Efavirenz poisoning in a 12 year old HIV negative African boy

Efavirenz is an oral antiretroviral drug in the class of non nucleoside reverse transcriptase inhibitors. Toxicity at therapeutic doses has been documented but there is scarcity of data on presentation and management of Efavirenz overdose. We describe a case of Efavirenz poisoning in a 12-year old HIV Negative African boy with a very unique presentation after ingesting 3 grams of Efavirenz as a single dose. The most prominent problems were burning sensation in the throat immediately after ingestion then visual impairment one hour later then tremors, screaming at night and motor deficits in lower limbs for 5 days before admission. His medical history, physical exam and investigations revealed no other cause of his presentation other than the EFV. Unfortunately, it was not possible to do EFV levels. He was given supportive treatment and 10 days later he was completely well.Key words: Efavirenz, poisoning, intoxication, adverse reaction, HI

Defeating Paediatric Tuberculous Meningitis: Applying the WHO "Defeating Meningitis by 2030: Global Roadmap"

Children affected by tuberculous meningitis (TBM), as well as their families, have needs that lie at the intersections between the tuberculosis and meningitis clinical, research, and policy spheres. There is therefore a substantial risk that these needs are not fully met by either programme. In this narrative review article, we use the World Health Organization (WHO) “Defeating Meningitis by 2030: global roadmap” as a starting point to consider key goals and activities to specifically defeat TBM in children. We apply the five pillars outlined in the roadmap to describe how this approach can be adapted to serve children affected by TBM. The pillars are (i) prevention; (ii) diagnosis and treatment; (iii) surveillance; (iv) support and care for people affected by meningitis; and (v) advocacy and engagement. We conclude by calling for greater integration between meningitis and TB programmes at WHO and at national levels

Accuracy of Xpert Ultra in the diagnosis of pulmonary tuberculosis among children in Uganda: a sub-study from the SHINE trial

Background: Childhood tuberculosis presents significant diagnostic challenges associated with paucibacillary disease, and requires a more sensitive test. We evaluated the diagnostic accuracy of XpertMTB/Rif Ultra (Ultra) compared to other microbiological tests using respiratory samples from Ugandan children in the SHINE trial.Design/Methods: SHINE is a randomized trial evaluating shorter treatment in 1204 children with minimal TB disease in Africa/India. Among 352 samples and one cervical lymph node fine needle aspirate, one sample was randomly selected per patient and tested with Xpert MTB/Rif (Xpert), Lowenstein Jensen (LJ) and liquid (MGIT) cultures. We selected only uncontaminated stored sample pellet for Ultra testing. We estimated sensitivity of Xpert and Ultra against culture and a composite microbiological reference standard (any positive result).Results: Of 398 children, 353 (89%) had culture, Xpert and Ultra results. Median age was 2.8-years (IQR 1.3-5.3); 8.5% (30/353) HIV-infected, 54.4% (192/353) male. 31/353 (9%) were positive by LJ and/or MGIT; 36 (10%) by Ultra and 16 (5%) by Xpert. Sensitivities were (%; 95% CI), 58% (39-65% (18/31)) for Ultra and 45% (27-64% (14/31)) for Xpert against any culture-positive, with false-positives of <1% and 5.5% for Xpert and Ultra. Against a composite microbiological reference, sensitives were 72% (58-84% (36/50) for Ultra, and 32% (20-47% (16/50)) for Xpert. However, there were 17 samples that are positive only on Ultra (majority trace).Conclusions: Among children screened for minimal TB in Uganda, Ultra has higher sensitivity than Xpert. This represents an important advance for a condition which has posed a diagnostic challenge for decades

Pharmacokinetics of first-line drugs in children with tuberculosis using WHO-recommended weight band doses and formulations

