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.

Use of rilpivirine in HIV-1-infected individuals in routine clinical practice from 2012 to 2017 in France.

OBJECTIVES: We assessed virological outcomes of rilpivirine use in France from 2012 to 2017, in three groups of people living with HIV (PLHIV): (i) antiretroviral (ARV)-naive PLHIV; (ii) ARV-experienced PLHIV switching to rilpivirine while failing therapy; and (iii) ARV-experienced PLHIV switching to rilpivirine while virologically controlled. METHODS: Virological success (VS) was defined as a plasma HIV-1 viral load (VL) <50 copies/mL and virological failure (VF) as two consecutive VL >50 copies/mL or one VL >50 copies/mL followed by a treatment switch prior to the next VL measurement. The cumulative incidence of VS was assessed considering rilpivirine discontinuation, loss to follow-up and death as competing risks, while estimates of cumulative incidence of VF accounted for loss to follow-up and death. RESULTS: Among the 2166 ARV-naive PLHIV initiating rilpivirine, the 4 year cumulative incidence of VS was 91.0% and was associated with baseline VL. Among the 2125 ARV-experienced PLHIV switching to rilpivirine while failing therapy, the 4 year cumulative incidence of VS was 82.5% and was associated with lower VL, higher CD4 and less than three prior ARVs. Among the 11 828 ARV-experienced PLHIV switching to rilpivirine while virologically controlled, the 4 year cumulative incidence of VF was 9.6%. The risk of VF was lower among MSM, for PLHIV with CD4 ≥ 500 cell/mm3, without a prior AIDS event, or with a longer VL suppression at baseline. CONCLUSIONS: Rilpivirine-containing regimens yielded high rates of viral suppression in most participants, while it was ineffective when used outside the marketing authorization in naive participants.

Is the Risk of Myocardial Infarction in People With Human Immunodeficiency Virus (HIV) Associated With Atazanavir or Darunavir? A Nested Case-Control Study Within the French Hospital Database on HIV.

BACKGROUND: The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study has reported an increased risk of cardiovascular diseases in people with human immunodeficiency virus who were exposed to darunavir (DRV) but not to atazanavir (ATV). Our objective was to evaluate associations between ATV or DRV exposures and the risk of myocardial infarction (MI) in a nested case-control study within ANRS-CO4 French Hospital Database on HIV (FHDH). METHODS: Cases were individuals who had a first validated MI between 2006 and 2012. Up to 5 controls were selected at random with replacement among individuals with no history of MI, followed at the time of MI diagnosis, and matched for age and sex. Conditional logistic regression models were used to adjust for potential confounders (MI risk factors and HIV-related parameters) and for cumulative exposure to each antiretroviral drug (ARV). RESULTS: Overall, 408 MI cases and 1250 controls were included: 109 (27%) cases and 288 (23%) controls had been exposed to ATV, and 41 (10%) cases and 107 (9%) controls had been exposed to DRV. There was no significant association between exposure to ATV (adjusted odds ratio [OR] = 1.54; 95% confidence interval [CI], .87-2.73) or DRV (adjusted OR = 0.51; 95% CI, .11-2.32) and the risk of MI. CONCLUSIONS: In FHDH, exposures to ATV or to DRV were not significantly associated with the risk of MI, adjusting for complete ARV history, contrary to the analysis in DAD.

Propensity Score Analysis of Artesunate Versus Quinine for Severe Imported Plasmodium falciparum Malaria in France.

BACKGROUND: Little is known on the use of artesunate compared with quinine for the treatment of imported malaria cases in nonendemic countries with a high level of care. Therefore, we compared the 2 treatments in terms of mortality and hospital and intensive care unit (ICU) discharge rates. METHODS: We analyzed the cohort of all severe imported malaria patients reported to the French National Reference Center from 2011 to 2017. After controlling for differences between quinine- and artesunate-treated individuals using the inverse probability of treatment weighting method, 28-day mortality rate was compared between the groups as well as hospital and ICU discharge rates using Kaplan-Meier estimation and weighted Cox proportional hazard models. RESULTS: Overall, 1544 patients were enrolled. Fifty patients died, 18 in the quinine group (n = 460) and 32 in the artesunate group (n = 1084), corresponding to death rates of 3.9% and 2.9%, respectively. No difference was evident between quinine and artesunate either in mortality or in hospital discharge rate, with hazard ratios (HRs) of 1.03 (95% confidence interval [CI], 0.47-2.25) and 1.12 (95% CI, 0.94-1.34), respectively. Artesunate was associated with a faster ICU discharge rate (HR, 1.18. 95% CI, 1.02-1.36). CONCLUSIONS: In a country with a high level of care, artesunate was associated with a shorter length of stay in the ICU, which supports the actual therapeutic transition; however, no difference was found in terms of mortality or in hospital discharge rates between artesunate- and quinine-treated patients.

