Using observational data to emulate a randomized trial of dynamic treatment switching strategies

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 individual's 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

Efavirenz versus boosted atazanavir-containing regimens and immunologic, virologic, and clinical outcomes: A prospective study of HIV-positive individuals

Abstract 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/mm3 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

Elevated Risk of Viral Rebound on ART in Migrants Living in France: Role of Socioeconomic Factors

Background In Western countries, viral rebound on antiretroviral therapy (ART) appears to occur more frequently in migrants. We aimed to assess the respective roles of socioeconomic factors and migration on viral rebound in people living with HIV (PLHIV) in France. Methods We included PLHIV in France, enrolled from 2004 to 2008 in the French ANRS-COPANA cohort, who started a first ART and achieved undetectability (<50 copies/ml) within 1 year. Determinants of viral rebound were assessed using Cox models including geographical origin, HIV transmission group, and clinicobiological and sociodemographic data. Results Of 499 included individuals, 288 were born in France, 158 in sub-Saharan Africa (SSA) and 53 in another country. Kaplan\textendash Meier probabilities of viral rebound-free survival were similar for men having sex with men (MSM) and heterosexuals born in France, and lower in migrants from SSA or other countries ( P<0.001). The crude hazard ratio (HR) of viral rebound was 2.49 (95% CI, 1.59, 3.90) in migrants from SSA and 1.78 (0.94, 3.88) in migrants from other countries compared with MSM born in France. Educational level, financial difficulties and HIV status disclosure had the biggest impact on the difference between the crude and adjusted HRs for viral rebound in migrants. In multivariable analysis, viral rebound was no longer associated with geographical origin, but with protease inhibitor-containing ART, a VACS index ≥q35 as a potential indicator of frailty, poor financial status (difficulties or debts) and non-disclosure to friend(s). Conclusions Socioeconomic factors affect outcomes on ART, even in the context of free access to HIV care and treatment. Patient-centred strategies should be encouraged with the intervention of social workers to address basic needs and promote social support for more socially vulnerable individuals

Tuberculosis mortality during a civil war in Guinea-Bissau

CONTEXT: Tuberculosis (TB) is an increasing global problem, despite effective drug therapies. Access to TB therapy during conflict situations has not been studied. OBJECTIVE: To determine the effect of irregular TB treatment due to an armed conflict in Guinea-Bissau, West Africa. DESIGN, SETTING, AND PATIENTS: Ongoing retrospective cohort study conducted in the capital city of Bissau among 101 patients with TB who received irregular or no treatment during the civil war (war cohort; June 7-December 6, 1998) and 108 patients with TB who received treatment 12 months earlier (peace cohort; June 7-December 6, 1997) and comparison of an additional 42 patients who had completed treatment before June 6, 1998, and 69 patients who had completed treatment before June 6, 1997. MAIN OUTCOME MEASURE: Mortality rates, compared by irregular (war cohort) vs regular (peace cohort) access to treatment, by intensive vs continuation phase of treatment, and by those who had previously completed treatment for TB. RESULTS: Irregular treatment was associated with an increased mortality rate among patients with TB. The mortality rate ratio (MR) was 3.12 (95% confidence interval [CI], 1.20-8.12) in the war cohort, adjusting for age, sex, human immunodeficiency virus (HIV) infection, residence, and length of treatment. Each additional week of treatment before the war started increased probability of survival by 5% (95% CI, 0%-10%). In the intensive phase of treatment, the adjusted MR was 3.30 (95% CI, 1.04-10.50) and in the continuation phase it was 2.26 (95% CI, 0.33-15.34). Increased mortality among the war cohort was most marked in HIV-positive patients, who had an adjusted MR of 8.19 (95% CI, 1.62-41.25). Mortality was not increased in HIV-positive or HIV-negative patients who had completed TB treatment when the war started. CONCLUSIONS: Interruption of treatment had a profound impact on mortality among patients with TB during the war in Guinea-Bissau. Regular treatment for TB was associated with significantly improved survival for HIV-infected individuals. In emergencies, it is crucial to ensure availability of TB drugs

Comparison of early CD4 T-cell count in HIV-1 seroconverters in Côte d'Ivoire and France: the ANRS PRIMO-CI and SEROCO cohorts.

