Higher dose oral fluconazole for the treatment of AIDS-related cryptococcal meningitis (HIFLAC)--Report of A5225, a multicentre, phase I/II, two-stage, dose-finding, safety, tolerability and efficacy randomised, amphotericin B-controlled trial of the AIDS Clinical Trials Group

BACKGROUND: The WHO recommended 1200mg/day of fluconazole (FCZ) in the induction phase of cryptococcal meningitis (CM) in HIV prior to 2018 in regions where amphotericin-B (AMB) was unavailable. A 2-stage AMB-controlled, dose-escalation study to determine the maximum tolerated dose and the safety/efficacy of an induction-consolidation strategy of higher doses FCZ (1200mg-2000mg/day), adjusted for weight and renal function (eGFR)in adults with CM was undertaken. METHODS: In Stage-1, three induction doses of FCZ (1200mg/day, 1600mg/day and 2000mg/day) were tested in sequential cohortsand compared with AMB in a 3:1 ratio. A particular dose was not tested in Stage 2 if there were significant predetermined safety or efficacy concerns. In Stage-2, the 1200mg dose was excluded per protocol because of increased mortality, and participants were randomised to 1600mg, 2000mg FCZ or AMB in a 1:1:1 ratio. FINDINGS: One hundred and sixty eight participants were enrolled with 48, 50, and 48 in the AMB, 1600mg and 2000mg cohorts. The Kaplan Meier proportion for mortality (90% CI) at 10 and 24 weeks for AMB was 17% (10, 29) and 24% (15, 37), compared to 20% (12, 32) and 30% (20, 43) for 1600mg, and 33% (23, 46) and 38% (27, 51) for 2000mg/day FCZ. With the exception of a higher incidence of gastrointestinal side effects in the 2000mg cohort, both induction doses of FCZ were safe and well tolerated. There were no life-threatening changes in electrocardiogram QTc which were similar across all doses of FCZ and AMB. The median (IQR) change in log10 cryptoccal colony forming units (CFU) from week 0 to week 2 was -8(-4.1,-1.9) for AMB; -2.5(-4.0, -1.4) for 1600mg FCZ and -8 (-3.2, -1.0) for 2000mg FCZ. The proportion (90% CI) CSF CM negative at 10 weeks was 81%(71,90) for AMB; 56%(45,69) for 1600mg FCZ and 60%(49,73) for 2000mg FCZ. INTERPRETATION: Induction phase weight and renal-adjusted doses of 1600mg and 2000mg/day FCZ for CM were safe and well tolerated except for increased GI side effects in the 2000mg/day dose, and had similar times to achieve CSF sterilization, but took significantly longer than AMB. The WHO recommended 1200mg FCZ was associated with a high mortality. While not statistically significant, mortality was numerically lower in the AMB compared to 1600mg and 2000mg FCZ These data make a case for a phase 3 study of higher doses of FZC

An evaluation of the respiratory health status of automotive spray-painters exposed to paints containing hexamethylene di-isocyanates in the greater Durban area

No Abstract

HIV/AIDS and admission to intensive care units: A comparison of India, Brazil and South Africa.

In resource-constrained settings and in the context of HIV-infected patients requiring intensive care, value-laden decisions by critical care specialists are often made in the absence of explicit policies and guidelines. These are often based on individual practitioners’ knowledge and experience, which may be subject to bias. We reviewed published information on legislation and practices related to intensive care unit (ICU) admission in India, Brazil and South Africa, to assess access to critical care services in the context of HIV. Each of these countries has legal instruments in place to provide their citizens with health services, but they differ in their provision of ICU care for HIV-infected persons. In Brazil, some ICUs have no admission criteria, and this decision vests solely on the ‘availability, and the knowledge and the experience’ of the most experienced ICU specialist at the institution. India has few regulatory mechanisms to ensure ICU care for critically ill patients including HIV-infected persons. SA has made concerted efforts towards non-discriminatory criteria for ICU admissions and, despite the shortage of ICU beds, HIV infected patients have relatively greater access to this level of care than in other developing countries in Africa, such as Botswana. Policymakers and clinicians should devise explicit policy frameworks to govern ICU admissions in the context of HIV status

Survey of ethical dilemmas facing intensivists in South Africa in the admission of patients with HIV infection requiring intensive care.

