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Summary: Background: No study has compared the virological and immunological status of young people with perinatally-acquired HIV infection (P-HIV) with that of people with HIV adulthood (A-HIV) having a similar duration of infection. Methods: 5 French cohorts of P-HIV and A-HIV patients with a known date of HIV-infection and receiving antiretroviral treatment (ART), were used to compare the following proportions of: virological failure (VF) defined as plasma HIV RNA ≥ 50 copies/mL, CD4 cell percentages and CD4:CD8 ratios, at the time of the most recent visit since 2012. The analysis was stratified on time since infection, and multivariate models were adjusted for demographics and treatment history. Findings: 310 P-HIV were compared to 1515 A-HIV (median current ages 20.9 [IQR:14.4–25.5] and 45.9 [IQR:37.9–53.5] respectively). VF at the time of the most recent evaluation was significantly higher among P-HIV (22.6%, 69/306) than A-HIV (3.3%, 50/1514); p ≤ 0.0001. The risk of VF was particularly high among the youngest children (2–5 years), adolescents (13–17 years) and young adults (18–24 years), compared to A-HIV with a similar duration of infection: adjusted Odds-Ratio (aOR) 7.0 [95% CI: 1.7; 30.0], 11.4 [4.2; 31.2] and 3.3 [1.0; 10.8] respectively. The level of CD4 cell percentages did not differ between P-HIV and A-HIV. P-HIV aged 6–12 and 13–17 were more likely than A-HIV to have a CD4:CD8 ratio ≥ 1: 84.1% vs. 58.8% (aOR = 3.5 [1.5; 8.3]), and 60.9% vs. 54.7% (aOR = 1.9 [0.9; 4.2]) respectively. Interpretation: P-HIV were at a higher risk of VF than A-HIV with a similar duration of infection, even after adjusting for treatment history, whereas they were not at a higher risk of immunological impairment. Exposure to viral replication among young patients living with HIV since birth or a very early age, probably because of lower adherence, could have an impact on health, raising major concerns about the selection of resistance mutations and the risk of HIV transmission. Funding: Inserm - ANRS MIE.

Background: The human immunodeficiency virus type 1 (HIV-1) cannot be eradicated even with suppressive antiretroviral therapy because its retrotranscribed genome integrates into the DNA of host cells, creating a long-term reservoir. Quantification of total HIV-1 DNA in peripheral blood is a biomarker of this reservoir that can predict progression of the infection, treatment response, and HIV-1-related complications. A deeper understanding of the reservoir may help develop a cures. Objective: This study aimed to characterize persons living with HIV-1 (PLWH) with unquantifiable total HIV-1 DNA in blood (below the quantification threshold) and identify associated factors. Methods: We have conducted a retrospective observational study. During the study period, all PLWH who had total leukocyte-associated HIV-1 DNA measured by quantitative PCR were included. We have isolated a population of participants with HIV-1 DNA levels below the quantification threshold (40 copies/106 leukocytes). Results: Out of 1094 patients analysed, 62 had unquantifiable and 1032 quantifiable HIV-1 DNA levels in blood. We have found that those with unquantifiable HIV-1 DNA had a higher CD4 T cell nadir (p = 0.006) and a lower viral load zenith (p

Abstract 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.

Background: In the current context of research on HIV reservoirs, offering new insights into the persistence of HIV DNA in infected cells, which prevents viral eradication, may aid in identifying cure strategies. This study aimed to describe the establishment of stable integrated forms among total HIV DNA during primary infection (PHI) and their dynamics during the natural history of infection. Methods: Total and integrated HIV DNA were quantified in blood from 74 PHI patients and 97 recent seroconverters (