Use of darunavir in HIV-1-infected individuals in routine clinical practice from 2012 to 2016 in France.

OBJECTIVES: We assessed virological outcomes of darunavir use in France from 2012 to 2016, in three groups of people living with HIV (PLHIV): (i) antiretroviral (ARV)-naive PLHIV; (ii) ARV-experienced PLHIV switching to darunavir while failing therapy; and (iii) ARV-experienced PLHIV switching to darunavir while virologically controlled. METHODS: Virological success (VS) was defined as a plasma HIV-1 viral load (VL) <50 copies/mL and virological failure (VF) as two consecutive VL >50 copies/mL or one VL >50 copies/mL followed by a treatment switch prior to the next VL measurement. The cumulative incidence of VS was assessed considering darunavir discontinuation, loss to follow-up and death as competing risks, while estimates of cumulative incidence of VF accounted for loss to follow-up and death. RESULTS: Among the 3235 ARV-naive PLHIV initiating darunavir, the 4 year cumulative incidence of VS was 80.9% and was associated with lower VL and higher CD4 cell counts. Among the 3485 ARV-experienced PLHIV switching to darunavir while failing therapy, the 4 year cumulative incidence of VS was 82.2% and was associated with lower VL. Among the 3005 ARV-experienced PLHIV switching to darunavir while virologically controlled, the 4 year cumulative incidence of VF was 12.6%. The risk of VF was higher with darunavir monotherapy [subdistribution hazard ratio (sHR)=1.67, 95% CI 1.15-2.42] while no difference was observed with dual therapy (sHR = 1.00, 95% CI 0.71-1.42) relative to triple therapy or more. CONCLUSIONS: Darunavir-containing regimens yielded similarly high rates of viral suppression in PLHIV whether they were ARV naive or ARV experienced switching to darunavir while failing therapy, or of maintaining VS in ARV-experienced PLHIV switching to darunavir while virologically controlled.

Impact of etravirine on hospitalization rate between 2005 and 2011 among heavily treated HIV-1-infected individuals on failing regimens.

BACKGROUND: Etravirine (ETR), a non-nucleoside reverse transcriptase inhibitor (NNRTI) available in France since 2006, is indicated for antiretroviral-experienced HIV-infected adults, in combination with a ritonavir-boosted protease inhibitor (PI). To assess its clinical impact in routine care, we compared hospitalization rates according to ETR + PI prescription or not, among heavily treated HIV-1 infected individuals on failing regimens between 2005 and 2011. METHODS: From the French Hospital Database on HIV (ANRS CO4), we selected heavily treated individuals (prior exposure to at least 2 nucleoside reverse transcriptase inhibitor (NRTI), 2PI and 1 NNRTI) with viral load (VL) > 50 copies/mL who started a new antiretroviral (ARV) regimen between 2005 and 2011. Using an intention-to-continue-treatment approach, hospitalization rates were calculated for the individuals who received ETR + PI, during the months after initiating ETR + PI (ETR + PI) or for the individuals who received ETR + PI, in the months before ETR + PI initiation and for the individuals who never received ETR + PI (no ETR + PI). hospitalization from an AIDS-defining cause and hospitalization from a non-AIDS defining cause rates were also calculated. Poisson regression models were used to compare the incidences between the two groups, with adjustment for potential confounders. RESULTS: Of 3884 patients who met the inclusion criteria, 838 (21.6%) received ETR + PI. During 13,986 person-years (P-Y) of follow-up, there were 2484 hospitalizations in 956 individuals. The hospitalization rates per 1000 P-Y were 169.0 among individuals exposed to ETR + PI and 179.3 among those not exposed to ETR + PI. After adjustment, the respective hospitalization rates were 148.8 and 186.7 per 1000 P-Y, with an estimated relative risk of 0.80 (95%CI: 0.71-0.90), AIDS hospitalization rates were 11.5 and 22.7 per 1000 P-Y, with an estimated relative risk of 0.51(95%CI: 0.39-0.66) and non-AIDS hospitalization rates were 139.5 and 152.2 per 1000 P-Y, with an estimated relative risk of 0.92 (95%CI: 0.80-1.05). CONCLUSIONS: Between 2005 and 2011, access to ETR + PI was associated with a 20% reduction in the hospitalization rate among heavily treated HIV-1-infected individuals. This reduction was mainly due to a reduction in the AIDS hospitalization rate.