Background: Dispersible paediatric fixed dose combination (FDCs) tablets delivering higher doses of first-line antituberculosis drugs in WHO-recommended weight-bands were introduced in 2015. We report the first pharmacokinetic data for these FDCs in Zambian and South African children in the treatment-shortening SHINE trial. // Methods: Children weighing 4.0-7.9 kg, 8.0-11.9 kg, 12.0-15.9 kg and 16.0-24.9 kg had 1, 2, 3 and 4 tablets daily (rifampicin/isoniazid/pyrazinamide 75/50/150 mg, with or without 100 mg ethambutol, or rifampicin/isoniazid 75/50 mg), respectively. Children 25.0-36.9 kg received doses recommended for adults <37kg (300, 150, 800, 550 mg daily for rifampicin, isoniazid, pyrazinamide, ethambutol). Pharmacokinetics were evaluated after at least 2 weeks of treatment. // Results: Of 77 children evaluated, median (IQR) age was 3.7 (1.4-6.6) years, 40 (52%) were male and 20 (26%) HIV-positive. AUC24 for rifampicin, isoniazid, pyrazinamide and ethambutol were 32.5 (20.1-45.1), 16.7 (9.2 - 25.9), 317 (263 - 399) and 9.5 (7.5 – 11.5) mg.h/L, respectively, and lower in children compared to adults for rifampicin in 4.0-7.9 kg, 8-11.9kg and ≥25kg weight-bands, isoniazid in 4.0-7.9kg and ≥25kg, and ethambutol in all five weight-bands. Pyrazinamide exposures were similar to adults. // Conclusions: Recommended weight-band based FDC doses result in lower drug exposures in children in lower weight-bands and in those ≥25kg (on adult doses). Further adjustments to current doses are needed to match current target exposures in adults. The use of ethambutol at the current WHO-recommended doses requires further evaluation

Shorter treatment for minimal tuberculosis (TB) in children (SHINE): A study protocol for a randomised controlled trial

BACKGROUND: Tuberculosis (TB) in children is frequently paucibacillary and non-severe forms of pulmonary TB are common. Evidence for tuberculosis treatment in children is largely extrapolated from adult studies. Trials in adults with smear-negative tuberculosis suggest that treatment can be effectively shortened from 6 to 4 months. New paediatric, fixed-dose combination anti-tuberculosis treatments have recently been introduced in many countries, making the implementation of World Health Organisation (WHO)-revised dosing recommendations feasible. The safety and efficacy of these higher drug doses has not been systematically assessed in large studies in children, and the pharmacokinetics across children representing the range of weights and ages should be confirmed. METHODS/DESIGN: SHINE is a multicentre, open-label, parallel-group, non-inferiority, randomised controlled, two-arm trial comparing a 4-month vs the standard 6-month regimen using revised WHO paediatric anti-tuberculosis drug doses. We aim to recruit 1200 African and Indian children aged below 16 years with non-severe TB, with or without HIV infection. The primary efficacy and safety endpoints are TB disease-free survival 72 weeks post randomisation and grade 3 or 4 adverse events. Nested pharmacokinetic studies will evaluate anti-tuberculosis drug concentrations, providing model-based predictions for optimal dosing, and measure antiretroviral exposures in order to describe the drug-drug interactions in a subset of HIV-infected children. Socioeconomic analyses will evaluate the cost-effectiveness of the intervention and social science studies will further explore the acceptability and palatability of these new paediatric drug formulations. DISCUSSION: Although recent trials of TB treatment-shortening in adults with sputum-positivity have not been successful, the question has never been addressed in children, who have mainly paucibacillary, non-severe smear-negative disease. SHINE should inform whether treatment-shortening of drug-susceptible TB in children, regardless of HIV status, is efficacious and safe. The trial will also fill existing gaps in knowledge on dosing and acceptability of new anti-tuberculosis formulations and commonly used HIV drugs in settings with a high burden of TB. A positive result from this trial could simplify and shorten treatment, improve adherence and be cost-saving for many children with TB. Recruitment to the SHINE trial begun in July 2016; results are expected in 2020

Prevalence and factors associated with traditional herbal medicine use among patients on highly active antiretroviral therapy in Uganda

