Ibrahima Ndiaye

Mortality and causes of death in adults receiving highly active antiretroviral therapy in Senegal: a 7-year cohort study.

Objectives:To evaluate survival and investigate causes of death among HIV-1 infected adults receiving HAART in Senegal. Design:An observational prospective cohort. Methods:Mortality was assessed in the first patients enrolled between August 1998 and April 2002 in the Senegalese antiretroviral drug access initiative. First-line regimen combined two nucleoside reverse transcriptase inhibitors and either a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor. The most likely causes of death were ascertained through medical records or post-mortem interviews (verbal autopsy). Results:Four hundred and four patients (54.7% women) were enrolled in the study and were followed for a median of 46 months (interquartile range: 32–57 months) after HAART initiation. At baseline, 5% were antiretroviral therapy (ART) non-naive, 39 and 55% were respectively at CDC stage B and C, median age, CD4 cell count and viral load were 37 years, 128 cells/μl and 5.2 log cp/ml, respectively. Ninety-three patients died during follow-up and the overall incidence rate of death was 6.3/100 person-years [95% confidence interval (CI), 5.2–7.7]. During the first year after HAART initiation, 47 patients died and seven were lost to follow-up, yielding to a probability of dying of 11.7% (95% CI, 8.9–15.3%). The death rate, which was highest during the first year after HAART initiation, decreased with time yielding a cumulative probability of dying of 17.4% (95% CI, 13.9–21.5%) and 24.6% (95% CI, 20.4–29.4%) at 2 and 5 years. Causes of death were ascertained in 76 deaths. Mycobacterial infections, neurotropic infections and septicaemia were the most frequent likely causes of death. Conclusions:This study underlines the early mortality pattern after HAART initiation and highlights the leading role of mycobacterial infections in the causes of death.

Randomized, multicentre assessment of the efficacy and safety of ASAQ – a fixed-dose artesunate-amodiaquine combination therapy in the treatment of uncomplicated Plasmodium falciparum malaria

BackgroundThe use of artemisinin derivative-based combination therapy (ACT) such as artesunate plus amodiaquine is currently recommended for the treatment of uncomplicated Plasmodium falciparum malaria. Fixed-dose combinations are more adapted to patients than regimens involving multiple tablets and improve treatment compliance. A fixed-dose combination of artesunate + amodiaquine (ASAQ) was recently developed. To assess the efficacy and safety of this new combination and to define its optimum dosage regimen (once or twice daily) in the treatment of uncomplicated P. falciparum malaria, a multicentre clinical study was conducted.MethodsA multicentre, randomized, controlled, investigator-blinded, parallel-group study was conducted in five African centers in Cameroon, Madagascar, Mali and Senegal from March to December 2006. Efficacy and safety of ASAQ were assessed compared to those of artemether + lumefantrine (AL). The WHO protocol with a 28-day follow-up for assessing the drug therapeutic efficacy was used. Patients suffering from uncomplicated P. falciparum malaria were randomized to receive ASAQ orally once daily (ASAQ1), ASAQ twice daily (ASAQ2) or AL twice daily (AL) for three days. The primary outcome was PCR-corrected parasitological cure rate and clinical response.ResultsOf 941 patients initially randomized and stratified into two age groups (<5 years, and ≥5 years), 936 (99.5%) were retained for the intent to treat (ITT) analysis, and 859 (91.3%) patients for the per protocol (PP) analysis. Among ITT population, up to D28, PCR-corrected adequate parasitological and clinical response rates were 95.2% in the ASAQ1 group, 94.9% in the ASAQ2 group and 95.5% in the AL group. Moreover, the cure rate evaluated among PP population was ≥98.5% in both ASAQ therapeutic arms. Therapeutic response rates did not display any significant differences between age groups or between one geographical site and another. Altogether, this demonstrates the non-inferiority of ASAQ1 regimen compared to both ASAQ2 and AL regimens. During follow-up mild and moderate adverse events including gastrointestinal and/or nervous disorders were reported in 29.3% of patients, with no difference between groups in the nature, frequency or intensity of adverse events.ConclusionThe non-inferiority of ASAQ compared with AL was demonstrated. The fixed-dose combination artesunate + amodiaquine (ASAQ) is safe and efficacious even in young children under 5 years of age. Whilst administration on a twice-a-day basis does not improve the efficacy of ASAQ significantly, a once-a-day intake of this new combination clearly appears as an effective and safe therapy in the treatment of uncomplicated P. falciparum malaria both in adults and children. Implications of such findings are of primary importance in terms of public health especially in African countries. As most national policies plan to strengthen malaria control to reach the elimination of this disease, anti-malarial drugs such as the artesunate + amodiaquine fixed-dose ACT will play a pivotal role in this process.Trial registrationThe protocol was registered with the www.clinicaltrials.gov open clinical trial registry under the identifier number NCT00316329.

