Delphine Gabillard

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.).

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/μl 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/μl, 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/μl. 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

Summary: 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.

Impact of genotypic drug resistance mutations on clinical and immunological outcomes in HIV-infected adults on HAART in West Africa

Objectives:To analyse the association between the presence of resistance mutations and treatment outcomes. The impact of HIV-1 drug resistance mutations in African adults on HAART has so far never been reported. Methods:In 2004 in Abidjan, Côte d’Ivoire, 106 adults on HAART had plasma viral load measurements. Patients with detectable viral loads had resistance genotypic tests. Patients were followed until 2006. Main outcomes were serious morbidity and immunological failure (CD4 cell count < 200 cells/μl). Results:At study entry, the median previous time on HAART was 37 months and the median CD4 cell count was 266 cells/μl; 58% of patients had undetectable viral loads, 20% had detectable viral loads with no major resistance mutations, and 22% had detectable viral loads with one or more major mutations. The median change in CD4 cell count between study entry and study termination was +129 cells/μl in patients with undetectable viral loads, +51 cells/μl in those with detectable viral loads with no mutations and +3 cells/μl in those with detectable viral loads with resistance mutations. Compared with patients with undetectable viral loads, those with detectable viral loads with resistance mutations had adjusted hazard ratios of immunological failure of 4.32 (95%CI 1.38–13.57, P = 0.01). One patient died. The 18-month probability of remaining free of morbidity was 0.79 in patients with undetectable viral loads and 0.69 in those with resistance mutations (P = 0.19). Conclusion:In this setting with restricted access to second-line HAART, patients with major resistance mutations had higher rates of immunological failure, but most maintained stable CD4 cell counts and stayed alive for at least 20 months.

Morbidity Before and After HAART Initiation in Sub-Saharan African HIV-Infected Adults: A Recurrent Event Analysis

The 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.

Effect of Early Antiretroviral Therapy on Sexual Behaviors and HIV-1 Transmission Risk Among Adults With Diverse Heterosexual Partnership Statuses in Côte d'Ivoire

Background. The effect of early initiation of antiretroviral therapy (ART; ie, at CD4+ T-cell counts >350 cells/mm3) on sexual behaviors and human immunodeficiency virus type 1 (HIV) transmission risk has not been documented in populations other than HIV-serodiscordant couples in stable relationships. Methods. On the basis of data from a behavioral study nested in a randomized, controlled trial (Temprano-ANRS12136) of early ART, we compared proportions of risky sex (ie, unprotected sex with a partner of negative/unknown HIV status) reported 12 months after inclusion between participants randomly assigned to initiate ART immediately (hereafter, “early ART”) or according to ongoing World Health Organization criteria. Group-specific HIV transmission rates were estimated on the basis of sexual behaviors and viral load–specific per-act HIV transmission probabilities. The ratio of transmission rates was computed to estimate the protective effect of early ART. Results. Among 957 participants (baseline median CD4+ T-cell count, 478 cells/mm3), 46.0% reported sexual activity in the past month; of these 46.0%, sexual activity for 41.5% involved noncohabiting partners. The proportion of subjects who engaged in risky sex was 10.0% in the early ART group, compared with 12.8% in the standard ART group (P = .17). After accounting for sexual behaviors and viral load, we estimated that the protective effect of early ART was 90% (95% confidence interval, 81%–95%). Conclusion. Twelve months after inclusion, patients in the early and standard ART groups reported similar sexual behaviors. Early ART decreased the estimated risk of HIV transmission by 90%, suggesting a major prevention benefit among seronegative sex partners in stable or casual relationships with seropositive individuals.

Increasing rate of TAMs and etravirine resistance in HIV-1-infected adults between 12 and 24 months of treatment: the VOLTART cohort study in Côte d'Ivoire, West Africa.

Background:In sub-Saharan Africa, most HIV-infected patients receive antiretroviral therapy (ART) without virological monitoring. Longitudinal data on secondary resistance are rare. Methods:We conducted a prospective cohort study of HIV-1–infected adults initiating ART in 3 clinics using computerized monitoring systems. Patients had plasma HIV-1 RNA viral load (VL) tests at months 12 (M12) and 24 (M24) after ART initiation and HIV-1 resistance genotype tests if VL was detectable (≥300 copies/mL). Results:Overall, 1573 patients initiated ART with stavudine/zidovudine plus lamivudine plus nevirapine/efavirenz. At M12 and M24, 944 and 844 patients, respectively, remained in active follow-up. Among them, 25% (M12) and 27% (M24) had detectable VLs and 12% (M12) and 19% (M24) had virus resistant to at least 1 antiretroviral drug, accounting for 54% (M12) and 75% (M24) of patients with detectable VLs. Among the resistant strains, 95% (M12) and 97% (M24) were resistant to lamivudine/emtricitabine, efavirenz, and/or nevirapine, the frequency of thymidine analog mutations increased from 8.1% (M12) to 14.7% (M24) and etravirine resistance increased from 13.5% (M12) to 24.5% (M24). Conclusions:Of the patients with detectable VLs at M24, 25% still did not harbor resistant virus. Preventing mutations from emerging with adherence reinforcement in patients with detectable VLs remains important beyond M24. Switching therapy early in patients with resistance to 3 TC/FTC and/or to nonnucleoside reverse transcriptase inhibitors to prevent extended resistance to nucleoside reverse transcriptase inhibitors and etravirine resistance from occurring is also a major challenge.

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.

Projecting the clinical benefits and risks of using efavirenz-containing antiretroviral therapy regimens in women of childbearing age.

Objectives:To project the outcomes of using either efavirenz or nevirapine as part of initial antiretroviral therapy (ART) in women of childbearing age in Côte d’Ivoire. Methods:We used an HIV computer simulation model to project both the mothers survival and the birth defects at 10 years for a cohort of women who started ART with either efavirenz or nevirapine. The primary outcome was the ratio at 10 years of the difference in the number of women alive to the difference in the cumulative number of birth defects in women who started ART with efavirenz compared with nevirapine. In the base case analysis, the birth defect rate was 2.9% on efavirenz and 2.7% on nevirapine. In sensitivity analyses, we varied all inputs across confidence intervals reported in the literature. Results:In the base case analysis, for a cohort of 100 000 women, the additional number of women alive initiating ART with efavirenz at 10 years was 15 times the additional number of birth defects (women alive: nevirapine 67 969, efavirenz 68 880, difference = 911; birth defects: nevirapine 1128, efavirenz 1187, difference = 59). In sensitivity analysis, the teratogenicity rate with efavirenz had to be 6.3%, or 2.3 times higher than the rate with nevirapine, for the excess number of birth defects to outweigh the additional number of women alive at 10 years. Conclusion:In Côte d’Ivoire, initiating ART with efavirenz instead of nevirapine is likely to substantially increase the number of women alive at 10 years with a smaller potential number of birth defects.

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/mm3 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/m2), normal weight (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2) and obese (≥30 kg/m2). 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/mm3, median baseline BMI 22 kg/m2) 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/mm3: 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.