Incident Proteinuria differs by HIV Serostatus among Men with Pre-diabetes: The Multicenter AIDS Cohort Study.

BACKGROUND: Pre-diabetes is associated with proteinuria, a risk factor for chronic kidney disease. While people living with HIV (PWH) have a higher risk of proteinuria than people without HIV (PWOH), it is unknown whether incident proteinuria differs by HIV serostatus among pre-diabetic persons. METHODS: Urine protein-to-creatinine ratio (PCR) was measured at semi-annual visits among men in the Multicenter AIDS Cohort Study since April 2006. Men with pre-DM on or after April 2006 and no prevalent proteinuria or use of anti-diabetic medications were included. Pre-diabetes was defined as fasting glucose (FG) of 100-125 mg/dL confirmed within a year by a repeat FG or hemoglobin A1c 5.7-6.4%. Incident proteinuria was defined as PCR > 200 mg/g, confirmed within a year. We used Poisson regression models to determine whether incident proteinuria in participants with pre-diabetes differed by HIV serostatus and, among PWH, whether HIV-specific factors were related to incident proteinuria. RESULTS: Between 2006 and 2019, among 1276 men with pre-diabetes, 128/613 PWH (21%) and 50/663 PWOH (8%) developed proteinuria over a median 10-year follow-up. After multivariable adjustment, the incidence of proteinuria in PWH with pre-diabetes was 3.3 times [95% CI: 2.3-4.8 times] greater than in PWOH (p < 0.01). Among PWH, current CD4 count <500 cells/mm3 (p < 0.01) and current use of protease inhibitors (p = 0.03) were associated with incident proteinuria, while lamivudine and integrase inhibitor use were associated with a lower risk. CONCLUSION: Among men with pre-DM, the risk of incident proteinuria was 3 times higher in PWH. Strategies to preserve renal function are needed in this population.

Striking differences in weight gain after cART initiation depending on early or advanced presentation: results from the ANRS CO4 FHDH cohort.

BACKGROUND: Many studies have reported weight gain in ART-naive people living with HIV (PWH) initiating an integrase strand-transfer inhibitor-based regimen. We studied the impact of early or advanced presentation and that of individual drugs in PWH initiating combined ART (cART) between 2012 and 2018. METHODS: From the French Hospital Database HIV cohort, we assessed factors associated with a weight gain  ≥10%, weight change after cART initiation or BMI increase  ≥5 kg/m2 up to 30 months. The analyses were conducted overall, and among PWH with early (primary infection or CD4 >350/mm3 and viral load  <100 000 copies/mL, without AIDS) and advanced presentation (AIDS or CD4 <200/mm3, not during primary infection). RESULTS: At 30 months, 34.5% (95% CI: 33.5-35.6) of the 12 773 PWH had a weight gain ≥10%, with 20.9% (95% CI: 19.6-22.2) among the 5794 with early presentation and 63.1% (95% CI: 60.9-65.3) among the 3106 with advanced presentation. Weight gain was 2.8 kg (95% CI: 2.0-3.7) for those with early presentation and 9.7 kg (95% CI: 8.4-11.1) for those with advanced presentation. Most weight gain occurred in the first 12 months. Underweight and obese PWH were at significantly higher risk of a BMI increase  ≥5 kg/m2 than normal-weight PWH. Results differed within classes and by outcome. Raltegravir and dolutegravir were consistently associated with greater weight gain than the other third agents. Tenofovir alafenamide was also associated with higher weight gain than tenofovir disoproxil or abacavir. CONCLUSIONS: After initiating cART, PWH with early presentation exhibited a small weight gain, whereas it was large among those with advanced presentation. The choice of ART should account for the risk of weight gain, especially for PWH who present with advanced disease and/or are obese.

Injectable long acting antiretroviral for HIV treatment and prevention: perspectives of potential users.

BACKGROUND: The use of long acting injectable (LAA) antiretroviral drugs may be an alternative option for HIV treatment and prevention. Our study focused on patient perspectives to understand which individuals, among people with HIV (PWH) and pre-exposure prophylaxis (PrEP) users, would constitute the preferential target for such treatments in terms of expectations, tolerability, adherence and quality of life. METHODS: The study consisted in one self-administrated questionnaire. Data collected included lifestyle issues, medical history, perceived benefits and inconveniences of LAA. Groups were compared using Wilcoxon rank tests or Fisher's exact test. RESULTS: In 2018, 100 PWH and 100 PrEP users were enrolled. Overall, 74% of PWH and 89% of PrEP users expressed interest for LAA with a significantly higher rate for PrEP users (p = 0.001). No characteristics were associated with acceptance of LAA in both groups in term of demographics, lifestyle or comorbidities. CONCLUSION: PWH and PrEP users expressed a high level of interest in LAA, since a large majority seems to be in favor of this new approach. Further studies should be conducted to better characterize targeted individuals.

