Sophie Abgrall

Prevalence and comparative characteristics of long-term nonprogressors and HIV controller patients in the French Hospital Database on HIV.

Objective:To estimate the prevalence and characteristics of long-term nonprogressor (LTNP) and HIV controller patients in a very large French cohort of HIV1-infected patients. Methods:In the French Hospital Database on HIV [FHDH, Agence Nationale de Recherches sur le SIDA et les hépatites virales (ANRS) CO4], we selected patients who had been seen in 2005, who had been infected for more than 8 years, who were treatment-naive, and who remained asymptomatic. Patients with these characteristics then categorized as follows: LTNP (≥8 years of HIV infection and CD4 cell nadir ≥500/μl), elite LTNP (≥8 years of HIV infection, CD4 cell nadir ≥600/μl, and a positive CD4 slope), HIV controllers (>10 years of HIV infection with 90% of plasma viral load values ≤500 copies/ml), and elite controllers (same as HIV controllers, but with last plasma viral load value ≤50 copies/ml in 2005). Results:Among the 46 880 HIV1-infected patients followed in 2005 in the French Hospital Database on HIV, 0.4% (N = 202) were LTNP, 0.05% (N = 25) were elite LTNP, 0.22% (N = 101) were HIV controllers, and 0.15% (N = 69) were elite controllers. Ten elite LTNP patients (40%) were also HIV controllers, eight (32%) were elite controllers, and 60% had detectable plasma viral load (>50 copies/ml). Among the elite controllers, 32 (46%) were LTNP, eight (12%) were elite LTNP, and one-quarter had a last CD4 cell count less than 500/μl. Conclusion:LTNP, elite LTNP, HIV controller, and elite controller patients are rare phenotypes. Elite LTNP patients are less frequent than HIV controllers. There is little overlap among the four subgroups of patients.

Incidence and Risk Factors for Toxoplasmic Encephalitis in Human Immunodeficiency Virus-Infected Patients before and during the Highly Active Antiretroviral Therapy Era

The occurrence of toxoplasmic encephalitis (TE) was studied among 19,598 and 17,016 patients enrolled in the French Hospital Database on human immunodeficiency virus whose CD4 cell counts decreased to < or =200x10(6) cells/L before (1992-1995) or after (1996-1998) the availability of highly active antiretroviral therapy, respectively. The incidence of TE decreased from 3.9 cases per 100 person-years in the first period (95% confidence interval [CI], 3.7-4.1) to 1.0 cases per 100 person-years in the second period (95% CI, 0.9-1.1). After adjustment for known risk factors for TE, patients who received cotrimoxazole prophylaxis had a lower risk of TE (adjusted relative hazard, 0.6 and 0.5, respectively, for the first and second periods; P < .001). For patients treated with cotrimoxazole at inclusion, discontinuation of cotrimoxazole increased the risk of TE in both periods (adjusted relative hazard, 4.8 and 4.2, respectively; P < .001). Among patients whose CD4 cell counts increased to > 200 x 10(6) cells/L while undergoing highly active antiretroviral therapy, the incidence of TE was 0.1 cases per 100 person-years (95% CI, 0.0-0.2) and was not increased by discontinuation of cotrimoxazole.

Impact of Risk Factors for Specific Causes of Death in the First and Subsequent Years of Antiretroviral Therapy Among HIV-Infected Patients

Among HIV-infected patients who initiated antiretroviral therapy (ART), patterns of cause-specific death varied by ART duration and were strongly related to age, sex, and transmission risk group. Deaths from non-AIDS malignancies were much more frequent than those from cardiovascular disease.

Durability of first ART regimen and risk factors for modification, interruption or death in HIV-positive patients starting ART in Europe and North America 2002-2009.

