Effect of isoniazid preventive therapy on risk of death in west African, HIV-infected adults with high CD4 cell counts: long-term follow-up of the Temprano ANRS 12136 trial.

BACKGROUND: Temprano ANRS 12136 was a factorial 2 × 2 trial that assessed the benefits of early antiretroviral therapy (ART; ie, in patients who had not reached the CD4 cell count threshold used to recommend starting ART, as per the WHO guidelines that were the standard during the study period) and 6-month isoniazid preventive therapy (IPT) in HIV-infected adults in Côte d'Ivoire. Early ART and IPT were shown to independently reduce the risk of severe morbidity at 30 months. Here, we present the efficacy of IPT in reducing mortality from the long-term follow-up of Temprano. METHODS: For Temprano, participants were randomly assigned to four groups (deferred ART, deferred ART plus IPT, early ART, or early ART plus IPT). Participants who completed the trial follow-up were invited to participate in a post-trial phase. The primary post-trial phase endpoint was death, as analysed by the intention-to-treat principle. We used Cox proportional models to compare all-cause mortality between the IPT and no IPT strategies from inclusion in Temprano to the end of the follow-up period. FINDINGS: Between March 18, 2008, and Jan 5, 2015, 2056 patients (mean baseline CD4 count 477 cells per µL) were followed up for 9404 patient-years (Temprano 4757; post-trial phase 4647). The median follow-up time was 4·9 years (IQR 3·3-5·8). 86 deaths were recorded (Temprano 47 deaths; post-trial phase 39 deaths), of which 34 were in patients randomly assigned IPT (6-year probability 4·1%, 95% CI 2·9-5·7) and 52 were in those randomly assigned no IPT (6·9%, 5·1-9·2). The hazard ratio of death in patients who had IPT compared with those who did not have IPT was 0·63 (95% CI, 0·41 to 0·97) after adjusting for the ART strategy (early vs deferred), and 0·61 (0·39-0·94) after adjustment for the ART strategy, baseline CD4 cell count, and other key characteristics. There was no evidence for statistical interaction between IPT and ART (pinteraction=0·77) or between IPT and time (pinteraction=0·94) on mortality. INTERPRETATION: In Côte d'Ivoire, where the incidence of tuberculosis was last reported as 159 per 100 000 people, 6 months of IPT has a durable protective effect in reducing mortality in HIV-infected people, even in people with high CD4 cell counts and who have started ART. FUNDING: National Research Agency on AIDS and Viral Hepatitis (ANRS).

High prevalence of being Overweight and Obese HIV-infected persons, before and after 24 months on early ART in the ANRS 12136 Temprano Trial.

BACKGROUND: HIV is usually associated with weight loss. World health Organization (WHO) recommends early antiretroviral (ART) initiation, but data on the progression of body mass index (BMI) in participants initiating early ART in Africa are scarce. METHODS: The Temprano randomized trial was conducted in Abidjan to assess the effectiveness of early ART and Isoniazid (INH) prophylaxis for tuberculosis in HIV-infected persons with high CD4 counts below 800 cells/mm(3) without any indication for starting ART. Patients initiating early ART before December 2010 were included in this sub-study. BMI was categorized as: underweight (<18.5 kg/m(2)), normal weight (18.5-24.9 kg/m(2)), overweight (25-29.9 kg/m(2)) and obese (≥30 kg/m(2)). At baseline and after 24 months of ART, prevalence of being overweight or obese and factors associated with being overweight or obese were estimated using univariate and multivariate logistic regression. RESULTS: At baseline, 755 participants (78 % women; median CD4 count 442/mm(3), median baseline BMI 22 kg/m(2)) initiated ART. Among them, 19.7 % were overweight, and 7.2 % were obese at baseline. Factors associated with being overweight or obese were: female sex aOR 2.3 (95 % CI 1.4-3.7), age, aOR for 5 years 1.01 (95 % CI 1.0-1.2), high living conditions aOR 2.6 (95 % CI 1.5-4.4), High blood pressure aOR 4.3 (95 % CI 2.0-9.2), WHO stage 2vs1 aOR 0.7 (95 % CI 0.4-1.0) and Hemoglobin ≥95 g/dl aOR 3.0 (95 % CI 1.6-5.8). Among the 597 patients who attended the M24 visit, being overweight or obese increased from 20.4 to 24.8 % (p = 0.01) and 7.2 to 9.2 % (p = 0.03) respectively and factor associated with being overweight or obese was immunological response measured as an increase of CD4 cell count between M0-M24 (for +50 cells/mm(3): aOR 1.01; 95 % CI 1.05-1.13, p = 0.01). CONCLUSION: The weight categories overweight and obese are highly prevalent in HIV-infected persons with high CD4 cell counts at baseline, and increased over 24 months on ART in this Sub-Saharan African population.