Impact on renal function of daily and on-demand HIV pre-exposure prophylaxis in the ANRS-PREVENIR study.

OBJECTIVES: To assess the impact on the estimated glomerular filtration rate (eGFR) of different tenofovir disoproxil/emtricitabine dosing regimens for HIV pre-exposure prophylaxis (PrEP). PATIENTS AND METHODS: We included in the study individuals with baseline eGFR > 50 mL/min/1.73 m2 who initiated PrEP in the ongoing ANRS-PREVENIR PrEP cohort. We retrospectively classified PrEP users in three groups: 'on-demand' (reported at ≥75% of study visits), 'daily' (≥75% of study visits) or 'switches'. We compared the area under curve (AUC) of the eGFR variation from baseline (ΔeGFR) between groups using analysis of covariance, and assessed factors associated with a negative AUC of ΔeGFR. RESULTS: From May 2017 to October 2020, 1253 PrEP-naïve participants (98% of MSM) were included in the study with a median follow-up of 22 months. 499 (40%), 494 (39%) and 260 (21%) users were in the group daily, on-demand and switches, respectively, for a median number of pills taken per week of 6, 1.7 and 4. The mean AUC of the ΔeGFR was -1.09 mL/min/1.73 m2 in the daily PrEP group, -0.69 mL/min/1.73 m2 in the switches group and +0.18 mL/min/1.73 m2 with on-demand PrEP. In a model adjusted on baseline age and eGFR, the AUC of the ΔeGFR was significantly higher with on-demand PrEP compared to daily PrEP (P = 0.037). Independent factors associated with a negative AUC of ΔeGFR were a daily PrEP regimen, a switches regimen, an age > 40 years and a baseline eGFR≥90 mL/min/1.73 m². CONCLUSIONS: On-demand PrEP dosing had a smaller impact on eGFR evolution than daily PrEP, but the difference was not clinically relevant.

Perspectives of injectable long acting antiretroviral therapies for HIV treatment or prevention: understanding potential users' ambivalences.

Recent clinical trial data showed that injectable long-acting antiretroviral treatment (LA-ART) every four or eight weeks could become an alternative option for HIV treatment or prevention. The purpose of our study was to explore perceptions and potential users' points of views of this new mode of administration through individuals' therapeutic itinerary and their singular history with ART. Between 2018 and 2019, a qualitative study was conducted in two University Hospitals in Paris, France. In-depth interviews were conducted with 15 virologically controlled People Living with HIV (PLWH) and 13 men on pre-exposure prophylaxis (PrEP) for at least six months. Interviews, focused on the daily experience with ART, were recorded, transcribed, and analyzed using thematic content analysis. Collected discourses were organized around three emergent concerns: social, material and experimental. Each of these concerns was perceived as ambivalent, balanced by skepticism and hope. It revealed the complexity of each individual's relationship to their HIV treatment or PrEP, leading to balance the injectable LA-ART popularity reported within clinical trials. This new mode of administration may be a suitable alternative for some PLWH and PrEP users, a "simplification" compared to the oral route. It opens a window for "customizable" ART-treatment according to individuals' lives.

Mesures visant à renforcer l'observance pour les antirétroviraux : perceptions et expérience des PVVIH au Burkina Faso.

INTRODUCTION: Adherence to antiretroviral therapy is a major obstacle to achieving WHO target 3. In West Africa, however, there is a lack of evidence on the most feasible, acceptable and effective adherence reinforcement measures and users' perceptions of these measures. The purpose of this article is to analyze the perceptions of PLHIV (people living with HIV) on ART reinforcement measures in Burkina Faso. METHOD: In Ouagadougou and Bobo-Dioulasso care centers, THILAO Research Project (ANRS 12269) enrolled PLHIV experiencing therapeutic failure on 2nd line antiretroviral treatment, and offered to them adherence reinforcement measures. We conducted a qualitative socio-anthropological study to explore their perceptions. Data were collected through repeated individual interviews with 37 PLHIV. RESULTS: The 31 participants who completed interviews were relatively satisfied with the measures to support adherence. Three measures (pill organizer, weekly phone calls by a member of the team, cellphone alarm reminders) were perceived as simple, effective, discreet, adapted to both illiterate and educated people. Three other measures (home visits, involvement of a member of the family and SMS) were not highly appreciated as they expose to the disclosure of HIV+ status and /or stigmatization. Two measures (support group, frequent visits to the care center) were less selected because considered tedious. CONCLUSION: PLHIV chosed and used the most appropriate adherence measures for their profile / context. The most feasible and acceptable measures identified could be offered to PLHIV at risk of non-compliance in West African ART programs.