ObjectivesAnal cancer, usually driven by an oncogenic Human Papillomavirus, remains a leading cause of morbidity in men who have sex with men (MSM) living with HIV, despite combined antiretroviral therapy. Various recommendations advocate to perform regular examination and proctologist-performed samples to anticipate this risk and treat locally before cancer occurrence, an efficient strategy which has the drawback of requiring the proctologist's availability. This study evaluates the acceptability, feasibility, and efficiency of self-performed samples to screen for HPV-infection and HPV-related anal dysplasia among MSM living with HIV followed in Hôtel-Dieu Hospital.MethodsBetween February 2015 and June 2015, MSM living with HIV and referred to the day-care hospital were offered to perform an anal self-sampling for cytologic and virologic evaluation. A self-sampling kit was provided, and a tutorial video was shown. A subset of participants had a proctology appointment after they did the self-sampling, and thus had a clinical examination and an anal swab sampling performed by the proctologist, using the same sampling material.ResultsAnal self-sampling was offered to 103 patients, and 100 accepted. Sixty-three samples were interpretable, of which 36 (57%) were normal and 27 (43%) showed abnormal results. Virologic analysis was performed for 60 (95%) interpretable samples: 50/60 (83%) of them were positive for HPV. Among HPV-carrier patients, 42/50 (84%) were infected with at least one HR-HPV. Twenty patients had a proctologist consultation. All clinician-performed samples were interpretable and 14 (70%) self-samples were interpretable.ConclusionsThis study highlights the acceptable accuracy of self-sampling screening method among MSM living with HIV and try out its acceptability and feasibility as a secondary prevention device. Although it cannot replace a proctologist consultation for high risk patients, self-sampling should be studied further as one of the ways of screening for anal cancer among low-risk outpatients.

AIM:Metabolic risk factors are poorly documented for the first generation of young adults who have lived with HIV since childhood. We compared their metabolic profile with that of adults of same age from the general population. METHODS:We conducted a cross-sectional analysis of data from two populations: (1) COVERTE (ANRS-CO19), a French national cohort of 18 to 30-year-old patients HIV-infected since childhood, and (2) ENNS, a national cross-sectional population-based household survey on nutrition. Body mass index (BMI), blood pressure, waist circumference, fasting glucose, triglycerides, and HDL-, LDL- and total cholesterol were measured in both studies. Direct standardization on overweight and education level and logistic regression were used to compare the prevalence of metabolic abnormalities between the two populations. RESULTS:Data from 268 patients from COVERTE and 245 subjects from ENNS were analyzed. Tobacco use was similar in both groups. HIV-infected patients had increased mean waist-to-hip ratio and triglycerides to HDL-cholesterol ratio and decreased mean HDL-cholesterol as compared to their counterparts from the general population in both genders. In HIV-infected patients, metabolic syndrome was identified in 13.2% of men (95% confidence interval [CI]: 7.1-19.2) and 10.4% (95% CI: 5.4-15.3) of women versus 10.6% (95%CI: 1.5-19.7) and 1.7% (95%CI: 0-4.1) in subjects from the general population, respectively. CONCLUSION:Young adults infected with HIV since childhood had a higher prevalence of dyslipidemia and metabolically detrimental fat distribution than adults of same age of the general population, supporting close monitoring for cardiometabolic diseases.

To assess whether higher 25-hydroxyvitamin D (25OHD) levels are associated with subsequent better immune responses to hepatitis B and Streptococcus pneumoniae vaccination in HIV-infected patients.25OHD was measured on stored baseline plasma samples from two randomized vaccine trials in HIV-infected adults: the ANRS HB03 VIHVAC B trial and an immunological sub-study of the ANRS 114-PNEUMOVAC trial. In ANRS HB03 VIHVAC B, participants received three or four doses of recombinant HBV vaccine strategies. Anti-HBs IgG titers were measured four weeks after the last injection. Associations between baseline 25OHD levels and ordered IgG response categories were analyzed in multivariable proportional odds models. In the ANRS 114-PNEUMOVAC sub-study, two strategies of pneumococcal vaccination were tested, cellular immune responses were measured at repeated time points, and IgG responses four weeks after the last vaccine injection. Exploratory statistical analyses were performed on this sub-study data set.Three hundred and thirty-nine ANRS HB03 VIHVAC B and 25 ANRS 114-PNEUMOVAC sub-study participants were included in the analyses. Median age in each of the two studies was 43 years, 68% were male, and 77-92% on antiretroviral treatment. Median 25OHD level was 18 ng/mL (IQR: 12-25) and 24 ng/mL (IQR: 13-32) in the two trial populations, respectively. In the multivariable model, there was no significant association between baseline 25OHD level and vaccine responses in ANRS HB03 VIHVAC B (proportional odds ratio 0.83 per 10 ng/mL 25OHD increase; 95% confidence interval 0.65-1.07, p = 0.14). Exploratory analyses of ANRS 114-PNEUMOVAC showed consistent results.This study does not support a positive association between 25OHD and immune responses to hepatitis B or pneumococcal vaccination in HIV-infected patients.

