Progressive Multifocal Leukoencephalopathy in HIV-Infected Children: A Case Report and Literature Review

We report a case of a perinatally HIV-infected patient aged 9 years, who presented with right-sided hemiplegia. His initial CD4 T-cell was of 0.21% (4 cells/μL) and plasma HIV RNA virus of 185 976 copies/mL (log 5.27). Plasma and CSF samples were subsequently positive for JCV. Twelve days after the initiation of highly active antiretroviral therapy (HAART), the MRI showed progressive white matter lesions with asymmetrical deep and subcortical white matter lesions over the left frontotemporoparietal region and the right frontal lobe. Immune Reconstitution Inflammatory Syndrome (IRIS) was suspected, and the patient was treated with methylprednisolone. His clinical symptoms worsened and despite therapy the patient deteriorated

Impact of ivermectin components on Anopheles dirus and Anopheles minimus mosquito survival

Background: Ivermectin mass drug administration to humans or livestock is a potential vector control tool for malaria elimination. Racemic ivermectin is composed of two components, namely a major component (> 80%; ivermectin B1a), which has an ethyl group at C-26, and a minor component (< 20%; ivermectin B1b), which has a methyl group at C-26. There is no difference between the efficacy of ivermectin B1a and ivermectin B1b efficacy in nematodes, but only ivermectin B1b has been reported to be lethal to snails. The ratios of ivermectin B1a and B1b ratios in ivermectin formulations and tablets can vary between manufacturers and batches. The mosquito-lethal effects of ivermectin B1a and ivermectin B1b have never been assessed. As novel ivermectin formulations are being developed for malaria control, it is important that the mosquito-lethal effects of individual ivermectin B1a and ivermectin B1b compounds be evaluated. Methods: Racemic ivermectin, ivermectin B1a or ivermectin B1b, respectively, was mixed with human blood at various concentrations, blood-fed to Anopheles dirus sensu stricto and Anopheles minimus sensu stricto mosquitoes, and mortality was observed for 10 days. The ivermectin B1a and B1b ratios from commercially available racemic ivermectin and marketed tablets were assessed by liquid chromatography-mass spectrometry. Results: The results revealed that neither the lethal concentrations that kills 50% (LC50) nor 90% (LC90) of mosquitoes differed between racemic ivermectin, ivermectin B1a or ivermectin B1b for An. dirus or An. minimus, confirming that the individual ivermectin components have equal mosquito-lethal effects. The relative ratios of ivermectin B1a and B1b derived from sourced racemic ivermectin powder were 98.84% and 1.16%, respectively, and the relative ratios for ivermectin B1a and B1b derived from human oral ivermectin tablets were 98.55% and 1.45%, respectively. Conclusions: The ratio of ivermectin B1a and B1b does not influence the Anopheles mosquito-lethal outcome, an ideal study result as the separation of ivermectin B1a and B1b components at scale is cost prohibitive. Thus, variations in the ratio of ivermectin B1a and B1b between batches and manufacturers, as well as potentially novel formulations for malaria control, should not influence ivermectin mosquito-lethal efficacy

Born too soon in a resource-limited setting: a 10-year mixed methods review of a special care baby unit for refugees and migrants on the Myanmar-Thailand border

