Contemporary first-line antiretrovirals have considerably reduced liability for clinically significant drug-drug interactions (DDI). This systematic review evaluates the prevalence of DDI among ...people receiving antiretrovirals across 3 decades.
We searched 3 databases for studies reporting the prevalence of clinically significant DDIs in patients receiving antiretrovirals published between January 1987 and July 2022. Clinically significant DDIs were graded by severity. All data extractions were undertaken by 2 independent reviewers, adjudicated by a third.
Of 21,665 records returned, 13,474 were duplicates. After screening the remaining 13,596 abstracts against inclusion criteria, 122 articles were included for full-text analysis, from which a final list of 34 articles were included for data synthesis. The proportion of patients experiencing a clinically significant DDI did not change over time (P = 0.072). The most frequently reported classes of antiretrovirals involved in DDIs were protease inhibitors and non-nucleoside reverse transcriptase inhibitors; of note, integrase use in the most recent studies was highly variable and ranged between 0% and 89%.
The absolute risk of DDIs has not decreased over the period covered. This is likely related to continued use of older regimens and an ageing cohort of patients. A greater reduction in DDI prevalence can be anticipated with broader uptake of regimens containing unboosted integrase inhibitors or non-nucleoside reverse transcriptase inhibitors.
Experimental Human Pneumococcal Challenge (EHPC) involves the controlled exposure of adults to a specific antibiotic-sensitive Streptococcus pneumoniae serotype, to induce nasopharyngeal colonisation ...for the purpose of vaccine research. The aims are to review comprehensively the safety profile of EHPC, explore the association between pneumococcal colonisation and frequency of safety review and describe the medical intervention required to undertake such studies.
A single-centre review of all EHPC studies performed 2011-2021. All recorded serious adverse events (SAE) in eligible studies are reported. An unblinded meta-analysis of collated anonymised individual patient data from eligible EHPC studies was undertaken to assess the association between experimental pneumococcal colonisation and the frequency of safety events following inoculation.
In 1416 individuals (median age 21, IQR 20-25), 1663 experimental pneumococcal inoculations were performed. No pneumococcal-related SAE have occurred. 214 safety review events were identified with 182 (12.85%) participants presenting with symptoms potentially in keeping with pneumococcal infection, predominantly in pneumococcal colonised individuals (colonised = 96/658, non-colonised = 86/1005, OR 1.81 (95% CI 1.28-2.56, P = <0.001). The majority were mild (pneumococcal group = 72.7% 120/165 reported symptoms, non-pneumococcal = 86.7% 124/143 reported symptoms). 1.6% (23/1416) required antibiotics for safety.
No SAEs were identified directly relating to pneumococcal inoculation. Safety review for symptoms was infrequent but occurred more in experimentally colonised participants. Most symptoms were mild and resolved with conservative management. A small minority required antibiotics, notably those serotype 3 inoculated.
Outpatient human pneumococcal challenge can be conducted safely with appropriate levels of safety monitoring procedures in place.
IntroductionSince the introduction of pneumococcal conjugate vaccines, pneumococcal disease rates have declined for many vaccine-type serotypes. However, serotype 3 (SPN3) continues to cause ...significant disease and is identified in colonisation epidemiological studies as one of the top circulating serotypes in adults in the UK. Consequently, new vaccines that provide greater protection against SPN3 colonisation/carriage are urgently needed. The Experimental Human Pneumococcal Challenge (EHPC) model is a unique method of determining pneumococcal colonisation rates, understanding acquired immunity, and testing vaccines in a cost-effective manner. To enhance the development of effective pneumococcal vaccines against SPN3, we aim to develop a new relevant and safe SPN3 EHPC model with high attack rates which could be used to test vaccines using small sample size.Methods and analysisThis is a human challenge study to establish a new SPN3 EHPC model, consisting of two parts. In the dose-ranging/safety study, cohorts of 10 healthy participants will be challenged with escalating doses of SPN3. If first challenge does not lead into colonisation, participants will receive a second challenge 2 weeks after. Experimental nasopharyngeal (NP) colonisation will be determined using nasal wash sampling. Using the dose that results in ≥50% of participants being colonised, with a high safety profile, we will complete the cohort with another 33 participants to check for reproducibility of the colonisation rate. The primary outcome of this study is to determine the optimal SPN3 dose and inoculation regime to establish the highest rates of NP colonisation in healthy adults. Secondary outcomes include determining density and duration of experimental SPN3 NP colonisation and characterising mucosal and systemic immune responses to SPN3 challenge.Ethics and disseminationThis study is approved by the NHS Research and Ethics Committee (reference 22/NW/0051). Findings will be published in peer-reviewed journals and reports will be made available to participants.
