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Background: Data on HIV-1 controllers in Africa are scarce. We report the proportion of HIV-1 controllers in a group of adults prospectively monitored with frequent viral load measurements as part of a clinical trial in West Africa. Methods: For the Temprano trial, antiretroviral therapy (ART)-naive HIV-1 infected adults with no criteria for starting ART were randomized to start ART immediately or defer ART until the WHO starting criteria were met. Plasma viral load was measured every 6 months. The trial follow-up was 30 months. We considered all Temprano participants randomized to defer ART. Patients with all semestrial viral

Summary Background Lassa fever is a viral haemorrhagic fever endemic in parts of west Africa. New treatments are needed to decrease mortality, but pretrial reference data on the disease characteristics are scarce. We aimed to document baseline characteristics and outcomes for patients hospitalised with Lassa fever in Nigeria. Methods We did a prospective cohort study (LASCOPE) at the Federal Medical Centre in Owo, Nigeria. All patients admitted with confirmed Lassa fever were invited to participate and asked to give informed consent. Patients of all ages, including newborn infants, were eligible for inclusion, as were pregnant women. All participants received standard supportive care and intravenous ribavirin according to Nigeria Centre for Disease Control guidelines and underwent systematic biological monitoring for 30 days. Patients' characteristics, care received, mortality, and associated factors were recorded using standard WHO forms. We used univariable and multivariable logistic regression models to investigate an association between baseline characteristics and mortality at day 30. Findings Between April 5, 2018, and March 15, 2020, 534 patients with confirmed Lassa fever were admitted to hospital, of whom 510 (96%) gave consent and were included in the analysis. The cohort included 258 (51%) male patients, 252 (49%) female patients, 426 (84%) adults, and 84 (16%) children (younger than 18 years). The median time between first symptoms and hospital admission was 8 days (IQR 7–13). At baseline, 176 (38%) of 466 patients had a Lassa fever RT-PCR cycle threshold (Ct) lower than 30. From admission to end of follow-up, 120 (25%) of 484 reached a National Early Warning Score (second version; NEWS2) of 7 or higher, 67 (14%) of 495 reached a Kidney Disease–Improving Global Outcome (KDIGO) stage of 2 or higher, and 41 (8%) of 510 underwent dialysis. All patients received ribavirin for a median of 10 days (IQR 9–13). 62 (12%) patients died (57 [13%] adults and five [6%] children). The median time to death was 3 days (1–6). The baseline factors independently associated with mortality were the following: age 45 years or older (adjusted odds ratio 16·30, 95% CI 5·31–50·30), NEWS2 of 7 or higher (4·79, 1·75–13·10), KDIGO grade 2 or higher (7·52, 2·66–21·20), plasma alanine aminotransferase 3 or more times the upper limit of normal (4·96, 1·69–14·60), and Lassa fever RT-PCR Ct value lower than 30 (4·65, 1·50–14·50). Interpretation Our findings comprehensively document clinical and biological characteristics of patients with Lassa fever and their relationship with mortality, providing prospective estimates that could be useful for designing future therapeutic trials. Such trials comparing new Lassa fever treatments to a standard of care should take no more than 15% as the reference mortality rate and consider adopting a combination of mortality and need for dialysis as the primary endpoint. Funding Institut National de la Sante et de la Recherche Medicale, University of Oxford, EU, UK Department for International Development, Wellcome Trust, French Ministry of Foreign Affairs, Agence Nationale de Recherches sur le SIDA et les hepatites virales, French National Research Institute for Sustainable Development.

