Summary Background Intermittent preventive treatment (IPT) for malaria is used in infants, children, adults, and pregnant women. Dihydroartemisinin-piperaquine (DP) is an effective, well tolerated ...artemisinin-based combination therapy. The long half-life of piperaquine makes it attractive for IPT. We conducted a systematic review and meta-analysis to establish the efficacy and safety of repeated treatment with DP. Methods Following PRISMA guidelines, we searched multiple databases on Sept 1, 2016, with the terms: “human” AND “dihydroartemisinin-piperaquine” OR “DHA-PPQ”. Studies were eligible if they were randomised controlled trials (RCTs) or prospective cohort studies involving repeat exposures to standard 3-day courses of DP for either seasonal malaria chemoprevention, mass drug administration, or treatment of clinical malaria, conducted at any time and in any geographic location. Random-effects meta-analysis was used to generate pooled incidence rate ratios and relative risks, or risk differences. Findings 11 studies were included: two repeat treatment studies (one in children younger than 5 years and one in pregnant women), and nine IPT trials (five in children younger than 5 years, one in schoolchildren, one in adults, two in pregnant women). Comparator interventions included placebo, artemether-lumefantrine, sulfadoxine-pyrimethamine (SP), SP+amodiaquine, SP+piperaquine, SP+chloroquine, and co-trimoxazole. Of 14 628 participants, 3935 received multiple DP courses (2–18). Monthly IPT-DP was associated with an 84% reduction in the incidence of malaria parasitaemia measured by microscopy compared with placebo. Monthly IPT-DP was associated with fewer serious adverse events than placebo, daily co-trimoxazole, or monthly SP. Among 56 IPT-DP recipients (26 children, 30 pregnant women) with cardiac parameters, all QTc intervals were within normal limits, with no significant increase in QTc prolongation with increasing courses of DP. Interpretation Monthly DP appears well tolerated and effective for IPT. Additional data are needed in pregnancy and to further explore the cardiac safety with monthly dosing. Funding Bill & Melinda Gates Foundation and NIH.
Laws and policies affecting access to medicines have been in the global health spotlight for decades, yet our understanding of their effects remains substantially underdeveloped. The emerging field ...of legal epidemiology combined with the methods of implementation science presents an opportunity to help address this gap. Legal epidemiology refers to the scientific study and deployment of law as a factor in the cause, distribution, and prevention of disease and injury in a population. Legal epidemiology studies consist of a systematic collection and coding of laws and policies relating to a particular topic. Quasi-experimental or observational research methods can then be applied to take advantage of natural experiments resulting from heterogenous adoption and/or implementation of laws and policies. Often legal epidemiology studies fail to account for heterogenous law implementation processes, presenting a need and opportunity to integrate implementation science methods. Researchers may face challenges in integrating these methods for access to medicines studies, including data access issues and a complex legal and implementation environment. Yet, the opportunities presented by increasingly transparent legal environments, improved monitoring of medicine availability, universal health coverage expansion, and electronic health and insurance records integration may facilitate overcoming these challenges. Improved collaboration and communication between researchers, health authorities, manufacturers, and health providers from public and private sectors will be critical. In spite of the challenges, combining the fields of legal epidemiology and implementation science may present an important strategy toward creating a legal and policy environment that supports global and equitable access to medicines.
Antimicrobial resistance (AMR) is a serious threat to global public health. WHO emphasises the need for countries to monitor antibiotic consumption to combat AMR. Many low-income and middle-income ...countries (LMICs) lack surveillance capacity; we aimed to use multiple data sources and statistical models to estimate global antibiotic consumption.
In this spatial modelling study, we used individual-level data from household surveys to inform a Bayesian geostatistical model of antibiotic usage in children (aged <5 years) with lower respiratory tract infections in LMICs. Antibiotic consumption data were obtained from multiple sources, including IQVIA, WHO, and the European Surveillance of Antimicrobial Consumption Network (ESAC-Net). The estimates of the antibiotic usage model were used alongside sociodemographic and health covariates to inform a model of total antibiotic consumption in LMICs. This was combined with a single model of antibiotic consumption in high-income countries to produce estimates of antibiotic consumption covering 204 countries and 19 years.