Quantitation of HIV-1 RNA in dried blood spots by the real-time NucliSENS EasyQ HIV-1 assay in Senegal

Measurement of viral load in plasma remains the best marker for the follow-up of antiretroviral therapy. However, its use is limited in developing countries due to the lack of adequate facilities and equipment, and cryopreservation of plasma during storage and transportation. Practical and reliable methods adapted to field conditions for the collection, transportation and accurate measurement of HIV-1 viral load are needed for the optimum use of antiretroviral therapy in resource-limited countries. This study evaluated the use of dried blood spots (DBS) for the real-time quantitation of HIV-1 RNA levels with the NucliSENS EasyQ((R)) HIV-1 assay (bioMérieux, Lyon, France) under field conditions in Senegal (Africa). Dried blood spots and plasma from 41 patients living in suburban Dakar were used for determination of HIV-1 RNA concentrations and stability at 37 degrees C. Analysis was performed at the Dakar University Hospital laboratory. Extraction was done with the bioMérieux NucliSENS((R)) miniMAGtrade mark, and real-time detection was done with the bioMérieux NucliSENS((R)) EasyQ system. HIV-1 RNA concentrations in plasma were compared with concentrations in dried blood spots after 8 and 15 days at 37 degrees C. The study showed a strong concordance in RNA levels between plasma and dried blood spots, which appear to be very stable over time with no apparent degradation observed after 2 weeks at 37 degrees C (mean difference 0.065logIU/ml). These results suggest that the use of dried blood spots in combination with the NucliSENS EasyQ HIV-1 assay is well adapted for HIV-1 RNA level monitoring in centralized laboratories in developing countries.

Safety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a randomised, placebo-controlled, phase 2 trial

Summary Background HIV-1 infection is associated with increased risk of tuberculosis and a safe and effective vaccine would assist control measures. We assessed the safety, immunogenicity, and efficacy of a candidate tuberculosis vaccine, modified vaccinia virus Ankara expressing antigen 85A (MVA85A), in adults infected with HIV-1. Methods We did a randomised, double-blind, placebo-controlled, phase 2 trial of MVA85A in adults infected with HIV-1, at two clinical sites, in Cape Town, South Africa and Dakar, Senegal. Eligible participants were aged 18–50 years, had no evidence of active tuberculosis, and had baseline CD4 counts greater than 350 cells per μL if they had never received antiretroviral therapy or greater than 300 cells per μL (and with undetectable viral load before randomisation) if they were receiving antiretroviral therapy; participants with latent tuberculosis infection were eligible if they had completed at least 5 months of isoniazid preventive therapy, unless they had completed treatment for tuberculosis disease within 3 years before randomisation. Participants were randomly assigned (1:1) in blocks of four by randomly generated sequence to receive two intradermal injections of either MVA85A or placebo. Randomisation was stratified by antiretroviral therapy status and study site. Participants, nurses, investigators, and laboratory staff were masked to group allocation. The second (booster) injection of MVA85A or placebo was given 6–12 months after the first vaccination. The primary study outcome was safety in all vaccinated participants (the safety analysis population). Safety was assessed throughout the trial as defined in the protocol. Secondary outcomes were immunogenicity and vaccine efficacy against Mycobacterium tuberculosis infection and disease, assessed in the per-protocol population. Immunogenicity was assessed in a subset of participants at day 7 and day 28 after the first and second vaccination, and M tuberculosis infection and disease were assessed at the end of the study. The trial is registered with ClinicalTrials.gov, number NCT01151189. Findings Between Aug 4, 2011, and April 24, 2013, 650 participants were enrolled and randomly assigned; 649 were included in the safety analysis (324 in the MVA85A group and 325 in the placebo group) and 645 in the per-protocol analysis (320 and 325). 513 (71%) participants had CD4 counts greater than 300 cells per μL and were receiving antiretroviral therapy; 136 (21%) had CD4 counts above 350 cells per μL and had never received antiretroviral therapy. 277 (43%) had received isoniazid prophylaxis before enrolment. Solicited adverse events were more frequent in participants who received MVA85A (288 [89%]) than in those given placebo (235 [72%]). 34 serious adverse events were reported, 17 (5%) in each group. MVA85A induced a significant increase in antigen 85A-specific T-cell response, which peaked 7 days after both vaccinations and was primarily monofunctional. The number of participants with negative QuantiFERON-TB Gold In-Tube findings at baseline who converted to positive by the end of the study was 38 (20%) of 186 in the MVA85A group and 40 (23%) of 173 in the placebo group, for a vaccine efficacy of 11·7% (95% CI −41·3 to 44·9). In the per-protocol population, six (2%) cases of tuberculosis disease occurred in the MVA85A group and nine (3%) occurred in the placebo group, for a vaccine efficacy of 32·8% (95% CI −111·5 to 80·3). Interpretation MVA85A was well tolerated and immunogenic in adults infected with HIV-1. However, we detected no efficacy against M tuberculosis infection or disease, although the study was underpowered to detect an effect against disease. Potential reasons for the absence of detectable efficacy in this trial include insufficient induction of a vaccine-induced immune response or the wrong type of vaccine-induced immune response, or both. Funding European & Developing Countries Clinical Trials Partnership (IP.2007.32080.002), Aeras, Bill & Melinda Gates Foundation, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium.

