A Phase 3, Randomised, Controlled, Non-Inferiority Study in the Dominican Republic

[Posted 4/Mar/2024]

AUDIENCE: Infectious Disease, Pediatric

KEY FINDINGS: Two nOPV2 doses administered 1 week or 2 weeks apart from age 6 weeks to 8 weeks were safe and immunogenic. Immune responses after a 2-week interval were non-inferior to those after the standard 4-week interval, but marked responses after a 1-week interval suggest that schedules with an over 1-week interval can be used to provide flexibility to campaigns to improve coverage and hasten protection during circulating vaccine-derived poliovirus type 2 outbreaks.

BACKGROUND: The novel oral poliovirus vaccine type 2 (nOPV2) is now authorised by a WHO emergency use listing and widely distributed to interrupt outbreaks of circulating vaccine-derived poliovirus type 2. As protection of vulnerable populations, particularly young infants, could be facilitated by shorter intervals between the two recommended doses, we aimed to assess safety and non-inferiority of immunogenicity of nOPV2 in 1-week, 2-week, and 4-week schedules.

DETAILS: In this phase 3, open-label, randomised trial, healthy, full-term, infants aged 6-8 weeks from a hospital or a clinic in the Dominican Republic were randomly allocated (1:1:1 ratio) using a pre-prepared, computer-generated randomisation schedule to three groups to receive two doses of nOPV2 immunisations with a 1-week interval (group A), 2-week interval (group B), or 4-week interval (group C). The nOPV2 vaccine was given at a 0.1 mL dose and contained at least 105 50% cell culture infective dose. Neutralising antibodies against poliovirus types 1, 2, and 3 were measured before each immunisation and 4 weeks after the second dose. The primary outcome was the type 2 seroconversion rate 28 days after the second dose, and the non-inferiority margin was defined as a lower bound 95% CI of greater than -10%. Safety and reactogenicity were assessed through diary cards completed by the parent or guardian. Authors enrolled 905 infants between Dec 16, 2021, and March 28, 2022. 872 infants were included in the per-protocol analyses: 289 in group A, 293 in group B, and 290 in group C. Type 2 seroconversion rates were 87.5% (95% CI 83.2 to 91.1) in group A (253 of 289 participants), 91.8% (88.1 to 94.7) in group B (269 of 293 participants), and 95.5% (92.5 to 97.6) in group C (277 of 290 participants). Non-inferiority was shown for group B compared with group C (difference in rates -3.7; 95% CI -7.9 to 0.3), but not for group A compared with group C (-8.0; -12.7 to -3.6). 4 weeks after the second nOPV2 dose, type 2 neutralising antibodies increased in all three groups such that over 95% of each group was seroprotected against polio type 2, although final geometric mean titres tended to be highest with longer intervals between doses. Immunisation with nOPV2 was well tolerated with no causal association to vaccination of any severe or serious adverse event; one death from septic shock during the study was unrelated to the vaccine.

Copyright © Elsevier Ltd. All rights reserved.

Source: Mejia, L. R., Mendez, L. P., Bandyopadhyay, A. S., et al. (2024). Safety and Immunogenicity of Shorter Interval Schedules of the Novel Oral Poliovirus Vaccine Type 2 in Infants: A Phase 3, Randomised, Controlled, Non-Inferiority Study in the Dominican Republic. The Lancet. 2024; 24(3): 275-284. Published: March, 2024. DOI: 10.1016/S1473-3099(23)00519-4.

A Retrospective Cohort Study

[Posted 6/Jul/2024]

AUDIENCE: Ob/Gyn, Infectious Disease

KEY FINDINGS: Among predominantly asymptomatic STIs, M. genitalium detected at baseline visit was significantly associated with low birth weight, while T. vaginalis detected at the repeat visit in later pregnancy was significantly associated with preterm birth. Further research is warranted to study the impact of etiological testing of STIs at more than one antenatal visit and empirical treatment on pregnancy outcomes.

BACKGROUND: There is a high prevalence and incidence rate of asymptomatic sexually transmitted infections (STIs) during pregnancy in adolescent girls and young women in Africa. The association between STIs and pregnancy outcomes in a hyperepidemic HIV setting has not been well described.

