Abstract

Background: We evaluated dolutegravir pharmacokinetics in infants with human immunodeficiency virus (HIV) receiving dolutegravir twice daily (BID) with rifampicin-based tuberculosis (TB) treatment compared with once daily (OD) without rifampicin.

Methods: Infants with HIV aged 1-12 months, weighing ≥3 kg, and receiving dolutegravir BID with rifampicin or OD without rifampicin were eligible. Six blood samples were taken over 12 (BID) or 24 hours (OD). Dolutegravir pharmacokinetic parameters, HIV viral load (VL) data, and adverse events (AEs) were reported.

Results: Twenty-seven of 30 enrolled infants had evaluable pharmacokinetic curves. The median (interquartile range) age was 7.1 months (6.1-9.9), weight was 6.3 kg (5.6-7.2), 21 (78%) received rifampicin, and 11 (41%) were female. Geometric mean ratios comparing dolutegravir BID with rifampicin versus OD without rifampicin were area under curve (AUC)0-24h 0.91 (95% confidence interval, .59-1.42), Ctrough 0.95 (0.57-1.59), Cmax 0.87 (0.57-1.33). One infant (5%) receiving rifampicin versus none without rifampicin had dolutegravir Ctrough <0.32 mg/L, and none had Ctrough <0.064 mg/L. The dolutegravir metabolic ratio (dolutegravir-glucuronide AUC/dolutegravir AUC) was 2.3-fold higher in combination with rifampicin versus without rifampicin. Five of 82 reported AEs were possibly related to rifampicin or dolutegravir and resolved without treatment discontinuation. Upon TB treatment completion, HIV viral load was <1000 copies/mL in 76% and 100% of infants and undetectable in 35% and 20% of infants with and without rifampicin, respectively.

Conclusions: Dolutegravir BID in infants receiving rifampicin resulted in adequate dolutegravir exposure, supporting this treatment approach for infants with HIV-TB coinfection.

Abstract

Background: Patients who develop severe illness due to COVID-19 are more likely to be admitted to hospital and acquire bacterial co-infections, therefore the WHO recommends empiric treatment with antibiotics. Few reports have addressed the impact of COVID-19 management on emergence of nosocomial antimicrobial resistance (AMR) in resource constrained settings. This study aimed to ascertain whether being admitted to a COVID-19 ward (with COVID-19 infection) compared to a non-COVID-19 ward (as a COVID-19 negative patient) was associated with a change in the prevalence of bacterial hospital acquired infection (HAI) species or resistance patterns, and whether there were differences in antimicrobial stewardship (AMS) and infection prevention and control (IPC) guidelines between COVID-19 and non-COVID-19 wards. The study was conducted in Sudan and Zambia, two resource constrained settings with differing country-wide responses to COVID-19.

Methods: Patients suspected of having hospital acquired infections were recruited from COVID-19 wards and non-COVID-19 wards. Bacteria were isolated from clinical samples using culture and molecular methods and species identified. Phenotypic and genotypic resistance patterns were determined by antibiotic disc diffusion and whole genome sequencing. Infection prevention and control guidelines were analysed for COVID-19 and non-COVID-19 wards to identify potential differences.

Results: 109 and 66 isolates were collected from Sudan and Zambia respectively. Phenotypic testing revealed significantly more multi-drug resistant isolates on COVID-19 wards in both countries (Sudan p = 0.0087, Zambia p = 0.0154). The total number of patients with hospital acquired infections (both susceptible and resistant) increased significantly on COVID-19 wards in Sudan, but the opposite was observed in Zambia (both p = ≤ 0.0001). Genotypic analysis showed significantly more β-lactam genes per isolate on COVID-19 wards (Sudan p = 0.0192, Zambia p = ≤ 0.0001).

Conclusions: Changes in hospital acquired infections and AMR patterns were seen in COVID-19 patients on COVID-19 wards compared to COVID-19 negative patients on non-COVID-19 wards in Sudan and Zambia. These are likely due to a potentially complex combination of causes, including patient factors, but differing emphases on infection prevention and control, and antimicrobial stewardship policies on COVID-19 wards were highlighted.