[Adherence reinforcement for antiretroviral therapy: PLHIV's perceptions and experience in Burkina Faso]. / Mesures visant à renforcer l'observance pour les antirétroviraux : perceptions et expérience des PVVIH au Burkina Faso.

INTRODUCTION: Adherence to antiretroviral therapy is a major obstacle to achieving WHO target 3. In West Africa, however, there is a lack of evidence on the most feasible, acceptable and effective adherence reinforcement measures and users' perceptions of these measures. The purpose of this article is to analyze the perceptions of PLHIV (people living with HIV) on ART reinforcement measures in Burkina Faso. METHOD: In Ouagadougou and Bobo-Dioulasso care centers, THILAO Research Project (ANRS 12269) enrolled PLHIV experiencing therapeutic failure on 2nd line antiretroviral treatment, and offered to them adherence reinforcement measures. We conducted a qualitative socio-anthropological study to explore their perceptions. Data were collected through repeated individual interviews with 37 PLHIV. RESULTS: The 31 participants who completed interviews were relatively satisfied with the measures to support adherence. Three measures (pill organizer, weekly phone calls by a member of the team, cellphone alarm reminders) were perceived as simple, effective, discreet, adapted to both illiterate and educated people. Three other measures (home visits, involvement of a member of the family and SMS) were not highly appreciated as they expose to the disclosure of HIV+ status and /or stigmatization. Two measures (support group, frequent visits to the care center) were less selected because considered tedious. CONCLUSION: PLHIV chosed and used the most appropriate adherence measures for their profile / context. The most feasible and acceptable measures identified could be offered to PLHIV at risk of non-compliance in West African ART programs.

Secret intake of antiretroviral treatment and HIV-1 viremia in a public routine clinic in Burkina Faso: a surprising relationship.

In sub-Saharan Africa, where people living with HIV are frequently stigmatized, the intake of antiretroviral treatment (ART) remains a critical issue for many patients. Although the secret intake of ART may hinder the adherence to treatment, data on its specific impact on therapeutic effectiveness are lacking. We therefore assessed the association between secret intake of ART (i.e., hidden from family) and HIV-1 viremia among patients treated in a public routine clinic in Burkina Faso. We performed a cross-sectional study from December 2012 to September 2013 among patients on ART at the Day Care Unit in Bobo Dioulasso. Patients were eligible for the study if they were 15 years old or over, infected with HIV-1 or HIV-1 + 2, and on ART for at least six months. HIV-1 viral load was measured using Biocentric or Abbott Real Time assay. Study-specific data were collected by social workers using face-to-face interviews, and medical data using the routine electronic database. The association between secret intake of ART and viral load >300 copies/mL was assessed using a multivariate logistic regression. Of 771 patients (women 81.4%; median age 41 years; median time on ART 51 months), 408 reported secret intake of ART and 363 declared open intake. Compared to the latter, patients who hid their intake were younger, more likely to be women and to be involved in a polygamist or in a non-cohabiting union. Viremia was observed in 4.4% of patients hiding ART intake and 9.4% of those taking it openly. By multivariate analysis, secret intake of ART was significantly associated with a lower risk of viremia (adjusted odds ratio 0.41, 95% confidence interval 0.22-0.76). The unexpected relation between secret intake of ART and viremia found in this study requires further investigations. Quantitative and qualitative studies need to be performed.

Changes in bone turnover markers with HIV seroconversion and ART initiation.

Background: Osteoporosis is common among HIV-infected persons and contributes to risk of fragility fracture. While ART initiation is associated with decreases in bone mineral density and increases in bone turnover, the impact of HIV on bone metabolism is unclear. Methods: We identified men at the Chicago site of the Multicenter AIDS Cohort Study who HIV seroconverted while under observation. Concentrations of 25-OH vitamin D, bone turnover markers [procollagen type 1 N terminal propeptide (P1NP), osteocalcin (OC), C-telopeptide (CTX)] and sclerostin were measured from stored serum obtained at pre-HIV infection, pre-ART and post-ART initiation timepoints. Mixed models, with each biomarker as an outcome, were fitted. Timepoint, age, CD4 count (cells/mm 3 ), HIV-viral suppression, season and an age by timepoint interaction term were considered as fixed effects. Results: Data from 52 participants revealed that median duration between HIV seroconversion and ART initiation was 8.7 years (IQR 3.7-11.6). Median CD4 and plasma HIV-RNA concentrations were 445 (IQR 298.5-689) and 20 184 copies/mL (IQR 6237-64 340), respectively, at the pre-ART timepoint. Multivariate analyses demonstrated pre-HIV infection levels of OC that were higher than pre-ART levels (6.8 versus 5.7 ng/mL, P = 0.04); and pre-ART levels of sclerostin that were higher than post-ART levels (0.033 versus 0.02 ng/mL, P <0.001). No changes in P1NP, CTX and 25-OH vitamin D levels were detected. Conclusions: HIV seroconversion was associated with decreased OC levels while ART initiation was associated with decreases in sclerostin, a negative regulator of bone formation. Our results suggest that both HIV infection and ART have an impact on bone metabolism in white men.

