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.).

Psychosocial correlates of inconsistent condom use among HIV-infected patients enrolled in a structured ART interruptions trial in Côte d'Ivoire: results from the TRIVACAN trial (ANRS 1269).

OBJECTIVE: To investigate the relationship between unsafe sexual behaviours and poor self-perceived health among people living with HIV and AIDS (PLWHA) in western Africa. METHODS: In March 2006, a survey was conducted among patients continuing their participation in the TRIVACAN trial (ANRS 1269) in Côte d'Ivoire, in which patients had been randomized to either continuous or interrupted antiretroviral therapy (ART) (2-months-off/4-months-on cycles [2/4-ART]) after 6-18 months of continuous ART (C-ART). Socio-demographic and psychosocial information, including data on sexual behaviours during the previous 6 months, was collected using face-to-face interviews. Sexually active patients with either a steady partner (serodiscordant or of unknown HIV status) or casual partners were considered to have unsafe sexual behaviours if they reported inconsistent condom use (ICU). RESULTS: Seventy-seven of the 192 patients reported ICU. In multivariate logistic regression, men were significantly less likely to report ICU than women (OR [95% CI] = 0.45 [0.20-0.98]). After adjustment for educational level and reduced sexual activity since ART initiation, concealment of HIV status (2.08 [1.02-4.25]) and poor self-perceived health (2.32 [0.97-5.52]) were independently associated with ICU. CONCLUSION: HIV prevention strategies in resource-limited settings should take into account self-perceived health and difficulties to disclose HIV status. Counselling interventions need to be developed to help PLWHA to adopt or negotiate safe behaviours respecting their individual cultures.

Implementation of an intensive adherence intervention in patients with second-line antiretroviral therapy failure in four west African countries with little access to genotypic resistance testing: a prospective cohort study.

BACKGROUND: The decision about whether to switch to third-line antiretroviral therapy (ART) in patients with treatment failure on second-line therapy is difficult in settings with little access to genotypic resistance testing. In this study, we used a standardised algorithm including a wide range of adherence-enhancing interventions followed by a new viral load measurement to decide whether to switch to third-line therapy in this situation. The decision, made on the basis of effectiveness of the adherence reinforcement to drive viral resuppression, did not use genotypic resistance testing. METHODS: In this prospective cohort study, adults in four west African countries with treatment failure of a boosted protease inhibitor ART regimen were offered nine adherence reinforcement interventions, and followed up for 64 weeks. We measured viral load at week 12 and used the results to decide ART treatment at week 16: if successful resuppression (plasma HIV-1 RNA <400 copies per mL or had decreased by ≥2 log10 copies per mL compared with baseline), patients continued the same second-line regimen; otherwise they switched to a third-line regimen based on ritonavir-boosted darunavir and raltegravir. The primary endpoint was virological success at week 64 (plasma HIV-1 RNA <50 copies per mL). After study termination we did genotypic resistance testing on frozen plasma samples collected at baseline, and retrospectively determined the appropriateness of the week 16 decision on the basis of the baseline genotypic susceptibility score. FINDINGS: Between March 28, 2013, and May 11, 2015, of the 198 eligible participants, five died before week 16. Of the 193 remaining, 130 (67%) reached viral resuppression and continued with second-line ART, and 63 (33%) switched to third-line ART at week 16. Post-study genotypic resistance testing showed that the baseline genotypic susceptibility score was calculable in 166 patients, of whom 57 (34%) had a score less than 2. We retrospectively concluded that the week 16 decision was appropriate in 145 (75%) patients. At week 64, four patients (2%) were lost to follow-up, ten (5%) had died, and 101 (52%) had a viral load less than 50 copies per mL. INTERPRETATION: Poor adherence is the first problem to tackle in patients for whom second-line ART is failing when resistance tests are not routinely available and is effectively a manageable problem. Lack of access to genotypic resistance testing should not be an obstacle to the prescription of third-line ART in patients who do not achieve viral resuppression after adherence reinforcement. FUNDING: French Agency for Research on AIDS and Viral Hepatitis.

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.

Lack of indinavir-associated nephrological complications in HIV-infected adults (predominantly women) with high indinavir plasma concentration in Abidjan, Côte d'Ivoire.

To report the tolerance of indinavir combined with ritonavir (IDV/r 800/100 mg) twice daily (bid) in sub-Saharan African HIV-infected adults. HAART-naives patients started zidovudine plus lamivudine plus IDV/r 800/100 mg bid. Follow-up included standardized documentation of morbidity, CD4(+) cell count, creatininemia, plasma HIV-1 RNA, and IDV minimal plasma concentration (C(min)) measurements at month 1 (M1), M3, and M6. Seventy HIV-1-infected adults (68 women, median CD4 235/mm(3)) started HAART. At M6, 63% had undetectable viral load, and the median gain in CD4 since baseline was +128/mm(3). During the first 6 months, 21 patients experimented with 23 treatment modifications (reduction in IDV/r 400/100 mg bid, n = 11; switch to efavirenz, n = 11; zidovudine replaced by stavudine, n = 1), including 22 for digestive intolerance and 1 for severe anemia. At M1, M3, and M6, 67, 59, and 48 patients were still receiving IDV/r 800/100 mg bid, of whom 70%, 72%, and 60% had IDV Cmin above 5 ng/ml, respectively. In these patients, at M1, M3, and M6, the mean (+/- SD) IDV C(min) were 3431 +/- 3835 ng/ml, 2288 +/- 2116 ng/ml, and 1543 +/- 2398 ng/ml, respectively. There was no renal insufficiency of any grade, and no symptoms of urinary stones. The IDV/r 800/100 mg bid-containing regimen led to high IDV Cmin and a high rate of digestive intolerance. There was a surprising lack of nephrological side effects during the 6 months of follow-up, supporting the hypothesis that nephrological tolerance of IDV might be higher in sub-Saharan African individuals than in Americans or Europeans.

