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We assessed the impact of early antiretroviral treatment (ART) on human immunodeficiency virus (HIV) antibody detection by rapid tests in 44 individuals after several years of successful ART. HIV self-tests and point-of-care tests were negative in 30% and 7%-9% of cases, respectively. These data reinforce the message that patients should never be retested after entering HIV care.

Background: We aimed to determine the consequences of delayed human immunodeficiency virus type 1 (HIV-1) infection diagnosis by comparing long-term outcomes depending on the time of combination antiretroviral therapy (cART) initiation in patients diagnosed during primary HIV infection (PHI)., Methods: We selected patients from the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) PRIMO cohort, treated for ≥36 months, with sustained HIV RNA <50 copies/mL: 77 treated within 1 month following PHI diagnosis (immediate ART) and 73 treated >12 months after infection (deferred ART). We measured inflammatory biomarkers from PHI through the last visit on cART, and CD4+ and CD8+ T-cell activation and plasma ultrasensitive HIV RNA at the last visit. Inflammation/activation levels were compared with those of uninfected controls. We modeled CD4+ count, CD4:CD8 ratio, and HIV DNA dynamics on cART., Results: The decrease of HIV DNA levels was more marked in the immediate than deferred ART group, leading to a sustained mean difference of -0.6 log10 copies/106 peripheral blood mononuclear cells. Immediate ART led to improved CD4+ T-cell counts and CD4:CD8 ratios over the first 4 years of cART. At the last visit (median, 82 months), there was no difference between groups in CD4+ counts, CD4:CD8 ratio, ultrasensitive HIV RNA, or inflammation/activation marker levels. Long-term suppressive cART failed to normalize inflammation levels, which were not associated with immunovirological markers., Conclusions: Antiretroviral therapy initiated during PHI promotes long-term reduction of HIV reservoir size. In patients with sustained virologic suppression, inflammation may be driven by non-HIV-related factors.

Objective: To compare regimens consisting of either ritonavir-boosted atazanavir or efavirenz and a nucleoside reverse transcriptase inhibitor (NRTI) backbone with respect to clinical, immunologic, and virologic outcomes., Design: Prospective studies of human immunodeficiency virus (HIV)-infected individuals in Europe and the United States included in the HIV-CAUSAL Collaboration., Methods: HIV-positive, antiretroviral therapy-naive, and acquired immune deficiency syndrome (AIDS)-free individuals were followed from the time they started an atazanavir or efavirenz regimen. We estimated an analog of the "intention-to-treat" effect for efavirenz versus atazanavir regimens on clinical, immunologic, and virologic outcomes with adjustment via inverse probability weighting for time-varying covariates., Results: A total of 4301 individuals started an atazanavir regimen (83 deaths, 157 AIDS-defining illnesses or deaths) and 18,786 individuals started an efavirenz regimen (389 deaths, 825 AIDS-defining illnesses or deaths). During a median follow-up of 31 months, the hazard ratios (95% confidence intervals) were 0.98 (0.77, 1.24) for death and 1.09 (0.91, 1.30) for AIDS-defining illness or death comparing efavirenz with atazanavir regimens. The 5-year survival difference was 0.1% (95% confidence interval: -0.7%, 0.8%) and the AIDS-free survival difference was -0.3% (-1.2%, 0.6%). After 12 months, the mean change in CD4 cell count was 20.8 (95% confidence interval: 13.9, 27.8) cells/mm lower and the risk of virologic failure was 20% (14%, 26%) lower in the efavirenz regimens., Conclusion: Our estimates are consistent with a smaller 12-month increase in CD4 cell count, and a smaller risk of virologic failure at 12 months for efavirenz compared with atazanavir regimens. No overall differences could be detected with respect to 5-year survival or AIDS-free survival.