Background. Maturing of the burgeoning HIV epidemic in South Africa has resulted in an increased demand for intensive care. Objectives. To investigate the influence of ethical dilemmas facing South African intensivists on decisions about access to intensive care for patients with HIV infection in resource-limited settings. Methods. A cross-sectional, descriptive, quantitative, analytical, anonymous attitudes-and-perception questionnaire survey of 90 intensivists. The main outcome measure was the rating of factors influencing decisions on admission to intensive care and responses to 5 hypothetical clinical scenarios. Results. The number of intensivists who considered the prognosis of the acute disease and of the underlying disease to be most important was 87.9% (n=74). Most (71.6%; n=63) intensivists cited availability of an intensive care unit (ICU) bed as influencing the decision to admit. Intensivists comprising 26.8% (n=22) of the total group rated as probably important or least important the ‘resources available’; ‘bed used to the prejudice of another patient’ was stated by 16.4% (n=14); and ‘policy of the intensive care unit’ by 17% (n=14). Nearly two-thirds (65.9%; n=58) would respect an informed refusal of treatment. A similar number would comply with a written ‘Do not resuscitate’ (DNR) order. In patients with no real chance of recovering a meaningful life, 81.6% (n=71) of intensivists would withhold sophisticated therapy (e.g. not start mechanical ventilation or dialysis etc.) and 75.9% (n=63) would withdraw sophisticated therapy (e.g. discontinue mechanical ventilation, dialysis etc.). Conclusions. A combination of factors was identified as influencing the decision to admit patients to intensive care. Prognosis and disease status were identified as the main factors influencing admission. Patients with HIV/AIDS were not discriminated against in admission to intensive care

TB/HIV pleurisy reduces Th17 lymphocyte proportion independent of the cytokine microenvironment

T-helper (Th) 17 cells are a pro-inflammatory subset of CD4+ effector T-cells critical in mucosal immunity. Imbalances in Th17 cell proportion have been implicated in the pathogenesis of several diseases; however, this has not been adequately explored in tuberculosis (TB) and human immunodeficiency virus (HIV) co-infection. Since Th17 cells are predominantly mucosally associated, we assessed Th17 proportion and associated microenvironment in pleural effusions from patients co-infected with TB/HIV. Our results show that TB+HIV+ pleurisy results in significantly reduced frequency of CD4+IL-17+RORC+STAT3+ Th17 cells compared to TB−HIV−ex vivo (p = 0.0054) and was confirmed in conditioned media studies in vitro (p = 0.0001). This was not associated with alterations in Th17 polarising cytokines IL-6, IL-21 and IL-23 or changes in Th17 signature cytokines IL-17A and F. However, the mRNA expression of Th17 signalling molecules, IL-6 (p = 0.0022), IL-6R (p = 0.0247), IL-1β (p = 0.0022) and signal transducer and activator (STAT) 3 (p = 0.0022) were significantly upregulated. Notably, TB+HIV+ pleural fluid contained significantly higher concentrations of IL-1β (p = 0.0008), IL-22 (p = 0.0115), IL-31 (p = 0.0210), TNF-α (p = 0.0251) and IFN-γ (p = 0.0026) than TB−HIV− pleural fluid ex vivo. Taken together, this suggests a reduced portion of Th17 lymphocytes in TB/HIV pleurisy is independent of locally mediated cytokine polarisation.The National Research Foundation, KwaZulu-Natal Research Institute for Tuberculosis and HIV and College of Health Sciences, University of KwaZulu-Natal.http://intl.elsevierhealth.com/journals/tube2017-07-31hb2016Physiolog