International audienceOBJECTIVE: We compared CD4+ decline among untreated HIV-1-infected seroconverters living in Côte d'Ivoire (CI) and in France. METHODS: HIV-1-infected adults were enrolled in the ANRS1220 PRIMO-CI (CI, 1997-2006) and ANRSCO2 SEROCO (France, 1988-1995) cohorts. CD4+ count and percentage declines were estimated from enrollment until 24 months of seroconversion by linear random-effect models adjusted for time since seroconversion, age, gender, cell-associated HIV DNA, HIV RNA, and country. RESULTS: Overall 521 seroconverters (CI 148, 62% men; France 373, 77% men) were enrolled after a median of 7.6 months since seroconversion. Median follow-up duration was 12.7 months. Median age was 28 years. Median baseline CD4+ count was 472 and 560 cells per cubic millimeter, respectively. Median baseline HIV RNA was 4.4 and 4.0 log10 copies per milliliter and median HIV DNA was 3.0 and 2.8 log10 copies per 10(6) peripheral blood mononuclear cells, respectively. In adjusted models, CD4+ count and percentage at baseline were lower in CI than in France (P < 0.01), and the difference did not vary during follow-up (P = 0.55). Low HIV RNA and low HIV DNA at baseline were associated with higher CD4+ count at baseline. CONCLUSIONS: CD4+ count and percentage were lower in CI than in France. These differences were already observed during early infection and remained similar after adjustment

Prevalence of SARS-Cov-2 antibodies and living conditions: the French national random population-based EPICOV cohort

International audienceBackground: We aimed to estimate the seroprevalence of SARS-CoV-2 infection in France and to identify the populations most exposed during the first epidemic wave. Methods: Random selection of individuals aged 15 years or over, from the national tax register (96% coverage). Socioeconomic data, migration history, and living conditions were collected via self-computer-assisted-web or computer-assisted-telephone interviews. Home self-sampling was performed for a random subsample, to detect IgG antibodies against spike protein (Euroimmun), and neutralizing antibodies with in-house assays, in dried blood spots (DBS). Results: The questionnaire was completed by 134,391 participants from May 2nd to June 2st, 2020, including 17,441 eligible for DBS 12,114 of whom were tested. ELISA-S seroprevalence was 4.5% [95% CI 3.9-5.0] overall, reaching up to 10% in the two most affected areas. High-density residences, larger household size, having reported a suspected COVID-19 case in the household, working in healthcare, being of intermediate age and non-daily tobacco smoking were independently associated with seropositivity, whereas living with children or adolescents did not remain associated after adjustment for household size. Adjustment for both residential density and household size accounted for much of the higher seroprevalence in immigrants born outside Europe, twice that in French natives in univariate analysis. Conclusion: The EPICOV cohort is one of the largest national representative population-based seroprevalence surveys for COVID-19. It shows the major role of contextual living conditions in the initial spread of COVID-19 in France, during which the availability of masks and virological tests was limited

Hospitalization of HIV positive patients: Significant demand affecting all hospital sectors