The soluble CD14 (sCD14) level was found associated with mortality during the chronic phase of human immunodeficiency virus (HIV) infection. Here we assessed its prognostic value in 138 patients with primary HIV infection. Higher sCD14 levels were associated with death, from myocardial infarction, but this was based on 3 deaths only. Among 68 untreated patients, those with higher sCD14 levels had more rapid spontaneous CD4 cell decline during the first 18 months following primary infection. This association persisted after adjustment for age, the CD4 cell count, and HIV viral load at diagnosis., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Combined antiretroviral therapy (cART) initiation during primary human immunodeficiency virus (HIV) infection (PHI) yields a larger decrease in cell-associated HIV-DNA (CA-HIV-DNA) than initiation during the chronic phase. Our objective was to model the short and long-term decay of CA-HIV-DNA blood reservoir in patients initiating cART during PHI and to assess the impact of the timing of cART initiation on CA-HIV-DNA decay., Methods: We included patients enrolled during PHI in the Agence Nationale de Recherche sur le Sida PRIMO cohort, treated within the month following enrollment and achieving sustained virologic response. The decay of CA-HIV-DNA over time while on successful cART was modeled with a 3-slope linear mixed-effects model according to the delay between estimated date of infection and cART initiation., Results: Three hundred twenty-seven patients were included, accounting for 1305 CA-HIV-DNA quantifications. Median time between infection and cART initiation was 41 days (interquartile range, 33-54 days). Median follow-up under cART was 2.3 years (range, 0.4-16.6 years). The timing of cART initiation had significant impact on the first slope of decrease: The earlier cART was initiated after HIV infection, the faster CA-HIV-DNA level decreased during the first 8 months of cART: -0.171, -0.131, and -0.068 log10 copies/10(6) peripheral blood mononuclear cells (PBMCs) per month when cART was initiated 15 days, 1 month, and 3 months after infection, respectively (P < .0001). The predicted mean CA-HIV-DNA level achieved after 5 years of successful cART was 1.62 and 2.24 log10 copies/10(6) PBMCs when cART was initiated 15 days and 3 months after infection, respectively (P = .0006)., Conclusions: This study provides strong arguments in favor of cART initiation at the earliest possible time point after HIV infection., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

In patients who are receiving prolonged antiretroviral treatment (ART), HIV can persist within a small pool of long-lived resting memory CD4(+) T cells infected with integrated latent virus. This latent reservoir involves distinct memory subsets. Here we provide results that suggest a progressive reduction of the size of the blood latent reservoir around a core of less-differentiated memory subsets (central memory and stem cell-like memory (TSCM) CD4(+) T cells). This process appears to be driven by the differences in initial sizes and decay rates between latently infected memory subsets. Our results also suggest an extreme stability of the TSCM sub-reservoir, the size of which is directly related to cumulative plasma virus exposure before the onset of ART, stressing the importance of early initiation of effective ART. The presence of these intrinsic dynamics within the latent reservoir may have implications for the design of optimal HIV therapeutic purging strategies.

Objective: 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., Methods: 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., Results: 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., Conclusion: 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.

Background: To analyze the time trends of the viral subtype distributions according to gender, risk group, and geographical origin of the patients in 1128 primary human immunodeficiency virus type 1 infection (PHI), diagnosed in France (1996-2010). To study whether the viral diversity had an impact on the virological and immunological responses in patients initiating combined antiretroviral therapy (cART) soon after infection., Methods: The study population comprised PHI patients enrolled in the ANRS-PRIMO-cohort. Subtypes were determined by phylogenetic analysis of reverse transcriptase gene. Viral suppression (<400 copies/mL and <50 copies/mL) and CD4 T-cell counts increase were assessed for those who initiated cART at PHI diagnosis., Results: Non-B subtypes (285/1128, 25.3%) were present in all regions of France and all risk groups, and increased in frequency over time. Non-B strains were highly diverse and included 6 subtypes, 10 circulating recombinant forms (CRFs), and several unique recombinant forms (URFs). Virological response in patients infected with a non-B virus was similar to that of patients with a subtype-B virus over the first 2 years of cART. Patients infected with either a CRF02&#95;AG strain or another non-B virus had better immunological responses than those infected with a subtype-B virus., Conclusions: Over the last 15 years in France, viral diversity has increased in all risk groups. This is the first large study comparing the responses of patients treated since PHI and showing a similar virological and immunological response to cART between the 2 groups of patients (B and non-B). Our results are encouraging for countries where non-B strains predominate in view of the increasing availability of cART.

Objective: To compare regimens consisting of either efavirenz or nevirapine and two or more nucleoside reverse transcriptase inhibitors (NRTIs) among HIV-infected, antiretroviral-naive, and AIDS-free individuals with respect to clinical, immunologic, and virologic outcomes., Design: Prospective studies of HIV-infected individuals in Europe and the US included in the HIV-CAUSAL Collaboration., Methods: Antiretroviral therapy-naive and AIDS-free individuals were followed from the time they started an NRTI, efavirenz or nevirapine, classified as following one or both types of regimens at baseline, and censored when they started an ineligible drug or at 6 months if their regimen was not yet complete. We estimated the 'intention-to-treat' effect for nevirapine versus efavirenz regimens on clinical, immunologic, and virologic outcomes. Our models included baseline covariates and adjusted for potential bias introduced by censoring via inverse probability weighting., Results: A total of 15 336 individuals initiated an efavirenz regimen (274 deaths, 774 AIDS-defining illnesses) and 8129 individuals initiated a nevirapine regimen (203 deaths, 441 AIDS-defining illnesses). The intention-to-treat hazard ratios [95% confidence interval (CI)] for nevirapine versus efavirenz regimens were 1.59 (1.27, 1.98) for death and 1.28 (1.09, 1.50) for AIDS-defining illness. Individuals on nevirapine regimens experienced a smaller 12-month increase in CD4 cell count by 11.49 cells/μl and were 52% more likely to have virologic failure at 12 months as those on efavirenz regimens., Conclusions: Our intention-to-treat estimates are consistent with a lower mortality, a lower incidence of AIDS-defining illness, a larger 12-month increase in CD4 cell count, and a smaller risk of virologic failure at 12 months for efavirenz compared with nevirapine., (© 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins)

