Rifampicin and clarithromycin (extended release) versus rifampicin and streptomycin for limited Buruli ulcer lesions: a randomised, open-label, non-inferiority phase 3 trial.

BACKGROUND: Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans infection that damages the skin and subcutis. It is most prevalent in western and central Africa and Australia. Standard antimicrobial treatment with oral rifampicin 10 mg/kg plus intramuscular streptomycin 15 mg/kg once daily for 8 weeks (RS8) is highly effective, but streptomycin injections are painful and potentially harmful. We aimed to compare the efficacy and tolerability of fully oral rifampicin 10 mg/kg plus clarithromycin 15 mg/kg extended release once daily for 8 weeks (RC8) with that of RS8 for treatment of early Buruli ulcer lesions. METHODS: We did an open-label, non-inferiority, randomised (1:1 with blocks of six), multicentre, phase 3 clinical trial comparing fully oral RC8 with RS8 in patients with early, limited Buruli ulcer lesions. There were four trial sites in hospitals in Ghana (Agogo, Tepa, Nkawie, Dunkwa) and one in Benin (Pobè). Participants were included if they were aged 5 years or older and had typical Buruli ulcer with no more than one lesion (caterories I and II) no larger than 10 cm in diameter. The trial was open label, and neither the investigators who took measurements of the lesions nor the attending doctors were masked to treatment assignment. The primary clinical endpoint was lesion healing (ie, full epithelialisation or stable scar) without recurrence at 52 weeks after start of antimicrobial therapy. The primary endpoint and safety were assessed in the intention-to-treat population. A sample size of 332 participants was calculated to detect inferiority of RC8 by a margin of 12%. This study was registered with ClinicalTrials.gov, NCT01659437. FINDINGS: Between Jan 1, 2013, and Dec 31, 2017, participants were recruited to the trial. We stopped recruitment after 310 participants. Median age of participants was 14 years (IQR 10-29) and 153 (52%) were female. 297 patients had PCR-confirmed Buruli ulcer; 151 (51%) were assigned to RS8 treatment, and 146 (49%) received oral RC8 treatment. In the RS8 group, lesions healed in 144 (95%, 95% CI 91 to 98) of 151 patients, whereas lesions healed in 140 (96%, 91 to 99) of 146 patients in the RC8 group. The difference in proportion, -0·5% (-5·2 to 4·2), was not significantly greater than zero (p=0·59), showing that RC8 treatment is non-inferior to RS8 treatment for lesion healing at 52 weeks. Treatment-related adverse events were recorded in 20 (13%) patients receiving RS8 and in nine (7%) patients receiving RC8. Most adverse events were grade 1-2, but one (1%) patient receiving RS8 developed serious ototoxicity and ended treatment after 6 weeks. No patients needed surgical resection. Four patients (two in each study group) had skin grafts. INTERPRETATION: Fully oral RC8 regimen was non-inferior to RS8 for treatment of early, limited Buruli ulcer and was associated with fewer adverse events. Therefore, we propose that fully oral RC8 should be the preferred therapy for early, limited lesions of Buruli ulcer. FUNDING: WHO with additional support from MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, Sanofi-Pasteur, and BuruliVac

Independent Evaluation of the Rapid Scale-Up Program to Reduce Under-Five Mortality in Burkina Faso

We conducted a prospective evaluation of the “Rapid Scale-Up” (RSU) program in Burkina Faso, focusing on the integrated community case management (iCCM) component of the program. We used a quasi-experimental design in which nine RSU districts were compared with seven districts without the program. The evaluation included documentation of program implementation, assessments of implementation and quality of care, baseline and endline coverage surveys, and estimation of mortality changes using the Lives Saved Tool. Although the program trained large numbers of community health workers, there were implementation shortcomings related to training, supervision, and drug stockouts. The quality of care provided to sick children was poor, and utilization of community health workers was low. Changes in intervention coverage were comparable in RSU and comparison areas. Estimated under-five mortality declined by 6.2% (from 110 to 103 deaths per 1,000 live births) in the RSU area and 4.2% (from 114 to 109 per 1,000 live births) in the comparison area. The RSU did not result in coverage increases or mortality reductions in Burkina Faso, but we cannot draw conclusions about the effectiveness of the iCCM strategy, given implementation shortcomings. The evaluation results highlight the need for greater attention to implementation of iCCM programs

What is the most effective strategy to identify HBV-infected pregnant women eligible for antiviral prophylaxis in Burkina Faso ?