Efficacy and safety of once-daily ritonavir-boosted atazanavir or darunavir in combination with a dual nucleos(t)ide analogue backbone in HIV-1-infected combined ART (cART)-naive patients with severe immunosuppression: a 48 week, non-comparative, randomized, multicentre trial (IMEA 040 DATA trial).

OBJECTIVES: Boosted PIs are commonly prescribed in patients presenting with advanced HIV infection. We assessed the efficacy and tolerability of once-daily ritonavir-boosted atazanavir or darunavir plus two NRTIs in HIV-1-infected ART-naive patients with severe immunosuppression, targeting at least an 85% success rate at week 48. METHODS: This 48 week, open-label, non-comparative, randomized, multicentre trial included ART-naive patients with CD4 cell counts <200 cells/mm(3), with plasma HIV-1 RNA >1000 copies/mL and without genotypic mutations conferring resistance to the study drugs. Patients were randomized (1:1) to receive once-daily atazanavir/ritonavir (300/100 mg) or darunavir/ritonavir (800/100 mg) plus tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine. The primary endpoint was treatment success, defined as plasma HIV-1 RNA ≤50 copies/mL at week 48 and no permanent PI/ritonavir discontinuation. The study was registered with ClinicalTrials.gov (NCT01928407). RESULTS: One hundred and twenty patients were enrolled: 77% were men, 30% were born in Africa and 39% had AIDS. The median baseline CD4 and plasma HIV-RNA values were 69 cells/mm(3) and 5.4 log10 copies/mL. All but four patients received tenofovir disoproxil fumarate/emtricitabine. The week 48 treatment success rate was 66% (95% CI 54%-78%) with atazanavir/ritonavir and 80% (95% CI 68%-89%) with darunavir/ritonavir. The median CD4 cell count increased similarly in the two groups (Δweek 48 to week 0: +194 cells/mm(3)). Adverse events occurred in 23 and 18 patients, respectively. CONCLUSIONS: Despite good adherence, neither study regimen reached the predefined objective, suggesting a need for more potent regimens for patients with advanced HIV infection.

Inaccuracy of haemoglobin A1c among HIV-infected men: effects of CD4 cell count, antiretroviral therapies and haematological parameters.

BACKGROUND: There is limited evidence that among HIV-infected patients haemoglobin A1c (HbA1c) values may not accurately reflect glycaemia. We assessed HbA1c discordance (observed HbA1c - expected HbA1c) and associated factors among HIV-infected participants in the Multicenter AIDS Cohort Study (MACS). METHODS: Fasting glucose (FG) and HbA1c were measured at each semi-annual MACS visit since 1999. All HIV-infected and HIV-uninfected men for whom at least one FG and HbA1c pair measurement was available were evaluated. Univariate median regression determined the association between HbA1c and FG by HIV serostatus. The relationship between HbA1c and FG in HIV-uninfected men was used to determine the expected HbA1c. Generalized estimating equations determined factors associated with the Hb1Ac discordance among HIV-infected men. Clinically significant discordance was defined as observed HbA1c - expected HbA1c ≤-0.5%. RESULTS: Over 13 years, 1500 HIV-uninfected and 1357 HIV-infected men were included, with a median of 11 visits for each participant. At an FG of 125 mg/dL, the median HbA1c among HIV-infected men was 0.21% lower than among HIV-uninfected men and the magnitude of this effect increased with FG >126 mg/dL. Sixty-three percent of HIV-infected men had at least one visit with clinically significant HbA1c discordance, which was independently associated with: low CD4 cell count (<500 cells/mm(3)); a regimen containing a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor or zidovudine; high mean corpuscular volume; and abnormal corpuscular haemoglobin. CONCLUSION: HbA1c underestimates glycaemia in HIV-infected patients and its use in patients with risk factors for HbA1c discordance may lead to under-diagnosis and to under-treatment of established diabetes mellitus.

Care of hepatitis C virus infection in France: modifications in three consecutive surveys between 1995 and 2010.