African histoplasmosis caused by Histoplasma capsulatum var. duboisii is an invasive fungal infection endemic in central and west Africa. Most of its ecology and pathogenesis remain unknown. H. capsulatum var. capsulatum is an AIDS-defining opportunistic infection in HIV-infected patients who are living in or have traveled to histoplasmosis-endemic areas. In contrast, reports concerning African histoplasmosis during HIV infection are rare, although both pathogens coexist in those regions. We report 3 cases of imported African histoplasmosis diagnosed in France in HIV-infected patients and a literature review on similar cases.

The ANRS-EP38-IMMIP study aimed to provide a detailed assessment of the immune status of perinatally infected youths living in France. We studied Gag-specific CD4 and CD8 T-cell proliferation and the association between the proliferation of these cells, demographic factors and HIV disease history. We included 93 youths aged between 15 and 24 years who had been perinatally infected with HIV. Sixty-nine had undergone valid CFSE-based T-cell proliferation assays. Gag-specific proliferation of CD4 and CD8 T cells was detected in 12 (16%) and 30 (38%) patients, respectively. The Gag-specific proliferation of CD4 and CD8 T cells was more frequently observed in black patients than in patients from other ethnic groups (CD4: 32% vs. 4%, P = 0.001; CD8: 55% vs. 26%, P = 0.02). Among aviremic patients, the duration of viral suppression was shorter in CD8 responders than in CD8 nonresponders (medians: 54 vs. 20 months, P = 0.04). Among viremic patients, CD8 responders had significantly lower plasma HIV RNA levels than CD8 nonresponders (2.7 vs. 3.7 log10 HIV-RNA copies/ml, P = 0.02). In multivariate analyses including sex and HIV-1 subtype as covariables, Gag-specific CD4 T-cell proliferation was associated only with ethnicity, whereas Gag-specific CD8 T-cell proliferation was associated with both ethnicity and the duration of viral suppression. Both CD4 and CD8 responders reached their nadir CD4 T-cell percentages at younger ages than their nonresponder counterparts (6 vs. 8 years, P = 0.04 for both CD4 and CD8 T-cell proliferation). However, these associations were not significant in multivariate analysis. In conclusion, after at least 15 years of HIV infection, Gag-specific T-cell proliferation was found to be more frequent in black youths than in patients of other ethnic groups, despite all the patients being born in the same country, with similar access to care.

Combination antiretroviral therapy (cART) reduces HIV-associated morbidities and mortalities but cannot cure the infection. Given the difficulty of eradicating HIV-1, a functional cure for HIV-infected patients appears to be a more reachable short-term goal. We identified 14 HIV patients (post-treatment controllers [PTCs]) whose viremia remained controlled for several years after the interruption of prolonged cART initiated during the primary infection. Most PTCs lacked the protective HLA B alleles that are overrepresented in spontaneous HIV controllers (HICs); instead, they carried risk-associated HLA alleles that were largely absent among the HICs. Accordingly, the PTCs had poorer CD8+ T cell responses and more severe primary infections than the HICs did. Moreover, the incidence of viral control after the interruption of early antiretroviral therapy was higher among the PTCs than has been reported for spontaneous control. Off therapy, the PTCs were able to maintain and, in some cases, further reduce an extremely low viral reservoir. We found that long-lived HIV-infected CD4+ T cells contributed poorly to the total resting HIV reservoir in the PTCs because of a low rate of infection of naïve T cells and a skewed distribution of resting memory CD4+ T cell subsets. Our results show that early and prolonged cART may allow some individuals with a rather unfavorable background to achieve long-term infection control and may have important implications in the search for a functional HIV cure.

ObjectivesLow 25(OH)D has been associated with dyslipidemia, insulin resistance and inflammation in both general and HIV-infected (mostly treated) populations. We investigated these associations in antiretroviral-naïve HIV-infected persons.DesignWe measured plasma 25(OH)D, metabolic, immunologic and inflammatory markers in 355 persons (204 Whites, 151 Blacks) at enrollment in the ANRS COPANA cohort.Methods25(OH)D levels were categorized Results25(OH)D insufficiency (ConclusionsSevere vitamin D deficiency was associated with low CD4 counts and increased markers of inflammation in ARV-naïve HIV-infected persons.