We analysed 209 surveys done between 2000 and 2018, covering 284 045 children with lower respiratory tract infections. We identified large national and subnational variations of antibiotic usage in LMICs, with the lowest levels estimated in sub-Saharan Africa and the highest in eastern Europe and central Asia. We estimated a global antibiotic consumption rate of 14·3 (95% uncertainty interval 13·2–15·6) defined daily doses (DDD) per 1000 population per day in 2018 (40·2 37·2–43·7 billion DDD), an increase of 46% from 9·8 (9·2–10·5) DDD per 1000 per day in 2000. We identified large spatial disparities, with antibiotic consumption rates varying from 5·0 (4·8–5·3) DDD per 1000 per day in the Philippines to 45·9 DDD per 1000 per day in Greece in 2018. Additionally, we present trends in consumption of different classes of antibiotics for selected Global Burden of Disease study regions using the IQVIA, WHO, and ESAC-net input data. We identified large increases in the consumption of fluoroquinolones and third-generation cephalosporins in North Africa and Middle East, and south Asia.
To our knowledge, this is the first study that incorporates antibiotic usage and consumption data and uses geostatistical modelling techniques to estimate antibiotic consumption for 204 countries from 2000 to 2018. Our analysis identifies both high rates of antibiotic consumption and a lack of access to antibiotics, providing a benchmark for future interventions.
Fleming Fund, UK Department of Health and Social Care; Wellcome Trust; and Bill & Melinda Gates Foundation.
The increasing number and global distribution of pathogens resistant to antimicrobial drugs is potentially one of the greatest threats to global health, leading to health crises arising from ...infections that were once easy to treat. Infections resistant to antimicrobial treatment frequently result in longer hospital stays, higher medical costs, and increased mortality. Despite the long-standing recognition of antimicrobial resistance (AMR) across many settings, there is surprisingly poor information about its geographical distribution over time and trends in its population prevalence and incidence. This makes reliable assessments of the health burden attributable to AMR difficult, weakening the evidence base to drive forward research and policy agendas to combat AMR. The inclusion of mortality and morbidity data related to drug-resistant infections into the annual Global Burden of Disease Study should help fill this policy void.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The most recent World Medicines Situation Report published in 2011 found substantial medicine availability and affordability challenges across WHO regions, including Africa. Since publication of the ...2011 report, medicine availability and affordability has risen on the international agenda and was included in the Sustainable Development Goals as Target 3.8. While numerous medicine availability and affordability studies have been conducted in Africa since the last World Medicines Situation Report, there has not been a systematic analysis of the methods used in these studies, measures of medicine availability and affordability, categories of medicines studied, or geographic distribution. Filling this knowledge gap can help inform future medicine availability and affordability studies, design systems to monitor progress toward Sustainable Development Goal Target 3.8 in Africa and beyond, and inform policy and program decisions to improve medicine availability and affordability.
We conducted a systematic scoping review of studies assessing medicine availability or affordability conducted in the WHO Africa region published from 2009-2021.
Two hundred forty one articles met our eligibility criteria. 88% of the articles (213/241) reported descriptive studies, while 12% (28/241) reported interventional studies. Of the 198 studies measuring medicine availability, the most commonly used measure of medicine availability was whether a medicine was in stock on the date of a survey (124/198, 63%). We also identified multiple other availability methods and measures, including retrospective stock record reviews and self-reported medicine availability surveys. Of the 59 articles that included affordability measures, 32 (54%) compared the price of the medicine to the daily wage of the lowest paid government worker. Other affordability measures were patient self-reported affordability, capacity to pay measures, and comparing medicines prices with a population-level income standard (such as minimum wage, poverty line, or per capita income). The most commonly studied medicines were antiparasitic and anti-bacterial medicines. We did not identify studies in 22 out of 48 (46%) countries in the WHO Africa Region and more than half of the studies identified were conducted in Ethiopia, Kenya, Tanzania, and/or Uganda.