BACKGROUND & AIMS: To determine the characteristics of hepatitis C (HCV)- infected patients in 2010 and compare this survey with those reported in 1995 and 2001. PATIENTS AND METHODS: Observational multicentre study conducted in 2010 in French internal medicine, infectious diseases and hepatology departments. RESULTS: A total of 1621 HCV infected patients (mean age 50.1 ± 10.7 years; sex ratio M/F 1.8; genotype 1: 55.7%) were included. Of these, 910 (56.1%) were HIV­HCV co-infected, 463 (40.4%) were asymptomatic and 184 (16.1%) had cirrhosis at inclusion in this study. Positive viraemia was found in 1,025 patients (65.5%) at inclusion in this study. A complete pretreatment evaluation including investigation for HCV RNA, genotype determination and liver fibrosis was performed in 96.5, 80.5 and 68.7% of the 1,621 patients respectively. Previous and ongoing HCV treatments were noted in 49.6% and 20.1% of patients respectively. A sustained virological response (SVR) was observed in 271/801 (38.3%) patients, i.e. 44.1% and 30.7% in co-infected and mono-infected patients respectively. Cirrhosis was more frequent in the 2010 than in the 2001 and 1995 surveys (16.1% vs. 10.4% and 7.4% respectively; P < 0.0001). A complete pretreatment evaluation was performed in 57.9% and 50.9% of patients in 2010 and 2001 (P < 0.0001). Liver fibrosis evaluation was more frequent in 2010 than in the 2001 and 1995 surveys (68.7% vs. 62.7% and 28.7%, respectively, P < 0.0001). CONCLUSION: The care of HCV-infected patients has changed significantly in 'real life' through an improvement of pretreatment evaluation before the antiviral introduction and the increased use of antivirals. New HCV therapy combinations including protease inhibitors are warranted to increase the SVR rate.

One-Year Frailty Transitions Among Persons With HIV Aged 70 Years or Older on Antiretroviral Treatment.

Background: People with HIV (PWH) are aging. Frailty is an age-related condition predictive of hospitalization and mortality. Here, we assessed the frequency and factors associated with frailty transitions at 1-year follow-up in elderly PWH. Methods: Five hundred eight PWH aged 70 years or older who were on antiretroviral treatment were included in the French multicenter SEPTAVIH study in 2019-2020. Participants were classified as robust, prefrail, or frail according to Fried frailty phenotype at baseline and at 1 year. Logistic regression models were used to evaluate socioeconomic and medical factors associated with transition between frailty states. Models were adjusted for gender, age at baseline, education, and period of HIV diagnosis (before vs after 1996). Results: Seventeen PWH died during the 1-year follow-up. Of the remaining 491 PWH (median age, 73 years), frailty status worsened for 18% of participants and improved for 14% at 1 year. Advanced age, baseline CD4+ T-cell count <350 cells/mm3, and type 2 diabetes were associated with transition from prefrailty to frailty (adjusted odds ratio [aOR], 1.10 per 1-year positive difference; 95% CI, 1.01-1.20; aOR, 3.05; 95% CI, 1.14-8.18; and aOR, 2.63; 95% CI, 1.05-6.57; respectively). Being female was associated with more frequent improvement from prefrailty to robustness (aOR, 2.50; 95% CI, 1.09-5.55). Conclusions: Preventing frailty in elderly PWH is a long-term problem, beginning with the early diagnosis of HIV infection and the management of comorbidities.

Doxycycline prophylaxis and meningococcal group B vaccine to prevent bacterial sexually transmitted infections in France (ANRS 174 DOXYVAC): a multicentre, open-label, randomised trial with a 2 × 2 factorial design.