Objectives:To estimate the incidence of and risk factors for modifications to first antiretroviral therapy (ART) regimen, treatment interruption and death. Methods:A total of 21 801 patients from 18 cohorts in Europe and North America starting ART on regimens including at least two nucleoside reverse transcriptase inhibitors and boosted protease inhibitor or non-nucleoside reverse transcriptase inhibitor during 2002–2009 were included. Incidence of modifications (change of drug class, substitution/addition within class, or switch to nonstandard regimen), interruption or death and associations with patient characteristics were estimated using competing-risks methods. Results:During median 28 months follow-up, 8786 (40.3%) patients modified first ART, 2346 (10.8%) interrupted and 427 (2.0%) died before changing regimen. Three-year cumulative percentages of modification, interruption and death were 47, 12 and 2%, respectively. After adjustment, rates of interruption were highest for IDUs and lowest for MSM, and higher for patients starting ART with CD4 cell count above 350 cells/&mgr;l than other patients. Compared to efavirenz, patients on lopinavir and other protease inhibitors had higher rates of modification and interruption, on atazanavir had lower rates of class change, and on nevirapine higher rates of interruption. Those on tenofovir/emtricitabine backbone had lowest rates of substitutions and switches to nonstandard regimen, and on abacavir/lamivudine lowest rates of interruption. Rates of substitution and switches to nonstandard regimen were lower in 2006–2009. Conclusion:Rates of modification and interruption were high, particularly in the first year of ART. Decreased rates of substitutions or switches to nonstandard regimen in recent years may be linked to greater use of well tolerated once-daily drugs.

The effect of injecting drug use history on disease progression and death among HIV-positive individuals initiating combination antiretroviral therapy: collaborative cohort analysis

We examined whether determinants of disease progression and causes of death differ between injecting drug users (IDUs) and non‐IDUs who initiate combination antiretroviral therapy (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.

Impact of late presentation on the risk of death among HIV-infected people in France (2003-2009).

Objective:A recent consensus defines “late presentation” (LP) during the course of HIV infection as presentation with AIDS whatever the CD4 cell count or with CD4 <350 cells per cubic millimeter. Here, using this new definition, we examined the frequency and predictors of LP and its impact on mortality. Methods:In antiretroviral-naive patients enrolled in the French Hospital Database on HIV between 2003 and 2009, we studied risk factors for LP by multivariable logistic regression. The impact of LP on mortality was analyzed according to the level of immunodeficiency by using Cox multivariable models adjusted for potential confounders, with follow-up categorized into 0–6, 6–12, and 12–48 months. Results:There were 11,038 (53.9%) late presenters among the 20,496 patients included in the study. Compared with patients presenting for care with CD4 ≥350 cells per cubic millimeter, patients presenting with AIDS had a very high risk of death with crude hazard ratio ranging from 48.3 during the first 6 months of follow-up to 4.8 during months 12–48; the corresponding values among AIDS-free patients with CD4 ⩽200 cells per cubic millimeter were 8.1 and 2.3. Importantly, patients presenting with CD4 between 200 and 350 cells per cubic millimeter also had a significantly increased risk of death beyond 6 months of follow-up (hazard ratio: 3.0 and 1.8 for months 6–12 and 12–48, respectively). Results were similar after adjustment. Conclusions:LP with HIV infection is still very frequent in France and is associated with higher mortality, even among patients with only moderate immunodeficiency. Encouraging early testing and access to care is still urgently needed.

Cohort Profile: French hospital database on HIV (FHDH-ANRS CO4)

The French Hospital Database on HIV (FHDH) is a hospital-based multicentre open cohort with inclusions ongoing since 1989. The research objectives focus mainly on mid- and long-term clinical outcomes and therapeutic strategies, as well as severe AIDS and non-AIDS morbidities, and public health issues relative to HIV infection. FHDH also serves to describe HIV-infected patients receiving hospital care in France. FHDH includes data on more than 120,000 HIV-infected patients from 70 French general or university hospitals distributed throughout France. Patients are eligible for inclusion if they are infected by HIV-1 or HIV-2 and give their written informed consent. Standardized variables are collected at each outpatient visit or hospital admission during which a new clinical manifestation is diagnosed, a new treatment is prescribed or a change in biological markers is noted, and/or at least every 6 months. Since its inception, variables collected in FHDH include demographic characteristics, HIV-related biological markers, the date and type of AIDS and non AIDS-defining events, antiretroviral treatments and the date and causes of death, as reported in the medical records. Since 2005, data have also been collected on: co-infection with hepatitis B or C virus; alcohol and tobacco use; and non HIV-related biomarkers. Anyone can submit a research project by completing a standardized form available on the FHDH website (http://www.ccde.fr/_fold/fl-1385734776-429.pdf) or from the corresponding author, describing the context and objectives of the study. All projects are reviewed by the scientific committee.

