NNRTI, and 50% and 7% of patients for PI, respectively.This study shows that, among highly treatment-experienced patients on effective highly active antiretroviral therapy, resistance genotyping of HIV-1 DNA detects fewer resistance mutations than previous analyses of HIV-1 RNA. These results have implications for patient management and for the design of switch studies.

The aim of the study was to evaluate the predictive value of clinical and molecular risk factors, including peripheral blood mononuclear cell (PBMC) mitochondrial DNA (mtDNA) and mitochondrial RNA (mtRNA), for the development of lactic acidosis (LA) and symptomatic hyperlactataemia (SHL).In a substudy of a large multicentre, randomized trial of three antiretroviral regimens, all containing didanosine (ddI) and stavudine (d4T), in antiretroviralnaïve, HIV-1-infected patients, patients with LA/SHL ('cases') were compared with those without LA/SHL in a univariate analysis, with significant parameters analysed in a multivariate model. In a molecular substudy, PBMC mtDNA and mtRNA from cases and matched controls at baseline and time of event were examined.In 911 subjects followed for a median of 192 weeks, 24 cases were identified (14 SHL and 10 LA). In univariate analysis, cases were more likely to be female (P=0.05) and to have a high body mass index (BMI) (P=0.02). In multivariate analyses, only BMI remained an independent predictor of the development of LA/SHL (P=0.03). Between cases and controls there was no significant difference in mtDNA copy number at baseline (389 vs. 411 copies/cell, respectively; P=0.60) or at time of event (329 vs. 474 copies/cell, respectively; P=0.21), in the change in mtDNA copy number from baseline to event (-65 vs. +113 copies/cell, respectively; P=0.12), in mtRNA expression at baseline or time of event, or in the change in mtRNA expression from baseline to event.The development of LA/SHL was associated with increased BMI, but PBMC mtDNA and mtRNA did not predict LA/SHL. This demonstrates the ineffectiveness of routine measurement of PBMC mtDNA in patients on ddI and d4T as a means of predicting development of LA/SHL.

ANRS 127 was a randomized pilot trial involving naïve patients receiving two dual-boosted protease inhibitor (PI) combinations. Virological response, defined as a plasma HIV RNA level of gag,gag-pol, and thegag-polframeshift region. The wholegaggene and protease-coding region were amplified and sequenced at baseline and at week 16 for 48 patients still on the allocated regimen at week 16. No major PI resistance-associated mutations were detected either at baseline or in the 26 patients who did not achieve virological response at week 16. Baseline cleavage site substitutions in the product of thegagopen reading frame at positions 128 (p17/p24) (P= 0.04) and 449 (p1/p6gag) (P= 0.01) were significantly more frequent in those patients not achieving virological response. Conversely, baseline cleavage site mutation at position 437 (TFP/p6pol) was associated with virological response (P= 0.04). In multivariate analysis adjusted for baseline viral load, these 3 substitutions remained independently associated with virological response. We demonstrated here,in vivo, an impact of baseline polymorphicgagmutations on virological response in naïve patients receiving a combination of two protease inhibitors. However, it was not possible to link the substitutions selected under PI selective pressure with virological failure.

Comparative judgement, which is seminal to any kind of science performing measurements, has been applied to clinical reasoning for many centuries. The need for systematizing the observational methods used in medicine in order to draw more reliable inferences about the effects of therapies has been active all along the 19th century. This has resulted in controlled studies which yielded important advances in clinical and therapeutic knowledge, although their designs were not fully satisfactory. Clinical trials have gained their status of "hard science", methodology allowing causal inference, by the end of the 1940s after having adopted the statistical theories developed in the 1930s by Fisher for experimental design in agronomy. A long way has been run since the first controlled randomized trial. However, half a century later, modern clinical trial remains essentially a controlled randomized prospective study using methods to limit potential biases and to establish statistical significance.