Abstract

Background: Pneumonia is the primary cause of death among HIV-infected children in Africa, with mortality rates as high as 35-40% in infants hospitalized with severe pneumonia. Bacterial pathogens and Pneumocystis jirovecii are well known causes of pneumonia-related death, but other important causes such as cytomegalovirus (CMV) and tuberculosis (TB) remain under-recognized and undertreated. The immune response elicited by CMV may be associated with the risk of developing TB and TB disease progression, and CMV may accelerate disease caused both by HIV and TB. Minimally invasive autopsies confirm that CMV and TB are unrecognized causes of death in children with HIV. CMV and TB may also co-infect the same child. The aim of this study is to compare the impact on 15-day and 1-year mortality of empirical treatment against TB and CMV plus standard of care (SoC) versus SoC in HIV-infected infants with severe pneumonia.

Methods: This is a Phase II-III, open-label randomized factorial (2 × 2) clinical trial, conducted in six African countries. The trial has four arms. Infants from 28 to 365 days of age HIV-infected and hospitalized with severe pneumonia will be randomized (1:1:1:1) to (i) SoC, (ii) valganciclovir, (iii) TB-T, and (iv) TB-T plus valganciclovir. The primary endpoint of the study is all-cause mortality, focusing on the short-term (up to 15 days) and long-term (up to 1 year) mortality. Secondary endpoints include repeat hospitalization, duration of oxygen therapy during initial admission, severe and notable adverse events, adverse reactions, CMV and TB prevalence at enrolment, TB incidence, CMV viral load reduction, and evaluation of diagnostic tests such as GeneXpert Ultra on fecal and nasopharyngeal aspirate samples and urine TB-LAM.

Discussion: Given the challenges in diagnosing CMV and TB in children and results from previous autopsy studies that show high rates of poly-infection in HIV-infected infants with respiratory disease, this study aims to evaluate a new approach including empirical treatment of CMV and TB for this patient population. The potential downsides of empirical treatment of these conditions include toxicity and medication interactions, which will be evaluated with pharmacokinetics sub-studies.

Trial registration: ClinicalTrials.gov , NCT03915366, Universal Trial Number U111-1231-4736, Pan African Clinical Trial Registry PACTR201994797961340.

Abstract

Objectives: To conduct a diagnostic validation study of SARS-CoV-2 diagnostic kits.

Methods: We compared SARS-CoV-2 diagnostic test results from 3 RT-PCR assays used by the Zambian government between November 2020 and February 2021 (Panther Fusion assay, Da An Gene’s 2019-nCoV RNA kit and Maccura’s PCR Kit) with the Altona RealStar RT-PCR kit which served as the gold standard. We also evaluated results from rapid antigen testing and whether comorbidities were linked with increased odds of infection.

Results: We recruited 244 participants, 61% (149/244) were positive by at least 1 PCR assay. Da An Gene, Maccura, and Panther Fusion assays had sensitivities of 0.0% (95% confidence interval [CI] 0%-41%), 27.1% (95% CI 15%-42%), and 76% (95% CI 65%-85%), respectively, but specificity was low (<85% for all 3 assays). HIV and TB were not associated with SARS-CoV-2, whereas female sex (OR 0.5 [0.3-0.9], p = 0.026) and chronic pulmonary disease (0.1 [0.0-0.8], p = 0.031) were associated with lower odds of SARS-CoV-2 infection. Of 44 samples, 84% sequenced were Beta variant.

Conclusions: The RT-PCR assays evaluated did not meet WHO recommended minimum sensitivity of 80%. Local diagnostic validation studies should be embedded within preparedness plans for future outbreaks to improve the public health response.

Keywords: COVID-19; RDTs; SARS-CoV-2; comorbidities; diagnostics; lateral flow test; real time- PCR; serology.

