[Primary isoniazid preventive therapy : A strategy still relevant in the era of test and treat ; literature review]. / Chimioprophylaxie antituberculeuse primaire à l'isoniazide : une stratégie d'actualité à l'ère du tester et traiter ; revue de la littérature.

BACKGROUND: Tuberculosis remains a public health threat responsible as recently as 2018 for more than one million deaths. Chemoprophylaxis with isoniazid is one of the strategies implemented to control the disease. Although it is not yet widely prescribed, its utilization raises additional questions in the "test and treat" era of for anti-retroviral therapy. The objective of this study is to review the different randomized controlled trials of antitubercular Isoniazid Preventive Therapy (IPT). We have distinguished (a) "efficacy trials" (ET) comparing IPT to a placebo or the absence of chemoprophylaxis and (b) "IPT regimen trials" (RT) comparing IPT to one or several other regimens. METHODS: Literature search (keywords from published articles found in the Medline and Scopus data bases: "tuberculosis", "prophylaxis", "HIV", "randomized controlled trial") and standardized reading of selected articles reporting results from randomized trials of IPT in HIV-infected people. RESULTS: Eighteen selected trials (11 ET and 7 RT), including 19,725 participants. The regimens studied were 3H, 6H, 9H, 12H, 12H, 36H/2RZ, 3RH, 3RZ, 3RHZ, and 3HP [H: Isoniazid, R: Rifampicin, Z: Pyrazinamide, P: Rifapentine]. LOCATIONS: Ten in Africa, three in Haiti, one in India, one in the USA, one in the Americas and two multi-continental trials. In ET with or without antiretrovirals (ART), IPT significantly reduces the risk of tuberculosis, by 32 to 71%. In ET prior to ART, IPT does not appear to reduce mortality. In ET in patients receiving ART, on the other hand, IPT reduces mortality. As regards RT, there seems to be no reason to prefer other regimens to IPT. Tolerance is good. Importantly, IPT may reduce (rather than worsen) the risk of multidrug-resistant bacilli selection by decreasing the number of TB episodes and, consequently, the number of curative tuberculosis treatments. CONCLUSION: Far from becoming obsolete due to ARV treatment, IPT has remained a timely and relevant intervention.

Capacity Building in Sub-Saharan Africa as Part of the INTENSE-TBM Project During the COVID-19 Pandemic.

Tuberculous meningitis (TBM) is the most severe and disabling form of tuberculosis (TB), with at least 100,000 cases per year and a mortality rate of up to 50% in individuals co-infected with human immunodeficiency virus type 1 (HIV-1). To evaluate the efficacy and safety of an intensified anti-tubercular regimen and an anti-inflammatory treatment, the INTENSE-TBM project includes a phase III randomised clinical trial (TBM-RCT) in four countries in sub-Saharan Africa (SSA). Within this framework, we designed a comprehensive capacity-building work package ensuring all centres had, or would acquire, the ability to conduct the TBM-RCT and developing a network of skilled researchers, clinical centres and microbiology laboratories. Here, we describe these activities, identify strengths/challenges and share tools adaptable to other projects, particularly in low- and lower-middle income countries with heterogeneous settings and during the coronavirus disease 2019 (COVID-19) pandemic. Despite major challenges, TBM-RCT initiation was achieved in all sites, promoting enhanced local healthcare systems and encouraging further clinical research in SSA. In terms of certified trainings, the achievement levels were 95% (124/131) for good clinical practice, 91% (39/43) for good clinical laboratory practice and 91% (48/53) for infection prevention and control. Platform-based research, developed as part of capacity-building activities for specific projects, may be a valuable tool in fighting future infectious diseases and in developing high-level research in Africa.