Prevalence of and Risk Factors for Anal Oncogenic Human Papillomavirus Infection Among HIV-Infected Women in France in the Combination Antiretroviral Therapy Era.

BACKGROUND: Little is known about the type-specific prevalence of anal human papillomavirus (HPV) infection and risk factors for anal high-risk (HR) HPV infection in human immunodeficiency virus (HIV)-infected women. METHODS: A cross-sectional study of anal and cervical HPV infection was nested within a gynecological cohort of HIV-infected women. Specimens were tested for type-specific DNA using a polymerase chain reaction-based assay. RESULTS: The study population consisted of 311 women with a median age of 45.3 years, of whom 42.8% originated from sub-Saharan Africa and 96.8% were receiving combination antiretroviral therapy. The median CD4(+)cell count was 612/µL, and the HIV load was <50 copies/mL in 84.1%. HR-HPV types were detected in the anal canal in 148 women (47.6%) and in the cervix in 82 (26.4%). HPV-16 was the most prevalent type in both the anal canal (13.2% of women) and the cervix (5.1%). In multivariable analysis, factors associated with prevalent anal HR-HPV infection were CD4(+)count <350/µL (odds ratio, 2.9; 95% confidence interval, 1.3-6.5), concurrent cervical lesions (2.6; 1.0-4.3), and cervical HR-HPV infection (1.8; 1.0-3.2). CONCLUSIONS: The high prevalence of HR-HPV types, including HPV-16, in the anal canal of HIV-positive women is concerning. Anal cancer screening should be considered for HIV-positive women as part of their routine care.

Switching to Raltegravir From a Virologically Effective Boosted Protease Inhibitor Regimen: A Comparative Effectiveness Analysis From the French Hospital Database on HIV (FHDH-ANRS CO4).

BACKGROUND: In individuals with viral load (VL) suppression on a boosted protease inhibitor (PI) regimen, a switch to raltegravir (RAL) can be an option in case of comorbidities, but the SWITCHMRK trials challenged this strategy. Here, among individuals with VL suppression on a boosted PI, we compared outcomes between those who continued on the same regimen and those who switched to RAL. METHODS: In this cohort study from the French Hospital Database on HIV, each individual who switched to RAL was matched with up to 3 individuals who continued PI, were being followed up during the calendar period of the switch, and had the same duration of VL suppression (both ±6 months). The primary endpoint was a composite endpoint of hospitalization, or AIDS event or death, and secondary endpoints the immunovirologic responses. To control for measured confounders, the inverse probability treatment weighting (IPTW) method was applied to estimate hazards ratios between the 2 groups. RESULTS: We matched 282 RAL switchers with 838 nonswitchers. Although several variables differed significantly between the groups, including a higher prevalence of comorbidities in the RAL group, the IPTW method yielded standardized differences <10% for all variables. After IPTW, there was no difference in the risk of hospitalization or AIDS event or death between the 2 groups (13.6% and 10.5%, respectively; hazard ratio, 1.16 [95% confidence interval, .74-1.83]) and no difference in the likelihood of virologic failure or CD4 cell gain. CONCLUSIONS: In individuals with controlled VL on a boosted PI regimen who switched to RAL, none of the endpoints differed with nonswitchers after IPTW.

High Prevalence of Anal Human Papillomavirus-Associated Cancer Precursors in a Contemporary Cohort of Asymptomatic HIV-Infected Women.