Our results revealed a wide range of medicine availability and affordability assessment methodologies and measures, including cross-sectional facility surveys, population surveys, and retrospective data analyses. Our review also indicated a need for greater focus on medicines for certain non-communicable diseases, greater geographic diversity of studies, and the need for more intervention studies to identify approaches to improve access to medicines in the region.
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CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Falsified and substandard drugs are a global health problem, particularly in low- and middle-income countries (LMIC) that have weak pharmacovigilance and drug regulatory systems. Poor quality ...medicines have important health consequences, including the potential for treatment failure, development of antimicrobial resistance, and serious adverse drug reactions, increasing healthcare costs and undermining the public's confidence in healthcare systems. This article presents a review of the methods employed for the analysis of pharmaceutical formulations. Technologies for detecting substandard and falsified drugs were identified primarily through literature reviews. Key-informant interviews with experts augmented our methods when warranted. In order to aid comparisons, technologies were assigned a suitability score for use in LMIC ranging from 0-8. Scores measured the need for electricity, need for sample preparation, need for reagents, portability, level of training required, and speed of analysis. Technologies with higher scores were deemed the most feasible in LMICs. We categorized technologies that cost $10,000 USD or less as low cost, $10,000-100,000 USD as medium cost and those greater than $100,000 USD as high cost technologies (all prices are 2013 USD). This search strategy yielded information on 42 unique technologies. Five technologies were deemed both low cost and had feasibility scores between 6-8, and an additional four technologies had medium cost and high feasibility. Twelve technologies were deemed portable and therefore could be used in the field. Many technologies can aid in the detection of substandard and falsified drugs that vary from the simplest of checklists for packaging to the most complex mass spectrometry analyses. Although there is no single technology that can serve all the requirements of detecting falsified and substandard drugs, there is an opportunity to bifurcate the technologies into specific niches to address specific sections within the workflow process of detecting products.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Pregnant persons with COVID-19 may present with severe illness and adverse pregnancy or birth outcomes.•Data about the safety of vaccination against COVID-19 for pregnant persons is ...limited.•COVID-19 vaccines selected by COVAX showed no evidence of pregnancy-associated safety concerns.•Pregnant persons may consider receiving these vaccines.•Benefits could be higher for pregnant persons at high risk of exposure or with comorbidities.
Rapid assessment of COVID-19 vaccine safety during pregnancy is urgently needed.
We conducted a rapid systematic review, to evaluate the safety of COVID-19 vaccines selected by the COVID-19 Vaccines Global Access-Maternal Immunization Working Group in August 2020, including their components and their technological platforms used in other vaccines for pregnant persons. We searched literature databases, COVID-19 vaccine pregnancy registries, and explored reference lists from the inception date to February 2021 without language restriction. Pairs of reviewers independently selected studies through COVIDENCE, and performed the data extraction and the risk of bias assessment. Discrepancies were resolved by consensus. Registered on PROSPERO (CRD42021234185).
We retrieved 6757 records and 12 COVID-19 pregnancy registries from the search strategy; 38 clinical and non-clinical studies (involving 2,398,855 pregnant persons and 56 pregnant animals) were included. Most studies (89%) were conducted in high-income countries and were cohort studies (57%). Most studies (76%) compared vaccine exposures with no exposure during the three trimesters of pregnancy. The most frequent exposure was to AS03 adjuvant, in the context of A/H1N1 pandemic influenza vaccines, (n = 24) and aluminum-based adjuvants (n = 11). Only one study reported exposure to messenger RNA in lipid nanoparticles COVID-19 vaccines. Except for one preliminary report about A/H1N1 influenza vaccination (adjuvant AS03), corrected by the authors in a more thorough analysis, all studies concluded that there were no safety concerns.
This rapid review found no evidence of pregnancy-associated safety concerns of COVID-19 vaccines or of their components or platforms when used in other vaccines. However, the need for further data on several vaccine platforms and components is warranted, given their novelty. Our findings support current WHO guidelines recommending that pregnant persons may consider receiving COVID-19 vaccines, particularly if they are at high risk of exposure or have comorbidities that enhance the risk of severe disease.