The INTENSE-TBM project aimed to design a comprehensive work-package on capacity building, ensuring all centres would acquire the ability to conduct a phase III randomised clinical trial on TBM in sub-Saharan Africa, to reduce tuberculous meningitis mortality and morbidity in patients with/without HIV-1 co-infection. Therefore, the INTENSE-TBM project is an example of how an international clinical research consortium can provide opportunities to enhance local capacity building and promote centres without previous experience in clinical research. This article provides practical approaches for implementing effective capacity-building programmes. We highlight how to overcome limitations imposed by the COVID-19 pandemic to successfully complete clinics, laboratory set-ups and personnel training, so as to optimise resources and empower African institutions on a local level. At the same time, our experience shows how capacity-building programmes can deliver long-lasting impact that extends beyond the original aims of the project (e.g. HIV and TB), and support local health systems in fighting other infectious disease (e.g. COVID-19). Research projects in low- and lower-middle income countries with heterogeneous settings could stand to benefit the most.

Delayed-onset paraparesis in Lassa fever: A case report.

Lassa fever (LF) is an endemic viral hemorrhagic fever in West Africa. Among the serious complications of the disease are neurological manifestations whose spectrum is incompletely known. Here we report the case of a 61-year-old man who developed a delayed-onset paraparesis a few weeks after getting infected with Lassa virus, thereby suggesting a possible association between LF and spinal cord disorders.

Precore G1896A mutation is associated with reduced rates of HBsAg seroclearance in treated HIV hepatitis B virus co-infected patients from Western Africa.

The nucleotide substitution G1896A on the precore (pc) region has been implicated in virological and serological responses during treatment in hepatitis B virus (HBV)-infected patients. Whether this mutation affects the therapeutic course of HIV-HBV co-infected patients, especially from Western Africa, is unknown. In this prospective cohort study, 86 antiretroviral (ARV)-naïve HIV-HBV co-infected patients from Côte d'Ivoire, initiating ARV-treatment containing lamivudine (n = 53) or tenofovir (n = 33), had available baseline pc sequences. Association of the pcG1896A mutation with time to undetectable HBV-DNA, hepatitis B "e" antigen (HBeAg) seroclearance (in HBeAg-positive patients), and hepatitis B surface antigen (HBsAg) seroclearance was evaluated using Cox proportional hazards regression. At ARV-initiation, median HBV-DNA was 6.04 log10 copies/mL (IQR = 3.70-7.93) with 97.7% harbouring HBV genotype E. Baseline pcG1896A mutation was identified in 51 (59.3%) patients, who were more commonly HBeAg-negative (P < .001) and had basal core promotor A1762T/G1764A mutations (P < .001). Patients were followed for a median 36 months (IQR = 24-36). Cumulative proportion of undetectable HBV-DNA was significantly higher in patients with baseline mutation (pcG1896A = 86.6% vs no pcG1896A = 66.9%, P = .04), but not after adjusting for baseline HBV-DNA levels and anti-HBV agent (P = .2). No difference in cumulative proportion of HBeAg seroclearance was observed between mutation groups (pcG1896A = 57.1% vs no pcG1896A = 54.3%, P = .7). Significantly higher cumulative proportion of HBsAg seroclearance was observed in patients without this mutation (pcG1896A = 0% vs no pcG1896A = 36.9%, P < .001), even after adjusting for baseline HBsAg quantification and anti-HBV agent (P < .001). In conclusion, lacking the pcG1896A mutation before ARV initiation appeared to increase HBsAg seroclearance rates during treatment. The therapeutic implications of this mutation need further exploration in this setting.

Screening for active tuberculosis before isoniazid preventive therapy among HIV-infected West African adults.

SETTING: TEMPRANO was a multicentre, open-label trial in which human immunodeficiency virus (HIV) infected adults with high CD4 counts were randomised into early or deferred antiretroviral therapy (ART) arms with or without 6-month isoniazid preventive therapy (IPT) in a setting where the World Health Organization (WHO) recommends IPT in HIV-infected patients. Despite the WHO recommendation, IPT coverage remains low due to fear of the presence of undiagnosed active TB before prescribing IPT, and the related risk of drug resistance. OBJECTIVE: To report the frequency of undiagnosed TB in patients enrolled for IPT and describe the results of a 1-month buffer period to avoid prescribing IPT for active TB cases. DESIGN: Patients were screened using a clinical algorithm and chest X-ray at Day 0 and started on isoniazid at Month 1 if no sign/symptom suggestive of TB appeared between Day 0 and Month 1. RESULTS: Of 1030 patients randomised into IPT arms. 10% never started IPT at Month 1. Of these, 23 had active TB, including 16 with prevalent TB. Among the 927 patients who started IPT, 6 had active TB, including 1 with prevalent TB. Only 1 patient with active TB received IPT due to the 1-month buffer period between Day 0 and IPT initiation. CONCLUSION: In this study, 1.6% of adults considered free of active TB based on clinical screening at pre-inclusion actually had active TB.