HIV-associated tuberculosis and immigration in a high-income country: incidence trends and risk factors in recent years.

Objective:To examine trends in tuberculosis incidence rates in France during the combination antiretroviral therapy (cART) period. Methods:From the French Hospital Database on HIV, we selected 72 580 patients (including 14 491 migrants) with no history of tuberculosis, followed between 1 January 1997 and 31 December 2008. We then examined incidence rates of tuberculosis and its risk factors. Results:A total of 2625 patients were diagnosed with tuberculosis either at enrolment (N = 932) or during follow-up (N = 1693). During follow-up, the incidence rate of tuberculosis was 0.40/100 patient-years overall, 0.20 among nonmigrants and 1.03 among migrants. Adjusted risk of tuberculosis was 2.01 [95% confidence interval (CI) 1.79–2.26] times higher in migrants than in nonmigrants. The adjusted incidence rate of tuberculosis significantly increased in both migrants and nonmigrants after 2000–2001, with adjusted risks of 2.50 (95% CI 1.54–4.06) and 1.85 (95% CI 1.27–2.69) in 2008 compared with that in 1997, respectively. Other factors independently associated with a higher incidence of tuberculosis were medical follow-up less than or equal to 6 months, no previous antiretroviral therapy, lower CD4 cell count and higher viral load. Nonmigrant patients belonging to HIV-transmission groups other than homosexual men, residing in the Paris area or in French West Indies or with AIDS status were at a supplementary risk. Conclusion:The incidence of tuberculosis is increasing among both migrant and nonmigrant HIV-infected patients in France. This is partly because sub-Saharan African migrants represent an increasing fraction of the HIV-infected population in France and also because of late access to care. Co-prescribing tuberculosis preventive therapy with cART might benefit selected patients, such as migrants and patients with late access to care.

Modeling the time course of CD4 T-lymphocyte counts according to the level of virologic rebound in HIV-1-infected patients on highly active antiretroviral therapy

Objective To study the influence of the level of virologic rebound during combination antiretroviral therapy on the time course of the CD4 count. Methods Between January 1997 and December 1999, we enrolled 3736 patients from the French Hospital HIV Database who had an undetectable viral load on a first course of highly active antiretroviral therapy (HAART). Four levels of virologic rebound were defined on the basis of viral load values during the year following initial undetectability on HAART: group 1, all viral loads <500 copies/mL; group 2, all viral loads <5000 copies/mL; group 3, all viral loads <10,000 copies/mL; and group 4, at least 1 viral load >10,000 copies/mL. We developed a continuous time-homogeneous Markov process with 5 reversible stages defined by CD4 count intervals. Results CD4 counts increased continuously over time in each group. The smaller the virologic rebound, the stronger was the increase in the CD4 count (P < 0.0001). The mean CD4 cell count increments between months 2 and 6 were 26, 20, 11, and 2 cells/mm3 in groups 1, 2, 3, and 4, respectively. The rate of gain fell after month 6 and was almost nil in group 4. Conclusion After achieving an undetectable viral load on HAART, immunologic reconstitution is possible whatever the subsequent level of viral replication, except among patients with high-level rebound, meaning that in patients with a long history of antiretroviral therapy and a reduced choice of antiretroviral drugs due to acquisition of resistances, delay in antiretroviral therapy switch can be possible in patients with low or intermediate rebound.