•COVID-19 during pregnancy imposes a risk of severe disease and adverse birth outcomes.•Data about the safety of vaccination against COVID-19 for pregnant women is limited.•COVID-19 vaccination ...coverage among pregnant persons is suboptimal.•We found no safety concerns for COVID-19 vaccination during pregnancy.•Our findings support authorized or approved COVID-19 vaccines for pregnant persons.
Assessment of COVID-19 vaccines safety during pregnancy is urgently needed.
We conducted a systematic review and meta-analysis to evaluate the safety of COVID-19 vaccines, including their components and technological platforms used in other vaccines during pregnancy and animal studies to complement direct evidence. We searched literature databases from its inception to September 2021 without language restriction, COVID-19 vaccine websites, and reference lists of other systematic reviews and the included studies. Pairs of reviewers independently selected, data extracted, and assessed the risk of bias of the studies. Discrepancies were resolved by consensus. (PROSPERO CRD42021234185).
We retrieved 8,837 records from the literature search; 71 studies were included, involving 17,719,495 pregnant persons and 389 pregnant animals. Most studies (94%) were conducted in high-income countries, were cohort studies (51%), and 15% were classified as high risk of bias. We identified nine COVID-19 vaccine studies, seven involving 309,164 pregnant persons, mostly exposed to mRNA vaccines. Among non-COVID-19 vaccines, the most frequent exposures were AS03 and aluminum-based adjuvants.
A meta-analysis of studies that adjusted for potential confounders showed no association with adverse outcomes, regardless of the vaccine or the trimester of vaccination.
Neither the reported rates of adverse pregnancy outcomes nor reactogenicity exceeded expected background rates, which was the case for ASO3- or aluminum-adjuvanted non-COVID-19 vaccines in the proportion meta-analyses of uncontrolled studies/arms. The only exception was postpartum hemorrhage after COVID-19 vaccination (10.40%; 95% CI: 6.49–15.10%), reported by two studies; however, the comparison with non-exposed pregnant persons, available for one study, found non-statistically significant differences (adjusted OR 1.09; 95% CI 0.56–2.12). Animal studies showed consistent results with studies in pregnant persons.
We found no safety concerns for currently administered COVID-19 vaccines during pregnancy. Additional experimental and real-world evidence could enhance vaccination coverage. Robust safety data for non-mRNA-based COVID-19 vaccines are still needed.
As pre-exposure prophylaxis (PrEP) becomes more widely used in heterosexual populations, an important consideration is its safety in infants who are breastfed by women taking PrEP. We investigated ...whether tenofovir and emtricitabine are excreted into breast milk and then absorbed by the breastfeeding infant in clinically significant concentrations when used as PrEP by lactating women.
We conducted a prospective short-term, open-label study of daily oral emtricitabine-tenofovir disoproxil fumarate PrEP among 50 HIV-uninfected breastfeeding African mother-infant pairs between 1-24 wk postpartum (ClinicalTrials.gov Identifier: NCT02776748). The primary goal was to quantify the steady-state concentrations of tenofovir and emtricitabine in infant plasma ingested via breastfeeding. PrEP was administered to women through daily directly observed therapy (DOT) for ten consecutive days and then discontinued thereafter. Non-fasting peak and trough samples of maternal plasma and breast milk were obtained at drug concentration steady states on days 7 and 10, and a single infant plasma sample was obtained on day 7. Peak blood and breast milk samples were obtained 1-2 h after the maternal DOT PrEP dose, while maternal trough samples were obtained at the end of the PrEP dosing interval (i.e., 23 to 24 h) after maternal DOT PrEP dose. Tenofovir and emtricitabine concentrations were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays. Of the 50 mother-infant pairs enrolled, 48% were ≤12 wk and 52% were 13-24 wk postpartum, and median maternal age was 25 y (interquartile range IQR 22-28). During study follow-up, the