IntroductionDespite widely available vaccinations, Streptococcus pneumoniae (SPN) remains a major cause of morbidity and mortality worldwide, causing community-acquired pneumonia, meningitis, otitis ...media, sinusitis and bacteraemia. Here, we summarise an ethically approved protocol for a double-blind, randomised controlled trial investigating the effect of the 13-valent pneumococcal conjugate vaccine (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPV23) on pneumococcal nasopharyngeal colonisation acquisition, density and duration using experimental human pneumococcal challenge (EHPC).Methods and analysisHealthy adult participants aged 18–50 years will be randomised to receive PCV13, PPV23 or placebo and then undergo one or two EHPCs involving intranasal administration of SPN at 1-month post-vaccination with serotype 3 (SPN3) and 6 months with serotype 6B (SPN6B). Participants randomised to PCV13 and placebo will also be randomised to one of two clinically relevant SPN3 strains from distinct lineages within clonal complex 180, clades Ia and II, creating five study groups. Following inoculation, participants will be seen on days 2, 7, 14 and 23. During the follow-up period, we will monitor safety, colonisation status, density and duration, immune responses and antigenuria. The primary outcome of the study is comparing the rate of SPN3 acquisition between the vaccinated (PCV13 or PPV23) and unvaccinated (placebo) groups as defined by classical culture. Density and duration of colonisation, comparison of acquisition rates using molecular methods and evaluation of the above measurements for individual SPN3 clades and SPN6B form the secondary objectives. Furthermore, we will explore the immune responses associated with these vaccines, their effect on colonisation and the relationship between colonisation and urinary pneumococcal antigen detection.Ethics and disseminationThe study is approved by the NHS Research and Ethics Committee (Reference: 20/NW/0097) and by the Medicines and Healthcare products Regulatory Agency (Reference: CTA 25753/0001/001–0001). Findings will be published in peer-reviewed journals.Trial registration numberISRCTN15728847, NCT04974294.
Tuberculosis (TB) remains a major challenge in many domains including diagnosis, pathogenesis, prevention, treatment, drug resistance and long-term protection of the public health by vaccination. A ...controlled human infection model (CHIM) could potentially facilitate breakthroughs in each of these domains but has so far been considered impossible owing to technical and safety concerns.
A systematic review of mycobacterial human challenge studies was carried out to evaluate progress to date, best possible ways forward and challenges to be overcome. We searched MEDLINE (1946 to current) and CINAHL (1984 to current) databases; and Google Scholar to search citations in selected manuscripts. The final search was conducted 3
February 2022. Inclusion criteria: adults ≥18 years old; administration of live mycobacteria; and interventional trials or cohort studies with immune and/or microbiological endpoints. Exclusion criteria: animal studies; studies with no primary data; no administration of live mycobacteria; retrospective cohort studies; case-series; and case-reports. Relevant tools (Cochrane Collaboration for RCTs and Newcastle-Ottawa Scale for non-randomised studies) were used to assess risk of bias and present a narrative synthesis of our findings.
The search identified 1,388 titles for review; of these 90 were reviewed for inclusion; and 27 were included. Of these, 15 were randomised controlled trials and 12 were prospective cohort studies. We focussed on administration route, challenge agent and dose administered for data extraction. Overall, BCG studies including fluorescent BCG show the most immediate utility, and genetically modified
is the most tantalising prospect of discovery breakthrough.