International audience; Objectives: To assess the efficacy of inhaled ciclesonide in reducing the risk of adverse outcomes in COVID-19 outpatients at risk of developing severe illness.Methods: COVERAGE is an open-label, randomized controlled trial. Outpatients with documented COVID-19, risk factors for aggravation, symptoms for ≤7 days, and absence of criteria for hospitalization are randomly allocated to either a control arm or one of several experimental arms, including inhaled ciclesonide. The primary efficacy endpoint is COVID-19 worsening (hospitalization, oxygen therapy at home, or death) by Day 14. Other endpoints are adverse events, maximal follow-up score on the WHO Ordinal Scale for Clinical Improvement, sustained alleviation of symptoms, cure, and RT-PCR and blood parameter evolution at Day 7. The trial's Safety Monitoring Board reviewed the first interim analysis of the ciclesonide arm and recommended halting it for futility. The results of this analysis are reported here.Results: The analysis involved 217 participants (control 107, ciclesonide 110), including 111 women and 106 men. Their median age was 63 years (interquartile range 59-68), and 157 of 217 (72.4%) had at least one comorbidity. The median time since first symptom was 4 days (interquartile range 3-5). During the 28-day follow-up, 2 participants died (control 2/107 [1.9%], ciclesonide 0), 4 received oxygen therapy at home and were not hospitalized (control 2/107 [1.9%], ciclesonide 2/110 [1.8%]), and 24 were hospitalized (control 10/107 [9.3%], ciclesonide 14/110 [12.7%]). In intent-to-treat analysis of observed data, 26 participants reached the composite primary endpoint by Day 14, including 12 of 106 (11.3%, 95% CI: 6.0%-18.9%) in the control arm and 14 of 106 (13.2%; 95% CI: 7.4-21.2%) in the ciclesonide arm. Secondary outcomes were similar for both arms.Discussion: Our findings are consistent with the European Medicines Agency's COVID-19 task force statement that there is currently insufficient evidence that inhaled corticosteroids are beneficial for patients with COVID-19.

Asymptomatic HIV-infected people who start ART early may feel less motivated and neglect compliance. This might promote the emergence of resistance.In the Temprano trial, ART-naive HIV-infected adults with high CD4 counts were randomly assigned to start ART immediately (immediate group) or defer ART until the WHO criteria were met (deferred group). All participants were monitored for 30 months. Those in the deferred group who started ART were monitored for longer, until they had completed 30 months on ART. We compared the rate of virological failure and drug resistance between the immediate and deferred groups 30 months after ART initiation.Of the 2056 participants in Temprano, 1033 were assigned to start ART immediately and 1023 to defer ART. Of the latter, 488 started ART during trial follow-up. Patients in the deferred group who started ART had a lower median CD4 count (280 versus 465 cells/mm3) and a higher median plasma HIV-1 RNA (5.1 versus 4.7 log10 copies/mL) at baseline. During follow-up, participants in both groups had similar antiretroviral drug exposure. Thirty months after ART initiation, patients in the deferred group had a higher rate of virological failure (35.3% versus 29.9%, P = 0.04) and a lower genotypic susceptibility score (P = 0.04).Starting ART early decreases the risk of virological failure and drug resistance in the medium term. This benefit is of particular importance in countries where access to viral load monitoring and the number of antiretroviral drug lines is limited.

BACKGROUND Several biomarkers of inflammation and coagulation were reported to be associated with HIV disease progression in different settings. In this article, we report the association between 11 biomarkers and medium-term mortality in HIV-infected West African adults. METHODS In Temprano ANRS 12136, antiretroviral therapy (ART)-naive HIV-infected adults with high CD4 counts were randomly assigned either to start ART immediately or defer ART until the World Health Organization criteria were met. Participants who completed the 30-month trial follow-up were invited to participate in a posttrial phase. The posttrial phase end point was all-cause death. We used multivariate Cox proportional models to analyze the association between baseline plasma biomarkers [IL-1ra, IL-6, soluble vascular cell adhesion molecule 1 (sVCAM-1), sCD14, D-dimer, fibrinogen, IP-10, sCD163, albumin, high-sensitivity C-reactive protein, and 16S rDNA] and all-cause death in the Temprano participants randomized to defer ART. RESULTS Four hundred seventy-seven patients (median age 35 years, 78% women, and median CD4 count: 379 cells/mm) were randomly assigned to defer starting ART until the World Health Organization criteria were met. The participants were followed for 2646 person-years (median 5.8 years). In the follow-up, 89% of participants started ART and 30 died. In the multivariate analysis adjusted for the study center, sex, baseline CD4 count, isoniazid preventive therapy, plasma HIV-1 RNA, peripheral blood mononuclear cell HIV-1 DNA, and ART, the risk of death was significantly associated with baseline sVCAM-1 (≥1458 vs.

Background Asymptomatic HIV-infected people who start ART early may feel less motivated and neglect compliance. This might promote the emergence of resistance. Methods In the Temprano trial, ART-naive HIV-infected adults with high CD4 counts were randomly assigned to start ART immediately (immediate group) or defer ART until the WHO criteria were met (deferred group). All participants were monitored for 30 months. Those in the deferred group who started ART were monitored for longer, until they had completed 30 months on ART. We compared the rate of virological failure and drug resistance between the immediate and deferred groups 30 months after ART initiation. Results Of the 2056 participants in Temprano, 1033 were assigned to start ART immediately and 1023 to defer ART. Of the latter, 488 started ART during trial follow-up. Patients in the deferred group who started ART had a lower median CD4 count (280 versus 465 cells/mm3) and a higher median plasma HIV-1 RNA (5.1 versus 4.7 log10 copies/mL) at baseline. During follow-up, participants in both groups had similar antiretroviral drug exposure. Thirty months after ART initiation, patients in the deferred group had a higher rate of virological failure (35.3% versus 29.9%, P = 0.04) and a lower genotypic susceptibility score (P = 0.04). Conclusions Starting ART early decreases the risk of virological failure and drug resistance in the medium term. This benefit is of particular importance in countries where access to viral load monitoring and the number of antiretroviral drug lines is limited.