Guidelines for initiating HIV treatment are regularly revised. We explored how physicians in France have applied these evolving guidelines for ART initiation over the last decade in two different situations: chronic (CHI) and primary HIV-1 infection (PHI), since specific recommendations for PHI are also provided in France.Data came from the ANRS PRIMO (1267 patients enrolled during PHI in 1996-2010) and COPANA (800 subjects enrolled at HIV diagnosis in 2004-2008) cohorts. We defined as guidelines-inconsistent during PHI and CHI, patients meeting criteria for ART initiation and not treated in the following month and during the next 6 months, respectively.ART initiation during PHI dramatically decreased from 91% of patients in 1996-99 to 22% in 2007 and increased to 60% in 2010, following changes in recommendations. In 2007, however, after the CD4 count threshold was raised to 350 cells/mm(3) in 2006, only 55% of the patients with CD4≤350 were treated and 66% in 2008. During CHI, ART was more frequently initiated in patients who met the criteria at entry (96%) than during follow-up: 83% when recommendation to treat was 200 and 73% when it was 350 cells/mm(3). Independent risk factors for not being treated during CHI despite meeting the criteria were lower viral load, lower educational level, and poorer living conditions.HIV ART initiation guidelines are largely followed by practitioners in France. What can still be improved, however, is time to treat when CD4 cell counts reach the threshold to treat. Risk factors for lack of timely treatment highlight the need to understand better how patients' living conditions and physicians' perceptions influence the decision to initiate treatment.

OBJECTIVE: In October 2009 the French National Authority for Health recommended that HIV testing be proposed at least once to all persons aged 15 to 70 years in all healthcare settings. We examined whether routine HIV screening with a rapid test in emergency departments (EDs) was feasible without dedicated staff, and whether newly diagnosed persons could be linked to care. METHODS: This one-year study started in December 2009 in 6 EDs in the Paris area, using the INSTI™ test. Eligible individuals were persons 18 to 70 years old who did not present for a vital emergency, for blood or sexual HIV exposure, or for HIV screening. Written informed consent was required. RESULTS: Among 183 957 eligible persons, 11 401 were offered HIV testing (6.2%), of whom 7936 accepted (69.6%) and 7215 (90.9%) were tested (overall screening rate 3.9%); 1857 non eligible persons were also tested. Fifty-five new diagnoses of HIV infection were confirmed by Western blot (0.61% (95% CI 0.46-0.79). There was one false-positive rapid test result. Among the newly diagnosed persons, 48 (87%) were linked to care, of whom 36 were not lost to follow-up at month 6 (75%); median CD4 cell count was 241/mm(3) (IQR: 52-423/mm(3)). CONCLUSIONS: Screening rates were similar to those reported in opt-in studies with no dedicated staff. The rate of new diagnoses was similar to that observed in free anonymous test centres in the Paris area, and well above the prevalence (0.1%) at which testing has been shown to be cost-effective.

Persistent immune activation plays a central role in driving Human Immunodeficiency Virus (HIV) disease progression. Whether CD4+CD25+ regulatory T cells (Tregs) are harmful by suppressing HIV-specific immune responses and/or beneficial through a decrease in immune activation remains debatable. We analysed the relationship between proportion and number of regulatory T cells (Tregs) and immune activation in HIV-infected patients interrupting an effective antiretroviral therapy (ART). Twenty-five patients were included in a substudy of a prospective multicenter trial of treatment interruption (TI) (ANRS 116). Proportions and numbers of Tregs and the proportion of activated CD4 and CD8 T cells were assessed at baseline and month 12 (M12) of TI. Specific anti-HIV CD4 and CD8 responses were investigated at baseline and M12. Non parametric univariate analyses and multivariate linear regression models were conducted. At baseline, the proportion of Tregs negatively correlated with the proportion of HLA-DR+CD8+T cells (r=-0.519). Following TI, the proportion of Tregs increased from 6.3% to 7.2% (p=0.029); absolute numbers of Tregs decreased. The increase in the proportion of HLA-DR+CD38+CD8+T cells was significantly related to the increase in proportion of Tregs (p=0.031). At M12, the proportion of Tregs did not negatively correlate with CD8 T-cell activation. Nevertheless, Tregs retain a suppressive function since depletion of Treg-containing CD4+CD25+ cells led to an increase in lymphoproliferative responses in most patients studied. Our data suggest that Tregs are efficient in controlling residual immune activation in patients with ART-mediated viral suppression. However, the insufficient increase in the proportion and/or the decrease in the absolute number of Tregs result in a failure to control immune activation following TI.ClinicalTrials.gov NCT00118677.