International audienc

No effect of test and treat on sexual behaviours at population level in rural South Africa

Context:Within the community-randomized ANRS 12249 Treatment-as-Prevention trial conducted in rural South Africa, we analysed sexual behaviours stratified by sex over time, comparing immediate antiretroviral therapy irrespective of CD4+ cell count vs. CD4+-guided antiretroviral therapy (start at CD4+ cell count > 350 cells/μl then >500 cells/μl) arms.Methods:As part of the 6-monthly home-based trial rounds, a sexual behaviour individual questionnaire was administered to all residents at least 16 years. We considered seven indicators: sexual intercourse in the past month; at least one regular sexual partner in the past 6 months; at least one casual sexual partner in the past 6 months and more than one sexual partner in the past 6 months; condom use at last sex (CLS) with regular partner, CLS with casual partner, and point prevalence estimate of concurrency. We conducted repeated cross-sectional analyses, stratified by sex. Generalized Estimating Equations models were used, including trial arm, trial time, calendar time and interaction between trial arm and trial time.Results:CLS with regular partner varied between 29–51% and 23–46% for men and women, respectively, with significantly lower odds among women in the control vs. intervention arm by trial end (P < 0.001). CLS with casual partner among men showed a significant interaction between arm and trial round, with no consistent pattern. Women declared more than one partner in the past 6 months in less than 1% of individual questionnaires; among men, rates varied between 5–12%, and odds significantly and continuously declined between calendar rounds 1 and 7 [odds ratio = 4.2 (3.24–5.45)].Conclusion:Universal Test and Treat was not associated with increased sexual risk behaviours

No effect of test and treat on sexual behaviours at population level in rural South Africa

CONTEXT: Within the community-randomised ANRS 12249 Treatment-as-Prevention (TasP) trial conducted in rural South Africa, we analysed sexual behaviours stratified by sex over time, comparing immediate ART irrespective of CD4 count vs CD4-guided ART (start at CD4>350 then >500) arms. METHODS: As part of the 6-monthly home-based trial rounds, a sexual behaviour questionnaire (IQ) was administered to all residents ≥16 years. We considered seven indicators: sexual intercourse in the past month; at least one regular sexual partner in the past six months; at least one casual sexual partner in the past six months and more than one sexual partner in the past six months; condom use at last sex (CLS) with regular partner, CLS with casual partner, and point prevalence estimate of concurrency. We conducted repeated cross-sectional analyses, stratified by sex. GEE models were used, including trial arm, trial time, calendar time and interaction between trial arm and trial time. RESULTS: CLS with regular partner varied between 29%-51% and 23%- 46% for men and women, respectively, with significantly lower odds among women in the control versus intervention arm by trial end (p < 0.001). CLS with casual partner among men showed a significant interaction between arm and trial round, with no consistent pattern. Women declared more than one partner in the past 6 months in less that 1% of IQs; among men, rates varied between 5%-12%, and odds significantly and continuously declined between calendar rounds 1 and 7 (OR = 4.2 [3.24-5.45]). CONCLUSION: Universal Test and Treat was not associated with increased sexual risk behaviours

Connaissances, attitudes et pratiques des populations face à la tuberculose dans trois régions du Burkina Faso

Au Burkina Faso, le dépistage précoce des cas de la tuberculose (TB) constitue encore un défi malgré l’implication communautaire dansla lutte contre la maladie depuis 2005. Des connaissances et attitudes adéquates face à la tuberculose devraient contribuer à améliorer la détection des cas. L’objectif de notre travail était de décrire les connaissances, attitudes et pratiques des communautésface à la tuberculose. Nous avonsréalisé une analyse des données d’enquête transversale menée en 2012 dans trois régions du Burkina Faso. Les participants ont été choisis selon un échantillonnage en grappe. Nous avons identifié les facteurs associés à la connaissance à partir d’une régression de Cox. Au total 2 261 individus ont été enquêtés. Le sexe féminin était majoritaire (56,2 %). Plus de 85 % des enquêtés ont déclaré avoir déjà entendu parler de la TB. Un tiers (30,4 %) de la population a une bonne connaissance de la tuberculose. Lesfacteurs associés à la connaissance sur la tuberculose sont : le sexe, l’âge, le niveau d’instruction et le lieu de résidence. Pour plus de 96 % de la population enquêtée, le centre de santé est le premier recours en cas de suspicion de symptômes de la tuberculose. Le niveau global de la connaissance de la TB reste faible dansla population générale au Burkina Faso. L’amélioration de la connaissance sur la TB tenant compte des disparités identifiées dans cette étude est nécessaire pour l’atteinte des objectifs en matière de lutte contre la TB au Burkina Faso. Mots-clés : tuberculose, connaissance, pratique, Cox, Burkina Faso. &nbsp; English Title: Knowledge, attitudes, and practices related to TB among the general population of three regions of Burkina FasoIn Burkina Faso, early detection of tuberculosis(TB) casesremain a challenge despite community involvement in the fight against the disease since 2005. Adequate knowledge and attitudes related to tuberculosis should help improve case detection. The aim of our study was to describe the knowledge, attitudes and practices of communities regarding tuberculosis. We performed an analysis of cross-sectional survey data conductedin 2012 in three regions of Burkina Faso. To select participants, we carried out a three-stage clustersampling. We identified the TB related knowledge associated factorsthrough a Cox regression. A total, 2261 individuals were surveyed. The female was in the majority (56.2 %). Over 85 % of those surveyed said they had heard from TB before. One-third (30.4 %) of the population has a good knowledge of tuberculosis. Factors associated with TB-related knowledge are gender, age, education, and place of residence. For more than 96 % of the population surveyed, the health center is the first resort in case of suspected symptoms of tuberculosis. The overall level of knowledge of TB remainslow in the general population in Burkina Faso. Improving knowledge about TB taking into account the disparities identified in this study is necessary for reaching national goals in Burkina Faso. Keywords: Tuberculosis, knowledge, practices, Cox, Burkina Fas