<p>Abstract</p> <p>Background</p> <p>In Africa, herbal medicines are often used as primary treatment for Human immunodeficiency virus (HIV) related problems. Concurrent use of traditional herbal medicines (THM) with antiretroviral drugs (ARVs) is widespread among HIV infected patients. However, the extent of THM use is not known in most settings in Sub-Saharan Africa. This study aimed at determining the prevalence and factors associated with THM use among HIV infected patients on highly active antiretroviral therapy (HAART) attending The AIDS Support Organization (TASO) in Uganda. TASO is a non-governmental organization devoted to offering HIV/AIDS care and treatment services in the population.</p> <p>Methods</p> <p>This was a cross-sectional study carried out in two TASO treatment centres in Uganda among 401 randomly selected eligible participants. We included participants who were 18 years and above, were enrolled on HAART, and consented to participate in the study. Data was collected using an interviewer-administered semi-structured questionnaire. THM use referred to someone who had ever used or was currently using herbal medicine while on highly active antiretroviral therapy (HAART) by the time of the study. Data was captured in Epi-data version 3.1 and exported to STATA version 9.0 for analysis.</p> <p>Results</p> <p>The prevalence of THM use was 33.7%. Patients on HAART for < 4 years were more likely to use THM (OR = 5.98, 95% CI 1.13 - 31.73) as well as those who experienced HAART side effects (OR = 3.66, 95% CI: 1.15 - 11.68). Older patients (≥39 years) were less likely to use THM (OR = 0.26 95% CI: 0.08 - 0.83). Participants with HAART adherence levels > 95% were less likely to use THM (OR = 0.09, 95% CI 0.01 - 0.65).</p> <p>Conclusion</p> <p>The prevalence of THM use among participants on HAART was high. This raises clinical and pharmacological concerns that need attention by the health care service providers.</p

Impact of systematic early tuberculosis detection using Xpert MTB/RIF Ultra in children with severe pneumonia in high tuberculosis burden countries (TB-Speed pneumonia): a stepped wedge cluster randomized trial

Background In high tuberculosis (TB) burden settings, there is growing evidence that TB is common in children with pneumonia, the leading cause of death in children under 5 years worldwide. The current WHO standard of care (SOC) for young children with pneumonia considers a diagnosis of TB only if the child has a history of prolonged symptoms or fails to respond to antibiotic treatments. As a result, many children with TB-associated severe pneumonia are currently missed or diagnosed too late. We therefore propose a diagnostic trial to assess the impact on mortality of adding the systematic early detection of TB using Xpert MTB/RIF Ultra (Ultra) performed on nasopharyngeal aspirates (NPA) and stool samples to the WHO SOC for children with severe pneumonia, followed by immediate initiation of anti-TB treatment in children testing positive on any of the samples. Methods TB-Speed Pneumonia is a pragmatic stepped-wedge cluster randomized controlled trial conducted in six countries with high TB incidence rate (Côte d’Ivoire, Cameroon, Uganda, Mozambique, Zambia and Cambodia). We will enrol 3780 children under 5 years presenting with WHO-defined severe pneumonia across 15 hospitals over 18 months. All hospitals will start managing children using the WHO SOC for severe pneumonia; one hospital will be randomly selected to switch to the intervention every 5 weeks. The intervention consists of the WHO SOC plus rapid TB detection on the day of admission using Ultra performed on 1 nasopharyngeal aspirate and 1 stool sample. All children will be followed for 3 months, with systematic trial visits at day 3, discharge, 2 weeks post-discharge, and week 12. The primary endpoint is all-cause mortality 12 weeks after inclusion. Qualitative and health economic evaluations are embedded in the trial. Discussion In addition to testing the main hypothesis that molecular detection and early treatment will reduce TB mortality in children, the strength of such pragmatic research is that it provides some evidence regarding the feasibility of the intervention as part of routine care. Should this intervention be successful, safe and well tolerated, it could be systematically implemented at district hospital level where children with severe pneumonia are referred. Trial registration ClinicalTrials.gov, NCT03831906. Registered 6 February 2019

Towards early inclusion of children in tuberculosis drugs trials : a consensus statement

Children younger than 18 years account for a substantial proportion of patients with tuberculosis worldwide. Available treatments for paediatric drug-susceptible and drug-resistant tuberculosis, albeit generally eff ective, are hampered by high pill burden, long duration of treatment, coexistent toxic eff ects, and an overall scarcity of suitable child-friendly formulations. Several new drugs and regimens with promising activity against both drug-susceptible and drug-resistant strains have entered clinical development and are either in various phases of clinical investigation or have received marketing authorisation for adults; however, none have data on their use in children. This consensus statement, generated from an international panel of opinion leaders on childhood tuberculosis and incorporating reviews of published literature from January, 2004, to May, 2014, addressed four key questions: what drugs or regimens should be prioritised for clinical trials in children? Which populations of children are high priorities for study? When can phase 1 or 2 studies be initiated in children? What are the relevant elements of clinical trial design? The consensus panel found that children can be included in studies at the early phases of drug development and should be an integral part of the clinical development plan, rather than studied after regulatory approval in adults is obtained.National Institute of Allergy and Infectious Diseases and National Institute of Health.Department of Health and Human Services.http://www.thelancet.com/infection2016-06-30hb201