Background Lassa Fever (LF), is a severe viral disease prevalent in Western Africa. It is classified as a priority disease by the World Health Organization (WHO). Ribavirin is the recommended therapy despite weak evidence of its efficacy. Promising therapeutic agents are becoming available for evaluation in human. Before launching therapeutic trials, we need data on the evolution of the disease under the best possible conditions of care. Methods We have initiated a prospective study in Nigeria to better understand the clinical course and prognostic factors of LF while implementing high quality standardized care. Inclusion criteria are: suspected or confirmed LF and informed consent. Participants are followed 60 days from admission and receive free of charge standardized supportive care and biological monitoring, as well as intravenous ribavirin for those with confirmed LF. Data are collected using standardized case report forms (CRF). Primary and secondary outcomes are fatality and severe morbidity, with special focus on acute kidney dysfunction and pregnancy complications. Factors associated with outcomes will be investigated. Results The cohort is planned for 3 years. Inclusions started in April 2018 at the Federal Medical Center Owo in Ondo State. A second site will open in Nigeria in 2020 and discussions are underway to open a site in Benin. 150 to 200 new participants are expected per year. Conclusions This cohort will: provide evidence to standardize LF case management; provide key inputs to design future clinical trials of novel therapeutics; and establish clinical research teams capable of conducting such trials in LF-endemic areas. Study registration The LASCOPE study was registered on ClinicalTrial.gov (NCT03655561).

Background: Several biomarkers of inflammation and coagulation were reported to be associated with HIV disease progression in different settings. Here we report the association between eleven biomarkers and medium-term mortality in HIV-infected adults who participated in a trial of early antiretroviral therapy (ART) in West Africa (Temprano ANRS 12136). Methods: In Temprano, ART-naive HIV-infected adults with high CD4 counts were randomly assigned either to start ART immediately or defer ART until the WHO criteria were met. Participants who completed the 30-month trial follow-up were invited to participate in a post-trial phase (PTP). The PTP endpoint was all-cause death. We used multivariate Cox proportional models to analyze the association between baseline plasma biomarkers (IL-1ra, IL-6, sVCAM-1, sCD14, D-dimer, Fibrinogen, IP-10, sCD163, albumin, hsCRP, 16S rDNA) and all-cause death in the Temprano participants randomized to defer ART. Findings: 477 patients (median age 35, 78% women) were randomly assigned to defer starting ART until the WHO criteria were met. At baseline, the median CD4 count was 379 cells/mm3, the median plasma HIV-1 RNA level 4·6 log10 copies/mL and the median PBMC HIV-1 DNA level 3·0 log10 copies per million PBMC. The participants were followed for 2646 person-years (median 5·8 years). In the follow-up, 89% of participants started ART and 30 died. In the multivariate analysis adjusted for the study center, sex, baseline CD4 count, isoniazid preventive therapy, plasma HIV-1 RNA, PBMC HIV-1 DNA and ART, the risk of death was significantly associated with baseline sVCAM-1 (≥ 1458 vs. < 1458: adjusted hazard ratio [aHR] 2·57, 95% CI 1·13-5·82) and sCD14 (≥ 2187 vs. < 2187: aHR 2·79, IQR 1·29-6·02) levels. Interpretation: In these sub-Saharan African adults with high CD4 counts, pre-ART plasma sVCAM-1 and sCD14 levels were independently associated with mortality. Trial Registration: Registered at Clinical Trials.gov (NCT00495651). Funding Statement: French National Agency for AIDS and viral hepatitis research (ANRS, Paris, France; Grants ANRS 12136, ANRS 12224, ANRS 12253). Declaration of Interests: All authors report no conflict of interest. Ethics Approval Statement: The Temprano protocol, which included the post-trial phase, was approved by the Cote d'Ivoire National Ethics Committee for Health Research. All patients gave written informed consent.

