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Objectives: The aim of this work was to provide a reference for the CD4 T-cell count response in the early months after the initiation of combination antiretroviral therapy (cART) in HIV-1-infected patients., Methods: All patients in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) cohort who were aged ≥ 18 years and started cART for the first time between 1 January 2005 and 1 January 2010 and who had at least one available measurement of CD4 count and a viral load ≤ 50 HIV-1 RNA copies/mL at 6 months (± 3 months) after cART initiation were included in the study. Unadjusted and adjusted references curves and predictions were obtained using quantile regressions., Results: A total of 28 992 patients were included in the study. The median CD4 T-cell count at treatment initiation was 249 [interquartile range (IQR) 150, 336] cells/μL. The median observed CD4 counts at 6, 9 and 12 months were 382 (IQR 256, 515), 402 (IQR 274, 543) and 420 (IQR 293, 565) cells/μL. The two main factors explaining the variation of CD4 count at 6 months were AIDS stage and CD4 count at cART initiation. A CD4 count increase of ≥ 100 cells/mL is generally required in order that patients stay 'on track' (i.e. with a CD4 count at the same percentile as when they started), with slightly higher gains required for those starting with CD4 counts in the higher percentiles. Individual predictions adjusted for factors influencing CD4 count were more precise., Conclusions: Reference curves aid the evaluation of the immune response early after antiretroviral therapy initiation that leads to viral control., (© 2016 British HIV Association.)

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.

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: Limited treatment options have been available for people with HIV who have had virological failure of the three original classes of HIV antiretroviral drugs-so-called triple-class virological failure (TCVF). However, introduction of new drugs and drug classes might have improved outcomes. We aimed to assess trends in virological and clinical outcomes for individuals with TCVF in 2000-09., Methods: In our cohort study, we analysed data for adults starting antiretroviral therapy from 1998 in cohorts participating in the PLATO II project, which is part of COHERE, a collaboration of European cohorts. TCVF was defined as virological failure to at least two nucleoside reverse transcriptase inhibitors, one non-nucleoside reverse-transcriptase inhibitor, and one ritonavir-boosted protease inhibitor, with virological failure of a drug defined as one viral-load measurement of greater than 500 copies per mL after at least 4 months of continuous use. We used multivariable generalised estimating equation logistic models and Poisson regression models to study trends in virological suppression and incidence of AIDS or death after TCVF. We adjusted for sex, transmission group, age, AIDS status, CD4 cell count, plasma viral loads at TCVF, achievement of virological response (<50 copies per mL), and number of drug failures before TCVF., Findings: 28 of 33 cohorts in COHERE contributed data to the PLATO II project, of which four had no participants eligible for inclusion in this study. 2476 (3%) of 91 764 participants from the remaining 24 cohorts had TCVF and at least one viral load measurement in 2000-09. The proportion of patients with virological response after TCVF increased from 19·5% in 2000 to 57·9% in 2009 (adjusted p<0·0001). Incidence of AIDS decreased from 7·7 per 100 person-years in 2000-02 to 2·3 in 2008 and 1·2 in 2009 (adjusted p<0·0001). Mortality decreased from 4·0 per 100 person-years between 2000 and 2002 to 1·9 in 2007 and 1·4 in 2008 (unadjusted p=0·023), but the trend was not significant after adjustment (p=0·22)., Interpretation: A substantial improvement in viral load suppression and accompanying decrease in the rates of AIDS in people after extensive failure to drugs from the three original antiretroviral classes during 2000-09 was probably mainly driven by availability of newer drugs with better tolerability and ease of use and small cross-resistance profiles, suggesting the public health benefit of the introduction of new drugs., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

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.

Background: In cohort or longitudinal studies, subjects are recruited some time after the beginning of the problem, as in HIV infection. The aim of this paper is to show several imputation techniques of the beginning of follow up and evaluate its use in the framework of a study of HIV progression., Methods: Three subcohorts of HIV+ subjects recruited in Valencia and Castellón CIPS up to 1996 are available. Seroconversion date was estimated for 244 Seroincidents, 887 seroprevalents with CD4 measurements and 337 without CD4 measurements. For seroincidents midpoint between last HIV- and first HIV+ visits was considered. For prevalent with CD4 serocon version date was imputed from 5 random samples of a progression model of infection to a CD4 level. For prevalent without CD4 seroconversion date was imputed from 5 random samples of HIV incidence density obtained from the other subcohorts. The imputation was repeated 500 times, assigning the seroconversion date as the median of imputations and obtaining confidence limits from 5 and 95 percentiles. Imputation validity was tested comparing time to AIDS and death for each one of the 3 groups., Results: 443 and 405 deaths were observed among the 1468 subjects. Median of seroconversion was January 1993 for incidents, January 1991 for prevalents with CD4 and November 1988 for prevalents without CD4. The latest group showed a worse survival and AIDS free time compared to the other two cohorts., Conclusions: The imputation tools used showed their usefulness to reduce the survival bias in observational studies. Their generalization depends on the viability of incident cohorts, the availability of a progression marker or a origin on time.