BACKGROUND: Although human immunodeficiency virus (HIV)-infected women are at high risk for anal cancer, few data have been published on prevalence of and risk factors for anal precancer and potential screening strategies in this risk group. METHODS: A cross-sectional anal screening study was nested in a gynecological cohort of HIV-infected women. Anal swab specimens were collected for cytology and human papillomavirus (HPV) testing. High-resolution anoscopy, with biopsy when indicated, was systematically performed. RESULTS: Among the 171 enrolled women, median age was 47.3 years and 98% were receiving combination antiretroviral therapy. Median CD4(+) count was 655 cells/µL and HIV load was <50 copies/mL in 89% of subjects. High-grade anal intraepithelial neoplasia or worse (HG-AIN+) was diagnosed in 12.9% (n = 21). In multivariable analysis, a history of cervical squamous intraepithelial lesion (odds ratio [OR], 4.2; 95% confidence interval [CI], 1.1-16.4) and anal HPV-16 infection (OR, 16.1; 95% CI, 5.4-48.3) was associated with increased risk of HG-AIN+. Abnormal anal cytology and HPV-16 infection performed best as a screening strategy for HG-AIN+ histology, with positive likelihood ratios of 3.4 (95% CI, 2.3-5.1) and 4.7 (95% CI, 2.5-8.7) and negative likelihood ratios of 0.2 (95% CI, .07-.8) and 0.4 (95% CI, .2-.9), respectively. CONCLUSIONS: HIV-infected women with a history of HPV-associated cervical disease are at increased risk for HG-AIN+ and should be offered anal cancer screening. Anal cytology and HPV-16 genotyping had the best screening performance. Anal cytology is easy to perform routinely; it may be the best candidate for screening for HG-AIN among HIV-infected women.

Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study.

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.

Better health-related quality of life after switching from a virologically effective regimen to a regimen containing efavirenz or nevirapine.

Switching antiretroviral therapy has been shown as safe and effective, but its impact on health-related quality of life (HRQL) was rarely measured. Our objective was to assess changes in HRQL after switching to an non-nucleoside reverse transcriptase inhibitors (NNRTI) containing regimen among NNRTI-naive HIV-infected patients with viral load (VL) <500 copies/mL. In this prospective observational study, the Hospital Anxiety and Depression, Symptoms checklist, specific World Health Organization Quality of Life (WHOQoL) and generic SF-12v2 HRQL questionnaires were used to assess anxiety, depression, symptoms, and HRQL at baseline and months 1 (M1), 6 (M6), and 12 (M12). The statistical significance of changes in the frequency of anxiety and depression was determined with the McNemar test. Mean changes in the number of symptoms and in HRQL scores were compared using Wilcoxon's paired test. Data were available for 239 patients at baseline (162 with a switch to nevirapine) and for 164 patients at M6. The median age of the patients was 42 years and 67% of patients were male. The proportion of anxious patients diminished at M6 (11%, P=0.02) but not yet at M1. There was no change in the frequency of depression. Significant reductions (p<0.01) were observed at M6 in the mean number of all symptoms (-3.3), lipodystrophy symptoms (-0.8), other symptoms (-2.5), bothersome symptoms (-1.7), bothersome lipodystrophy symptoms (-0.4), and bothersome other symptoms (-1.3). HRQL as assessed with WHOQoL, improved in the physical, independence, and spirituality domains, with a small effect sizes at M6. Both for symptoms and HRQL, these changes were already significant at M1 and persisted at M12. This study shows that in patients with controlled VL, switching to an NNRTI regimen was associated with less anxiety, fewer perceived symptoms, and a small improvement in HRQL, while maintaining virological suppression.

HIV Infection and Long-Term Residual Cardiovascular Risk After Acute Coronary Syndrome.

Background It is unclear whether HIV infection affects the long-term prognosis after an acute coronary syndrome (ACS). The objective of the current study was to compare rates of major adverse cardiac and cerebrovascular events after a first ACS between people living with HIV (PLHIV) and HIV-uninfected (HIV-) patients, and to identify determinants of cardiovascular prognosis. Methods and Results Consecutive PLHIV and matched HIV- patients with a first episode of ACS were enrolled in 23 coronary intensive care units in France. Patients were matched for age, sex, and ACS type. The primary end point was major adverse cardiac and cerebrovascular events (cardiac death, recurrent ACS, recurrent coronary revascularization, and stroke) at 36-month follow-up. A total of 103 PLHIV and 195 HIV- patients (mean age, 49 years [SD, 9 years]; 94.0% men) were included. After a mean of 36.6 months (SD, 6.1 months) of follow-up, the risk of major adverse cardiac and cerebrovascular events was not statistically significant between PLHIV and HIV- patients (17.8% and 15.1%, P=0.22; multivariable hazard ratio [HR], 1.60; 95% CI, 0.67-3.82 [P=0.29]). Recurrence of ACS was more frequent among PLHIV (multivariable HR, 6.31; 95% CI, 1.32-30.21 [P=0.02]). Stratified multivariable Cox models showed that HIV infection was the only independent predictor for ACS recurrence. PLHIV were less likely to stop smoking (47% versus 75%; P=0.01) and had smaller total cholesterol decreases (-22.3 versus -35.0 mg/dL; P=0.04). Conclusions Although the overall risk of major adverse cardiac and cerebrovascular events was not statistically significant between PLHIV and HIV- individuals, PLHIV had a higher rate of recurrent ACS. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00139958.

