Estimates Of Efficacy Research Articles

Improving precision of vaccine efficacy evaluation using immune correlate data in time-to-event models.

Understanding potential differences in vaccine-induced protection between demographic subgroups is key for vaccine development. Vaccine efficacy evaluation across these subgroups in phase 2b or 3 clinical trials presents challenges due to lack of precision: such trials are typically designed to demonstrate overall efficacy rather than to differentiate its value between subgroups. This study proposes a method for estimating vaccine efficacy using immunogenicity (instead of vaccination status) as a predictor in time-to-event models. The method is applied to two datasets from immunogenicity sub-studies of vaccine phase 3 clinical trials for zoster and dengue vaccines. Results show that using immunogenicity-based estimation of efficacy in subgroups using time-to-event models is more precise than the standard estimation. Incorporating immune correlate data in time-to-event models improves precision in estimating efficacy (i.e., yields narrower confidence intervals), which can assist vaccine developers and public health authorities in making informed decisions.

The long-term clinical efficacy and safety of lenvatinib plus pembrolizumab in endometrial cancer: data from routine clinical practice in Russia

Background. Endometrial cancer (EC) treatment outcomes need to be improved. Immunotargeted therapy lead to long-term and delayed effects compared to chemotherapy. Estimation of long-term efficacy and quality of life are crucial when we are talking about efficacy in whole.Aim. To evaluate the long-term clinical efficacy of lenvatinib plus pembrolizumab therapy in patients with EC.Materials and methods. The study included 43 patients with stages I-IV EC with mismatch repair-proficient tumors and treatment duration of more than 9 months. We evaluated median progression-free survival, objective response, duration of treatment depending on the line of therapy, prevalence and type of adverse events, and correction regimens. Results. Lenvatinib plus pembrolizumab treatment was safe and efficacious in recurrent EC. Median of progression-free survival (patients with response or stabilization more than 9 months) is 10.2 months (95 % confidence interval 9.1-13.0), median of follow up is 9.7 (1.4-33.8) months. There were no complete responses, partial response was in 12 (28 %) patients, disease stabilization was in 31 (72 %) patients. Regarding safety, the overall rate of any-grade adverse events was 56.3 %. The most common treatment-related adverse events were fatigue (32.6 %), hypertension (23.3 %), and hypothyroidism (18.6 %). Dose reduction was performed in 22 (51.2 %) patients.Conclusion. The combination of lenvatinib plus pembrolizumab has long-term efficacy and manageable profile of safety. The presence of a significant pool of patients with durable response allows improving the survival rate of such patients in Russia.

A meta-analytical approach for estimating methane suppression from dietary additives in ruminants

IntroductionMethane production inhibitors included in feed additives are increasingly used to suppress methane production in the rumen. Most products interact with the rumen microbiome and/or component biochemical pathways that scavenge free hydrogen ions (H+) to make methane (CH4 ). The capacity of these agents to inhibit rumen methane production is determined by the ability of the chemical to block methane production pathways, the amount of agent delivered to the rumen (i.e. the dose) and the absorption, distribution, metabolism and excretion (i.e. the pharmacokinetic) characteristics of the chemical that contribute to removal from the site of action (the rumen). The intrinsic inhibitory capacity of an agent determines the maximum rate of methane suppression. This maximal rate may reduce according to pharmacokinetic effects arising from dose rate and frequency. Most studies of additive methane reduction efficacy use total mixed ration (TMR; with the additive included into the ration) feeding systems and estimate methane reduction (absolute or relative) across a 24-hour period. Few studies report critical pharmacokinetic parameters, making it difficult to extrapolate findings into non-TMR systems (such as grazing) where differing doses and dose frequencies apply.MethodsWe consider the likely behaviour of a rumen-acting oral additive to reduce methane production applying basic pharmacokinetic principles to propose an analytical approach to data from multiple field studies employing different dose rates and dose frequencies to estimate methane suppression responses. This is based upon a logistic transformation of relative efficacy (percentage reduction in methane comparing treatment with control groups) as the dependent variable and includes total dose, dose frequency, quadratic and interaction terms between total dose and dose frequency as independent variables that potentially capture any pharmacokinetic effects on performance. The model was tested using simulation and verified against real data (cattle 3-nitrooxypropanol (3-NOP) methane-reduction studies).ResultsGood fit between predicted and observed methane suppression was obtained.DiscussionWe propose use of the general form of this logistic model with dose and dose frequency components included that address basic pharmacological impacts on methane suppression as the standard approach to meta-analysis.

