François Raffi

N-acetyl-β-D-glucosaminidase (NAG) isoenzymes release from human monocyte-derived macrophages in response to zymosan and human recombinant interferon-γ

Abstract Secretion of N -acetyl- β -D-glucosaminidase (NAG) isoenzymes by human blood monocyte-derived macrophages in response to zymosan and human recombinant interferon-γ was studied. Macrophages were found to release NAG in response to zymosan, but interferon-γ has no effect on secretion. Isoenzyme separation by isoelectric focusing demonstrates that non stimulated and zymosan or interferon-γ treated macrophages release predominantly NAG B and, to a lesser extent, NAG A isoenzymes. In all these conditions, the intracellular intermediate form NAG I could not be detected in the media. Thus, activated macrophages may not be the source of NAG intermediate forms I and P in pathological or maternal serum. In contrast, macrophages could contribute to a significant elevation of urinary activity and NAG B excretion in response to inflammatory conditions.

Long-term Immune Response to Hepatitis B Virus Vaccination Regimens in Adults With Human Immunodeficiency Virus 1: Secondary Analysis of a Randomized Clinical Trial

IMPORTANCE Data on long-term immune responses to hepatitis B virus (HBV) vaccination in adults with human immunodeficiency virus 1 (HIV-1) infection are scarce. OBJECTIVE To compare long-term (up to month 42) immune responses to the standard HBV vaccination regimen with a 4-injection intramuscular double-dose regimen and a 4-injection intradermal low-dose regimen. DESIGN, SETTING, AND PARTICIPANTS The phase 3, open-label, multicenter parallel-group (1:1:1 allocation ratio) randomized clinical trial was conducted from June 28, 2007, to October 23, 2008, at 33 centers in France. Participants included 437 HBV-seronegative adults with HIV-1 and CD4 cell counts of more than 200/μL. Follow-up was extended to September 12, 2012, and data were assessed from February 13, 2015, to January 22, 2016. The analysis was imputed for an intention-to-treat population. INTERVENTIONS Patients were randomly assigned to receive 3 intramuscular standard-dose (20-μg) injections of recombinant HBV vaccine at weeks 0, 4, and 24 (IM20 × 3 group) (145 participants), 4 intramuscular double-dose (40-μg) injections at weeks 0, 4, 8, and 24 (IM40 × 4 group) (148 participants), or 4 intradermal low-dose (4-μg) injections at weeks 0, 4, 8, and 24 (ID4 × 4 group) (144 participants). MAIN OUTCOMES AND MEASURES The previously published primary trial end point was the percentage of responders at week 28, defined as patients with hepatitis B surface antibody (HBsAb) levels of at least 10 mIU/mL among patients who received at least 1 vaccine dose. The secondary trial end points included the percentage of responders at months 18, 30, and 42 and the duration of response from week 28. Multiple imputation was used to address missing measurements during the follow-up. RESULTS Among the 437 patients randomized, 426 received at least 1 dose of vaccine. Of these, 287 were men (67.4%) and they had a mean (SD) age of 42.9 (9.7) years. The percentage of responders at month 42 was 41% (95% CI, 33%-49%) in the IM20 × 3 group, 71% (95% CI, 64%-79%) in the IM40 × 4 group (P < .001 vs the IM20 × 3 group), and 44% (95% CI, 35%-53%) in the ID4 × 4 group (P = .64 vs IM20 × 3 group). Fifteen percent of the patients had HBsAb titers of less than 10 mIU/mL at 33.1 months in the IM40 × 4 group, 8.7 months in the IM20 × 3 group, and 6.8 months in the ID4 × 4 group. CONCLUSIONS AND RELEVANCE In this follow-up of a trial of adults with HIV-1 infection, the IM40 × 4 regimen of recombinant HBV vaccine improved long-term immune response compared with the standard regimen. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00480792.

Triple nucleoside reverse transcriptase inhibitor- vs. nonnucleoside reverse transcriptase inhibitor-containing regimens as first-line therapy: efficacy and durability in a prospective cohort of French HIV-infected patients

Based on the short‐term results of the AIDS Clinical Trials Group (ACTG) A5095 trial, zidovudine (ZDV)/lamivudine (3TC)/abacavir (ABC) is no longer recommended as a first‐line antiretroviral regimen. Data on the efficacy of this triple nucleoside reverse transcriptase inhibitor (NRTI) combination compared with the gold‐standard nonnucleoside reverse transcriptase inhibitor (NNRTI) regimen could provide important information.

