Rémonie Seng

When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study.

BACKGROUND Most clinical guidelines recommend that AIDS-free, HIV-infected persons with CD4 cell counts below 0.350 × 10(9) cells/L initiate combined antiretroviral therapy (cART), but the optimal CD4 cell count at which cART should be initiated remains a matter of debate. OBJECTIVE To identify the optimal CD4 cell count at which cART should be initiated. DESIGN Prospective observational data from the HIV-CAUSAL Collaboration and dynamic marginal structural models were used to compare cART initiation strategies for CD4 thresholds between 0.200 and 0.500 × 10(9) cells/L. SETTING HIV clinics in Europe and the Veterans Health Administration system in the United States. PATIENTS 20, 971 HIV-infected, therapy-naive persons with baseline CD4 cell counts at or above 0.500 × 10(9) cells/L and no previous AIDS-defining illnesses, of whom 8392 had a CD4 cell count that decreased into the range of 0.200 to 0.499 × 10(9) cells/L and were included in the analysis. MEASUREMENTS Hazard ratios and survival proportions for all-cause mortality and a combined end point of AIDS-defining illness or death. RESULTS Compared with initiating cART at the CD4 cell count threshold of 0.500 × 10(9) cells/L, the mortality hazard ratio was 1.01 (95% CI, 0.84 to 1.22) for the 0.350 threshold and 1.20 (CI, 0.97 to 1.48) for the 0.200 threshold. The corresponding hazard ratios were 1.38 (CI, 1.23 to 1.56) and 1.90 (CI, 1.67 to 2.15), respectively, for the combined end point of AIDS-defining illness or death. LIMITATIONS CD4 cell count at cART initiation was not randomized. Residual confounding may exist. CONCLUSION Initiation of cART at a threshold CD4 count of 0.500 × 10(9) cells/L increases AIDS-free survival. However, mortality did not vary substantially with the use of CD4 thresholds between 0.300 and 0.500 × 10(9) cells/L.

Increasing HIV-1 Non-B Subtype Primary Infections in Patients in France and Effect of HIV Subtypes on Virological and Immunological Responses to Combined Antiretroviral Therapy

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_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.

Impact of antiretroviral therapy on tuberculosis incidence among HIV-positive patients in high-income countries.

BACKGROUND The lower tuberculosis incidence reported in human immunodeficiency virus (HIV)-positive individuals receiving combined antiretroviral therapy (cART) is difficult to interpret causally. Furthermore, the role of unmasking immune reconstitution inflammatory syndrome (IRIS) is unclear. We aim to estimate the effect of cART on tuberculosis incidence in HIV-positive individuals in high-income countries. METHODS The HIV-CAUSAL Collaboration consisted of 12 cohorts from the United States and Europe of HIV-positive, ART-naive, AIDS-free individuals aged ≥18 years with baseline CD4 cell count and HIV RNA levels followed up from 1996 through 2007. We estimated hazard ratios (HRs) for cART versus no cART, adjusted for time-varying CD4 cell count and HIV RNA level via inverse probability weighting. RESULTS Of 65 121 individuals, 712 developed tuberculosis over 28 months of median follow-up (incidence, 3.0 cases per 1000 person-years). The HR for tuberculosis for cART versus no cART was 0.56 (95% confidence interval [CI], 0.44-0.72) overall, 1.04 (95% CI, 0.64-1.68) for individuals aged >50 years, and 1.46 (95% CI, 0.70-3.04) for people with a CD4 cell count of <50 cells/μL. Compared with people who had not started cART, HRs differed by time since cART initiation: 1.36 (95% CI, 0.98-1.89) for initiation <3 months ago and 0.44 (95% CI, 0.34-0.58) for initiation ≥3 months ago. Compared with people who had not initiated cART, HRs <3 months after cART initiation were 0.67 (95% CI, 0.38-1.18), 1.51 (95% CI, 0.98-2.31), and 3.20 (95% CI, 1.34-7.60) for people <35, 35-50, and >50 years old, respectively, and 2.30 (95% CI, 1.03-5.14) for people with a CD4 cell count of <50 cells/μL. CONCLUSIONS Tuberculosis incidence decreased after cART initiation but not among people >50 years old or with CD4 cell counts of <50 cells/μL. Despite an overall decrease in tuberculosis incidence, the increased rate during 3 months of ART suggests unmasking IRIS.