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).

Haematological changes in adults receiving a zidovudine-containing HAART regimen in combination with cotrimoxazole in Côte d'Ivoire.

OBJECTIVE: Neutropenia is the most frequent side effect of cotrimoxazole in sub-Saharan Africa. We estimated the incidence of haematological disorders during the first 6 months of a zidovudine-containing highly active antiretroviral therapy (HAART) regimen in sub-Saharan African adults receiving cotrimoxazole. METHODS: Prospective cohort study in Abidjan, with blood cell count measurement at baseline (HAART initiation), month 1, month 3 and month 6. RESULTS: A total of 498 adults [baseline: 80% currently on cotrimoxazole prophylaxis; median CD4 count 237/mm3 [interquartile range (IQR) 181;316]; median neutrophil count 1647/mm3 (IQR 1221;2256); median haemoglobin 113 g/l (IQR 102;122)] started zidovudine (AZT)/lamivudine/efavirenz. During follow-up, 118 patients had a grade 3-4 neutropenia [(56.3/100 person-years (PY)], 23 had a grade 3-4 anaemia (9.6/100 PY) and no cases of grade 3-4 thrombocytopenia. Of the 118 patients with grade 3-4 neutropenia, 86 (73%) had to stop cotrimoxazole because neutropenia persisted, and one (<1%) had to stop AZT because of persistent neutropenia after cotrimoxazole was stopped (neutropenia-related HAART modification: 0.4/100 PY). Of the 23 patients with grade 3-4 anaemia, 11 had to stop AZT (anaemia-related HAART modification: 4.4/100 PY). In patients who stopped cotrimoxazole but not AZT, the median gain in neutrophils at 1 month was +540/mm3 (IQR +150;+896). CONCLUSIONS: At baseline, most patients had a normal neutrophil count and 80% of them were already receiving cotrimoxazole. An unexpectedly high rate of grade 3-4 neutropenia occurred shortly after introduction of AZT. Almost all of the persistent severe neutropenia disappeared after cotrimoxazole was stopped. This suggests an accentuated drug interaction between the two drugs in these sub-Saharan African individuals. Grade 3-4 anaemia was much less frequent, but remained the first cause of AZT discontinuation.

Medication possession ratio: predicting and decreasing loss to follow-up in antiretroviral treatment programs in Côte d'Ivoire.

BACKGROUND: In antiretroviral therapy (ART) programs, decreasing loss to follow up (LTFU) is a major priority. METHODS: We conducted a prospective study in Abidjan. Adults who started ART between June 2005 and May 2008 and were still in care 6 months later had monthly visits, biannual CD4 counts, computerized data collection and home visits (routine follow-up). A subset of patients also had biannual plasma HIV-1 RNA measurements, with a physician and a research assistant hired to pay particular attention to their visits (enhanced follow-up). We analyzed the association between 18-month outcomes and pre-ART characteristics, medication possession ratio (MPR) and type of follow-up. Patients were LTFU if their last visit was before month-18 and they had not returned to care by month-24. RESULTS: 2,074 patients started ART, of whom 1,636 (79%) were still in care at month-6. The routine (n = 999) and enhanced (n = 637) groups had similar baseline characteristics. From month-6 to month-18, they had similar death rates (routine 3.6%, enhanced 3.9%, P = 0.74), but the enhanced group had significantly less LTFU (routine 11.3%, enhanced 5.8%, P < 0.001). In multivariate analysis, the risk of LTFU from month-6 to month-18 was 46% lower with enhanced follow-up, 56% higher in patients living outside the centre area, and 4.0 fold higher in patients with a low MPR (<80%) between ART initiation and month-6. CONCLUSIONS: In patients still in care at 6 months, a low MPR in the first 6 months was strongly associated with further LTFU. Simple follow-up enhancement halved the LTFU rate in the following year.

Incidence and determinants of mortality and morbidity following early antiretroviral therapy initiation in HIV-infected adults in West Africa.

OBJECTIVE: To estimate the incidence and risk factors of mortality and severe morbidity during the first months following antiretroviral therapy (ART) initiation in West African adults. METHODS: A cohort study in Abidjan in which 792 adults started ART with a median CD4 cell count of 252 cells/mul and were followed for a median of 8 months. Severe morbidity was defined as all World Health Organization stage 3 or 4-defining morbidity events other than oral candidiasis. RESULTS: In patients with pre-ART CD4 cell count < 200, at 200-350 and > 350 cells/mul, incidence of mortality was 5.0 [95% confidence interval (CI), 2.6-8.7], 1.7 (95% CI, 0.6-3.8) and 0.0 (95% CI, 0.0-3.4]/100 person-years, and incidence of severe morbidity was 13.3 (95% CI, 9.0-19.1), 9.5 (95% CI, 6.2-12.9) and 7.9 (95% CI, 3.4-15.5)/100 person-years, respectively. The most frequent diseases were invasive bacterial diseases (32/65 episodes, 49%) and tuberculosis (25/65 episodes, 38%). Both diseases followed the same curve of decreasing incidence over time. Patients who experienced severe morbidity had higher risks of mortality, virological failure and immunological failure. Other independent risk factors for mortality and/or severe morbidity were: at baseline, high viral load, advanced clinical stage, past history of tuberculosis, low BMI, low haemoglobin and low CD4 cell count; during follow-up: low CD4 cell count and persistently detectable viral load. CONCLUSION: These data give new arguments to reinforce the hypothesis that, in this region, ART should be started before the CD4 cell count drops below 350 cells/mul. Further studies should assess whether patients with low BMI, low haemoglobin, high viral load or past history of tuberculosis should start ART earlier.

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.