Host and disease factors are associated with cognitive function in European HIV-infected adults prior to initiation of antiretroviral therapy

Deficits in cognitive function remain prevalent in HIV‐infected individuals. The aim of this European multicentre study was to assess factors associated with cognitive function in antiretroviral therapy (ART)‐naïve HIV‐infected subjects at the time of enrolment in the NEAT 001/Agence Nationale de Recherche sur le SIDA (ANRS) 143 study.

Tenofovir alafenamide plus emtricitabine versus abacavir plus lamivudine for treatment of virologically suppressed HIV-1-infected adults: A randomised, double-blind, active-controlled, non-inferiority phase 3 trial

BACKGROUND Abacavir and tenofovir alafenamide offer reduced bone toxicity compared with tenofovir disoproxil fumarate. We aimed to compare safety and efficacy of tenofovir alafenamide plus emtricitabine with that of abacavir plus lamivudine. METHODS In this randomised, double-blind, active-controlled, non-inferiority phase 3 trial, HIV-1-positive adults (≥18 years) were screened at 79 sites in 11 countries in North America and Europe. Eligible participants were virologically suppressed (HIV-1 RNA <50 copies per mL) and on a stable three-drug regimen containing abacavir plus lamivudine. Participants were randomly assigned (1:1) by a computer-generated allocation sequence (block size 4) to switch to fixed-dose tablets of tenofovir alafenamide (10 mg or 25 mg) plus emtricitabine (200 mg) or remain on abacavir (600 mg) plus lamivudine (300 mg), with matching placebo, while continuing to take the third drug. Randomisation was stratified by the third drug (boosted protease inhibitor vs other drug) at screening. Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to treatment group. The primary endpoint was the proportion of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 48 (assessed by snapshot algorithm), with a 10% non-inferiority margin. We analysed the primary endpoint in participants enrolled before May 23, 2016 (when target sample size was reached), and we analysed safety in all enrolled participants who received at least one dose of study drug (including patients enrolled after these dates). This study was registered with ClinicalTrials.gov, number NCT02469246. FINDINGS Study enrolment began on June 29, 2015, and the cutoff enrolment date for the week 48 primary endpoint analysis was May 23, 2016. 501 participants were randomly assigned and treated. At week 48, virological suppression was maintained in 227 (90%) of 253 participants receiving tenofovir alafenamide plus emtricitabine compared with 230 (93%) of 248 receiving abacavir plus lamivudine (difference -3·0%, 95% CI -8·2 to 2·0), showing non-inferiority. Few participants discontinued treatment because of adverse events: 12 (4%) of 280 participants in the tenofovir alafenimide plus emtricitabine group and nine (3%) of 276 in the abacavir plus lamivudine group. Three participants had serious, treatment-related adverse events: one each with renal colic and neutropenia in the tenofovir alafenamide plus emtricitabine group, and one myocardial infarction in the abacavir plus lamivudine group. There were no treatment-related deaths. INTERPRETATION Tenofovir alafenamide, in combination with emtricitabine and various third drugs, maintained high efficacy with a renal and bone safety profile similar to that of abacavir. In virologically suppressed patients, a regimen containing tenofovir alafenamide could be an alternative to those containing abacavir, without concern for new onset of renal or bone toxicities or hyperlipidaemia. FUNDING Gilead Sciences Inc.

Hepatitis C virus incidence in HIV-infected and in preexposure prophylaxis (PrEP)-using men having sex with men

HCV incidence still appears on the rise in HIV‐infected MSM in France. We assessed the incidence of HCV infection in HIV‐positive and in preexposure prophylaxis (PrEP)‐using MSM.

Low-dose ritonavir-boosted darunavir in virologically suppressed HIV-1-infected adults: an open-label trial (ANRS 165 Darulight)

Objectives To assess whether low-dose ritonavir-boosted darunavir (darunavir/r) in combination with two NRTIs could maintain virological suppression in patients on a standard regimen of darunavir/r + two NRTIs. Design A multicentre, Phase II, non-comparative, single-arm, open-label study. Setting Tertiary care hospitals in France. Subjects One hundred HIV-1-infected adults with no darunavir or NRTI resistance-associated mutations (RAMs) and a plasma HIV RNA level ≤50 copies/mL for ≥12 months on once-daily darunavir/r (800/100 mg) + two NRTIs for ≥6 months were switched to darunavir/r 400/100 mg with the same NRTIs. Primary outcome measure Proportion of patients with treatment success: plasma HIV RNA level ≤50  copies/mL up to 48 weeks without any change in the study regimen, in a modified ITT (mITT) analysis. Results At baseline, most patients were male (78%), with a median age of 43 years, median duration of HIV RNA ≤50 copies/mL of 35 months and median CD4 T cell count of 633 cells/mm3. Seventy-six percent received tenofovir/emtricitabine and 24% abacavir/lamivudine. Five patients were excluded from the mITT analysis. The rate of treatment success through to week 48 was 91.6% (87/95; 95% CI 84.1%-96.3%). No RAM was detected in three amplifiable genotypes. A total of 212 adverse events (AEs) occurred in 64 patients (64%); 9 AEs were serious, none leading to treatment discontinuation. Conclusions In HIV-infected patients well suppressed with darunavir/r (800/100 mg) and two NRTIs, a reduction of the darunavir dose to 400 mg/day maintained virological efficacy and was safe over 48 weeks.