No evidence of a change in HIV-1 virulence since 1996 in France

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.

Rapid CD4+ cell decrease after transient cART initiated during primary HIV infection (ANRS PRIMO and SEROCO cohorts).

Objective:To modelize the rate of CD4+ cell count decline and its determinants after cessation of combination antiretroviral therapy (cART) started during primary HIV infection (PHI) and compare it with never-treated patients. Methods:Kinetics of CD4+ counts were analyzed on the square root scale by using a mixed-effects model in 170 patients who received cART during PHI from the Primary Infection (PRIMO) cohort and 123 never-treated patients from the Seroconverters (SEROCO) cohort. Results:After cART interruption in the PRIMO cohort, the CD4+ cell count fell rapidly during the first 5 months and more slowly thereafter. The timing of treatment initiation had no influence on the rate of CD4+ cell decline. In contrast, a larger increase in CD4+ cell counts during cART was associated with a steeper decline and a larger loss of CD4+ cells after treatment interruption. The mean CD4+ cell loss 3 years postinterruption was 383 cells per microliter. In the SEROCO cohort, the CD4+ T-cell decline was less steep (3-year CD4+ loss 239 cells/μL). As a result, the mean CD4+ cell counts were similar (416 cells/μL) 3 years after cART interruption (PRIMO) or after infection (SEROCO). Conclusions:These data question the benefit of a limited course of cART even when initiated within 3 months after PHI diagnosis.

Blood Epstein–Barr virus DNA load and risk of progression to AIDS-related systemic B lymphoma

AIDS‐related lymphoma (ARL) remains the main cause of AIDS‐related deaths in the combined antiretroviral therapy (cART) era. Although most ARLs are associated with the Epstein–Barr virus (EBV), whether patients with high EBV burden are more at risk of developing ARL is unknown. This study investigated the relationship between high blood EBV DNA loads and subsequent progression to ARL.

Comparative effectiveness of immediate antiretroviral therapy versus CD4-based initiation in HIV-positive individuals in high-income countries: observational cohort study

BACKGROUND Recommendations have differed nationally and internationally with respect to the best time to start antiretroviral therapy (ART). We compared effectiveness of three strategies for initiation of ART in high-income countries for HIV-positive individuals who do not have AIDS: immediate initiation, initiation at a CD4 count less than 500 cells per μL, and initiation at a CD4 count less than 350 cells per μL. METHODS We used data from the HIV-CAUSAL Collaboration of cohort studies in Europe and the USA. We included 55,826 individuals aged 18 years or older who were diagnosed with HIV-1 infection between January, 2000, and September, 2013, had not started ART, did not have AIDS, and had CD4 count and HIV-RNA viral load measurements within 6 months of HIV diagnosis. We estimated relative risks of death and of death or AIDS-defining illness, mean survival time, the proportion of individuals in need of ART, and the proportion of individuals with HIV-RNA viral load less than 50 copies per mL, as would have been recorded under each ART initiation strategy after 7 years of HIV diagnosis. We used the parametric g-formula to adjust for baseline and time-varying confounders. FINDINGS Median CD4 count at diagnosis of HIV infection was 376 cells per μL (IQR 222-551). Compared with immediate initiation, the estimated relative risk of death was 1·02 (95% CI 1·01-1·02) when ART was started at a CD4 count less than 500 cells per μL, and 1·06 (1·04-1·08) with initiation at a CD4 count less than 350 cells per μL. Corresponding estimates for death or AIDS-defining illness were 1·06 (1·06-1·07) and 1·20 (1·17-1·23), respectively. Compared with immediate initiation, the mean survival time at 7 years with a strategy of initiation at a CD4 count less than 500 cells per μL was 2 days shorter (95% CI 1-2) and at a CD4 count less than 350 cells per μL was 5 days shorter (4-6). 7 years after diagnosis of HIV, 100%, 98·7% (95% CI 98·6-98·7), and 92·6% (92·2-92·9) of individuals would have been in need of ART with immediate initiation, initiation at a CD4 count less than 500 cells per μL, and initiation at a CD4 count less than 350 cells per μL, respectively. Corresponding proportions of individuals with HIV-RNA viral load less than 50 copies per mL at 7 years were 87·3% (87·3-88·6), 87·4% (87·4-88·6), and 83·8% (83·6-84·9). INTERPRETATION The benefits of immediate initiation of ART, such as prolonged survival and AIDS-free survival and increased virological suppression, were small in this high-income setting with relatively low CD4 count at HIV diagnosis. The estimated beneficial effect on AIDS is less than in recently reported randomised trials. Increasing rates of HIV testing might be as important as a policy of early initiation of ART. FUNDING National Institutes of Health.