A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa.

BACKGROUND: In sub-Saharan Africa, the burden of human immunodeficiency virus (HIV)-associated tuberculosis is high. We conducted a trial with a 2-by-2 factorial design to assess the benefits of early antiretroviral therapy (ART), 6-month isoniazid preventive therapy (IPT), or both among HIV-infected adults with high CD4+ cell counts in Ivory Coast. METHODS: We included participants who had HIV type 1 infection and a CD4+ count of less than 800 cells per cubic millimeter and who met no criteria for starting ART according to World Health Organization (WHO) guidelines. Participants were randomly assigned to one of four treatment groups: deferred ART (ART initiation according to WHO criteria), deferred ART plus IPT, early ART (immediate ART initiation), or early ART plus IPT. The primary end point was a composite of diseases included in the case definition of the acquired immunodeficiency syndrome (AIDS), non-AIDS-defining cancer, non-AIDS-defining invasive bacterial disease, or death from any cause at 30 months. We used Cox proportional models to compare outcomes between the deferred-ART and early-ART strategies and between the IPT and no-IPT strategies. RESULTS: A total of 2056 patients (41% with a baseline CD4+ count of ≥500 cells per cubic millimeter) were followed for 4757 patient-years. A total of 204 primary end-point events were observed (3.8 events per 100 person-years; 95% confidence interval [CI], 3.3 to 4.4), including 68 in patients with a baseline CD4+ count of at least 500 cells per cubic millimeter (3.2 events per 100 person-years; 95% CI, 2.4 to 4.0). Tuberculosis and invasive bacterial diseases accounted for 42% and 27% of primary end-point events, respectively. The risk of death or severe HIV-related illness was lower with early ART than with deferred ART (adjusted hazard ratio, 0.56; 95% CI, 0.41 to 0.76; adjusted hazard ratio among patients with a baseline CD4+ count of ≥500 cells per cubic millimeter, 0.56; 95% CI, 0.33 to 0.94) and lower with IPT than with no IPT (adjusted hazard ratio, 0.65; 95% CI, 0.48 to 0.88; adjusted hazard ratio among patients with a baseline CD4+ count of ≥500 cells per cubic millimeter, 0.61; 95% CI, 0.36 to 1.01). The 30-month probability of grade 3 or 4 adverse events did not differ significantly among the strategies. CONCLUSIONS: In this African country, immediate ART and 6 months of IPT independently led to lower rates of severe illness than did deferred ART and no IPT, both overall and among patients with CD4+ counts of at least 500 cells per cubic millimeter. (Funded by the French National Agency for Research on AIDS and Viral Hepatitis; TEMPRANO ANRS 12136 ClinicalTrials.gov number, NCT00495651.).

Pharmacovigilance for antiretroviral drugs in Africa: lessons from a study in Abidjan, Cote d'Ivoire.