In the Trilège trial, following induction with a zidovudine, lamivudine, and indinavir regimen, human immunodeficiency virus (HIV) replication was less suppressed by 2-drug maintenance therapy than by triple-drug therapy.To identify mechanisms of virologic failure in the 3 arms of the Trilège trial.Case-control study conducted from February to October 1998.Three urban hospitals in Paris, France.Fifty-eight case patients with virologic failure (HIV RNA rebound to500 copies/mL in 2 consecutive samples) randomized to 3 therapy groups: triple drug (zidovudine, lamivudine, and indinavir), 8; zidovudine-lamivudine, 29; and zidovudine-indinavir, 21; the case patients were randomly matched with 58 control patients with sustained viral suppression.At virologic failure (S1 sample) and 6 weeks later (S2 sample), assessment of protease and reverse transcriptase gene mutations, plasma indinavir level, and degree of viral load rebound; pill count during induction and maintenance periods.Only 1 primary resistance mutation, M184V, was detected in S1 plasma samples from 4 of 6 patients in the triple-drug and in all 22 in the zidovudine-lamivudine therapy groups and in S2 plasma samples from 3 of 6 in the triple-drug and 20 of 21 in the zidovudine-lamivudine groups. Of controls, M184V was detected in 11 of 13 S1 plasma samples and in 10 of 11 S2 plasma samples. Indinavir levels were undetectable in all S1 samples but 2 in 7 triple-drug cases tested and in the expected range in 11 of 18 S1 and 5 of 12 S2 zidovudine-indinavir case plasma samples tested. Maintenance adherence rates were lower for cases vs controls for zidovudine (P = .05) and indinavir (P = .05). Low indinavir levels, lower adherence rates for zidovudine (P = .04) and lamivudine (P = .03), and rebound to near-baseline values suggested adherence as cause of early failure for 4 of 8 triple-drug cases. In the zidovudine-lamivudine arm, for which case and control adherence rates did not differ significantly (P = .96), most failures occurred late with low rebound, suggesting suboptimal drug potency. In the zidovudine-indinavir arm, virologic failures may be related to both mechanisms.During the maintenance phase early and late virologic failures appeared to be related more to problems of adherence and antiretroviral treatment potency, respectively, than to selection of resistant mutant viruses.

Intermittent interleukin-2 therapy for HIV-1 by continuous intravenous infusion leads to sustained increase of CD4 T cells. This method of administration is, however, inconvenient and has limiting toxic effects. We did a randomised study to compare safety and efficacy of antiviral treatment alone or combined with various interleukin-2 regimens in HIV-1-infected patients.94 symptom-free patients, naïve to antiretroviral treatment, with CD4-T-cell counts of 250-550 cells/microL at baseline were randomly assigned zidovudine and didanosine alone (n=26) or combined with interleukin-2 administered intravenously (12 million IU/day, n=22) or subcutaneously (3 million IU/m2 twice daily, n=24) for 5 days, or were given polyethylene-glycol-modified (PEG) interleukin-2 (2 million IU/m2 intravenous bolus, n=22) administered every 2 months from week 2 to week 50 (seven cycles). Safety and immunological and virological results were monitored until week 56.CD4-T-cell count increased to higher than baseline by a mean of 564 cells/microL (subcutaneous group), 676 cells/microL (intravenous group), 105 cells/microL (PEG group), and 55 cells/microL (antiretroviral-therapy group, p=0.0001). 68% and 77% of patients in the subcutaneous and intravenous groups, respectively, achieved an 80% increase of CD4 T cells (p0.001). In these two groups, 50% of patients restored a CD4/CD8-T-cell ratio of more than 1. The groups did not differ significantly for changes in plasma HIV-1 RNA loads throughout the study. The duration of common side-effects of interleukin-2 was shorter in the subcutaneous group, which enabled outpatient treatment. Naïve and memory CD4 T cells, CD28 expression on CD4 and CD8 T cells, and restoration of in-vitro proliferative response to mitogens and recall antigens increased in the intravenous and subcutaneous groups.Subcutaneous interleukin-2 is a convenient regimen that, as well as intravenous therapy, improves immunological function in HIV-1-infected patients receiving two nucleosides. Larger studies are needed to show whether immunological improvements translate into clinical benefit.