DETAILS: Pregnant women, HIV-1 negative and <28 weeks' gestation at three primary health clinics in KwaZulu-Natal, South Africa were enrolled from February 2017 to March 2018. Vaginal swabs collected at the first and later antenatal visits were stored and retrospectively tested for HSV-2, Trichomonas vaginalis, Chlamydia trachomatis and Neisseria gonorrhoeae at the end of the study. The association between STIs detected at first and later antenatal visits and pregnancy outcome was assessed using multivariable logistic regression models adjusted for maternal age and treatment received for symptomatic STIs. Testing positive Mycoplasma genitalium at the first antenatal visit was significantly associated with low birth weight (odds ratio [OR] 5.22; 95% confidence interval [CI]: 1.10-15.98). Testing positive for T. vaginalis at the repeat visit was significantly associated with preterm births (OR 2.37; 95% CI: 1.11-5.03), low birth weight (OR 2.56; 1.16-5.63) and a composite adverse pregnancy outcome (OR 2.11; 95% CI: 1.09-4.08). Testing positive for HSV-2 at the repeat visit was also likely associated with experiencing a preterm birth or any adverse pregnancy outcome (OR 3.39; 95% CI: 0.86-13.3) (P = 0.096).

Copyright © John Wiley & Sons, Inc. All rights reserved

Source: Govender, V., Moodley, D., Naidoo, M., et al. (2024). Sexually Transmitted Infections in Pregnancy and Adverse Pregnancy Outcomes: A Retrospective Cohort Study. International Journal of Gynecology and Obstetrics. 2024; Published: July, 2024. DOI: 10.1002/ijgo.15529.

An Individual Participant Data Meta-Analysis

[Posted 26/Jun/2024]

AUDIENCE: Infectious Disease, Family Medicine

KEY FINDINGS: The majority of people in the community who have pulmonary tuberculosis do not report cough, a quarter report no tuberculosis-suggestive symptoms at all, and a quarter of those not reporting any cough have positive sputum smears, suggesting infectiousness. In high-incidence settings, subclinical tuberculosis could contribute considerably to the tuberculosis burden and to Mycobacterium tuberculosis transmission.

BACKGROUND: Subclinical pulmonary tuberculosis, which presents without recognisable symptoms, is frequently detected in community screening. However, the disease category is poorly clinically defined. We explored the prevalence of subclinical pulmonary tuberculosis according to different case definitions.

DETAILS: Authors did a one-stage individual participant data meta-analysis of nationally representative surveys that were conducted in countries with high incidence of tuberculosis between 2007 and 2020, that reported the prevalence of pulmonary tuberculosis based on chest x-ray and symptom screening in participants aged 15 years and older. Screening and diagnostic criteria were standardised across the surveys, and tuberculosis was defined by positive Mycobacterium tuberculosis sputum culture. We estimated proportions of subclinical tuberculosis for three case definitions: no persistent cough (ie, duration >=2 weeks), no cough at all, and no symptoms (ie, absence of cough, fever, chest pain, night sweats, and weight loss), both unadjusted and adjusted for false-negative chest x-rays and uninterpretable culture results. Authors identified 34 surveys, of which 31 were eligible. Individual participant data were obtained and included for 12 surveys (620 682 participants) across eight countries in Africa and four in Asia. Data on 602 863 participants were analysed, of whom 1944 had tuberculosis. The unadjusted proportion of subclinical tuberculosis was 59.1% (n=1149/1944; 95% CI 55.8-62.3) for no persistent cough and 39.8% (773/1944; 36.6-43.0) for no cough of any duration. The adjusted proportions were 82.8% (95% CI 78.6-86.6) for no persistent cough and 62.5% (56.6-68.7) for no cough at all. In a subset of four surveys, the proportion of participants with tuberculosis but without any symptoms was 20.3% (n=111/547; 95% CI 15.5-25.1) before adjustment and 27.7% (95% CI 21.0-36.4) after adjustment. Tuberculosis without cough, irrespective of its duration, was more frequent among women (no persistent cough: adjusted odds ratio 0.79, 95% CI 0.63-0.97; no cough: adjusted odds ratio 0.76, 95% CI 0.62-0.93). Among participants with tuberculosis, 29.1% (95% CI 25.2-33.3) of those without persistent cough and 23.1% (18.8-27.4) of those without any cough had positive smear examinations.

Copyright © Elsevier Ltd. All rights reserved.

Source: Stuck, L., Klinkenberg, E., Ali, N. A., et al. (2024). Prevalence of Subclinical Pulmonary Tuberculosis in Adults in Community Settings: An Individual Participant Data Meta-Analysis. The Lancet. 2024; Published: June, 2024. DOI: 10.1016/S1473-3099(24)00011-2.

[Posted 6/May/2024]

AUDIENCE: Infectious Disease, Family Medicine

KEY FINDINGS: The associations among persistent viral RNA, immunometabolism, and patient-reported outcomes provide mechanistic insights for addressing the challenges posed by long COVID.

BACKGROUND: With an estimated 65 million individuals affected by post-COVID-19 condition (also known as long COVID), non-invasive biomarkers are direly needed to guide clinical management. To address this pressing need, authors used blood transcriptomics in a general practice-based case-control study.