BackgroundDiabetes mellitus (DM) is a major and increasing public health problem that may be underdiagnosed and undertreated among persons living with HIV (PLWH).ObjectiveTo describe the diagnosis, treatment and follow-up of DM among PLWH.MethodsThis study was performed inside a monocentric cohort of 1494 PLWH. DM was defined as having a FG ≥126 mg/dL twice or a HbA1c ≥6.5%, or a history of diabetes, or receiving antidiabetic treatment. The first visit mentioning a diagnosis of DM was considered as the baseline visit. Chi-Square or Fisher exact test were used to examine the association between categorical variables and DM, Wilcoxon or Student t-test were used for continuous variables.Results156 PLWH with DM were included. Compared to non-diabetic participants, they were more likely to be native of Sub Saharan Africa (31.6% vs. 22.4%, p = 0.027) and older (54.6 vs. 49.9 years, p 25 for 46.1% vs. 35.3%, p = 0.020) and a poorer control of HIV (HIV RNAConclusionIn a setting of HIV-control, HIV care providers should focus on metabolic issues. The management of DM and associated risk factors is mandatory to prevent cardiovascular disease in PLWH.

Introduction: Although prostate cancer (PCa) incidence is lower in HIV+ men than in HIV- men, the usefulness of prostate-specific antigen (PSA) screening in this population is not well defined and may have higher false negative rates than in HIV- men. We aimed to describe the kinetics and predictive value of PSA in HIV+ men., Methods: Men with PCa (n=21) and up to two matched controls (n=40) with prospectively stored plasma samples before PCa (or matched date in controls) were selected. Cases and controls were matched on date of first and last sample, age, region of residence and CD4 count at first sample date. Total PSA (tPSA), free PSA (fPSA), testosterone and sex hormone binding globulin (SHBG) were measured. Conditional logistic regression models investigated associations between markers and PCa. Sensitivity and specificity of using tPSA >4 µg/L to predict PCa was calculated. Mixed models were used to describe kinetics., Results: Sixty-one men were included with a median six (IQR 2-9) years follow-up. Time between last sample and PCa was seven (4-11) months. Cases and controls were well matched at first sample, with a median age of 51 (IQR 48-57) and CD4 of 437 (243-610) cells/mm(3). Median tPSA [2.8 (IQR: 1.6-4.6) and 0.8 (0.5-1.2) µg/L] and fPSA [0.4 (0.2-0.8) and 0.3 (0.2-0.4) µg/L] levels were higher in cases than controls at first sample. Both tPSA and fPSA increased significantly over time in cases (Figure 1), to a median at last sample of 6.1 (4.7-9.5) and 0.9 (0.6-1.3) µg/L, respectively, but were stable in controls, with a median at last sample of 0.8 (0.5-1.4) and 0.2 (0.2-0.4) µg/L (Figure). Higher levels of tPSA and fPSA were associated with higher odds of PCa at first sample [OR for 2-fold higher 4.7 (CI: 1.7-12.9) and 5.4 (1.7-17.4)]. Elevated tPSA values in cases were detectable ≥5 years before PCa (p<0.01). Testosterone [overall median 19.4 (IQR 15.3-23.9) nmol/L at first sample) and SHBG [50.0 (34.0-66.0) nmol/L] levels were similar in cases and controls at first and last sample (all p>0.7). The most informative predictor of PCa was tPSA (AUC=0.9), followed by fPSA (0.8). Testosterone (AUC = 0.5) and SHBG (0.5) were poor predictors of PCa. Overall, tPSA level >4 µg/L had 99% specificity and 37% sensitivity. Performance was best in the year prior to PCa (specificity: 99%, sensitivity: 88%)., Conclusions: PSA was highly predictive of PCa in HIV+ men. Our results indicate that PSA screening in HIV+ men may be useful, and further work is needed to identify potentially age-related cut-offs to maximize sensitivity and specificity to identify those for further evaluation at early stages of PCa.