HIV-1 co-infection prevalence in two cohorts of early HIV-1 seroconverters in France.

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.

Using observational data to emulate a randomized trial of dynamic treatment-switching strategies: an application to antiretroviral therapy

Background When a clinical treatment fails or shows suboptimal results, the question of when to switch to another treatment arises. Treatment switching strategies are often dynamic because the time of switching depends on the evolution of an individuals time-varying covariates. Dynamic strategies can be directly compared in randomized trials. For example, HIV-infected individuals receiving antiretroviral therapy could be randomized to switching therapy within 90 days of HIV-1 RNA crossing above a threshold of either 400 copies/ml (tight-control strategy) or 1000 copies/ml (loose-control strategy). Methods We review an approach to emulate a randomized trial of dynamic switching strategies using observational data from the Antiretroviral Therapy Cohort Collaboration, the Centers for AIDS Research Network of Integrated Clinical Systems and the HIV-CAUSAL Collaboration. We estimated the comparative effect of tight-control vs. loose-control strategies on death and AIDS or death via inverse-probability weighting. Results Of 43 803 individuals who initiated an eligible antiretroviral therapy regimen in 2002 or later, 2001 met the baseline inclusion criteria for the mortality analysis and 1641 for the AIDS or death analysis. There were 21 deaths and 33 AIDS or death events in the tight-control group, and 28 deaths and 41 AIDS or death events in the loose-control group. Compared with tight control, the adjusted hazard ratios (95% confidence interval) for loose control were 1.10 (0.73, 1.66) for death, and 1.04 (0.86, 1.27) for AIDS or death. Conclusions Although our effective sample sizes were small and our estimates imprecise, the described methodological approach can serve as an example for future analyses.

When to monitor CD4 cell count and HIV RNA to reduce mortality and aids-defining illness in virologically suppressed hiv-positive persons on antiretroviral therapy in high-income countries: A prospective observational study

Objective: To illustrate an approach to compare CD4 cell count and HIV-RNA monitoring strategies in HIV-positive individuals on antiretroviral therapy (ART). Design: Prospective studies of HIV-positive individuals in Europe and the USA in the HIV-CAUSAL Collaboration and The Center for AIDS Research Network of Integrated Clinical Systems. Methods: Antiretroviral-naive individuals who initiated ART and became virologically suppressed within 12 months were followed from the date of suppression. We compared 3 CD4 cell count and HIV-RNA monitoring strategies: once every (1) 3 ± 1 months, (2) 6 ± 1 months, and (3) 9–12 ± 1 months. We used inverse-probability weighted models to compare these strategies with respect to clinical, immunologic, and virologic outcomes. Results: In 39,029 eligible individuals, there were 265 deaths and 690 AIDS-defining illnesses or deaths. Compared with the 3-month strategy, the mortality hazard ratios (95% CIs) were 0.86 (0.42 to 1.78) for the 6 months and 0.82 (0.46 to 1.47) for the 9–12 month strategy. The respective 18-month risk ratios (95% CIs) of virologic failure (RNA >200) were 0.74 (0.46 to 1.19) and 2.35 (1.56 to 3.54) and 18-month mean CD4 differences (95% CIs) were −5.3 (−18.6 to 7.9) and −31.7 (−52.0 to −11.3). The estimates for the 2-year risk of AIDS-defining illness or death were similar across strategies. Conclusions: Our findings suggest that monitoring frequency of virologically suppressed individuals can be decreased from every 3 months to every 6, 9, or 12 months with respect to clinical outcomes. Because effects of different monitoring strategies could take years to materialize, longer follow-up is needed to fully evaluate this question.