Management of pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a potentially lethal disease mainly affecting young females. Although the precise mechanism of PAH is unknown, the past decade has seen the advent of many new classes of drugs with improvement in the overall prognosis of the disease. Unfortunately the therapeutic options for PAH in South Africa are severely limited. The Working Group on PAH is a joint effort by the South African Heart Association and the South African Thoracic Society tasked with improving the recognition and management of patients with PAH. This article provides a brief summary of the disease and the recommendations of the first meeting of the Working Group

A pilot study of once-daily antiretroviral therapy integrated with Tuberculosis directly observed therapy in a resource-limited setting.

To determine the feasibility and effectiveness of integrating highly active antiretroviral therapy (HAART) into existing tuberculosis directly observed therapy (TB/DOT) programs, we performed a pilot study in an urban TB clinic in South Africa. Patients with smear-positive pulmonary TB were offered HIV counseling and testing. Twenty HIV-positive patients received once-daily didanosine (400 mg) plus lamivudine (300 mg) plus efavirenz (600 mg) administered concomitantly with standard TB therapy Monday to Friday and self-administered on weekends. After completing TB therapy, patients were referred to an HIV clinic for continued treatment. At baseline, patients had a mean CD4 count of 230 cells/mm3 (range: 24–499 cells/mm3) and a mean viral load of 5.75 log10 (range: 3.81–7.53 log10). Seventeen completed combined standard TB and HIV therapy; 16 of 20 (80%) patients enrolled and 15 of 17 (88%) patients completing standard TB therapy achieved a viral load <50 copies/mL and mean CD4 count increase of 148 cells/mm3. TB was cured in 17 of 20 (85%) enrolled patients and 17 of 19 (89%) patients with drug-sensitive TB. Treatment was well tolerated, with minimal gastrointestinal, hepatic, skin, or neurologic toxicity. The project was well accepted and integrated into the daily TB clinic functions. This pilot study demonstrates that TB/DOT programs can be feasible and effective sites for HIV identification and the introduction and monitoring of a once-daily HAART regimen in resource-limited settings

Outcomes among HIV-1 Infected Individuals First Starting Antiretroviral Therapy with Concurrent Active TB or Other AIDS-Defining Disease

Background: Tuberculosis (TB) is common among HIV-infected individuals in many resource-limited countries and has been associated with poor survival. We evaluated morbidity and mortality among individuals first starting antiretroviral therapy (ART) with concurrent active TB or other AIDS-defining disease using data from the “Prospective Evaluation of Antiretrovirals in Resource-Limited Settings” (PEARLS) study. Methods: Participants were categorized retrospectively into three groups according to presence of active confirmed or presumptive disease at ART initiation: those with pulmonary and/or extrapulmonary TB (“TB” group), those with other non-TB AIDS-defining disease (“other disease”), or those without concurrent TB or other AIDS-defining disease (“no disease”). Primary outcome was time to the first of virologic failure, HIV disease progression or death. Since the groups differed in characteristics, proportional hazard models were used to compare the hazard of the primary outcome among study groups, adjusting for age, sex, country, screening CD4 count, baseline viral load and ART regimen. Results: 31 of 102 participants (30%) in the “TB” group, 11 of 56 (20%) in the “other disease” group, and 287 of 1413 (20%) in the “no disease” group experienced a primary outcome event (p = 0.042). This difference reflected higher mortality in the TB group: 15 (15%), 0 (0%) and 41 (3%) participants died, respectively (p<0.001). The adjusted hazard ratio comparing the “TB” and “no disease” groups was 1.39 (95% confidence interval: 0.93–2.10; p = 0.11) for the primary outcome and 3.41 (1.72–6.75; p<0.001) for death. Conclusions: Active TB at ART initiation was associated with increased risk of mortality in HIV-1 infected patients