DETAILS: Individuals with long COVID were diagnosed according to WHO criteria, and validated clinical scales were used to quantify patient-reported outcomes. Whole blood samples were collected from 48 individuals with long COVID and 12 control individuals matched for age, sex, time since acute COVID-19, severity, vaccination status, and comorbidities. Digital transcriptomic analysis was performed using the nCounter (Nanostring Technologies, Seattle, WA, USA) platform, as described for critical COVID-19. Consequently, 212 genes were identified to be differentially expressed between individuals with long COVID and controls, of which 70 remained significant after adjustment for false discovery rate correction. Several viral RNAs were upregulated: nucleocapsid, ORF7a, ORF3a, M^pro (a nirmatrelvir plus ritonavir [Paxlovid] target), and antisense ORF1ab RNA. Specifically, the upregulation of antisense ORF1ab RNA suggests ongoing viral replication. SARS-CoV-2-related host RNAs (ACE2/TMPRSS2 receptors, DPP4/FURIN proteases) and RNAs prototypical for memory B-cells and platelets were also upregulated. Multivariable logistic regression identified antisense SARS-CoV-2 and FYN RNA concentrations as independent predictors of long COVID (corrected for age and sex). Receiver operating characteristic curve analysis showed significant discrimination (area under curve [AUC] 0.94, 95% CI 0.86-1.00) between individuals with long COVID (n=48) and controls (n=12), with 93.8% sensitivity and 91.7% specificity. Single biomarkers antisense SARS-CoV-2 (AUC 0.78, 0.65-0.90) and FYN RNA (AUC 0.89, 0.79-0.99) were significant predictors with lower sensitivity (52.1% and 72.9%, respectively) but similar specificity (91.7% and 100%, respectively). Upon summarising transcriptomic results into biological pathways, authors found significantly decreased immunometabolism in individuals with long COVID, which was negatively correlated with the blood viral load. A qualitative analysis of individual SARS-CoV-2 transcript positivity revealed significant differences between individuals with long COVID and controls for antisense (65% vs 25%), ORF7a (60% vs 25%), and nucleocapsid (50% vs 8%) RNAs. Similarly, the SARS-CoV-2 transcript positivity with respect to the total blood viral load was also significantly different (60% vs 8%). By use of multivariable logistic regression, authors found that age and sex were not associated with the distinction between a low and high viral RNA load status. Conversely, the number of comorbidities (odds ratio [OR] 1.61, 95% CI 1.14-2.49) and COVID vaccine doses (OR 0.36, 0.14-0.79) emerged as independent predictors of distinguishing between low and high viral RNA load status. Authors found that viral and immune parameters, such as the antisense Orf1ab RNA concentrations and immunometabolism score, were also linked to the patient-reported anxiety or depression score. Individuals classified as having severe anxiety or depression (with a score of 4 and 5) displayed significantly higher antisense RNA concentrations and lower immunometabolism scores (p<0.05) than those categorised as mild (with scores of 1-3).

Copyright © Elsevier Ltd. All rights reserved.

Source: Menezes, S. M., Jamoulle, M., Carletto, M. P., et al. (2024). Blood Transcriptomic Analyses Reveal Persistent SARS-CoV-2 RNA and Candidate Biomarkers In Post-COVID-19 Condition. The Lancet. Published: April 24, 2024. DOI: 10.1016/S2666-5247(24)00055-7.

A Prospective, Open-Label, Non-Inferiority, Randomised Controlled Trial

[Posted 8/Apr/2024]

AUDIENCE: Infectious Disease, Family Medicine

KEY FINDINGS: The efficacy of linezolid at a daily dose of 600 mg for 5 days did not meet the non-inferiority criteria compared with BPG and, as a result, this treatment regimen should not be used to treat patients with early syphilis.

BACKGROUND: Management of syphilis, a sexually transmitted infection (STI) with increasing incidence, is challenged by drug shortages, scarcity of randomised trial data, an absence of non-penicillin alternatives for pregnant women with penicillin allergy (other than desensitisation), extended parenteral administration for neurosyphilis and congenital syphilis, and macrolide resistance. Linezolid was shown to be active against Treponema pallidum, the causative agent of syphilis, in vitro and in the rabbit model. We aimed to assess the efficacy of linezolid for treating early syphilis in adults compared with the standard of care benzathine penicillin G (BPG).