To define the factors associated with diagnosis of toxoplasmic encephalitis (TE) in AIDS patients; and to establish a rational procedure for the clinician faced with a decision concerning empiric antitoxoplasma therapy.A 15-month prospective multicentre cohort study in France.One hundred and eighty-six consecutive HIV-positive inpatients undergoing empiric antitoxoplasma therapy for a first episode of presumed TE were monitored. The clinician's initial estimation of the probability of response to antitoxoplasma therapy was recorded. In addition, a validation committee classified cases as TE or non-TE.Among the 186 patients, the following variables were significantly more frequent in TE (n = 113) than non-TE (n = 73) patients: fever (59% versus 40%). headache (55% versus 33%), seizures (22% versus 11%), suggestive lesions on the brain scan (98% versus 76%), positive Toxoplasma serology (97% versus 71%). Median CD4+ lymphocyte count was significantly higher in TE than in non-TE (27 x 10(6)/l versus 11 x 10(6)/l). The rate of TE in patients on systemic antiprotozoal prophylaxis at entry was 43% as compared with 75% in patients without previous prophylaxis. Pre-therapy estimation of response to empiric therapy was highly correlated with final diagnosis. Multivariate logistic regression analysis showed that the following variables contributed independently to the diagnosis of TE: clinician's estimation of response to treatment at entry75%; absence of systemic antiprotozoal prophylaxis; seizures; headache; suggestive lesions on CT or MRI brain scan; and positive Toxoplasma serology.A linear logistic model is proposed which uses significant variables, which are readily available. This model gives good accuracy to classify suspected cases of TE.

A randomized, unblinded study compared aerosolized pentamidine, 300 mg every month, and dapsone, 50 mg/day, for secondary prophylaxis of pneumocystosis in 196 AIDS patients. The study was prematurely discontinued due to excess mortality in the dapsone group. After a mean follow-up of 13 +/- 6.4 months, 22 (21%) of 103 patients in the pentamidine group were dead compared with 39 (42%) of 93 receiving dapsone; the estimated mortality rates at 18 months were 24.6% and 53.1%, respectively (P < .003, log-rank test). A negative interaction was observed between zidovudine and dapsone (P < .049, interaction test of Cox model), and the mean CD4 cell count during the study was lower in the dapsone (49 +/- 61/mm3) than in the pentamidine group (83 +/- 88/mm3; P < .002, t test). The lower survival might also be related to the oxidative effect of dapsone or to the addition of iron protoxalate to dapsone in this study. These results suggest caution in using dapsone as long-term therapy in advanced human immunodeficiency virus infection, especially in those receiving zidovudine.

Antiretroviral drugs already registered or currently in clinical trials are shortly described, including dideoxynucleosides, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, tat inhibitors and antisens molecules. In a second part, the treatment of patients with the nucleosides already on the market or in a pre-registration phase is reviewed, on the basis of an analysis of available phase III clinical trials. The third part describes the strategy of clinical trials and explains why "surrogate markers" including markers of viral replication cannot yet be the main criteria to evaluate the efficacy of a new drug in a phase III trial.

Introduction Chez des patients (pts) ayant ete en multi-echec, un traitement optimise comprenant l’ENF permet un bon controle virologique, mais il est difficile de prolonger ce traitement administre par voie sous-cutanee. Methodes 170 pts infectes par le VIH-1, avec un ARN VIH-1 Resultats Les pts etaient âges de 47,9 annees en mediane, 85 % etaient des hommes, 52 % au stade C du CDC, traites depuis 13.6 annees et par ENF depuis 2,3 annees en mediane ; la mediane des CD4 a l’inclusion et au nadir etait respectivement de 393/mm 3 et 50/mm 3 . En ITT, 1/85 (1,2 %) pts du bras MT et 1/84 (1,2 %) pts du bras SB ont presente un echec virologique entre S0 et S24 (difference 0,01 % ; IC95 % : − 6,7 ; + 6,8, p En analyse per protocole, 0/82 (0 %) pts du bras MT et 1/82 (1,2 %) pts du bras SB ont presente un echec virologique (difference 1,22 % ; CI95 % : − 5,6 ; + 8,1, p A S24, 88 % et 89 % des pts du bras MT et SB respectivement avaient une charge virale p = 0,31). La frequence des evenements biologiques de grade 3 et 4 etait de 7 % et 14 % dans le bras MT et SB respectivement ( p = 0,13). Conclusion Chez des pts ayant ete en multi-echec et controles par un traitement comprenant ENF, la substitution de l’ENF par le RAL est virologiquement non inferieure a la poursuite de l’ENF, avec une tolerance satisfaisante.