Lipodystrophy and metabolic disorders in HIV-1-infected adults on 4- to 9-year antiretroviral therapy in Senegal: a case-control study.

Objective:To assess adverse effects of long-term highly active antiretroviral therapy (HAART), that is, lipodystrophy and metabolic disorders, in a cohort of African patients. Methods:One hundred eighty HIV-1-infected patients treated with HAART for 4-9 years in Dakar and 180 age-matched and sex-matched controls were enrolled. Regional subcutaneous fat changes were assessed by physicians, and fasting blood samples were drawn. Centralization of body fat was estimated using skinfold ratio, waist circumference, and waist to hip ratio (WHR). Results:Mean duration of HAART was 5.4 years. Main drugs received were zidovudine, stavudine, and protease inhibitors. The prevalence of moderate-severe lipodystrophy was 31.1% (95% confidence interval: 24.3 to 37.9), with 13.3%, 14.5%, and 3.3% for lipoatrophy, lipohypertrophy, and mixed forms, respectively. Mild-severe lipodystrophy affected 65.0% (58.0; 72.0) of patients. Stavudine was the only independent risk factor (any vs. none: odds ratio = 2.8; 1.4 to 5.5). Patients had lower body mass index and skinfolds but greater centralization of body fat (WHR, P < 0.0001 and skinfold ratio, P < 0.001), fasting glucose (P < 0.0001), homeostasis model assessment insulin resistance, and triglyceride levels (P < 0.01 for both) than controls. Moderately-severely lipodystrophic patients had higher triglyceride and low-density lipoprotein cholesterol than other patients (P < 0.001 and P < 0.05, respectively). Conclusions:Moderate-severe lipodystrophy affected one third of West African patients on long-term HAART and was associated with a less favorable metabolic profile.

Repeated treatment of recurrent uncomplicated Plasmodium falciparum malaria in Senegal with fixed-dose artesunate plus amodiaquine versus fixed-dose artemether plus lumefantrine: a randomized, open-label trial

BackgroundThe use of artemisinin-based combination therapy (ACT) is currently recommended for treating uncomplicated malaria. The objective was to assess the efficacy and safety of repeated administrations of two fixed-dose presentations of ACT - artesunate plus amodiaquine (ASAQ) and artemether-lumefantrine (AL) - in subsequent episodes of Plasmodium falciparum malaria.MethodsA randomized comparative study was conducted in a rural community of central Senegal from August 2007 to January 2009. Children and adults with uncomplicated P. falciparum malaria were randomized to receive open-label ASAQ once daily or AL twice daily for three days. Drug doses were given according to body weight. Treatments for first episodes were supervised. For subsequent episodes, only the first intake of study drug was supervised. ECGs and audiograms were performed in patients ≥12 years of age. Primary outcome was adequate clinical and parasitological response rate (ACPR) after polymerase chain reaction (PCR) correction on day 28 for the first episode.ResultsA total of 366 patients were enrolled in the two groups (ASAQ 184, AL 182) and followed up during two malaria transmission seasons. In the intent-to-treat population, PCR-corrected ACPRs at day 28 for the first episode were 98.4% and 96.2%, respectively, in the ASAQ and AL groups. For the per-protocol population (ASAQ 183, AL 182), PCR-corrected ACPRs at day 28 for the first episode were 98.9% and 96.7%, respectively. A 100% ACPR rate was obtained at day 28 in the 60 and four patients, respectively, who experienced second and third episodes. Treatment-related adverse events were reported in 11.7% of the patients, without significant differences between the two groups. A better improvement of haemoglobin at day 28 was noted in the ASAQ versus the AL group (12.2 versus 11.8 g/dL; p = 0.03). No sign of ototoxicity was demonstrated. A prolongation of the QTc interval was observed in both groups during treatment with no clinical consequence.ConclusionsStudy results confirmed the satisfactory efficacy and safety profile of ASAQ and AL. Moreover, in patients who were treated at least twice, repeated administration of ASAQ or AL did not identify any major safety issues.Trial registrationClinicalTrials.gov identifier NCT00540410.