Anticardiolipin antibodies in HIV infection are independently associated with antibodies to the membrane proximal external region of gp41 and with cell-associated HIV DNA and immune activation.

BACKGROUND: The demonstration of in vitro cardiolipin reactivity with 2 human immunodeficiency virus (HIV)-specific, broadly neutralizing antibodies (2F5 and 4E10) has prompted reevaluation of autoimmune manifestations in HIV infection. METHODS: We evaluated autoantibodies, particularly anticardiolipin (aCL), in 67 untreated, asymptomatic, HIV-infected individuals with slow progression of HIV disease and their correlation with 2F5-, 4E10-, b12-, and 2G12-like antibodies directed against epitopes involved in broad neutralization, as well as their correlation with immune activation and virological and clinical indicators. Fifty individuals with chronic HIV infection and standard disease progression were control patients. RESULTS: The majority of the study patients with slow progression of HIV disease were men (78%); their median age was 37 years, their median CD4+ cell count was 672 cells/mL, and their median plasma HIV load was 6200 copies/mL. The majority of the control patients were also men (76%), and most (62%) were receiving highly active antiretroviral therapy; their median age was 43 years, their median CD4+ cell count was 202 cells/mL, and their median plasma HIV load was 2265 copies/mL. aCL immunoglobulin G was detected at similar levels in 49% of patients with slow progression of HIV disease and in 58% of control patients. Viral load was positively associated with aCL in both groups (P < .001), independent of CD4+ cell counts. In patients with slow progression of HIV disease, aCL levels were also correlated with plasma HIV load and cell-associated DNA level (r = 0.486 and r = 0.516, respectively; P < .001), with the proportion of activated CD4+ cells, human leukocyte antigen-DR+ cells (r = 0.445; P = or < .001) but not activated CD8+ T cells, and with the level of B cell activation (quantified by soluble CD23; r = 0.354; P = .007). The level of aCL antibodies was associated with the level of antibodies to the membrane proximal region of gp41 (P = .003). CONCLUSION: aCL is frequently detected in HIV-infected patients, regardless of disease stage, and is strongly linked with the level of viral replication, the level of CD4+ T and B cell activation, and the level of antibodies to the membrane proximal external region of gp41, independent of CD4+ cell deficiency.

Impact of Antiretroviral Drugs on Fracture Risk in HIV-Infected Individuals: A Case-Control Study Nested Within the French Hospital Database on HIV (FHDH-ANRS CO4).

BACKGROUND: HIV-infected patients have lower bone mineral density and a higher incidence of fractures than the general population of the same age and sex. To assess the impact of antiretroviral (ARV) drugs exposure on the risk of osteoporotic fractures, we conducted a nested case-control study. METHODS: Cases were individuals enrolled while ARV-naive, with a first prospectively recorded fracture between 2000 and 2010. Controls were randomly selected after matching for sex, age (±3 years), period of HIV diagnosis (<1997/≥1997), and clinical center. The risk of fracture was analyzed with conditional logistic regression models, using different ways to model ARV exposure. All exposure variables and potential confounders were included in multivariable models. RESULTS: Among 861 reviewed cases, 261 fractures were osteoporotic and 254 of cases were matched to at least one control (376 controls). The median year of fracture diagnosis was 2007 (interquartile range 2004-2009): 49% of patients had been exposed to tenofovir disoproxil fumarate (TDF) and 82% to protease inhibitors (PIs). After taking into account the transmission group, AIDS status, geographic origin, body mass index, current smoking status, alcohol consumption, exposure to systemic glucocorticoids, and the period of enrollment, there was no association between the risk of fracture and exposure to TDF [odds ratio for cumulative exposure: 1.04 (0.86-1.27), similar results for ever-exposed subjects], to nucleoside reverse transcriptase inhibitors, or to PIs [odds ratio for cumulative PI exposure: 1.02 (0.92-1.12)]. CONCLUSIONS: We found no evidence of an excess risk of fracture after exposure to TDF or PIs. This has important implications for the debate concerning tenofovir alafenamide versus generic TDF.