Background: Preterm birth is a major public health concern with the largest burden of morbidity and mortality falling within low- and middle-income countries (LMIC). Materials and methods: This sequential explanatory mixed methods study was conducted in special care baby units (SCBUs) serving migrants and refugees along the Myanmar-Thailand border. It included a retrospective medical records review, qualitative interviews with mothers receiving care within SCBUs, and focus group discussions with health workers. Changes in neonatal mortality and four clinical outcomes were described. A mix of ethnographic phenomenology and implementation frameworks focused on cultural aspects, the lived experience of participants, and implementation outcomes related to SCBU care. Results: From 2008–2017, mortality was reduced by 68% and 53% in very (EGA 28–32 weeks) and moderate (EGA 33–36 weeks) preterm neonates, respectively. Median SCBU stay was longer in very compared to moderate preterm neonates: 35 (IQR 22, 48 days) vs. 10 days (IQR 5, 16). Duration of treatments was also longer in very preterm neonates: nasogastric feeding lasted 82% (IQR 74, 89) vs. 61% (IQR 40, 76) of the stay, and oxygen therapy was used a median of 14 (IQR 7, 27) vs. 2 (IQR 1, 6) days respectively. Nine interviews were conducted with mothers currently receiving care in the SCBU and four focus group discussions with a total of 27 local SCBU staff. Analysis corroborated quantitative analysis of newborn care services in this setting and incorporated pertinent implementation constructs including coverage, acceptability, appropriateness, feasibility, and fidelity. Coverage, acceptability, and appropriateness were often overlapping outcomes of interest highlighting financial issues prior to or while admitted to the SCBU and social issues and support systems adversely impacting SCBU stays. Interview and FGD findings highlight the barriers in this resource-limited setting as they impact the feasibility and fidelity of providing evidence-based SCBU care that often required adaptation to fit the financial and environmental constraints imposed by this setting. Discussion: This study provides an in-depth look at the nature of providing preterm neonatal interventions in a SCBU for a vulnerable population in a resource-limited setting. These findings support implementation of basic evidence-based interventions for preterm and newborn care globally, particularly in LMICs

Primaquine in glucose-6-phosphate dehydrogenase deficiency: an adaptive pharmacometric assessment of ascending dose regimens in healthy volunteers

Background: Primaquine is an 8-aminoquinoline antimalarial. It is the only widely available treatment to prevent relapses of Plasmodium vivax malaria. The 8-aminoquinolines cause dose-dependent haemolysis in glucose-6-phosphate dehydrogenase deficiency (G6PDd). G6PDd is common in malaria endemic areas but testing is often not available. As a consequence primaquine is underused. Methods: We conducted an adaptive pharmacometric study to characterise the relationship between primaquine dose and haemolysis in G6PDd. The aim was to explore shorter and safer primaquine radical cure regimens compared to the currently recommended 8-weekly regimen (0.75 mg/kg once weekly), potentially obviating the need for G6PD testing. Hemizygous G6PDd healthy adult Thai and Burmese male volunteers were admitted to the Hospital for Tropical Diseases in Bangkok. In Part 1, volunteers were given ascending dose primaquine regimens whereby daily doses were increased from 7.5 mg up to 45 mg over 15–20 days. In Part 2 conducted at least 6 months later, a single primaquine 45 mg dose was given. Results: 24 volunteers were enrolled in Part 1, and 16 in Part 2 (13 participated in both studies). In three volunteers, the ascending dose regimen was stopped because of haemolysis (n=1) and asymptomatic increases in transaminases (n=2; one was hepatitis E positive). Otherwise the ascending regimens were well tolerated with no drug-related serious adverse events. In Part 1, the median haemoglobin concentration decline was 3.7 g/dL (range: 2.1–5.9; relative decline of 26% [range: 15–40%]). Primaquine doses up to 0.87 mg/kg/day were tolerated subsequently without clinically significant further falls in haemoglobin. In Part 2, the median haemoglobin concentration decline was 1.7 g/dL (range 0.9–4.1; relative fall of 12% [range: 7–30% decrease]). The ascending dose primaquine regimens gave seven times more drug but resulted in only double the haemoglobin decline. Conclusions: In patients with Southeast Asian G6PDd variants, full radical cure treatment can be given in under 3 weeks compared with the current 8-week regimen. Funding: Medical Research Council of the United Kingdom (MR/R015252/1) and Wellcome (093956/Z/10/C, 223253/Z/21/Z)