Scaling up antiretroviral therapy for HIV-infected children in Côte d'Ivoire: determinants of survival and loss to programme.

OBJECTIVE: To investigate deaths and losses to follow-up in a programme designed to scale up antiretroviral therapy (ART) for HIV-infected children in Côte d'Ivoire. METHODS: Between 2004 and 2007, HIV-exposed children at 19 centres were offered free HIV serum tests (polymerase chain reaction tests in those aged < 18 months) and ART. Computerized monitoring was used to determine: (i) the number of confirmed HIV infections, (ii) losses to the programme (i.e. death or loss to follow-up) before ART, (iii) mortality and loss-to-programme rates during 12 months of ART, and (iv) determinants of mortality and losses to the programme. FINDINGS: The analysis included 3876 ART-naïve children. Of the 1766 with HIV-1 infections (17% aged < 18 months), 124 (7.0%) died, 52 (2.9%) left the programme, 354 (20%) were lost to follow-up before ART, 259 (15%) remained in care without ART, and 977 (55%) started ART (median age: 63 months). The overall mortality rate during ART was significantly higher in the first 3 months than in months 4-12: 32.8 and 6.9 per 100 child-years of follow-up, respectively. Loss-to-programme rates were roughly double mortality rates and followed the same trend with duration of ART. Independent predictors of 12-month mortality on ART were pre-ART weight-for-age z-score < -2, percentage of CD4+ T lymphocytes < 10, World Health Organization HIV/AIDS clinical stage 3 or 4, and blood haemoglobin < 8 g/dl. CONCLUSION: The large-scale programme to scale up paediatric ART in Côte d'Ivoire was effective. However, ART was often given too late, and early mortality and losses to programme before and just after ART initiation were major problems.

Scaling up antiretroviral therapy for HIV-infected children in Côte d'Ivoire: determinants of survival and loss to programme

Objective: To investigate deaths and losses to follow-up in a programme designed to scale up antiretroviral therapy (ART) for HIV- infected children in Cote d'Ivoire. Methods Between 2004 and 2007; HIV-exposed children at 19 centres were offered free HIV serum tests (polymerase chain reaction tests in those aged 18 months) and ART. Computerized monitoring was used to determine: (i) the number of confirmed HIV infections; (ii) losses to the programme (i.e. death or loss to follow-up) before ART; (iii) mortality and loss-to-programme rates during 12 months of ART; and (iv) determinants of mortality and losses to the programme. Findings The analysis included 3876 ART-naive children. Of the 1766 with HIV-1 infections (17aged 18 months); 124 (7.0) died; 52 (2.9) left the programme; 354 (20) were lost to follow-up before ART; 259 (15) remained in care without ART; and 977 (55) started ART (median age: 63 months). The overall mortality rate during ART was significantly higher in the first 3 months than in months 4-12: 32.8 and 6.9 per 100 child-years of follow-up; respectively. Loss-to-programme rates were roughly double mortality rates and followed the same trend with duration of ART. Independent predictors of 12-month mortality on ART were pre-ART weight- for-age z-score -2; percentage of CD4+ T lymphocytes 10; World Health Organization HIV/AIDS clinical stage 3 or 4; and blood haemoglobin 8 g/dl. Conclusion The large-scale programme to scale up paediatric ART in Cote d'Ivoire was effective. However; ART was often given too late; and early mortality and losses to programme before and just after ART initiation were major problems

[Impact of access to antiretroviral therapy in Côte d'Ivoire]. / Bilan de l'accès aux antirétroviraux en Côte d'Ivoire.