DETAILS: Authors did a multicentre, open-label, non-inferiority, randomised controlled trial to assess the efficacy of linezolid for treating early syphilis compared with BPG. Authors recruited participants with serological or molecular confirmation of syphilis (either primary, secondary, or early latent) at one STI unit in a public hospital and two STI community clinics in Catalonia (Spain). Participants were randomly allocated in a 1:1 ratio using a computer-generated block randomisation list with six participants per block, to receive either oral linezolid (600 mg once per day for 5 days) or intramuscular BPG (single dose of 2.4 million international units) and were assessed for signs and symptoms (once per week until week 6 and at week 12, week 24, and week 48) and reagin titres of non-treponemal antibodies (week 12, week 24, and week 48). The primary endpoint was treatment response, assessed using a composite endpoint that included clinical response, serological response, and absence of relapse. Clinical response was assessed at 2 weeks for primary syphilis and at 6 weeks for secondary syphilis following treatment initiation. Serological cure was defined as a four-fold decline in rapid plasma reagin titre or seroreversion at any of the 12-week, 24-week, or 48-week timepoints. The absence of relapse was defined as the presence of different molecular sequence types of T pallidum in recurrent syphilis. Non-inferiority was shown if the lower limit of the two-sided 95% CI for the difference in rates of treatment response was higher than -10%. The primary analysis was done in the per-protocol population. The trial is registered at ClinicalTrials.gov (NCT05069974) and was stopped for futility after interim analysis. Between Oct 20, 2021, and Sept 15, 2022, 62 patients were assessed for eligibility, and 59 were randomly assigned to linezolid (n=29) or BPG (n=30). In the per-protocol population, after 48 weeks' follow-up, 19 (70%) of 27 participants (95% CI 49.8 to 86.2) in the linezolid group had responded to treatment and 28 (100%) of 28 participants (87.7 to 100.0) in the BPG group (treatment difference -29.6, 95% CI -50.5 to -8.8), which did not meet the non-inferiority criterion. The number of drug-related adverse events (all mild or moderate) was similar in both treatment groups (five [17%] of 29, 95% CI 5.8 to 35.8 in the linezolid group vs five [17%] of 30, 5.6 to 34.7, in the BPG group). No serious adverse events were reported during follow-up.

Copyright © Elsevier Ltd. All rights reserved.

Source: Ubals, M., Nadal-Baron, P., Arando, M., et al. (2024). Oral Linezolid Compared With Benzathine Penicillin G for Treatment of Early Syphilis in Adults (Trep-AB Study) in Spain: A Prospective, Open-Label, Non-Inferiority, Randomised Controlled Trial. The Lancet. 2024; 24(4): 404-416. Published: April, 2024. DOI: 10.1016/S1473-3099(23)00683-7.

[Posted 12/Mar/2024]

AUDIENCE: Nursing

KEY FINDINGS: Making Time for Exercise Self-efficacy was more significant than Resisting Relapse for both physical function and functional exercise capacity. Interventions to promote achievement of physical activity need to use multiple measurement strategies.

BACKGROUND: Objective of this study is to determine if there were differences between the subjective and objective assessments of physical activity while controlling for sociodemographic, anthropometric, and clinical characteristics. A total of 810 participants across eight sites located in three countries. Both univariate and multivariant analyses were used.

DETAILS: Subjective instruments were the two subscales of Self-efficacy for Exercise Behaviors Scale: Making Time for Exercise and Resisting Relapse and Patient-Reported Outcomes Measurement Information System, which measured physical function. The objective measure of functional exercise capacity was the 6-minute Walk. Physical function was significantly associated with Making Time for Exercise (β = 1.76, p = .039) but not with Resisting Relapse (β = 1.16, p = .168). Age (β = -1.88, p = .001), being employed (β = 16.19, p < .001) and race (βs = 13.84–31.98, p < .001), hip–waist ratio (β = -2.18, p < .001), and comorbidities (β = 7.31, p < .001) were significant predictors of physical functioning. The model predicting physical function accounted for a large amount of variance (adjusted R2 = .938). The patterns of results predicting functional exercise capacity were similar. Making Time for Exercise self-efficacy scores significantly predicted functional exercise capacity (β = 0.14, p = .029), and Resisting Relapse scores again did not (β = -0.10, p = .120). Among the covariates, age (β = -0.16, p < .001), gender (β = -0.43, p < .001), education (β = 0.08, p = .026), and hip–waist ratio (β = 0.09, p = .034) were significant. This model did not account for much of the overall variance in the data (adjusted R2 = .081). We found a modest significant relationship between physical function and functional exercise capacity (r = 0.27).

Copyright © SAGE Publications. All rights reserved.

Source: Nokes, K. M., Sokhela, D. G., Orton, P, M., et al. (2024). Exploring the Interrelationships Between Physical Function, Functional Exercise Capacity, and Exercise Self-Efficacy in Persons Living with HIV. XXXXXXXX. 2024; 33(2-3): 165-175. Published: March, 2024. DOI: 10.1177/10547738241231626.