Ivermectin metabolites reduce Anopheles survival

Ivermectin mass drug administration to humans or livestock is a potential vector control tool for malaria elimination. The mosquito-lethal effect of ivermectin in clinical trials exceeds that predicted from in vitro laboratory experiments, suggesting that ivermectin metabolites have mosquito-lethal effect. The three primary ivermectin metabolites in humans (i.e., M1 (3″-O-demethyl ivermectin), M3 (4-hydroxymethyl ivermectin), and M6 (3″-O-demethyl, 4-hydroxymethyl ivermectin) were obtained by chemical synthesis or bacterial modification/metabolism. Ivermectin and its metabolites were mixed in human blood at various concentrations, blood-fed to Anopheles dirus and Anopheles minimus mosquitoes, and mortality was observed daily for fourteen days. Ivermectin and metabolite concentrations were quantified by liquid chromatography linked with tandem mass spectrometry to confirm the concentrations in the blood matrix. Results revealed that neither the LC50 nor LC90 values differed between ivermectin and its major metabolites for An. dirus or An. minimus., Additionally, there was no substantial differences in the time to median mosquito mortality when comparing ivermectin and its metabolites, demonstrating an equal rate of mosquito killing between the compounds evaluated. These results demonstrate that ivermectin metabolites have a mosquito-lethal effect equal to the parent compound, contributing to Anopheles mortality after treatment of humans

Born too soon in a resource-limited setting: A 10-year mixed methods review of a special care baby unit for refugees and migrants on the Myanmar-Thailand border

BackgroundPreterm birth is a major public health concern with the largest burden of morbidity and mortality falling within low- and middle-income countries (LMIC).Materials and methodsThis sequential explanatory mixed methods study was conducted in special care baby units (SCBUs) serving migrants and refugees along the Myanmar-Thailand border. It included a retrospective medical records review, qualitative interviews with mothers receiving care within SCBUs, and focus group discussions with health workers. Changes in neonatal mortality and four clinical outcomes were described. A mix of ethnographic phenomenology and implementation frameworks focused on cultural aspects, the lived experience of participants, and implementation outcomes related to SCBU care.ResultsFrom 2008–2017, mortality was reduced by 68% and 53% in very (EGA 28–32 weeks) and moderate (EGA 33–36 weeks) preterm neonates, respectively. Median SCBU stay was longer in very compared to moderate preterm neonates: 35 (IQR 22, 48 days) vs. 10 days (IQR 5, 16). Duration of treatments was also longer in very preterm neonates: nasogastric feeding lasted 82% (IQR 74, 89) vs. 61% (IQR 40, 76) of the stay, and oxygen therapy was used a median of 14 (IQR 7, 27) vs. 2 (IQR 1, 6) days respectively. Nine interviews were conducted with mothers currently receiving care in the SCBU and four focus group discussions with a total of 27 local SCBU staff. Analysis corroborated quantitative analysis of newborn care services in this setting and incorporated pertinent implementation constructs including coverage, acceptability, appropriateness, feasibility, and fidelity. Coverage, acceptability, and appropriateness were often overlapping outcomes of interest highlighting financial issues prior to or while admitted to the SCBU and social issues and support systems adversely impacting SCBU stays. Interview and FGD findings highlight the barriers in this resource-limited setting as they impact the feasibility and fidelity of providing evidence-based SCBU care that often required adaptation to fit the financial and environmental constraints imposed by this setting.DiscussionThis study provides an in-depth look at the nature of providing preterm neonatal interventions in a SCBU for a vulnerable population in a resource-limited setting. These findings support implementation of basic evidence-based interventions for preterm and newborn care globally, particularly in LMICs

Pharmacometrics of high dose ivermectin in early COVID-19: an open label, randomized, controlled adaptive platform trial (PLATCOV)

Background: There is no generally accepted methodology for in vivo assessment of antiviral activity in SARS-CoV-2 infections. Ivermectin has been recommended widely as a treatment of COVID-19, but whether it has clinically significant antiviral activity in vivo is uncertain. Methods: In a multicentre open label, randomized, controlled adaptive platform trial, adult patients with early symptomatic COVID-19 were randomized to one of six treatment arms including high-dose oral ivermectin (600 µg/kg daily for 7 days), the monoclonal antibodies casirivimab and imdevimab (600 mg/600 mg), and no study drug. The primary outcome was the comparison of viral clearance rates in the modified intention-to-treat population. This was derived from daily log10 viral densities in standardized duplicate oropharyngeal swab eluates. This ongoing trial is registered at https://clinicaltrials.gov/ (NCT05041907). Results: Randomization to the ivermectin arm was stopped after enrolling 205 patients into all arms, as the prespecified futility threshold was reached. Following ivermectin, the mean estimated rate of SARS-CoV-2 viral clearance was 9.1% slower (95% confidence interval [CI] –27.2% to +11.8%; n=45) than in the no drug arm (n=41), whereas in a preliminary analysis of the casirivimab/imdevimab arm it was 52.3% faster (95% CI +7.0% to +115.1%; n=10 (Delta variant) vs. n=41). Conclusions: High-dose ivermectin did not have measurable antiviral activity in early symptomatic COVID-19. Pharmacometric evaluation of viral clearance rate from frequent serial oropharyngeal qPCR viral density estimates is a highly efficient and well-tolerated method of assessing SARS-CoV-2 antiviral therapeutics in vitro