BACKGROUND: Increased rates of sexually transmitted infections (STIs) are reported among men who have sex with men (MSM) and new interventions are needed. We aimed to assess whether post-exposure prophylaxis (PEP) with doxycycline could reduce the incidence of chlamydia or syphilis (or both) and whether the meningococcal group B vaccine (4CMenB) could reduce the incidence of gonorrhoea in this population. METHODS: ANRS 174 DOXYVAC is a multicentre, open-label, randomised trial with a 2 × 2 factorial design conducted at ten hospital sites in Paris, France. Eligible participants were MSM aged 18 years or older, HIV negative, had a history of bacterial STIs within the 12 months before enrolment, and who were already included in the ANRS PREVENIR study (a cohort of MSM using pre-exposure prophylaxis with tenofovir and emtricitabine for HIV prevention). Participants were randomly assigned (2:1) to doxycycline PEP (two pills of 100 mg each orally within 72 h after condomless sex, with no more than three doses of 200 mg per week) or no PEP groups and were also randomly assigned (1:1) to the 4CMenB vaccine (GlaxoSmithKline, Paris, France; two intramuscular injections at enrolment and at 2 months) or no vaccine groups, using a computer-generated randomisation list with a permuted fixed block size of four. Follow-up occurred for at least 12 months (with visits every 3 months) up to 24 months. The coprimary outcomes were the risk of a first episode of chlamydia or syphilis (or both) after the enrolment visit at baseline for the doxycycline intervention and the risk of a first episode of gonorrhoea starting at month 3 (ie, 1 month after the second vaccine dose) for the vaccine intervention, analysed in the modified intention-to-treat population (defined as all randomly assigned participants who had at least one follow-up visit). This trial is registered with ClinicalTrials.gov, NCT04597424 (ongoing). FINDINGS: Between Jan 19, 2021, and Sept 19, 2022, 556 participants were randomly assigned. 545 (98%) participants were included in the modified intention-to-treat analysis for the doxycycline PEP and no PEP groups and 544 (98%) were included for the 4CMenB vaccine and no vaccine groups. The median follow-up was 14 months (IQR 9-18). The median age was 40 years (34-48) and all 545 participants were male. There was no interaction between the two interventions (p≥0·1) for the primary outcome. The incidence of a first episode of chlamydia or syphilis (or both) was 8·8 per 100 person-years (35 events in 362 participants) in the doxycycline PEP group and 53·2 per 100 person-years (80 events in 183 participants) in the no PEP group (adjusted hazard ratio [aHR] 0·17 [95% CI 0·12-0·26]; p<0·0001). The incidence of a first episode of gonorrhoea, starting from month 3 was 58·3 per 100 person-years (103 events in 274 participants) in the 4CmenB vaccine group and 77·1 per 100 person-years (122 events in 270 participants) in the no vaccine group (aHR 0·78 [95% CI 0·60-1·01]; p=0·061). There were no deaths during the study. One drug-related serious adverse event (fixed-drug eruption) occurred in the doxycycline PEP group. Six (2%) participants in the doxycycline group discontinued doxycycline PEP because of gastrointestinal adverse events. INTERPRETATION: Doxycycline PEP strongly reduced the incidence of chlamydia and syphilis in MSM, but we did not show efficacy of the 4CmenB vaccine for gonorrhoea. Doxycycline PEP should be assessed in other populations, such as heterosexual men and women, and its effect on antimicrobial resistance carefully monitored. FUNDING: ANRS Maladies Infectieuses Emergentes. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

HIV controllers maintain a population of highly efficient Th1 effector cells in contrast to patients treated in the long term.

HIV controllers are rare individuals who spontaneously control HIV replication in the absence of antiretroviral therapy. To identify parameters of the CD4 response that may contribute to viral control rather than merely reflect a persistently low viremia, we compared the T helper profiles in two groups of patients with more than 10 years of viral suppression: HIV controllers from the Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS) CO18 cohort (n = 26) and efficiently treated patients (n = 16). Cells specific for immunodominant Gag and cytomegalovirus (CMV) peptides were evaluated for the production of 10 cytokines and cytotoxicity markers and were also directly quantified ex vivo by major histocompatibility complex (MHC) class II tetramer staining. HIV controller CD4(+) T cells were characterized by a higher frequency of gamma interferon (IFN-γ) production, perforin(+)/CD107a(+) expression, and polyfunctionality in response to Gag peptides. While interleukin 4 (IL-4), IL-17, and IL-21 production did not differ between groups, the cells of treated patients produced more IL-10 in response to Gag and CMV peptides, pointing to persistent negative immunoregulation after long-term antiretroviral therapy. Gag293 tetramer-positive cells were detected at a high frequency (0.12%) and correlated positively with IFN-γ-producing CD4(+) T cells in the controller group (R = 0.73; P = 0.003). Tetramer-positive cells were fewer in the highly active antiretroviral therapy (HAART) group (0.04%) and did not correlate with IFN-γ production, supporting the notion of a persistent immune dysfunction in HIV-specific CD4(+) T cells of treated patients. In conclusion, HIV controllers maintained a population of highly efficient Th1 effectors directed against Gag in spite of a persistently low antigenemia, while patients treated in the long term showed a loss of CD4 effector functions.

Switching to darunavir/ritonavir 800/100 mg once-daily containing regimen maintains virological control in fully suppressed pre-treated patients infected with HIV-1.

The objective of this study was to evaluate the switch to once-daily darunavir/ritonavir 800/100 mg in treatment-experienced patients with suppressed HIV-1 replication on a twice-daily ritonavir-boosted protease-inhibitor (bid PI/r) containing regimen, that is in a setting where genotypic resistance test cannot be performed. In this open label, non-comparative, multicenter study, patients on a bid PI/r-containing triple combination, with suppressed viral replication, were switched to once-daily darunavir/r 800/100 mg containing triple combination. The primary endpoint was the proportion of patients with plasma HIV-RNA < 50 copies/ml 24 weeks after the switch. Intensive darunavir pharmacokinetic evaluation was performed at Week 4 (W4) in 11 patients. Eighty-five patients were enrolled. All had HIV-RNA < 50 copies/ml at screening with a pre-exposure to a median of 2 PI/r (1-5). By intent-to-treat analysis (missing = failure), 78/85 patients (92%, 95% CI [83;96]) maintained an HIV-RNA < 50 copies/ml at W24. Seven patients experienced protocol-defined treatment failure between baseline and W24: Two had confirmed low-level viral rebound, one discontinued study treatment for adverse event, three withdrew their consent, and one was lost to follow-up. By on-treatment analysis, 78/80 patients (97%, 95% CI [91;99]) maintained an HIV-RNA < 50 copies/ml at W24. Results were similar at Week 48. The median area under the darunavir plasma concentration-time curve measured in 11 patients was 61,380 ng hr/ml; darunavir median trough concentration 1,340 ng/ml and darunavir half-life was 12.2 hr. Tolerability of once-daily darunavir/r 800/100 mg was excellent. Optimally suppressed, treatment-experienced patients can switch safely from a twice-daily PI/r regimen to a once-daily darunavir/r 800/100 mg containing regimen.