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 /=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

Background: High HIV-1 DNA levels in peripheral blood mononuclear cells (PBMC) were associated with a higher risk of severe morbidity and a faster decline in CD4 count in ART-naive patients. We report the association between HIV-1 DNA and mortality in HIV-infected adults in a trial of early ART in West Africa. Methods: In the Temprano trial, HIV-infected adults were randomly assigned to start ART immediately or defer ART. After trial termination, HIV-1 DNA was measured in whole blood samples frozen at baseline. We analyzed the association between baseline PBMC HIV-1 DNA and long-term mortality. Results: 2,019 patients were followed for 9,253 patient-years (median 4.9 years). At baseline, the median CD4 count was 462/mm3 [IQR 368-571], the median plasma HIV-1 RNA 4.7 log10 copies/ml [IQR 4.0-5.2], and the median HIV-1 DNA 2.9log10 copies/million PBMC [IQR 2.5-3.3]. During follow-up, 86 participants died. In univariate analysis, the hazard ratio [HR] of death was 2.67 (95% CI, 1.68-4.22) for patients with HIV-1 DNA ≥3 log10 copies/million PBMC vs. others, and 2.10 (95% CI, 1.38-3.21) for patients with HIV-1 RNA ≥5 log10 copies/ml vs. others. In multivariate Cox regression analysis, HIV-1 DNA levels ≥3 log10 copies/million PBMC were strongly associated mortality (adjusted HR = 2.09, 95% CI 1.24-3.52, p = 0.005) while the association between baseline plasma HIV-1 RNA and mortality was not significant. Conclusions: In these African adults who started ART with high CD4 counts, HIV-1 DNA was a strong independent predictor of death. The HIV reservoir still plays a prognostic role in the early ART era. Trial Registration: Clinical Trials.gov (NCT00495651). Funding Statement: This trial was supported by grants from the French National Agency for AIDS and viral hepatitis research (ANRS, Paris, France; Grants ANRS 12136, ANRS 12224, ANRS 12253. Declaration of Interests: All authors report no conflict of interest. Ethics Approval Statement: The Temprano protocol, which included the post-trial phase, was approved by the Cote d'Ivoire National Ethics Committee for Health Research.

BackgroundUniversal antiretroviral therapy (ART), as per the 2015 WHO recommendations, might reduce population HIV incidence. We investigated the effect of universal test and treat on HIV acquisition at population level in a high prevalence rural region of South Africa.MethodsWe did a phase 4, open-label, cluster randomised trial of 22 communities in rural KwaZulu-Natal, South Africa. We included individuals residing in the communities who were aged 16 years or older. The clusters were composed of aggregated local areas (neighbourhoods) that had been identified in a previous study in the Hlabisa subdistrict. The study statisticians randomly assigned clusters (1:1) with MapInfo Pro (version 11.0) to either the control or intervention communities, stratified on the basis of antenatal HIV prevalence. We offered residents repeated rapid HIV testing during home-based visits every 6 months for about 4 years in four clusters, 3 years in six clusters, and 2 years in 12 clusters (58 cluster-years) and referred HIV-positive participants to trial clinics for ART (fixed-dose combination of tenofovir, emtricitabine, and efavirenz) regardless of CD4 cell count (intervention) or according to national guidelines (initially ≤350 cells per μL and FindingsBetween March 9, 2012, and June 30, 2016, we contacted 26 518 (93%) of 28 419 eligible individuals. Of 17 808 (67%) individuals with a first negative dried blood spot test, 14 223 (80%) had subsequent dried blood spot tests, of whom 503 seroconverted after follow-up of 22 891 person-years. Estimated HIV incidence was 2·11 per 100 person-years (95% CI 1·84–2·39) in the intervention group and 2·27 per 100 person-years (2·00–2·54) in the control group (adjusted hazard ratio 1·01, 95% CI 0·87–1·17; p=0·89). We documented one case of suicidal attempt in a woman following HIV seroconversion. 128 patients on ART had 189 life-threatening or grade 4 clinical events: 69 (4%) of 1652 in the control group and 59 (4%) of 1367 in the intervention group (p=0·83).InterpretationThe absence of a lowering of HIV incidence in universal test and treat clusters most likely resulted from poor linkage to care. Policy change to HIV universal test and treat without innovation to improve health access is unlikely to reduce HIV incidence.FundingANRS, GiZ, and 3ie.