Clinical antiviral efficacy of remdesivir in coronavirus disease 2019: an open-label, randomized controlled adaptive platform trial (PLATCOV)

Background Uncertainty over the therapeutic benefit of parenteral remdesivir in coronavirus disease 2019 (COVID-19) has resulted in varying treatment guidelines. Methods In a multicenter open-label, controlled, adaptive, pharmacometric platform trial, low-risk adult patients with early symptomatic COVID-19 were randomized to 1 of 8 treatment arms including intravenous remdesivir (200 mg followed by 100 mg daily for 5 days) or no study drug. The primary outcome was the rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance (estimated under a linear model fit to the daily log10 viral densities, days 0–7) in standardized duplicate oropharyngeal swab eluates, in a modified intention-to-treat population. This ongoing adaptive trial is registered at ClinicalTrials.gov (NCT05041907). Results The 2 study arms enrolled 131 patients (remdesivir n = 67, no study drug n = 64) and estimated viral clearance rates from a median of 18 swab samples per patient (a total of 2356 quantitative polymerase chain reactions). Under the linear model, compared with the contemporaneous control arm (no study drug), remdesivir accelerated mean estimated viral clearance by 42% (95% credible interval, 18%–73%). Conclusions Parenteral remdesivir accelerates viral clearance in early symptomatic COVID-19. Pharmacometric assessment of therapeutics using the method described can determine in vivo clinical antiviral efficacy rapidly and efficiently

A systematic review and an individual patient data meta-analysis of ivermectin use in children weighing less than fifteen kilograms: Is it time to reconsider the current contraindication?

BACKGROUND: Oral ivermectin is a safe broad spectrum anthelminthic used for treating several neglected tropical diseases (NTDs). Currently, ivermectin use is contraindicated in children weighing less than 15 kg, restricting access to this drug for the treatment of NTDs. Here we provide an updated systematic review of the literature and we conducted an individual-level patient data (IPD) meta-analysis describing the safety of ivermectin in children weighing less than 15 kg. METHODOLOGY/PRINCIPAL FINDINGS: A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for IPD guidelines by searching MEDLINE via PubMed, Web of Science, Ovid Embase, LILACS, Cochrane Database of Systematic Reviews, TOXLINE for all clinical trials, case series, case reports, and database entries for reports on the use of ivermectin in children weighing less than 15 kg that were published between 1 January 1980 to 25 October 2019. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42017056515. A total of 3,730 publications were identified, 97 were selected for potential inclusion, but only 17 sources describing 15 studies met the minimum criteria which consisted of known weights of children less than 15 kg linked to possible adverse events, and provided comprehensive IPD. A total of 1,088 children weighing less than 15 kg were administered oral ivermectin for one of the following indications: scabies, mass drug administration for scabies control, crusted scabies, cutaneous larva migrans, myiasis, pthiriasis, strongyloidiasis, trichuriasis, and parasitic disease of unknown origin. Overall a total of 1.4% (15/1,088) of children experienced 18 adverse events all of which were mild and self-limiting. No serious adverse events were reported. CONCLUSIONS/SIGNIFICANCE: Existing limited data suggest that oral ivermectin in children weighing less than 15 kilograms is safe. Data from well-designed clinical trials are needed to provide further assurance

Spread of artemisinin resistance in Plasmodium falciparum malaria.

BACKGROUND: Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. METHODS: Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. RESULTS: The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. CONCLUSIONS: Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.)