Almazole D, a new type of antibacterial 2,5-disubstituted oxazolic dipeptide from a red alga of the coast of Senegal

Abstract Almazole D ((+)-5), a potently antibacterial dipeptide from a delesseriacean seaweed collected at Almadies, North of Dakar, is a novel variant of 2,5-disubstituted oxazolic dipeptides conceivably deriving from oxidative deamination rather than decarboxylation of tryptophan.

Changes in the renal function after tenofovir-containing antiretroviral therapy Initiation in a Senegalese cohort (ANRS 1215)

To describe and compare the changes in renal function between HIV-1 infected adult patients receiving antiretroviral therapy (ART) with and without tenofovir (TDF). The population consisted of 40 patients starting a TDF-containing regimen and 388 patients starting regimen not containing TDF, and followed during 42 months. The estimated glomerular filtration rate (eGFR) was calculated using the Cockroft-Gault and MDRD equations and modeled separately for the first 12 months and the subsequent period. Between baseline and 12 months, the eGFR decreased significantly in patients receiving TDF (-10.40 ml/min), whereas it increased in the other +4.33 ml/min). A significant variability in the eGFR trajectories of patients receiving TDF was observed; 12 (30%) of them experienced a persistent decrease, 5 (12%) had an initial transient increase, and 23 (58%) a steady slow increase in eGFR. The characteristics at baseline of the patients with persistent decrease were not different from the other patients but their immune reconstitution was impaired. After 12 months, patients receiving TDF experienced a higher rate of transition from mild renal impairment (60-90 ml/min/1.73 m(2)) to moderate renal impairment (30-60 ml/min/1.73 m(2)) when compared with patients not receiving TDF. A significant though moderate decline in the renal function was observed in one-third of the patients receiving TDF compared to patients not receiving TDF. Moreover, this impairment was persistent after the first year of treatment.

Diabetes and Hypertension among Patients Receiving Antiretroviral Treatment Since 1998 in Senegal: Prevalence and Associated Factors

Cardiovascular risk factors in people on antiretroviral treatment (ART) are poorly documented in resource-constrained settings. A cross-sectional study was conducted in 2009 to assess prevalence of diabetes and hypertension in a sample of 242 HIV-infected patients who had initiated ART between 1998 and 2002 in Dakar, Senegal (ANRS 1215 observational cohort). World Health Organization (WHO) criteria were applied to diagnose diabetes and hypertension. Multiple logistic regressions were used to identify factors associated with diabetes and hypertension. Patients had a median age of 46 years and had received ART for a median duration of about 9 years. 14.5% had diabetes and 28.1% had hypertension. Long duration of ART (≥119 months), older age, higher body mass index (BMI), and higher levels of total cholesterol were associated with higher risks of diabetes. Older age, higher BMI at ART initiation, and higher levels of triglycerides were associated with higher risk of hypertension. This study shows that diabetes and hypertension were frequent in these Senegalese HIV patients on ART. It confirms the association between duration of ART and diabetes and highlights the need to implement programs for prevention of cardiovascular risk factors in HIV patients from resource-constrained settings.

Almazole A and almazole B, unusual marine alkaloids of an unidentified red seaweed of the family delesseriaceae from the coasts of Senegal

Abstract Almazole A 1 -slowly equilibrating in solution between the major Z 1a and the minor E 1b forms- and almazole B 2 , unusual marine alkaloids for embodying a 2,5-disubstituted oxazole ring, were isolated from an unidentified red seaweed of the family Delesseriaceae from the coasts of Senegal.