PURPOSE OF REVIEW: In this review we describe the challenges faced by using clinical cohorts to perform Monitoring and Evaluation (M&E) and the possible solutions for increasing and strengthening health systems in low-income and middle-income countries. RECENT FINDINGS: HIV scale-up has facilitated the transition from paper-based medical records to electronic medical records at hundreds of sites in most of the countries in sub-Saharan Africa and the implementation of national HIV databases. However National M&E systems in resource-limited settings tend to be chronically challenged by persistently incomplete reporting and inaccurate data which undermines their usefulness. In low-income and middle-income countries new information technologies such as Web-based systems and mobile phone networks are expanding rapidly. Their use will improve data quality and therefore reduce participant dropout and improve reporting rates. These systems have the potential to allow real time access to summary reports and to integrate data from other settings such as maternal and infant health clinics. SUMMARY: The efforts to address the AIDS pandemic in sub-Saharan Africa will require enhanced information systems. Stronger systems are needed to deliver primary healthcare for those with and without HIV and it is also essential to build and take advantage of synergies across health information systems.

OBJECTIVE: To determine the rates and causes of first antiretroviral treatment changes in HIV-infected adults in Cote dIvoire. METHODS: We evaluated adults who initiated antiretroviral treatment in an outpatient clinic in Abidjan. We recorded baseline and follow-up data including drug prescriptions and reasons for changing to alternative first-line regimens (drug substitution for any reason but failure) or second-line regimens (switch for failure). RESULTS: Two thousand and twelve HIV-infected adults (73% women) initiated antiretroviral treatment. At baseline 9% of all patients were on treatment for tuberculosis and 3% of women were pregnant. First-line antiretroviral treatment consisted of two nucleoside reverse transcriptase inhibitors (58% stavudine-lamivudine 42% zidovudine-lamivudine) and efavirenz (63%) nevirapine (32%) or indinavir (5%). Median follow-up time was 16.9 months. During this time 205 (10%) patients died and 261 (13%) were lost to follow-up. Overall the rate of treatment modifications was 20.7/100 patient-years. The most common modifications were drug substitutions for intolerance (12.4/100 patient-years) pregnancy (4.5/100 patient-years) and tuberculosis (2.5/100 patient-years). The rates of intolerance-related substitutions were 17.9/100 patient-years for stavudine 6.3/100 patient-years for nevirapine 3.9/100 patient-years for zidovudine and 0.1/100 patient-years for efavirenz. Twenty percent of efavirenz substitutions resulted from pregnancy and 18% of nevirapine substitutions were related to tuberculosis treatment. CONCLUSION: During the first months following antiretroviral treatment initiation a third of all treatment changes occurred for reasons other than intolerance to the drug or treatment failure. In Africa drug forecasting is crucial to ensuring the success of HIV treatment programmes. Drugs that do not require interruptions during pregnancy or tuberculosis treatment should be made more readily available as first-line drugs in sub-Saharan Africa.

International audience; OBJECTIVE: To assess the rates and determinants of mortality, loss to follow-up and immunological failure in a nongovernmental organization-implemented program of access to antiretroviral treatment in C?d'Ivoire. METHODS: In each new treatment center, professionals were trained in HIV care, and a computerized data system was implemented. Individual patient and program level determinants of survival, loss to follow-up and immunological failure were assessed by multivariate analysis. RESULTS: Between May 2004 and February 2007, 10,211 patients started antiretroviral treatment in 19 clinics (median preantiretroviral treatment CD4 cell count, 123 cells/microl; initial regimen zidovudine-lamivudine-efavirenz, 20%; stavudine-lamivudine-efavirenz, 22%; stavudine-lamivudine-nevirapine, 52%). At 18 months on antiretroviral treatment, the median gain in CD4 cell count was +202 cells/microl, the probability of death was 0.15 and the probability of being loss to follow-up was 0.21. In addition to the commonly reported determinants of impaired outcomes (low CD4 cell count, low BMI, low hemoglobin, advanced clinical stage, old age and poor adherence), two factors were also shown to independently jeopardize prognosis: male sex (men vs. women: hazard ratio = 1.52 for death, 1.27 for loss to follow-up, 1.31 for immunological failure); and attending a recently opened clinic (inexperienced vs. experienced centers: hazard ratio = 1.40 for death, 1.58 for loss to follow-up). None of the three outcomes was associated with the drug regimen. DISCUSSION: In this rapidly scaling-up program, survival and immune reconstitution were good; women and patients followed up in centers with longer experience had better outcomes; outcomes were similar in zidovudine/stavudine-based regimens and in efavirenz/nevirapine-based regimens. Decreasing the rate of loss to follow-up should now be the top priority in antiretroviral treatment rollout.