Les auteurs etudient, en conditions controlees, l’influence de la temperature sur les modalites (frequence, intensites, localisations) du parasitisme par Leishmania infantum Nicolle, 1908 (souche canine cevenole) chez l’un de ses vecteurs habituels, Phlebotomus ariasi Tonnoir, 1921. Une experimentation preliminaire permet de selectionner quatre paliers thermiques distants chacun de 5° C : 10°, 15°, 20°, 25° C. Les paliers immediatement superieurs (30° C) et inferieurs (5° C) sont lethaux pour l’hote ou le parasite. L’echec de l’elevage de masse oblige a utiliser les imagos ♀ preleves directement sur le terrain : les captures realisees a l’aspirateur-nasse sont placees le soir meme dans une moustiquaire a maille fine, en contact avec un chien leishmanien a fort pouvoir infestant. Les individus gorges sont retires le lendemain, places en tube individuel et repartis dans une serie d’enceintes a temperature constante (± 1,5° C). L’examen du tube digestif est realise entre le 6e et le 10e jour, periode durant laquelle, pour chaque niveau thermique, aucune modification de la frequence des Phlebotomes infestes n’est observee. En fin d’experience, l’analyse des donnees (test du χ2 ) montre que l’augmentation de la temperature ::1 —majore, de facon significative, la frequence globale des Phlebotomes infestes ;2 —accelere la multiplication des promastigotes dans l’intestin moyen ;3 —determine leur passage dans le segment thoracique (a partir de 15° C) ;4 —favorise l’amarrage des flagelles a la paroi des cellules intestinales retrosphincteriennes (a partir de 20° C).L’utilisation d’un modele exponentiel pour deduire la taille de la population parasitee aux diverses temperatures utilisees permet de situer l’optimum thermique de L. infantum aux environs de 25° C. Ces resultats expliquent, pro parte , la discrete dissociation altitudinale observee en Cevennes entre la leishmaniose viscerale qui plafonne a 600 m et le vecteur qui peut depasser 1 000 m.

A double blind controlled clinical trial was undertaken to test the effectiveness of oral hypoglycaemic drugs in improving blood glucose and plasma insulin levels of borderline diabetic patients. Between 1969 and 1971, 120 men aged 25 to 55 with borderline impairment of glucose tolerance according to standard criteria at 2 successive oral glucose tolerance tests entered the study. They were randomized into 4 groups according to treatment: dimethylbiguanide + glibenclamide (n=29), placebo B + glibenclamide (n=28), placebo S + dimethylbiguanide (n=30), placebo B + S (n= 33). In each group drugs were taken twice a day before breakfast and lunch at a total dosage of 1.7 g/ day dimethylbiguanide and/or 4 mg/day glibenclamide. Treatment was stopped after 2 years. Patients returned 2 months after entry into the trial, then every 4 months for 2 years. Treatment was continued up to each oral glucose tolerance test except before the last test (drugs stopped 15 days before). 29 patients weighed 20% or more over their ideal body weight and 23 between 10% and 20%. After a dietary survey, these men were subjected to a total colorie restricted diet according to their excess weight. Results indicate that during the 2 years of treatment, no significant lasting effect of the biguanide on blood glucose and plasma insulin levels was detectable. During the oral glucose tolerance test at 14 months in the groups receiving sulphonylurea a significant decrease of blood glucose levels was observed at 0, 180 and 240 min. Glibenclamide had no effect on weight reduction while biguanide administration was accompanied by a significant weight reduction.

Les auteurs etudient l’infestation d’une population naturelle de Phlebotomus ariasi en introduisant, dans une localite des Cevennes riche en Phlebotomes, un chien leishmanien de pouvoir infestant connu.En fin d’experimentation le taux d’infestation de la population phlebotomienne libre est de 14 % [5,8 %-26,7 %], Ce taux tres eleve demontre les grandes possibilites d’infestation in natura de Phlebotomus ariasi et confirme ipso facto les dangers encourus par les chiens receptifs places au contact de chiens leishmaniens dans les zones de forte densite vectorielle.