Expression, Purification and Characterization of GMZ2'.10C, a Complex Disulphide-Bonded Fusion Protein Vaccine Candidate against the Asexual and Sexual Life-Stages of the Malaria-Causing Plasmodium falciparum Parasite

PURPOSE: Production and characterization of a chimeric fusion protein (GMZ2'.10C) which combines epitopes of key malaria parasite antigens: glutamate-rich protein (GLURP), merozoite surface protein 3 (MSP3), and the highly disulphide bonded Pfs48/45 (10C). GMZ2'.10C is a potential candidate for a multi-stage malaria vaccine that targets both transmission and asexual life-cycle stages of the parasite. METHODS: GMZ2'.10C was produced in Lactococcus lactis and purified using either an immunoaffinity purification (IP) or a conventional purification (CP) method. Protein purity and stability was analysed by RP-HPLC, SEC-HPLC, 2-site ELISA, gel-electrophoresis and Western blotting. Structural characterization (mass analysis, peptide mapping and cysteine connectivity mapping) was performed by LC-MS/MS. RESULTS: CP-GMZ2'.10C resulted in similar purity, yield, structure and stability as compared to IP-GMZ2'.10C. CP-GMZ2'.10C and IP-GMZ2'.10C both elicited a high titer of transmission blocking (TB) antibodies in rodents. The intricate disulphide-bond connectivity of C-terminus Pfs48/45 was analysed by tandem mass spectrometry and was established for GMZ2'.10C and two reference fusion proteins encompassing similar parts of Pfs48/45. CONCLUSION: GMZ2'.10C, combining GMZ2' and correctly-folded Pfs48/45 can be produced by the Lactoccus lactis P170 based expression system in purity and quality for pharmaceutical development and elicit high level of TB antibodies. The cysteine connectivity for the 10C region of Pfs48/45 was revealed experimentally, providing an important guideline for employing the Pfs48/45 antigen in vaccine design

Pharmacokinetics of plasma lopinavir and ritonavir in tuberculosis-HIV co-infected African adult patients also receiving rifabutin 150 or 300 mg three times per week

Background: To evaluate the pharmacokinetic of plasma lopinavir (LPV) and ritonavir (RTV) when co-administered with three times weekly (TPW) rifabutin (RBT) at a dose of either 150 or 300 mg in African tuberculosis (TB) and HIV co-infected adult patients. Methods: This is a pharmacokinetic study conducted in Ouagadougou among patients treated with a standard dosage of LPV/RTV 400/100 mg twice daily and RBT 150 mg TPW (arm A = 9 patients) or rifabutin 300 mg TPW (arm B = 7 patients) based regimens. Patients were recruited from the Bogodogo and Kossodo district hospitals in Ouagadougou from May 2013 to December 2015. Study inclusion criteria were that the patients were between 18 and 60 years of age, HIV-1 infected with pulmonary tuberculosis confirmed or suspected. Subsequent blood samples for pharmacokinetic monitoring were collected at 1, 2, 3, 4, 6, 8 and 12 h after combined drug ingestion for plasma drug monitoring using HPLC/MS assays. Results: The medians LPV Cmax and Tmax were respectively, 20 μg/mL and 4 h for the RBT 150 mg group (arm A) and 7.7 μg/mL and 3 h for the RBT 300 mg group (arm B). The AUC0-12 of LPV was 111.8 μg h/mL in patients belonging to arm A versus 69.9 μg/mL for those in arm B (p = 0.313). The C0 of LPV was lower than 4 μg/mL in three patients receiving RBT 300 mg. Of note, the RTV plasma concentrations were nearly halved among patients on RBT 300 mg compared to those on lower RBT doses. The AUC0-12 of RTV in arm A was 12.7 μg h/mL versus 6.6 μg h/ml in arm B (p = 0.313). Conclusion: In our study, the pharmacokinetic of LPV and RTV was found to be highly variable when coadministrated with RBT 150 mg or 300 mg three times per week. There is a need for specific large study to verify clinical and virological effects of this variation, especially when coadministrated with RBT of 300 mg TPW, and to prevent viral resistance in response to under-dosing of LPV. Trial registration PACTR201310000629390. Registered 28 October 2013, http://www.pactr.org

Lancet HIV

BACKGROUND: Universal 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. METHODS: We 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 muL and <500 cells per muL from January, 2015; control). Participants and investigators were not masked to treatment allocation. We used dried blood spots once every 6 months provided by participants who were HIV negative at baseline to estimate the primary outcome of HIV incidence with cluster-adjusted Poisson generalised estimated equations in the intention-to-treat population after 58 cluster-years of follow-up. This study is registered with ClinicalTrials.gov, number NCT01509508, and the South African National Clinical Trials Register, number DOH-27-0512-3974. FINDINGS: Between 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). INTERPRETATION: The 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. FUNDING: ANRS, GiZ, and 3ie