Abstract

Transmission dynamics and the maintenance of mammarenaviruses in nature are poorly understood. Using metagenomic next-generation sequencing (mNGS) and RT-PCR, we investigated the presence of mammarenaviruses and co-infecting helminths in various tissues of 182 Mastomys natalensis rodents and 68 other small mammals in riverine and non-riverine habitats in Zambia. The Luna virus (LUAV) genome was the only mammarenavirus detected (7.7%; 14/182) from M. natalensis. Only one rodent from the non-riverine habitat was positive, while all six foetuses from one pregnant rodent carried LUAV. LUAV-specific mNGS reads were 24-fold higher in semen than in other tissues from males. Phylogenetically, the viruses were closely related to each other within the LUAV clade. Helminth infections were found in 11.5% (21/182) of M. natalensis. LUAV-helminth co-infections were observed in 50% (7/14) of virus-positive rodents. Juvenility (OR = 9.4; p = 0.018; 95% CI: 1.47-59.84), nematodes (OR = 15.5; p = 0.001; 95% CI: 3.11-76.70), cestodes (OR = 10.8; p = 0.025; 95% CI: 1.35-86.77), and being male (OR = 4.6; p = 0.036; 95% CI: 1.10-18.90) were associated with increased odds of LUAV RNA detection. The role of possible sexual and/or congenital transmission in the epidemiology of LUAV infections in rodents requires further study, along with the implications of possible helminth co-infection.

Abstract

Background: The emergence of high consequence pathogens such as Ebola and SARS-CoV-2, along with the continued burden of neglected diseases such as rabies, has highlighted the need for preparedness for emerging and endemic infectious diseases of zoonotic origin in sub-Saharan Africa (SSA) using a One Health approach. To identify trends in SSA preparedness, the World Health Organization (WHO) Joint External Evaluation (JEE) reports were analysed. JEEs are voluntary, collaborative processes to assess country’s capacities to prevent, detect and rapidly respond to public health risks. This report aimed to analyse the JEE zoonotic disease preparedness data as a whole and identify strengths and weaknesses.

Methods: JEE zoonotic disease preparedness scores for 44 SSA countries who had completed JEEs were analysed. An overall zoonotic disease preparedness score was calculated as an average of the sum of all the SSA country zoonotic disease preparedness scores and compared to the overall mean JEE score. Zoonotic disease preparedness indicators were analysed and data were collated into regions to identify key areas of strength.

Results: The mean ‘Zoonotic disease’ preparedness score (2.35, range 1.00-4.00) was 7% higher compared to the mean overall JEE preparedness score (2.19, range 1.55-3.30), putting ‘Zoonotic Diseases’ 5th out of 19 JEE sub-areas for preparedness. The average scores for each ‘Zoonotic Disease’ category were 2.45 for ‘Surveillance Systems’, 2.76 for ‘Veterinary Workforce’ and 1.84 for ‘Response Mechanisms’. The Southern African region scored highest across the ‘Zoonotic disease’ categories (2.87).A multisectoral priority zoonotic pathogens list is in place for 43% of SSA countries and 70% reported undertaking national surveillance on 1-5 zoonotic diseases. 70% of SSA countries reported having public health training courses in place for veterinarians and 30% had veterinarians in all districts (reported as sufficient staffing). A multisectoral action plan for zoonotic outbreaks was in place for 14% countries and 32% reported having an established inter-agency response team for zoonotic outbreaks. The zoonotic diseases that appeared most in reported country priority lists were rabies and Highly Pathogenic Avian Influenza (HPAI) (both 89%), anthrax (83%), and brucellosis (78%).

Conclusions: With ‘Zoonotic Diseases’ ranking 5th in the JEE sub-areas and a mean SSA score 7% greater than the overall mean JEE score, zoonotic disease preparedness appears to have the attention of most SSA countries. However, the considerable range suggests that some countries have more measures in place than others, which may perhaps reflect the geography and types of pathogens that commonly occur. The category ‘Response Mechanisms’ had the lowest mean score across SSA, suggesting that implementing a multisectoral action plan and response team could provide the greatest gains.