In 1998 UNAIDS implemented the national drug access initiative (DAI) in Côte d'Ivoire. The Ivorian government took the DAI over in 2000 with the support of the Global Fund and Presidential Emergency Program For AIDS Relief (PEPFAR). The ensuing affordability of antiretroviral therapy (ART), medical staff training, and healthcare equipment allowed Ministry of Health to improve HIV care throughout the country. Since 2008 ART and follow-up monitoring have been free of charge for people living with HIV/AIDS (PLWHA). In January 2009 a total of 57,833 PLWHA received ART and follow-up at 274 HIV care centers. Use of ART has improved the life expectancy of PLWHA. However morbidity and mortality remained high during the first year of ART implementation with respective frequencies of 5-10% person-year (PY) and 2-3% PY. Morbidity was mainly related to infectious disease (tuberculosis and bacteriaemia) and earlier onset of adverse events (AE). In most cases ART has been well tolerated. The main adverse effects have been anemia, neuropathy, skin toxicity and liver enzyme elevation. The incidence of stage 3/4 AE has been low (< 2 %PY). Although overall compliance has been good (<80%), data among children and adults suggest the need for further work to reinforce support mechanisms. Convincing results have been obtained in the management of PLWHA. Nevertheless greater funding and commitment must be given to management of opportunistic infections and side effects and to development of nutrition support services.

Bilan de l'acces aux antiretroviraux en Cote d'Ivoire

L'initiative nationale d'acces aux antiretroviraux en Cote d`Ivoire a debute en 1998 sous l'egide de l'ONUSIDA. Le relais a ete assure par le gouvernement ivoirien en 2000 avec le soutien du FondsMondial et du PEPFAR (President Emergency Program ForAids Reliefs). L'accessibilite financiere; la formation du personnel de soins et l'equipement des structures sanitaires ont permis la decentralisation de la prise en charge sur tout le territoire national. Depuis aout 2008; le traitement antiretroviral est gratuit de meme que le suivi biologique. Fin janvier 2009; l'on denombrait 57 833 patients sous antiretroviraux; suivis dans 274 centres de prise en charge. L'utilisation des multitherapies antiretrovirales a considerablement modifie le pronostic avec une amelioration de l'esperance de vie des patients infectes par le VIH. Cependant la morbidite et la mortalite restent encore preoccupantes au cours de la premiere annee suivant la mise en route du traitement avec des incidences respectives variant entre 5 et 10patients-annee (PA) et 2 et 3PA. La morbidite est principalement en rapport avec les infections (tuberculose; bacteriemies) et les effets secondaires precoces. Les traitements antiretroviraux sont globalement bien toleres; les principaux effets secondaires etant l'anemie; les neuropathies; les reactions cutanees et les hypertransaminasemies. Les effets secondaires de grade 3 et 4 ont une incidence faible (2PA). L'observance est bonne; estimee a 80; mais des donnees obtenues chez les enfants et sur certains sites de prise en charge incitent a renforcer les dispositifs d'appui a l'observance. Des resultats probants ont ete obtenus dans la prise en charge antiretrovirale des personnes vivant avec l eVIH .Aussi les efforts sont-ils a poursuivre pour le financement et la prise en charge des infections opportunistes et des effets secondaires et pour l'appui nutritionnel

CD4+ T-lymphocytes natural decrease in HAART-naïve HIV-infected adults in Abidjan.

OBJECTIVE: To study the CD4 natural decrease and its determinants in sub-Saharan African HIV-infected adults. METHOD: We performed a 7-year prospective cohort study, with biannual CD4 measurement. Follow-up was censored at the first severe morbidity event or at HAART initiation. Changes in CD4 values were studied by jointly modelling (a) the correlation between repeated measures through a linear mixed model and (b) the time to drop-out through a survival model. RESULTS: 690 patients were followed up during 1,382 person-years. Contrasting with the baseline CD4 count and percentage, which were associated with numerous variables, the slopes of both CD4 count and CD4 percentage in the absence of severe morbidity episode were only associated with the follow-up time and with the baseline body mass index (BMI). The mean annual natural decrease in CD4 count (CD4%) was estimated at -81/mm3 (-2.2%), -69/mm3 (-1.7%), and -55/mm3 (-1.2%) for patients with baseline BMI at 16 kg/m2, 20.4 kg/m2, and 25 kg/m2, respectively (p < .001). A steeper decline in the CD4 count was independently associated with a shorter event-free follow-up time. CONCLUSION: These estimates of the CD4 natural decrease in sub-Saharan African patients, while they did not experience any episode of severe morbidity and before they initiate HAART, are in the bracket of those previously reported in industrialized countries. In sub-Saharan African settings with CD4 count being measured less frequently than in industrialized countries, the CD4 should be monitored more closely among adults with low BMI.

