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.)

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)

Relationship of CD4(+) T-cell counts and plasma HIV-1 RNA levels with serological HBeAg/anti-HBe patterns obtained in West-African HBV-HIV-1-co-infected children

HBeAg/anti-HBe and hepatitis B virus (HBV) DNA from 34 HIV-1-infected children from Ivory Coast with chronic hepatitis B (CHB) were longitudinally analyzed according to CD4 and HIV-1 RNA. The mean CD4% value was significantly (p=0.03) lower in 59 (52.7%) samples showing a usual CHB (HBeAg-positive/anti-HBe-negative and HBV DNA-positive), as compared with 30 (26.8%) HBeAg-positive/anti-HBe-positive and HBV DNA-positive and 23 (20.5%) HBeAg-negative/anti-HBe-positive and HBV DNA-negative (15.1% vs. 18.5% and 20.0%). The mean HIV-1 RNA concentrations were significantly (p=0.01) higher in specimens HBV DNA-positive (4.47 and 4.30 log(10)/ml, respectively) vs. HBV DNA-negative (3.43 log(10)/ml). HIV-1 has a significant impact on CHB acquired in childhood

HBV and HCV prevalence and viraemia in HIV-positive and HIV-negative pregnant women in Abidjan, Cote d'Ivoire : the ANRS 1236 study

A retrospective survey estimating the prevalence of hepatitis viruses B (HBV) and C (HCV) was conducted on samples taken in 1,002 African pregnant women (501 diagnosed as HIV-1 positive and 501 HIV-1 negative) participating in a clinical trial program conducted in Abidjan, Cote d'Ivoire (West Africa). Hepatitis B markers studied were HBs antigen (HBsAg), and if positive, HBe antigen/anti-HBe antibodies and HBV DNA. Two third generation (G3) HCV enzyme immunoassays (EIAs) were used for primary HCV screening. All anti-HCV antibody-positive sera were assessed further with supplementary assays (one another G3 EIA, RIBA 3.0, and HCV RNA). HCV genotypes were also determined. HBsAg was found in a similar proportion among HIV-positive (45/499, 9.0%, 95% confidence interval [95% CI], 6.6-11.9) and HIV-negative (40/498,8.0%,95% CI, 5.8-10.8) women (P=0.58). The diagnosis of chronic hepatitis B, based on HBV DNA positive results, was more frequent in HIV-positive women (26.7%), compared to HIV-negative women (9.4%) (P=0.06). In the case of hepatitis C infection, after supplementary testing allowing the elimination of frequent false-positive screening results, a prevalence rate of about 1% was found, both in HIV-positive (6/501, 1.2%, 95% CI, 0.442.59) and HIV-negative (4/501, 0.8%, 95% CI, 0.22-2.03) women (P=0.53). Of the 10 samples confirmed positive and assessed for HCV RNA, eight (80%) were viraemic and belonged to HCV genotypes 1 or 2. The relative high frequency of HIV/HBV coinfection in Cote d'Ivoire emphasises the need for monitoring the risk of hepatotoxicity by antiretroviral therapy in such patients. We propose an accurate and cost-efficient algorithm for HCV diagnosis in Africa

Morbidity before and after HAART initiation in Sub-Saharan African HIV-infected adults: a recurrent event analysis.: HIV morbidity recurrence in Abidjan

International audienceThe incidence and determinants of severe morbidity recurrence in sub-Saharan African HIV-infected adults on antiretroviral therapy (ART) have never been reported. In a prospective cohort study of HIV-infected adults in Abidjan the association of severe morbidity occurrence and recurrence with follow-up CD4 counts and ART on/off status was analyzed by means of multivariate failure analysis for recurrent events (Prentice, Williams, and Peterson model). A total of 608 patients (median CD4 290/mm3 ) was followed off ART for 1824 person-years (PY). Of these 187 started HAART (median CD4 174/mm3 ) and were followed for 328 PY. The incidence of first, second, and third severe morbidity events was 40.6/100 PY, 68.4/100 PY, and 93.9/100 PY during the off-ART period, and 28.4/100 PY, 39.4/100 PY, and 37.6/100 PY during the on-ART period, respectively. The rates of recurrences were higher than the rates of first episodes for almost all diseases, even after stratifying by CD4 count and by ART on/off status. In multivariate analysis, the time-updated CD4 count was independently associated with increasing rates of morbidity first events and recurrences, after adjustment on other covariates (p > 10(4) ). By contrast, there was no association between the ART on/off status and the morbidity rates after adjustment for CD4 count (p = 0.37). Introducing ART led to a clear reduction in morbidity, mainly related to the ART-induced increase in CD4 count. In HIV-infected patients on ART, the incidence of severe morbidity varied with the past history of morbidity. The past history of morbidity should be taken into account when comparing HIV morbidity rates before and after ART initiation