Christine Danel

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.).

Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea

Background Ebola virus disease (EVD) is a highly lethal condition for which no specific treatment has proven efficacy. In September 2014, while the Ebola outbreak was at its peak, the World Health Organization released a short list of drugs suitable for EVD research. Favipiravir, an antiviral developed for the treatment of severe influenza, was one of these. In late 2014, the conditions for starting a randomized Ebola trial were not fulfilled for two reasons. One was the perception that, given the high number of patients presenting simultaneously and the very high mortality rate of the disease, it was ethically unacceptable to allocate patients from within the same family or village to receive or not receive an experimental drug, using a randomization process impossible to understand by very sick patients. The other was that, in the context of rumors and distrust of Ebola treatment centers, using a randomized design at the outset might lead even more patients to refuse to seek care. Therefore, we chose to conduct a multicenter non-randomized trial, in which all patients would receive favipiravir along with standardized care. The objectives of the trial were to test the feasibility and acceptability of an emergency trial in the context of a large Ebola outbreak, and to collect data on the safety and effectiveness of favipiravir in reducing mortality and viral load in patients with EVD. The trial was not aimed at directly informing future guidelines on Ebola treatment but at quickly gathering standardized preliminary data to optimize the design of future studies. Methods and Findings Inclusion criteria were positive Ebola virus reverse transcription PCR (RT-PCR) test, age ≥ 1 y, weight ≥ 10 kg, ability to take oral drugs, and informed consent. All participants received oral favipiravir (day 0: 6,000 mg; day 1 to day 9: 2,400 mg/d). Semi-quantitative Ebola virus RT-PCR (results expressed in “cycle threshold” [Ct]) and biochemistry tests were performed at day 0, day 2, day 4, end of symptoms, day 14, and day 30. Frozen samples were shipped to a reference biosafety level 4 laboratory for RNA viral load measurement using a quantitative reference technique (genome copies/milliliter). Outcomes were mortality, viral load evolution, and adverse events. The analysis was stratified by age and Ct value. A “target value” of mortality was defined a priori for each stratum, to guide the interpretation of interim and final analysis. Between 17 December 2014 and 8 April 2015, 126 patients were included, of whom 111 were analyzed (adults and adolescents, ≥13 y, n = 99; young children, ≤6 y, n = 12). Here we present the results obtained in the 99 adults and adolescents. Of these, 55 had a baseline Ct value ≥ 20 (Group A Ct ≥ 20), and 44 had a baseline Ct value < 20 (Group A Ct < 20). Ct values and RNA viral loads were well correlated, with Ct = 20 corresponding to RNA viral load = 7.7 log10 genome copies/ml. Mortality was 20% (95% CI 11.6%–32.4%) in Group A Ct ≥ 20 and 91% (95% CI 78.8%–91.1%) in Group A Ct < 20. Both mortality 95% CIs included the predefined target value (30% and 85%, respectively). Baseline serum creatinine was ≥110 μmol/l in 48% of patients in Group A Ct ≥ 20 (≥300 μmol/l in 14%) and in 90% of patients in Group A Ct < 20 (≥300 μmol/l in 44%). In Group A Ct ≥ 20, 17% of patients with baseline creatinine ≥110 μmol/l died, versus 97% in Group A Ct < 20. In patients who survived, the mean decrease in viral load was 0.33 log10 copies/ml per day of follow-up. RNA viral load values and mortality were not significantly different between adults starting favipiravir within <72 h of symptoms compared to others. Favipiravir was well tolerated. Conclusions In the context of an outbreak at its peak, with crowded care centers, randomizing patients to receive either standard care or standard care plus an experimental drug was not felt to be appropriate. We did a non-randomized trial. This trial reaches nuanced conclusions. On the one hand, we do not conclude on the efficacy of the drug, and our conclusions on tolerance, although encouraging, are not as firm as they could have been if we had used randomization. On the other hand, we learned about how to quickly set up and run an Ebola trial, in close relationship with the community and non-governmental organizations; we integrated research into care so that it improved care; and we generated knowledge on EVD that is useful to further research. Our data illustrate the frequency of renal dysfunction and the powerful prognostic value of low Ct values. They suggest that drug trials in EVD should systematically stratify analyses by baseline Ct value, as a surrogate of viral load. They also suggest that favipiravir monotherapy merits further study in patients with medium to high viremia, but not in those with very high viremia. Trial registration ClinicalTrials.gov NCT02329054

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.

Pregnancy outcomes in women exposed to efavirenz and nevirapine: an appraisal of the IeDEA West Africa and ANRS Databases, Abidjan, Côte d'Ivoire.