The influence of temperature on the life-cycle of Leishmania infantum Nicolle, 1908 (isolated from a dog in the Cévennes) in a known vector (Phlebotomus ariasi Tonnoir, 1921) was studied with special reference to the proportion of flies infected and the intensity and localization of parasites in the sandfly. Wild female sandflies were caught at night by active searches and were put with a heavily infected dog in a mosquito net on the night of capture. On the following morning, engorged females were tubed individually and were then maintained at 10, 15, 20, or 25 degrees C (+/- 1.5 degrees). The temperatures were chosen after preliminary experiments which showed that temperatures of 30 degrees C or less than 5 degrees C were lethal to both the sandfly and, usually, the parasite. Midguts of the flies were dissected and examined 6 to 10 days after the infective feed. Although there were no obvious differences in the proportions of infected sandflies at different temperatures, a statistical analysis of the finding (chi 2 test) showed that raising the temperature: significantly increased the overall proportion of infected sandflies; speeded up the multiplication of promastigotes in the midgut; controlled the movement of parasites forwards into the thoracic midgut (from 15 degrees C); encouraged the attachment of the flagellates to the wall of the stomodaeal valve (from 20 degrees C). The use of an exponential model to deduce the size of the parasite population at the different temperatures led to the conclusion that the optimum temperature for L. infantum is in the region of 25 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Summary Background Data for on-demand pre-exposure prophylaxis (PrEP) are scarce. We implemented a cohort study to assess its efficacy, safety, and effect on sexual behaviour. Methods We invited men and transgender women who have sex with men, previously enrolled in the randomised placebo-controlled ANRS IPERGAY trial at seven sites (six in France and one in Canada), to participate in an open-label extension with on-demand tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg) to be taken before and after sexual intercourse. We assessed the incidence of HIV and other sexually transmitted infections (STIs), PrEP adherence, safety, and sexual behaviour. Statistical analyses included comparisons of proportions and incidence between the randomised phase of the ANRS IPERGAY trial and the open-label phase, and all participants were included in safety analyses. ANRS IPERGAY is registered with ClinicalTrials.gov, number NCT01473472. Findings Between Nov 4, 2014, and Jan 27, 2015, we enrolled 361 participants. Median follow-up was 18·4 months (IQR 17·7–19·1). One participant who discontinued PrEP acquired HIV infection. HIV incidence was 0·19 per 100 person-years (95% CI 0·01–1·08), compared with 6·60 per 100 person-years (3·60–11·05) in the placebo group of the randomised study, indicating a relative reduction of 97% (95% CI 81–100) in the incidence of HIV with on-demand PrEP. Participants used a median of 18 pills of study drugs per month (IQR 11–25), and at the 6 month visit 240 (71%) of 336 participants had tenofovir detected in plasma. Drug-related gastrointestinal events were reported in 49 participants (14%) but were self-limited. Only four participants (1%) discontinued PrEP, three because of an increase in plasma creatinine. The proportion of participants reporting condomless sex at their last receptive anal intercourse significantly increased from 77% (136 of 176 participants) at baseline to 86% (66 of 77 participants) at 18 months' follow-up (p for trend=0·0004). The incidence of a first bacterial STI during this open-label phase did not change significantly compared with the randomised phase (59·0 vs 49·1 per 100 person-years, respectively; p=0·11). Interpretation On-demand oral PrEP is highly effective at preventing HIV infection among high-risk men who have sex with men and therefore represents an alternative to daily PrEP, expanding choices for HIV prevention. High rates of STIs resulting from low condom use did not undermine PrEP efficacy, but warrant frequent testing. Funding ANRS (France Recherche Nord and Sud Sida-HIV Hepatites), the Canadian HIV Trials Network, Fonds Pierre Berge—Sidaction, Gilead Sciences, and the Bill & Melinda Gates Foundation.

International audience; Pre-Exposure Prophylaxis (PrEP) is changing the landscape of HIV prevention, and may bring changes in sexual behaviors. The double-blind phase (DBP) and open-label extension (OLE) study of the ANRS-IPERGAY trial allowed us to assess changes in sexual behavior of men who have sex with men (MSM) taking sexual activity-based (i.e., on-demand) PrEP. Generalized Estimating Equation (GEE) models found a significant decrease in the number of sexual partners (Coefficient [CI95%], p value; - 0.37[- 0.70 to - 0.04], p = 0.03) between the DBP and OLE as well as in the number of sexual relations (- 0.25 [- 0.49 to 0.00], 0.04). GEE estimates also showed that respondents' most recent sexual relation was less likely to have been with an unknown casual partner during the OLE than during the DBP (Odds Ratio [CI95%], p value: 0.75[0.62-0.92], 0.005). Furthermore, they showed an increase in the proportion of condomless anal sex in the OLE (1.32[1.04-1.67], 0.02), a decrease in the proportion of 'suboptimal PrEP adherence' over time (0.75[0.58-0.97], p = 0.03), a decrease in PrEP only use (0.73[0.55-0.96], 0.03) and in both PrEP and condom use over time (0.70[0.51-0.95], 0.02) and finally, a decrease in alcohol consumption between the DBP and OLE (0.74[0.61-0.90], 0.002). We observed both protective and risky behaviors in terms of HIV and STI risk after on-demand PrEP uptake in the OLE phase. Our findings are consistent with results from previous PrEP trials.