Drug Efficacy Estimation for Follow-on Companion Diagnostic Devices Through External Studies.

A therapeutic product is usually not suitable for all patients but for only a subpopulation. The safe and effective use of such a therapeutic product requires the co-approval of a companion diagnostic device which can be used to identify suitable patients. While the first-of-a-kind companion diagnostic device is often developed in conjunction with its intended therapeutic product and simultaneously validated through a randomized clinical trial, there remains room for the innovation of new and improved follow-on companion diagnostic devices designed for the same therapeutic product. However, conducting a new randomized trial or a bridging study for the follow on companion devices may be unethical, expensive or unpractical. Hence, there arises a need for an external study to evaluate the concordance between the FDA-approved comparator companion diagnostic device (CCD) and the subsequent follow-on companion diagnostic devices (FCD), indirectly validating the latter. In this article, we introduce a novel external study design, referred to as the targeted treatment design, as an extension of the existing concordance design. Additionally, we present corresponding statistical analysis methods. Our approach combines the CCD randomized trial data and the FCD external study data, enabling the estimation of drug efficacy within the FCD+ and FCD- subpopulations-the parameters crucial for the validation of the FCD. Theoretical results and simulation studies validate the proposed methods and we further illustrate the proposed methods through an application in a real example of non-small-cell lung cancer.

Effect of cervical traction on cervicogenic headache in patients with cervical radiculopathy: a preliminary randomized controlled trial

BackgroundCervical radiculopathy (CR) is a common condition, often associated with cervicogenic headache (CGH), a secondary headache arising from cervical spine disorders. Mechanical intermittent cervical traction (MICT) is frequently prescribed to treat CR symptoms. The purpose of the study was to make a preliminary estimate of efficacy of adding MICT to conventional rehabilitation on CGH in patients with cervical radiculopathy.MethodsA total of 36 CR patients with CGH were randomly allocated to 3 equally sized groups (A, B and C). The treatment consisted of twelve sessions of conventional rehabilitation (4 weeks) combined with MICT (2 kg for group A, 8 kg for group B and 12 kg for group C). Primary outcomes were CGH intensity (visual analog scale) and frequency (days per week). Secondary outcomes were radicular pain intensity (visual analog scale), cervical range of motion (cervical range of motion instrument), proprioception (cervical range of motion instrument) and muscle strength (MicroFET2 dynamometer), handgrip strength (handheld dynamometer), function (Neck Disability Index), kinesiophobia (Tampa Scale for KInesiophobia), anxiety and depression (Hospital Anxiety and Depresion questionnaire), and quality of life (World Health Organization Quality of Life). Patients were assessed at baseline, one, three and six months after the beginning of treatment. The post hoc Dunn testing was used to determine which traction load had the better effect on CGH symptoms.ResultsAt one, three and six months follow-ups, Group C exhibited the highest improvement in CGH intensity and frequency compared to the other groups (p = 0.021 and p = 0.023; p = 0.012 and p = 0.01; p = 0.005 and p = 0.005). Both groups C and B showed a significant improvement in radicular pain compared to group A at one month follow-up (p = 0.05).The improvement in group C was significantly better in terms of function (p = 0.049) and anxiety (p = 0.011) at three months and quality of life at six months (Psychological p = 0.046 and Environment p = 0.006).ConclusionsThe blend of conventional rehabilitation alongside 12 kg MICT seems to be efficacious in diminishing both the intensity and frequency of CGH in patients with CR. These advantages appear to last for up to six months following the treatment period, potentially leading to decreased CGH severity and occurrence rates, heightened functionality, reduced anxiety levels, and an overall enhancement in quality of life. These findings are preliminary and require confirmation in larger trials.Trial registrationThe study protocol was retrospectively registered at the Pan African Clinical Trial Registry (PACTR202401838955948). Date of registration is 16/01/2024.