Prevalence and risk factors of frailty among adults living with HIV aged 70 years or older.

OBJECTIVES AND DESIGN: Frailty is a phenotype associated with adverse health outcomes in older persons. It has been evaluated mainly in middle-aged persons with HIV (PWH). The French multicenter prospective ANRS EP66 SEPTAVIH study aimed to assess frailty prevalence and risk factors in PWH aged 70 years or older on antiretroviral treatment (ART) for at least 12 months. METHODS: At baseline, Fried frailty phenotype criteria, sociodemographic data, medical/HIV history, functional status, comorbidities, including impaired cognitive function, depression, history of falls, and co-medications were collected. We measured the prevalence of frailty and compared the characteristics of frail versus prefrail and robust participants using univariate (Kruskal-Wallis tests for continuous variables and Chi 2 tests for categorical variables) and multivariate analyses. RESULTS: Five hundred and ten PWH, mostly male (81.4%), were included with a median age of 73 years. The median HIV and ART durations were 22.7 years and 15.7 years, respectively. The prevalence of frailty was 13.5%, and of prefrailty 63.3%. In the multivariate analysis, increasing age [odds ratio (OR) 1.79 for each 5-year increment; 95% confidence interval (CI) 1.32-2.41], deprived socioeconomic status (OR 3.17; 95% CI 1.76-5.70), and multimorbidities (three or more) (OR 2.03; 95% CI 1.06-3.90) were associated with frailty. CONCLUSION: A low prevalence of frailty was reported (13.5%) in PWH aged 70 years or older, whereas two-thirds of them were prefrail. Age, low socioeconomic status, and multimorbidities, but no HIV-related factors, were associated with frailty, suggesting the need to target these factors to help promoting successful aging in this population.

Frailty and prefrailty phenotypes increase the odds of abnormal cognitive impairment screens in people with HIV.

OBJECTIVE: Evaluate whether prefrail and frail people with HIV (PWH) have a higher risk of cognitive impairment on screens. METHODS: Analysis of PWH aged 70 or older included in the ANRS EP66 SEPTAVIH cohort, on antiretroviral therapy for at least 12 months and with a MoCA test at enrolment. Adjusted risk of a Montreal Cognitive Assessment (MoCA) less than 26 was compared in frail/prefrail versus robust PWH. RESULTS: A total of 503 PWH were enrolled with a median age of 73 years, IQR [71-77], 81.5% were male, 73.8% were French natives, 32.9% had low socio-economic status (EPICES score >30.2), and 41.3% were college graduates; 27.3% had a history of clinical AIDS. A total of 294 (58.5%) PWH had a MoCA score less than 26; 182 (36%) a MoCA score 23 or less. Frailty, prefrailty and robustness were found in 13.1, 63.6 and 23.3% participants, respectively. PWH with a MoCA less than 26 had a significantly higher risk of being frail/prefrail, this before [odds ratio (OR) = 2.31; 95% confidence interval (CI) 1.50-3.57], and after adjustment for confounders (OR = 1.80; 95% CI 1.07-3.01). The risk of being frail/prefrail in patients with a MoCA 23 or less was higher (adjusted OR = 2.75; 95% CI 1.46-5.16). Other factors independently associated with a MoCA less than 26 were older age, birth outside of France and a lower education level and being diabetic. CONCLUSION: Abnormal MoCA screens were frequent in our cohort of PWH aged 70 or older with controlled HIV disease. Cognitive impairment should be systematically screened in frail/prefrail PWH. Frailty/prefrailty, diabetes and social factors, but not HIV-related factors, are important determinants of cognitive function in PWH with controlled disease.

Lack of TGF-ß production by hepatitis C virus-specific T cells during HCV acute phase is associated with HCV clearance in HIV coinfection.