[Severe opportunistic infections in HIV-positive adults in sub-Saharan Africa]. / Affections opportunistes sévères de l'adulte infecté par le VIH en Afrique sub-saharienne.

The threat for opportunistic diseases in HIV-infected adults in sub-Saharan Africa is characterized by a higher frequency of tuberculosis and invasive bacterial diseases than in Europe and by the presence of malaria. Since these three infections may occur early after the onset of immuno-deficiency, HIV-infected patients with less than 200 CD4/mm3 are more likely to develop an infectious episode with severe morbidity in sub-Saharan Africa than in Europe. For this reason the WHO now recommends starting cotrimoxazole prophylaxis at 350 and even 500 CD4/mml in sub-Saharan Africa. The question of whether antiretroviral treatment should also be initiated "earlier" in sub-Saharan Africa than in Europe has also been raised.

Impact of opportunistic diseases on chronic mortality in HIV-infected adults in Côte d'Ivoire.

OBJECTIVE: To estimate incidence rates of opportunistic diseases (ODs) and mortality for patients with and without a history of OD among HIV-infected patients in Côte d'Ivoire. METHODS: Using incidence density analysis, we estimated rates of ODs and chronic mortality by CD4 count in patients in a cotrimoxazole prophylaxis trial in Abidjan before the highly active antiretroviral therapy (HAART) era. Chronic mortality was defined as death without a history of OD or death more than 30 days after an OD diagnosis. We used Poisson's regression to examine the effect of OD history on chronic mortality after adjusting for age, gender, and current CD4 count. RESULTS: Two hundred and seventy patients (40% male, mean age 33 years, median baseline CD4 count 261 cells/microl) were followed up for a median of 9.5 months. Bacterial infections and tuberculosis were the most common severe ODs. Of 47 patients who died, 9 (19%) died within 30 days of an OD, 26 (55%) died more than 30 days after an OD, and 12 (26%) died with no OD history. The chronic mortality rate was 31.0/100 person-years for those with an OD history, and 11.1/100 person-years for those with no OD history (rate ratio (RR) 2.81, 95% confidence interval (CI): 1.43 - 5.54). Multivariate analysis revealed that OD history remained an independent predictor of mortality (RR 2.15, 95% CI: 1.07 - 4.33) after adjusting for CD4 count, age and gender. CONCLUSIONS: Before the HAART era, a history of OD was associated with increased chronic HIV mortality in Côte d'Ivoire, even after adjusting for CD4 count. These results provide further evidence supporting OD prophylaxis in HIV-infected patients.

Affections opportunistes sévères de l'adulte infecté par le VIH en Afrique sub-saharienne

Le spectre des maladie sopportunistes sévères chez l'adulte infecté par le VIH en Afrique sub-saharienne se caractérise par une plus grande fréquence de la tuberculose et des maladies bactériennes invasives qu'en Europe, et par la présence du paludisme. Ces trois groupes d'affections pouvant survenir assez tôt dans l'immunodépression, les adultes infectés par le VIH ont une probabilité plus élevée de développer un épisode de morbidité sévère au dessus de 200 CD4/mm3en Afrique sub-Saharienne qu'en Europe. Ceci explique notamment pourquoi l'OMS recommande de débuter la prophylaxie par le cotri-m ox a zole dès 350 voire 500 CD4/mm3 en Afrique sub-saharienne. La question de savoir si le traitement anti-rétrov i ral dev ra i tégalement être débuté «plus tôt» en Afrique sub-saharienne qu'en Europe est maintenant ouverte

[Compliance in HIV infected adults. Study of opportunistic infection prophylaxis with cotrimoxazole in Ivory Coast]. / Observance chez les adultes infectés par le VIH. Etude d'une prophylaxie des infections opportunistes par le cotrimoxazole en Côte d'Ivoire.