Background: In the current context of increasing unsafe sex, HIV incidence may have evolved, depending on HIV prevalence in sexual networks and, among HIV-infected persons who practice unsafe sex, on their infectivity and partners' HIV serostatus. We examined calendar trends in sexual behaviours at risk of HIV-1 transmission (SBR) among 967 adults followed since primary HIV infection (ANRS PRIMO cohort) and relationship with current treatments and viral load., Methods: Patients completed since 2000 self-administered questionnaires on sexual practices every 6 months. SBR with HIV-negative/unknown partners were analyzed among 155 heterosexual women, 142 heterosexual men and 670 MSM by using logistic generalized estimating equation models (6656 visits)., Results: During 2000-2009, the frequency of SBR did not increase significantly among women with steady partners; risk factors were a low education level and alcohol/smoking use. Among heterosexual men with steady partners, the frequency of SBR doubled since 2006; during this period, the only associated factor was combined antiretroviral treatment for at least 6 months or viral load less than 400 copies/ml. Among MSM, SBR increased gradually over time; SBR with steady partners was associated with a low education level and alcohol use. SBR was more frequent among MSM with casual partners; no association with viral load was found., Conclusion: In France, recent trends and risk factors in unprotected sex with HIV-negative/unknown partners differ according to sex/sexual preference. The recent increase in SBR among heterosexual men with low viral load may be related to increasing awareness of the 'treatment-as-prevention' concept. The lack of association between SBR and viral load among MSM supports use of treatment-as-prevention as part of diversified prevention strategies.

Objective: To estimate the effect of combined antiretroviral therapy (cART) on mortality among HIV-infected individuals after appropriate adjustment for time-varying confounding by indication., Design: A collaboration of 12 prospective cohort studies from Europe and the United States (the HIV-CAUSAL Collaboration) that includes 62 760 HIV-infected, therapy-naive individuals followed for an average of 3.3 years. Inverse probability weighting of marginal structural models was used to adjust for measured confounding by indication., Results: Two thousand and thirty-nine individuals died during the follow-up. The mortality hazard ratio was 0.48 (95% confidence interval 0.41-0.57) for cART initiation versus no initiation. In analyses stratified by CD4 cell count at baseline, the corresponding hazard ratios were 0.29 (0.22-0.37) for less than 100 cells/microl, 0.33 (0.25-0.44) for 100 to less than 200 cells/microl, 0.38 (0.28-0.52) for 200 to less than 350 cells/microl, 0.55 (0.41-0.74) for 350 to less than 500 cells/microl, and 0.77 (0.58-1.01) for 500 cells/microl or more. The estimated hazard ratio varied with years since initiation of cART from 0.57 (0.49-0.67) for less than 1 year since initiation to 0.21 (0.14-0.31) for 5 years or more (P value for trend <0.001)., Conclusion: We estimated that cART halved the average mortality rate in HIV-infected individuals. The mortality reduction was greater in those with worse prognosis at the start of follow-up.

Objective: We investigated temporal trends in the CD4 cell count and in plasma HIV RNA and total HIV DNA levels measured at the time of primary HIV infection, as proxies for HIV-1 virulence, taking changes in patient characteristics into account., Design: We studied 903 patients enrolled during primary HIV infection in the French multicenter ANRS PRIMO cohort from 1996 to 2007., Methods: Associations between the year of primary HIV infection and the values of the three markers were tested with regression models. The year of primary HIV infection was first introduced as a restricted cubic splines function in a regression model in order to explore the shape of the associations, and then as a continuous/categorical variable. The following confounders were considered in multiple regression analysis: time since infection and age (introduced as restricted cubic spline functions), sex, place of birth (Africa vs. others), symptomatic primary HIV infection, smoking, and virus-related factors (subtype B vs. non-B, and drug resistance mutations)., Results: Multivariate analysis showed no temporal trends in the CD4 cell count (square-root) or in HIV-1 RNA and DNA levels (log10) measured at the time of primary HIV infection. We observed the well described associations between the prognostic markers and the time since infection, sex, symptomatic primary HIV infection, and smoking., Conclusion: The CD4 cell count and HIV RNA and DNA levels measured at the time of primary HIV-1 infection remained stable across 12 consecutive years (1996-2007) in the ANRS PRIMO cohort, suggesting no major change in virulence, after taking into account changes in patient characteristics.