First-line highly active antiretroviral regimens in 2001-2002 in the French Hospital Database on HIV: combination prescribed and biological outcomes.

INTRODUCTION: We compared biological outcomes in antiretroviral-naive patients with viral load (VL) > 5,000 copies/ml starting combivir-based, three-drug highly active antiretroviral therapy regimens in 2001-2002 according to the third component, namely abacavir (ABC), nelfinavir (NFV), indinavir/ritonavir (IDV/r), lopinavir/ritonavir (LPV/r), nevirapine (NVP) or efavirenz (EFV). METHODS: We evaluated virological response (HIV RNA < 500 copies/ml) and immunological response (increase of > or = 50 CD4+ T-cells/microl) separately in patients with baseline VL < 100,000 copies/ml (n = 992) and a100,000 copies/ml (n = 1,048). Hazard ratios (HR) were calculated with Cox models stratified for quintiles of propensity scores, estimated by multinomial regression from baseline characteristics. RESULTS: Median follow up was 19 months. EFV had better virological efficacy than NFV and IDV/r among patients with baseline VL < 100,000 copies/ml, with respective HRs of 0.71 and 0.72, compared with 0.81 for NVP, 0.89 for ABC and 0.99 for LPV/r. The immunological efficacy of EFV was lower than that of LPV/r (1.37) and similar to that of NFV (0.96), IDV/r (0.81), NVP (1.08) and ABC (1.04). Among patients with baseline VL > or = 100,000 copies/ml, the virological efficacy of EFV was similar to that of NVP (0.90) and LPV/r (0.97) and better than that of NFV (0.62), ABC (0.75) and IDV/r (0.78). The immunological results found in these patients were similar to those observed in patients with baseline VL < 100,000 copies/ml. CONCLUSIONS: For first-line therapy, in this observational setting, EFV, LPV/r and NVP, when added to the combivir backbone, were more likely to drive viral load < 500 copies/ml. LPV/r showed the best immunological effectiveness.

Neutralizing Antibodies Against a Specific Human Immunodeficiency Virus gp41 Epitope are Associated With Long-term Non-progressor Status.

Antibodies (Abs) play a central role in human immunodeficiency virus (HIV) protection due to their multiple functional inhibitory activities. W614A-3S Abs recognize a specific form of a highly conserved motif of the gp41 envelope protein and can elicit viral neutralization to protect CD4+ T cells. Here, we describe in detail the neutralizing profile of W614A-3S Abs in untreated long-term non-progressor (LTNP) HIV-infected patients. W614A-3S Abs were detected in 23.5% (16/68) of untreated LTNP patients compared with <5% (5/104) of HIV-1 progressor patients. The W614A-3S Abs had efficient neutralizing activity that inhibited transmitted founder primary viruses and exhibited Fc-mediated inhibitory functions at low concentrations in primary monocyte-derived macrophages. The neutralizing capacity of W614A-3S Abs was inversely correlated with viral load (r=-0.9013; p<0.0001), viral DNA (r=-0.7696; p=0.0005) and was associated the preservation of high CD4+ T-cell counts and T-cell responses. This study demonstrates that W614A-3S neutralizing Abs may confer a crucial advantage to LTNP patients. These results provide insights for both pathophysiological research and the development of vaccine strategies.

Limited impact of immunosuppression and HAART on the incidence of cervical squamous intraepithelial lesions in HIV-positive women.

BACKGROUND: Although highly active antiretroviral therapy (HAART) has lowered the incidence of various opportunistic diseases, its impact on cervical squamous intraepithelial lesions (SILs) is unclear. Our objective was to compare the incidence of SILs in HIV-infected women receiving HAART versus those not receiving HAART and to determine the role of risk factors including immunosuppression in the pathogenesis of SIL. METHODS: A total of 298 HIV-infected women with normal Papanicolaou (Pap) smear and normal colposcopic findings at enrollment were followed-up until incident SIL or last follow-up visit. Cox regression modelling was used to assess risks factors for incident SIL. RESULTS: Eighty-eight women developed SILs, including 75 low-grade lesions, during a median follow-up of 28 months (16-52; incidence of 8.7 cases per 100 person-years). No invasive cervical cancers were identified. Incidence decreased from 10.7 to 6.5 per 100 person-years in non-receiving versus receiving HAART women (relative risk [RR]: 0.7; 95% confidence interval [CI]: 0.4-1.2, P=0.15, from the adjusted Cox model). Incident SIL was not associated to low CD4+ T-cell count (P=0.54). In multivariate analysis, the only significant risk factor for incident lesion was the age between 30-39 compared with over 40 (RR: 3.5; 95% CI: 1.4-8.9; P=0.02). CONCLUSION: No impact in the development of SIL was evidenced for CD4+ T-cell counts, but we cannot exclude a modest impact of HAART. All HIV-positive women should be offered to participate in cervical cancer screening programmes whether or not they receive effective antiretroviral therapy.