BACKGROUND: The compliance to a daily treatment for illimited duration and the factors that influence it have been rarely studied in sub-Saharian Africa. OBJECTIVE: Describe the compliance to prophylaxis with cotrimoxazole fort (one tablet per day) and its associated factors in patients infected by HIV participating in a clinical trial in Abidjan. METHOD: The tablets packed in individual blisters were provided every month, and the blisters were recuperated the following month. A global compliance ratio (GCR) was established for each patient (empty blisters at the end of the study/follow-up period during the study) and monthly compliance ratio [MCR] (empty blisters during a visit/time lapse since last visit). For each monthly visit foreseen in the protocol, a respect of the appointment ratio (RAR) was described (visits foreseen in the protocol respected that month/visits foreseen in the protocol). The association of GCR with the characteristics on inclusion was studied using logistic regression methods. RESULTS: 530 adults were followed-up for a mean of 10 months. The MCR and the RAR progressed in parallel, decreasing the first 5 months and stabilizing at around 0.80 for the RAR and 0.70 for the MCR. The mean GCR was of 0.77. Three hundred and nine patients (58%) were considered as compliant (0.80

[Bacillary angiomatosis in an adult infected with HIV-1 at an early stage of immunodepression in Abidjan, Côte d'Ivoire]. / Angiomatose bacillaire chez un adulte infecté par le VIH-1 à un stade d'immunodépression peu avancé à Abidjan, Côte d'Ivoire.

Human immunodeficiency virus (HIV)-associated bacillary angiomatosis has rarely been described in Africa. We report here the first case in Côte d'Ivoire. Although in industrialised countries bacillary angiomatosis has been described in patients with low CD4 count, this episode occurred in the first year following HIV-seroconversion in an adult patient with more than 500 CD4 cells per cubic millimetre. Symptoms rapidly and totally disappeared under erythromycin treatment, although with a relapse two years after the end of the first episode. In Africa where people living with HIV often present chronic cutaneous lesions, bacillary angiomatosis may be under-diagnosed. Bacillary angiomatosis must be systematically considered in face of lesions similar to Kaposi's sarcoma. Improving knowledge on symptoms of bacillary angiomatosis in Africa should lead to better treatment and a better estimation of its true frequency which may be underestimated.

HIV-1-related morbidity in adults, Abidjan, Côte d'Ivoire: a nidus for bacterial diseases.

We studied mortality and morbidity in 270 HIV-1-infected adults (60% women, median age 31 years, mean baseline CD4 count 331/mm(3) ) observed in a follow-up that lasted a median 10 months in Côte d'Ivoire. Survival and probability of remaining free from any episode of morbidity at 12 months were 0.80 and 0.50, respectively. Baseline CD4 count <200/mm(3) was the only variable associated with global morbidity and mortality, with hazard ratios of 2.50 and 7.57, respectively. The most frequent causes of morbidity were severe bacterial infections (incidence rate: 26.1 per 100 person-years [py]), followed by oral candidiasis (22.3% py), unexplained weight loss over 10% of baseline body weight (13.3% py), tuberculosis (10.1% py), unexplained chronic diarrhea (9.7% py), and isosporiasis (5.1% py). Nontyphoid Salmonella accounted for 37% of isolated strains during severe bacterial infections, followed by Streptococcus pneumoniae (34%), Escherichia coli (15%), and Shigella species (7%). A significant part of bacterial morbidity occurred in patients with baseline CD4 count > or = 200/mm(3), in whom the incidence rate of bacterial diseases was 21.3% py and the probability of remaining free from any bacterial infection at 12 months was 0.80 (vs. 36.4% py and 0.71 in patients with baseline CD4 count <200/mm(3); p =.07).