The TB-CHIM development group met in 2019 and 2022 to consider the results of the systematic review, to hear presentations from many of the senior authors whose work had been reviewed and to consider best ways forward. This paper reports both the systematic review and the deliberations.
PROSPERO ( CRD42022302785; 21 January 2022).
Background:
Tuberculosis (TB) remains a major challenge in many domains including diagnosis, pathogenesis, prevention, treatment, drug resistance and long-term protection of the public health by ...vaccination. A controlled human infection model (CHIM) could potentially facilitate breakthroughs in each of these domains but has so far been considered impossible owing to technical and safety concerns.
Methods:
A systematic review of mycobacterial human challenge studies was carried out to evaluate progress to date, best possible ways forward and challenges to be overcome. We searched MEDLINE (1946 to current) and CINAHL (1984 to current) databases; and Google Scholar to search citations in selected manuscripts. The final search was conducted 3
rd
February 2022. Inclusion criteria: adults ≥18 years old; administration of live mycobacteria; and interventional trials or cohort studies with immune and/or microbiological endpoints. Exclusion criteria: animal studies; studies with no primary data; no administration of live mycobacteria; retrospective cohort studies; case-series; and case-reports. Relevant tools (Cochrane Collaboration for RCTs and Newcastle-Ottawa Scale for non-randomised studies) were used to assess risk of bias and present a narrative synthesis of our findings.
Results:
The search identified 1,388 titles for review; of these 90 were reviewed for inclusion; and 27 were included. Of these, 15 were randomised controlled trials and 12 were prospective cohort studies. We focussed on administration route, challenge agent and dose administered for data extraction. Overall, BCG studies including fluorescent BCG show the most immediate utility, and genetically modified
Mycobacteria tuberculosis
is the most tantalising prospect of discovery breakthrough.
Conclusions:
The TB-CHIM development group met in 2019 and 2022 to consider the results of the systematic review, to hear presentations from many of the senior authors whose work had been reviewed and to consider best ways forward. This paper reports both the systematic review and the deliberations.
Registration:
PROSPERO (
CRD42022302785
; 21 January 2022).
Anti‐Infective Dosing in Special Populations: Pregnancy Hazenberg, Phoebe; Navaratnam, Kate; Busuulwa, Paula ...
Clinical pharmacology and therapeutics,
April 2021, 2021-Apr, 2021-04-00, Letnik:
109, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Substantial anatomical and physiological changes occur during pregnancy and labor, which impact on drug absorption, distribution, metabolism, and elimination. Reduced maternal concentrations may have ...a clinically important impact on the efficacy of anti‐infectives for mother, fetus, and neonate, with potential dosing implications. However, there is a paucity of pregnancy‐specific data examining this. Existing data on the pharmacokinetics of anti‐infectives in pregnancy are summarized and evaluated, with emphasis on agents that are used in treatment of HIV, tuberculosis, malaria, and common bacterial infections. Limitations and challenges in achieving ideal study designs in pregnant populations are highlighted, and key quality considerations for the generation of the highest quality evidence are outlined. PubMed was searched for each chosen anti‐infective. Pharmacokinetic studies which either compared pharmacokinetics from pregnant women against nonpregnant controls, or which assessed concentrations against a known minimum inhibitory concentration were included. Two independent reviewers extracted data from each study and appraised them using the 24‐point ClinPK Checklist. The main finding was that there is a lack of published data for anti‐infectives in pregnancy, despite their clinical importance. Of the studies identified, only those investigating cobicistat‐boosted antiretroviral regimens firmly concluded that these should not be used in pregnancy. Most studies concluded either that further research was needed, or that there were significant pharmacokinetic differences between pregnant and nonpregnant participants which had uncertain clinical significance. Challenges in applying existing quality grading systems to these studies were noted, suggesting a development of a refined system for appraisal of pharmacokinetic studies in "special populations" may be warranted.
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