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).

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.).

Avascular osteonecrosis of the femoral head in three West African HIV-infected adults with heterozygous sickle cell disease.

Three men (aged 33, 44 and 45 years, CD4(+) T-cell nadir 86 cells/mm(3), 99 cells/mm(3) and 12 cells/mm(3), respectively) were admitted to the Department of Infectious Diseases (Treichville Hospital, Abidjan, Côte d'Ivoire) for hip pain and impaired mobility. Their last available CD4(+) T-cell counts were 243 cells/mm(3), 245 cells/mm(3) and 8 cells/mm(3), respectively. They had all received antiretroviral therapy for >4 years, including lopinavir/ritonavir for >8 months. The other risk factors were hypertriglyceridaemia (n=3), smoking addiction (n=2), alcohol consumption (n=2) and lipodystrophy (n=1). All three patients had heterozygous haemoglobin AS sickle cell disease (percentage of haemoglobin S 41%, 45% and 50%, respectively). The diagnosis of avascular osteonecrosis of the femoral head (unilateral n=2 and bilateral n=1) was documented by CT scan. Only one patient underwent surgical arthroplasty. In resource-limited settings, avascular osteonecrosis is uneasy to diagnose and unlikely to be appropriately treated. Physicians should be aware of its symptoms and risk factors, including HIV infection and antiretroviral therapy. Future studies should explore whether these risk factors might include haemoglobin AS sickle cell disease, a common trait in the West African general population.

CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults in west Africa (Trivacan ANRS 1269 trial): a randomised trial.

BACKGROUND: Structured treatment interruptions of highly-active antiretroviral therapy (HAART) might be particularly relevant for sub-Saharan Africa, where cost-saving strategies could help to increase the number of patients on HAART. We did a randomised trial of structured treatment interruption in Abidjan, Côte d'Ivoire. METHODS: HIV-infected adults were randomised to receive continuous HAART (CT), CD4-guided HAART (CD4GT) with interruption and reintroduction thresholds at 350 and 250 cells per mm3, respectively, or 2-months-off, 4-months-on HAART. Primary endpoints were death and severe morbidity (any WHO stage 3 or 4 events and any events leading to death) at month 24. We report data from the CT and CD4GT groups until Oct 31, 2005, when the data safety monitoring board recommended to prematurely stop the CD4GT arm. Analyses were intention-to-treat. This study is registered at ClinicalTrials.gov, number NCT00158405. RESULTS: 326 adults (median CD4 count nadir 272 per mm3) were randomised to the CT or CD4GT groups and followed up for median of 20 months. Incidence of mortality (per 100 person-years) was not different between groups (CT 0.6, CD4GT 1.2; p=0.57). Incidence of severe morbidity (per 100 person-years) was higher in the CDG4T group (17.6) than in the CT group (6.7; p=0.001). The most frequent severe events were invasive bacterial diseases. 79% of severe morbidity episodes occurred in patients with CD4 count 200-500 per mm3. CONCLUSION: Patients on CD4GT had severe morbidity rates 2.5-fold higher than those on CT. This difference was mainly due to high rates of common diseases in patients with CD4 count 200-500 per mm3. This CD4-guided structured treatment interruption strategy should not be recommended in Abidjan.