Background: Although studies have reported large reductions in the risks of AIDS and death since the introduction of potent anti-retroviral therapies, few have evaluated whether this has been similar for all AIDS-defining diseases. We wished to evaluate changes over time in the risk of specific AIDS-defining diseases, as first events, using data from individuals with known dates of HIV seroconversion., Methods: Using a competing risks proportional hazards model on pooled data from 20 cohorts (CASCADE), we evaluated time from HIV seroconversion to each first AIDS-defining disease (16 groups) and to death without AIDS for four calendar periods, adjusting for exposure category, age, sex, acute infection, and stratifying by cohort. We compared results to those obtained from a cause-specific hazards model., Results: Of 6,941, 2,021 (29%) developed AIDS and 437 (6%) died without AIDS. The risk of AIDS or death remained constant to 1996 then reduced; relative hazard = 0.89 (95% CI: 0.77-1.03); 0.90 (95% CI: 0.81-1.01); and 0.32 (95% CI: 0.28-0.37) for 1979-1990, 1991-1993, and 1997-2001, respectively, compared to 1994-1996. Significant risk reductions in 1997-2001 were observed in all but two AIDS-defining groups and death without AIDS in a competing risks model (with similar results from a cause-specific model). There was significant heterogeneity in the risk reduction across events; from 96% for cryptosporidiosis, to 17% for death without AIDS (P < 0.0001)., Conclusion: These findings suggest that studies reporting a stable trend for particular AIDS diseases over the period 1979-2001 may not have accounted for the competing risks among other events or lack the power to detect smaller trends.

Our objective was to describe and compare the trends of incidence and prevalence of HIV-1 infection in intravenous drug users (IDUs) in Valencia, Spain in 1987-1992. A cohort study was carried out in AIDS Information Centers located in the Valencia Region (Spain). Point seroprevalence was calculated for in each year according to HIV status at the first contact. Incidence annual rates were calculated from those IDUs identified as seronegative in their first visit and who returned for a new testing. From a total of 4,207 IDUs who contacted these centers, 4,131 (98.2%) asked voluntarily for HIV-1 testing. The seroprevalence for the whole period was 48.4% (95% C.I., 46.88, 49.92). Follow-up information was available for 604 subjects of the total 2,130 subjects who were seronegative in their first visit. The incidence rate for the 1988-1992 period was 12.02/100 person-years (95% C.I., 9.62, 14.41). Prevalence showed an overall decreasing pattern with a minimum corresponding to the year 1992 (43.6%). Incidence rates increased mildly until 1990 (13.93 per 100 person-years), to stabilize beyond at approximately 10 per 100 person-years. Our incidence rates are very high regardless of the decline of prevalence. Effective risk reduction programs among IDUs have been almost nonexistent in Spain up to now and should become an immediate priority.

Background: In order to identify, in a sample of heroin intravenous drug users (IVDU), those factors associated with the predominant risk behaviour related to the transmission of HIV-1 infection--sharing of injection equipment--a cross-sectional survey was carried out in Valencia, Spain from 1987 to 1992., Methods: Informed consent and pertinent data were obtained from 3755 heroin IVDU recruited at two public AIDS Information Centres in two cities in the region of Valencia. Data were gathered on sociodemographic variables, and sexual and drug use behaviour by interview. The subjects were subsequently tested for HIV-1 antibody. A univariate analysis was carried out to identify variables that were significantly associated with sharing injection equipment. A logistic regression model was used to control for possible confounders., Results: The IVDU who were teenagers, prostitutes (OR = 1.95), who had antibodies to HIV-1 (OR = 1.30) or who had an IVDU steady partner were at significantly higher risk for sharing of injection equipment. Higher levels of education, condom use (OR = 0.65) and living in the smaller city (OR = 0.75) were inversely related to sharing injection equipment., Conclusions: Our results suggest that different subgroups of IVDU have different characteristics that place them at different risk for HIV-1 infection. These characteristics should guide the design and intensity of specific preventive interventions. Teenagers and IVDU with low educational levels should be targetted for special attention by health authorities.

Background: Cohort studies estimating rates of incidence are scarce despite they are the most appropriate for following the epidemics of HIV-1 and evaluating the effectiveness of preventive interventions. The rate of incidence of infection by HIV-1 in intravenous drug users (IVDU) and the determining factors for such infection are estimated in the present study., Methods: 3,693 IVDU attended in two centers for information and prevention of AIDS from 1987-1992, were included in the study. Out of 1,868 seronegative subjects, 579 attended a second visit in which a new serologic test was performed against HIV-1. The rates of incidence and 95% confidence intervals were calculated with a Poisson regression model being adjusted in order to control the confounding factors., Results: The estimated global incidence was 11.7/100 people/year (CI 95%: 9.6; 14.46). Those highest rates were observed in IVDU who exchanged syringes (23.5/100 people/year), in those who had more than one sexual partner in the previous month (21.2/100 people/year), in those referring a history of prostitution (22.6/100 people/year), in carriers of hepatitis B antigens (25.6/100 people/year) and in the IVDU younger than 20 years of age (16.5/100 people/year). The variables which independently predicted the rates of incidence were: the exchange of syringes (RR = 6.85; CI 95%: 3.99; 11.75), having more than one different sexual partner in the previous month (RR = 3.51; CI 95%: 1.70; 7.20) and age, with lower risk in those under the age of 20 (RR = 0.49; CI 95%: 0.25; 0.95)., Conclusions: The incidence of infection by type-1 human immunodeficiency virus observed in intravenous drug users is the highest described in Western countries. Preventive measures in general must be intensified particularly in subgroups of intravenous drug users with the greatest risk of seroconversion.