Position du problème Dans un contexte d’évolution des morbidités sévères chez les sujets vivant avec le VIH (PVVIH), l’objectif de cette étude était de décrire les motifs d’hospitalisation et les modes de prise en charge des sujets ayant recours à une hospitalisation. Méthodes Toutes les hospitalisations (≥24h) de PVVIH survenues au sein de 10 hôpitaux du sud de Paris (COREVIH Ile-de-France Sud) entre le 01/01/2011 et 31/12/2011 ont été identifiées. Les données hospitalières et la base de la file active du service référent VIH ont été croisées dans chaque hôpital. Un retour au dossier clinique individuel a été réalisé sur un échantillon aléatoire de sujets (65 % des patients hospitalisés identifiés au cours de cette année) pour recueillir des données cliniques et biologiques détaillées. Résultats Au total, 3013 hospitalisations (1489 patients) ont été enregistrées au cours de l’année 2011. Le taux estimé de patients hospitalisés sur les 10105 PVVIH régulièrement suivis dans le COREVIH Ile-de-France Sud en 2011 était d’environ 8 %. La majorité (58,5 %) de ces hospitalisations ont eu lieu hors secteur VIH. Les infections non classant SIDA représentaient la première cause d’admission (16,4 %), suivies des pathologies liées au VIH (15,6 %), des maladies hépatiques/gastro-intestinales (12,0 %) et des maladies cardiovasculaires (10,3 %). La durée médiane d’hospitalisation était de 5jours (IQR : 2–11), elle était plus longue pour les patients hospitalisés dans le service référent VIH que dans les autres services. Les patients hospitalisés avaient une infection par le VIH ancienne (>10ans) pour 61,4 % d’entre eux, souvent des comorbidités associées (co-infection VHC/VHB 40,5 %, tabac 45,8 %, hypertension artérielle 33,4 %, dyslipidémie 28,8 %, diabète 14,8 %). Les sujets âgés de plus de 60 ans représentaient 15 % des patients hospitalisés, étaient virologiquement contrôlés sous traitement antirétroviral pour la majorité d’entre eux, et les pathologies cardiovasculaires étaient leur principale raison d’admission. Conclusion Le recours à l’hospitalisation chez les PVVIH reste important, avec une grande variété de lieux et de causes d’admission mobilisant tous les secteurs de l’hôpital. Il est primordial de prévenir les comorbidités pour réduire ces recours et de conserver un lien entre le suivi devenu ambulatoire de ces patients et le recours spécialisé dans les hôpitaux

Opportunistic infections and AIDS malignancies early after initiating combination antiretroviral therapy in high-income countries.

BackgroundThere is little information on the incidence of AIDS-defining events which have been reported in the literature to be associated with immune reconstitution inflammatory syndrome (IRIS) after combined antiretroviral therapy (cART) initiation. These events include tuberculosis, mycobacterium avium complex (MAC), cytomegalovirus (CMV) retinitis, progressive multifocal leukoencephalopathy (PML), herpes simplex virus (HSV), Kaposi sarcoma, non-Hodgkin lymphoma (NHL), cryptococcosis and candidiasis.MethodsWe identified individuals in the HIV-CAUSAL Collaboration, which includes data from six European countries and the US, who were HIV-positive between 1996 and 2013, antiretroviral therapy naive, aged at least 18 years, had CD4 cell count and HIV-RNA measurements and had been AIDS-free for at least 1 month between those measurements and the start of follow-up. For each AIDS-defining event, we estimated the hazard ratio for no cART versus less than 3 and at least 3 months since cART initiation, adjusting for time-varying CD4 cell count and HIV-RNA via inverse probability weighting.ResultsOut of 96 562 eligible individuals (78% men) with median (interquantile range) follow-up of 31 [13,65] months, 55 144 initiated cART. The number of cases varied between 898 for tuberculosis and 113 for PML. Compared with non-cART initiation, the hazard ratio (95% confidence intervals) up to 3 months after cART initiation were 1.21 (0.90-1.63) for tuberculosis, 2.61 (1.05-6.49) for MAC, 1.17 (0.34-4.08) for CMV retinitis, 1.18 (0.62-2.26) for PML, 1.21 (0.83-1.75) for HSV, 1.18 (0.87-1.58) for Kaposi sarcoma, 1.56 (0.82-2.95) for NHL, 1.11 (0.56-2.18) for cryptococcosis and 0.77 (0.40-1.49) for candidiasis.ConclusionWith the potential exception of mycobacterial infections, unmasking IRIS does not appear to be a common complication of cART initiation in high-income countries