Impact of newly available drugs on clinical progression in patients with virological failure after exposure to three classes of antiretrovirals.

OBJECTIVE: To study the prognosis of HIV-infected patients with virological failure after exposure to three classes of antiretroviral drugs (ARVs). DESIGN: Cohort study. SETTING: French Hospital Database on HIV. PATIENTS: Patients previously exposed to at least two nucleoside reverse transcriptase inhibitors (NRTIs), two protease inhibitors and one non-NRTI, with viral load (/L) values of > 5000 copies/ml after the exposure criteria were met and a new treatment initiated between 1998 and 2001 with VL > 5000 copies/ml. MAIN OUTCOME MEASURES: Risk of new AIDS-defining-events (ADEs) or death from first introduction of a drug never used before occurring between 1998 and 2001 defined as baseline. RESULTS: The main baseline characteristics of the 1092 patients were: previous ADE in 49% of cases, median CD4 cell count 181 microl, median VL 4.9 log10 copies/ml, median duration of ARV therapy 5.0 years and previous exposure to a median of nine ARVs. The crude progression rates were 20.1/100 patient-years among patients included in 1998, 15.1 in 1999, 11.1 in 2000 and 8.6 in 2001. After adjustment for baseline characteristics, the calendar year of inclusion was associated with the risk of clinical progression (P < 0.001). When the types of newly available drugs used at baseline or during follow-up were introduced into the model, year of inclusion was no longer associated with the risk of clinical progression (P = 0.42), while exposure to amprenavir/r, lopinavir/r, abacavir or tenofovir was associated with a lower risk. CONCLUSIONS: The clinical prognosis of heavily pretreated patients experiencing virological failure improved between 1998 and 2001, mainly thanks to the use of newly available drugs with more favourable resistance profiles.

Durability and Effectiveness of Maraviroc-Containing Regimens in HIV-1-Infected Individuals with Virological Failure in Routine Clinical Practice.

INTRODUCTION: Limited data are available on the durability and effectiveness of maraviroc in routine clinical practice. We assessed the durability of maraviroc-containing regimens during a 30-month period, as well as their immunovirological and clinical efficacy, according to viral tropism in treatment-experienced individuals with viral load (VL) >50 copies/ml in the French Hospital Database on HIV. METHODS: Virological success was defined as VL<50 copies/ml, immunological success as a confirmed increase of at least 100 CD4 cells/mm3 measured twice at least one month apart, and clinical failure as hospitalization for a non-AIDS event, an AIDS event, or death. Multivariable Cox regression models adjusted for potential confounders were used to assess the influence of viral tropism on durability, the immunovirological responses, and clinical outcome. RESULTS: 356 individuals started maraviroc with VL>50 copies/ml of whom 223 harbored R5 viruses, 44 non-R5 viruses and 89 viruses of unknown tropism. Individuals with non-R5 viruses were more likely than individuals with R5 viruses to discontinue maraviroc (75% vs 34%, p<0.0001). At 30 months, the estimated rates of virological and immunological success were respectively 89% and 51% in individuals with R5 viruses and 48% and 23% in individuals with non-R5 viruses. In multivariable analysis, non-R5 viruses were associated with a lower likelihood of both virological success (hazard ratio (HR): 0.42; 95% confidence interval (CI), 0.25-0.70) and immunological success (HR: 0.37; 95% CI, 0.18-0.77). No difference in clinical outcome was found between individuals with R5 and non-R5 viruses. The effectiveness of maraviroc-containing regimens in individuals with unknown viral tropism was not significantly different from that in individuals with R5 viruses. A limitation of the study is the absence of genotypic susceptibility score. CONCLUSION: In this observational study, maraviroc-containing regimens yielded high rates of viral suppression and immunological responses in individuals with R5 viruses in whom prior regimens had failed.