Despite anecdotal reports of HIV-1 co-infections and super-infections, few large-scale prevalence studies are available on multiple HIV-1 infection. We systematically searched for HIV-1 co-infections by means of a heteroduplex mobility assay in 660 HIV-1 seroconverters from the two ANRS SEROCO and PRIMO cohorts. Our results strongly suggest that HIV-1 co-infection remains a rare phenomenon in HIV-1 seroconverters infected in France between 1986 and 2004.

Background: HIV-1 infection is associated with an increased incidence of and mortality from tuberculosis. Few community studies have examined the effect of HIV-2 on tuberculosis., Methods: We investigated the association between HIV-1, HIV-2 and active tuberculosis in four districts (population 42 709) in Bissau, capital of Guinea-Bissau, with the highest known seroprevalence of HIV-2 infection in the world. From May 1996 to June 1998, tuberculosis surveillance and active case finding among contacts was conducted. Patients were HIV-tested, given specific tuberculosis treatment for 8 months and followed regarding mortality. Simultaneously, an HIV sero-survey was performed in a random sample of 1748 permanent residents., Results: During a 25-month period, 366 tuberculosis cases were identified. After excluding cases among visitors to the area, and adjusting for age, the incidence of tuberculosis was 18.3 times higher (95% CI 12.9-26.0) among HIV-1-positive individuals, 13.7 times higher (9.0-20.7) among dually infected (HIV-1 and HIV-2), and 3.0 times higher (2.1-4.3) among HIV-2-infected compared with HIV-negative individuals. HIV-1 and dually infected tuberculosis patients had a higher mortality rate than HIV-negative tuberculosis patients [mortality ratio (MR) 2.68; CI 1.11-6.48 and 2.89; CI 1.13-7.39, respectively]. The survival of HIV-2-positive tuberculosis patients was similar to that of HIV-negative tuberculosis patients (MR 1.19; CI 0.46-3.06)., Conclusion: The presence of HIV-2 infection increases the incidence of tuberculosis compared with that in non-HIV-infected individuals, but does not affect tuberculosis-related mortality in the short term. In contrast, the presence of HIV-1 infection, alone or with HIV-2, has a several-fold greater impact on both the incidence of and mortality from tuberculosis.

Non-syncytium-inducing (NSI) variants seem to be more readily transmitted than syncytium-inducing (SI) variants, and the switch from NSI to SI during HIV-1 infection seems to be a key determinant to the evolution of AIDS. We investigated eventual differences in the SI capacity on MT-2 cells according to genetic subtypes of HIV-1 and correlated this observations with CD4 counts and duration of HIV infection. In total, 86 patients, most with known date of HIV contamination and infected with different genetic subtypes, have been studied: 11 subtype A, 46 subtype B, 22 subtype C, and 7 subtype E. Multivariate analysis used a Cox's proportional hazards regression. The number and percentage of patients infected with an SI strain were as follows: 3 of 11 (27%) for subtype A, 15 of 46 (33%) for subtype B, 0 of 22 (0%) for subtype C, and 5 of 7 (71%) for subtype E. After adjustment for time after seroconversion and CD4 counts, significantly fewer SI variants were observed in patients infected with subtype C (p < .002) and it was found that subjects infected with subtype E had a higher risk of being infected with an SI strain (rate ratio [RR] = 12.39%; 95% confidence interval [CI] 1.55-98.67; p < .001). Most of the subtype E-infected patients from our study switched from an NSI to SI phenotype early after seroconversion (<4 years). To predict the in vitro presence of SI variants, we scanned V3-loop sequences for mutations at positions 11 and/or 25. Overall, 54 of 55 (98.2%) NSI strains in vitro were predicted NSI, and only 4 of 12 (33.3%) of SI viruses were predicted SI. For patients in whom a switch from an NSI to an SI virus was observed, the SI phenotype could be detected earlier in vitro than by the corresponding V3-loop sequence. No SI strains were observed among patients infected with subtype C; however, longer follow-up is needed to see whether the appearance of SI variants in subtype E or the absence of SI variants in subtype C-infected patients is also associated respectively with a faster or slower progression to AIDS as described for subtype B.