Background:An increasing number of HIV-infected women become pregnant while receiving efavirenz (EFV). We compared the pregnancy outcomes of women exposed to EFV and to nevirapine (NVP) during the first trimester. Methods:A retrospective study in 4 HIV care centers participating to clinical trials and international cohort collaboration. All HIV-infected pregnant women who conceived on EFV-based or NVP-based antiretroviral therapy (ART) between 2003 and 2009 were included. Pregnancy outcomes were as follows: abortion (voluntary termination), miscarriage [unwanted termination <20 weeks of amenorrhea (WA)], stillborn (death ≥20 WA), preterm delivery (live-birth <37 WA), and low birth weight (LBW) (<2500 grams). Results:Overall, 344 HIV-infected pregnant women conceived on ART (213 on EFV and 131 on NVP). Median age was 29 years, and median CD4 count 217 cells per microliter at ART initiation. The overall proportion was 11.7% for abortion, 5.2% for miscarriage, 6.7% for stillborn, 10.8% for preterm delivery, and 20.2% for LBW. There was no difference between EFV and NVP exposure, except for abortion (14.3% vs 7.3%; P = 0.05). No external and visible congenital malformation was observed neither in women exposed to EFV nor in women exposed to NVP. Conclusions:Among women exposed to EFV, no significant increased risk of unfavorable pregnancy outcome was reported except for abortion.

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.

Prevalence and virological profiles of hepatitis B infection in human immunodeficiency virus patients

AIM To determine the prevalence of hepatitis B virus (HBV) in adult human immunodeficiency virus (HIV) patients with CD4+ T-cell count less than 500/mm(3) and without antiretroviral therapy; to describe different HBV-HIV coinfection virological profiles; and to search for factors associated with HBs antigen (HBsAg) presence in these HIV positive patients. METHODS During four months (June through September 2006), 491 patients were received in four HIV positive monitoring clinical centers in Abidjan. INCLUSION CRITERIA HIV-1 or HIV-1 and 2 positive patients, age ≥ 18 years, CD4+ T-cell count < 500/mL and formal and signed consent of the patient. Realized blood tests included HIV serology, CD4+ T-cell count, quantitative HIV RNA load and HBV serological markers, such as HBsAg and HBc antibody (anti-HBcAb). We performed HBeAg, anti-HBe antibody (anti-HBeAb), anti-HBc IgM and quantitative HBV DNA load in HBsAg positive patients. Anti-HBsAb had been tested in HIV patients with HBsAg negative and anti-HBcAb-positive. HBV DNA was also tested in 188 anti-HBcAb positive patients with HBsAg negative status and without anti-HBsAb. Univariate analysis (Pearson χ(2) test or Fischer exact test) and multivariate analysis (backward step-wise selection logistic regression) were performed as statistical analysis. RESULTS Mean age of 491 patients was 36 ± 8.68 years and 73.3% were female. Type-1 HIV was found in 97% and dual-type HIV (type 1 plus type 2) in 3%. World Health Organization (WHO) clinical stage was 1, 2, 3 and 4 respectively in 61 (12.4%), 233 (47.5%), 172 (35%) and 25 patients (5.1%). Median CD4+ T-cell count was 341/mm(3) (interquartile range: 221-470). One hundred and twelve patients had less than 200 CD4+ T-cell/mm(3). Plasma HIV-1 RNA load was elevated (≥ 5 log(10) copies/mL) in 221 patients (45%). HBsAg and anti-HBcAb prevalence was respectively 13.4% and 72.9%. Of the 66 HBsAg positive patients, 22 were inactive HBV carriers (33.3%), 21 had HBeAg positive hepatitis (31.8%) and 20 had HBeAg negative hepatitis (30.3%). HBeAg and anti-HBeAb were indeterminate in 3 of them. Occult B infection prevalence (HBsAg negative, anti-HBcAb positive, anti-HBsAb negative and detectable HBV DNA) was 21.3%. Three parameters were significantly associated with the presence of HBsAg: male [odds ratio (OR): 2.2; P = 0.005; 95% confidence interval (CI): 1.3-3.8]; WHO stage 4 (OR: 3.2; P = 0.01; 95% CI: 1.3-7.9); and aspartate aminotransferase (AST) level higher than the standard (OR: 1.9; P = 0.04; 95% CI: 1.02-3.8). CONCLUSION HBV infection prevalence is high in HIV-positive patients. HBeAg positive chronic hepatitis and occult HBV infection are more frequent in HIV-positive patients than in HIV negative ones. Parameters associated with HBsAg positivity were male gender, AIDS status and increased AST level.

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.