Patient profiles as organizing HIV clinicians’ ART adherence management: a qualitative analysis

ABSTRACT The effectiveness of antiretroviral therapy (ART) depends on optimal clinical management and patient adherence. Little is known about patient characteristics that clinicians consider in the management of ART adherence. Exploring this issue, five focus groups were conducted with 31 HIV-clinicians from across France. A qualitative typological analysis suggests that clinician management of patient adherence is based on characteristics that coalesce into seven patient profiles. For the “passive” patient, described as taking ART exactly as prescribed without questioning their doctor’s expertise, a directive and simple management style was preferred. The “misleading” patient is characterized as concerned with social desirability and as reporting no adherence difficulties for fear of displeasing their doctor. If clinical outcomes are suboptimal, the clinicians’ strategy is to remind them of the importance of open patient-clinician communication. The “stoic” patient is described as requesting and adequately taking the most potent ART available. Here, clinicians emphasize assessment of side effects, which the patient may minimize. The “hedonistic” patient’s festive lifestyle and sexual risk-taking are seen as compromising adherence; with them, clinicians stress the patient’s responsibility for their own health and that of their sexual partners. The “obsessive” patient is portrayed as having an irrational fear of ART failure and an inability to distinguish illusory from genuine adherence barriers. With this patient, clinicians seek to identify the latter. The “overburdened” patient is recognized as coping with life priorities that interfere with adherence and, with them, a forgiving ART is favored. The “underprivileged” patient is presented as having limited education, income and housing. In this case, clinicians seek to improve the patient’s living conditions and access to care. These results shed light on HIV clinicians’ ART adherence management. The value of these profiles for HIV care and patients should be investigated.

Efficacy, safety and patient-reported outcomes of ledipasvir/sofosbuvir in NS3/4A protease inhibitor-experienced individuals with hepatitis C virus genotype 1 and HIV coinfection with and without cirrhosis (ANRS HC31 SOFTRIH study)

Studies evaluating the efficacy and safety of the fixed‐dose combination ledipasvir (LDV)/sofosbuvir (SOF) in patients coinfected with HIV‐1 and hepatitis C virus (HCV) have mainly included treatment‐naïve patients without cirrhosis. We aimed to evaluate the efficacy and safety of this combination in treatment‐experienced patients with and without cirrhosis.

Impact of baseline plasma HIV-1 RNA and time to virological suppression on virological rebound according to first-line antiretroviral regimen

Objectives We investigated the risk of virological rebound in HIV-1-infected patients achieving virological suppression on first-line combined ART (cART) according to baseline HIV-1 RNA, time to virological suppression and type of regimen. Patients and methods Subjects were 10 836 adults who initiated first-line cART (two nucleoside or nucleotide reverse transcriptase inhibitors + efavirenz, a ritonavir-boosted protease inhibitor or an integrase inhibitor) from 1 January 2007 to 31 December 2014. Cox proportional hazards models with multiple adjustment and propensity score matching were used to investigate the effect of baseline HIV-1 RNA and time to virological suppression on the occurrence of virological rebound. Results During 411 436 patient-months of follow-up, risk of virological rebound was higher in patients with baseline HIV-1 RNA ≥100 000 copies/mL versus <100 000 copies/mL, in those achieving virological suppression in > 6 months versus <6 months, and lower with efavirenz or integrase inhibitors than with ritonavir-boosted protease inhibitors. Baseline HIV-1 RNA >100 000 copies/mL was associated with virological rebound for ritonavir-boosted protease inhibitors but not for efavirenz or integrase inhibitors. Time to virological suppression >6 months was strongly associated with virological rebound for all regimens. Conclusions In HIV-1-infected patients starting cART, risk of virological rebound was lower with efavirenz or integrase inhibitors than with ritonavir-boosted protease inhibitors. These data, from a very large observational cohort, in addition to the more rapid initial virological suppression obtained with integrase inhibitors, reinforce the positioning of this class as the preferred one for first-line therapy.