BACKGROUND: Although antiretroviral treatment (ART)-related adverse drug reactions (ADR) are documented in industrialised countries, there is no pre-existing surveillance system dedicated to ADR monitoring in most African countries. We assessed knowledge towards pharmacovigilance among ART prescribers and available capacity of HIV clinics to conduct ADR monitoring in Abidjan, Côte d'Ivoire. METHODS: A questionnaire was administered to ART prescribers to assess their knowledge towards the occurrence of ADRs. A retrospective ADR survey was also conducted based on a data query of treatment modification/interruptions in three HIV clinics. Clinical monitors went back to medical charts to review and validate the reasons of the treatment modification/interruptions. RESULTS: Of the 81 ART prescribers interviewed, 25 (31%) declared not grading ADRs and 12 (14.8%) declared notifying ADRs to the national regulatory authorities. Among 5252 adult ART-treated patients who attended the participating clinics in 2008, 599 treatment modifications were identified. Reasons for treatment modification/interruptions identified in the electronic database were documented in the medical charts in 554 cases (92.5%), ADR accounting for 273 cases (45.5%). Toxicity related to ART was graded in only 58 cases (21%) in the medical charts. DISCUSSION: This study describes challenges limiting the implementation of reliable pharmacovigilance activities in HIV clinics in Côte d'Ivoire. The lack of knowledge of ART prescribers concerning ADR grading does not support the spontaneous reporting of ADRs. Using treatment modification/interruptions for ADR monitoring appears feasible, but improvements are needed to respond to key questions related to drug toxicities in the context of ART scale-up in Africa.

Alcohol use and non-adherence to antiretroviral therapy in HIV-infected patients in West Africa.

AIM: To investigate the association between alcohol use and adherence to highly active antiretroviral treatment (HAART) among human immunodeficiency virus (HIV)-infected patients in sub-Saharan Africa. DESIGN AND SETTING: Cross-sectional survey conducted in eight adult HIV treatment centres from Benin, Côte d'Ivoire and Mali. Participants and measurements During a 4-week period, health workers administered the Alcohol Use Disorders Identification Test to HAART-treated patients and assessed treatment adherence using the AIDS Clinical Trials Group follow-up questionnaire. FINDINGS: A total of 2920 patients were enrolled with a median age of 38 years [interquartile range (IQR) 32-45 years] and a median duration on HAART of 3 years (IQR 1-4 years). Overall, 91.8% of patients were identified as adherent to HAART. Non-adherence was associated with current drinking [odds ratio (OR) 1.4; 95% confidence interval (CI) 1.1-2.0], hazardous drinking (OR 4.7; 95% CI 2.6-8.6) and was associated inversely with a history of counselling on adherence (OR 0.7; 95% CI 0.5-0.9). CONCLUSIONS: Alcohol consumption and hazardous drinking is associated with non-adherence to HAART among HIV-infected patients from West Africa. Adult HIV care programmes should integrate programmes to reduce hazardous and harmful drinking.

Tolerance and acceptability of an efavirenz-based regimen in 740 adults (predominantly women) in West Africa.

In sub-Saharan Africa, the position of efavirenz as a first-line nonnucleoside reverse transcriptase inhibitor remains to be discussed. We report here the 6-month efficacy and tolerance of an efavirenz-containing highly active antiretroviral therapy in a large cohort of HIV-1-infected adults. Seven hundred forty highly active antiretroviral therapy-naive adults (74% women; 14% with positive serum HBs antigen and 21% with abnormal baseline transaminase value) started zidovudine + lamivudine + efavirenz. At month 6, 1.2% of them were dead, 87% had undetectable viral load, and 7% had abnormal transaminase value. From months 1 to 6, the percentage of women who were actually using a contraceptive method increased from 58% to 80% (65% intramuscular progesterone and 35% oral estrogen/progesterone combination). The incidence of pregnancy was 2.6/100 woman-years (95% confidence interval, 0.67-4.51), and 86% of pregnant women voluntarily interrupted the pregnancy with no intervention on our part. Before month 6, only 0.8% of patients permanently discontinued efavirenz for severe adverse effects (neurologic, 0.6%; cutaneous, 0.1%; and hepatic, 0.1%). The leading cause of severe morbidity was tuberculosis. Considering the very high hepatic and cutaneous tolerance, efavirenz could be considered as a valuable first-line drug for women of childbearing age who agree to use contraception in sub-Saharan Africa, provided that the risk of teratogenicity should be closely monitored.