BACKGROUND & AIMS: Immunity and genetic factors govern the recovery from acute hepatitis C virus (HCV) infection. No predictive factors have been yet identified in patients coinfected with the human immunodeficiency virus (HIV). We investigated whether early T cell responses to HCV producing transforming-growth-factor beta (TGF-ß) predict the outcome of acute HCV coinfection, independently of the IL-28B gene polymorphism. METHODS: Intracellular cytokine staining assays against HCV-core, E1, NS2, and NS4 overlapping peptides were used for the analysis of peripheral HCV-specific TGF-ß-producing T cells. Patients were genotyped for IL-28B polymorphisms. Healthy donors' samples were tested as controls. Twenty-four acute hepatitis C-HIV+ patients were followed-up for 15 months defining two groups: (A) Recovered (n=16, 5 spontaneous recoveries, 11 sustained virologic response after treatment), (B) Chronic HCV (n=8, 4 spontaneous chronic course, 4 therapeutic failures). RESULTS: During the acute pretreatment phase, core/NS2-specific TGF-ß-producing CD4+ and/or CD8+ T cells were detected in 8/24 (33%) patients. Lack of anti-HCV TGF-ß+ cells was characteristic of healthy donors and Group A, except for 2 cases, with frequencies significantly lower than in Group B (p=0.04 and 0.01), and was associated with recovery in 14/16 cases. Presence of anti-HCV TGF-ß+ cells was associated with persistent viremia in 6/8 cases (p=0.005). This profile remained stable over time. Such TGF-ß production was independent of the rs129679860 SNP (p=1.0) which was not associated with recovery (p=1.0). CONCLUSIONS: During acute hepatitis C, pre-therapeutic HCV-specific TGF-ß-producing T cells are a new marker independent of the IL-28B gene polymorphism, predicting the lack of spontaneous or therapeutic HCV clearance.

Daily and on-demand HIV pre-exposure prophylaxis with emtricitabine and tenofovir disoproxil (ANRS PREVENIR): a prospective observational cohort study.

BACKGROUND: There are few data available regarding the use of on-demand pre-exposure prophylaxis (PrEP) for HIV prevention. We aimed to assess PrEP effectiveness, adherence, and safety in adults using daily or on-demand PrEP. METHODS: We conducted a prospective observational cohort study (ANRS PREVENIR) at 26 sites in the Paris region, France. We enrolled HIV-negative adults (aged ≥18 years) at high risk of HIV infection who were starting or continuing PrEP. PrEP was prescribed as a fixed-dose combination of tenofovir disoproxil and emtricitabine (245 mg and 200 mg, respectively, per pill). PrEP could be prescribed as a daily regimen with one pill per day or, in men who have sex with men (MSM) or in transgender women who have sex with men, as an on-demand regimen following the IPERGAY dosing recommendation. At enrolment and every 3 months thereafter, participants were tested for HIV and provided information regarding the PrEP dosing regimen used. Adherence to PrEP was assessed by self-report and by tenofovir diphosphate concentrations in dried blood spots. The primary outcome of HIV-1 incidence was assessed using Poisson regression among participants who started PrEP. This study is registered with ClinicalTrials.gov, NCT03113123, and EudraCT, 2016A0157744. FINDINGS: Between May 3, 2017, and May 2, 2019, 3082 people were assessed for eligibility and 3065 participants were enrolled. 3056 (99·7%) of 3065 participants reported using PrEP and were included in the analyses. The median age was 36 years (IQR 29-43), 1344 (44·0%) of 3056 participants were PrEP-naive, and 3016 (98·7%) were MSM. At enrolment, 1540 (50·5%) of 3049 participants opted for daily PrEP dosing and 1509 (49·5%) opted for on-demand PrEP dosing; these proportions remained stable during follow-up. Median follow-up was 22·1 months (IQR 15·9-29·7) and incidence of study discontinuation was 17·6 participants (95% CI 16·5-18·7) per 100 person-years. At the data cutoff on Sept 30, 2020, there had been six HIV-1 seroconversions (three participants using daily PrEP and three using on-demand PrEP; all were MSM) over 5623 person-years. Overall HIV-1 incidence was 1·1 cases (95% CI 0·4-2·3) per 1000 person-years, and did not differ between participants using daily PrEP and those using on-demand PrEP (incidence rate ratio 1·00, 95% CI 0·13-7·49; p=0·99). Four participants (two using daily PrEP and two using on-demand PrEP) discontinued PrEP due to treatment-related adverse events (nausea [n=2], vomiting and diarrhoea [n=1], and lumbar pain [n=1]). INTERPRETATION: In this study, which enrolled mainly MSM, HIV-1 incidence on PrEP was low and did not differ between participants using daily PrEP and those using on-demand PrEP. On-demand PrEP therefore represents a valid alternative to daily PrEP for MSM, providing greater choice in HIV prevention. FUNDING: ANRS/Maladies Infectieuses Emergentes, Gilead Sciences, SIDACTION, and Région Ile de France. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.