median (IQR) daily reported frequency of infant breastfeeding was 15 times (12 to 18) overall, 16 (14 to 19) for the ≤12 weeks, and 14 (12 to 17) for the 13-24 wk infant age groups. Overall, median (IQR) time-averaged peak concentrations in breast milk were 3.2 ng/mL (2.3 to 4.7) for tenofovir and 212.5 ng/mL (140.0 to 405.0) for emtricitabine. Similarly, median (IQR) time-averaged trough concentrations in breast milk were 3.3 ng/mL (2.3 to 4.4) for tenofovir and 183.0 ng/mL (113.0 to 250.0) for emtricitabine, reflecting trough-to-peak breast milk concentration ratios of 1.0 for tenofovir and 0.8 for emtricitabine, respectively. In infant plasma, tenofovir was unquantifiable in 46/49 samples (94%), but emtricitabine was detectable in 47/49 (96%) (median IQR concentration: 13.2 ng/mL 9.3 to 16.7). The estimated equivalent doses an infant would ingest daily from breastfeeding were 0.47 μg/kg (IQR 0.35 to 0.71) for tenofovir and 31.9 μg/kg (IQR 21.0 to 60.8) for emtricitabine, translating into a <0.01% and 0.5% relative dose when compared to the 6 mg/kg dose that is proposed for therapeutic treatment of infant HIV infection and for prevention of infant postnatal HIV infection; a dose that has not shown safety concerns. No serious adverse effects were recorded during study follow-up. The key study limitation was that only a single infant sample was collected to minimize venipunctures for the children. However, maternal daily DOT and specimen collection at drug concentration steady state provided an adequate approach to address the key research question. Importantly, there was minimal variation in breast milk concentrations of tenofovir and emtricitabine (respective median trough-to-peak concentration ratio ~1), demonstrating that infants were exposed to consistent drug dosing via breast milk.
In this short-term study of daily directly observed oral PrEP in HIV-uninfected breastfeeding women, the estimated infant doses from breast milk and resultant infant plasma concentrations for tenofovir and emtricitabine were 12,500 and >200-fold lower than the respective proposed infant therapeutic doses, and tenofovir was not detected in 94% of infant plasma samples. These data suggest that PrEP can be safely used during breastfeeding with minimal infant drug exposure.
ClinicalTrials.gov, Identifier: NCT02776748.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Prescription of tenofovir disoproxil fumarate (TDF) for patients with baseline creatinine clearances (CrCl) <60 mL/min is said to increase risk of further decline in CrCl. Study objectives were to ...assess incidence of improvement and predictors thereof; to assess incidence of decline and transition to lower stages of CrCl; and comparison of declines between patients with a baseline CrCl < 60mL/min (group‐I) and ≥ 60 mL/min (group‐II). The study was retrospective, included patients 16 yrs or older who received TDF‐containing ART. Improvement and decline were defined as ≥ 25% increase or decrease in CrCl, respectively. Binary logistic regression was performed to identify predictors of improvement. Groups I and II had 2862 and 7526 patients, respectively. In group‐I, improvement in CrCl was observed in 40.1% (n = 1146), and was associated with stage IV of CrCl (adjusted Odds Ratio aOR=13.4 95% CI: 6.7 ‐ 26.9, P < .001); male gender (aHR = 1.8 95% CI: 1.5 ‐ 2.2, P < .001); and a poor HIV‐status (aHR = 1.2 95% CI: 1.0 ‐ 1.4, P = .033). In group‐I and group‐II, respectively, decline occurred in 2.3% and 13.0%, (P < .001); transition to lower stages occurred in 1.0% and 25.2% (P < .001); and migration to stage IV CrCl occurred in 1.0% and 0.5% (P < .001). Improvement was more likely than decline in group‐I patients. Although, group‐I patients were more likely to experience new onset severe reduced CrCl than group‐II patients, the proportions were extremely low. TDF should not be withheld from HIV‐positive patients with a baseline CrCl < 60 mL/min.
Panel A shows median CrCl values for patients in the four stages of CrCl at baseline. Panel B shows the follow‐up median CrCl for the same baseline stages. A drop is observed for stages 1 and 2, while increases are observed for stages 3 and 4.
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