Leveraging extensive soil, vegetation, fire, and land treatment data to inform restoration across the sagebrush biome

ContextWidespread ecological degradation has prompted calls for massive global investments in ecological restoration, yet limited resources necessitate efficient application of restoration efforts. In western North America, altered fire regimes are increasing the scale of restoration needed to preserve the sagebrush (Artemisia species) biome but prioritizing and implementing effective restoration is complicated by the vast and heterogeneous sagebrush landscape, which includes gradients in climate, disturbance, and species composition.ObjectivesTo develop spatially explicit and context-dependent estimates of treatment efficacy and sagebrush recovery rates.MethodsWe leveraged a suite of spatio-temporally extensive datasets to evaluate the influence of restoration treatments and environmental conditions on trends in post-disturbance sagebrush cover, with an emphasis on understanding differences between sites recovering naturally and sites receiving restoration treatments. We used estimates from these models to develop spatially explicit projections for sagebrush recovery, conditional on disturbance, restoration practice, and environmental conditions.ResultsWe found seeding Artemisia spp. increased sagebrush cover over time relative to natural recovery, but this relationship depended on spring soil moisture availability and treatment methods. Natural recovery was positively influenced by soil moisture and sagebrush cover and negatively influenced by cumulative burns and annual herbaceous cover, while the influence of perennial herbaceous cover varied with soil moisture.ConclusionsOur results provide biome-wide insights and spatially explicit tools that can inform economic cost-effectiveness analyses, restoration prioritization tools, and other scientific endeavors to ensure managers have the tools and information needed to effectively steward the sagebrush biome in a rapidly changing world.

Best practice guide for patellofemoral pain based on synthesis of a systematic review, the patient voice and expert clinical reasoning

ObjectiveDefine a best practice guide for managing people with patellofemoral pain (PFP).MethodsA mixed-methods convergent segregated synthesis of meta-analysed data with a thematic analysis of semistructured interviews and focus groups. Agreement...

An Assessment of Antidepressant Activity of Etlingera elatior Alone and in Combination with Fluoxetine

Aim: Present study deals to access the antidepressant activity of Etlingera elatior leaves extract in rodent. Background: Etlingera elatior is a species of herbaceous perennial plant in the family Zingiberaceae; native to Indonesia, Thailand, Malaysia and New Guinea. Depression is one of the most common mental disorders affecting humans, pathological basis of which is not fully understood. The current antidepressant drugs have several adverse effects including their effects on cognition. Therefore, natural product are being evaluated for their antidepressant activities. Objective: In this study, Etlingera elatior leaf extracts are being evaluated for antidepressant activity in rodent models. A wide range of synthetic medicines that can be used to treat depression which may exerts various side effects such as dry mouth, gastrointestinal problems, nausea, respiratory problems, cardiac arrhythmias, drowsiness, anxiety etc. Hence, it becomes essential to discover new anti-depressant drug with more potency, efficacy and safety profile than those of marketed synthetic drugs. Methods: Using the forced swimming test, the tail suspension test, mouse 5-HTP-induced head twitches and estimation of brain lipid peroxidation modelsthe antidepressant efficacy of Etlingera elatior ethanolic extract was examined. Imipramine was used as reference standards. result: According to our study, Etlingera elatior significantly (p0.01) reduced immobility in tail suspension, forced swimming, and 5-HTP-induced head twitches in mice with depression that were comparable to imipramine. Results: According to our study, Etlingera elatior significantly (p 0.01) reduced immobility in tail suspension, forced swimming, and 5-HTP-induced head twitches in mice with depression that were comparable to imipramine. Conclusion: Based on the results obtained we can conclude that Etlingera elatior leaves extract possess significant antidepressant activity. The antidepressant effectiveness of Etlingera elatior leaves extract can be confirmed in the future by adding more models, and attempts can also be made to isolate and characterise the phytoconstituents responsible for the pharmacological action.

Prevention of postpartum methamphetamine use with micronized progesterone trial (PROMPT): A pilot randomized controlled trial protocol

While most pregnant individuals with methamphetamine use disorder (MUD) achieve abstinence, the postpartum period remains a vulnerable time for return to methamphetamine use (MU). Promising data from human and animal models, including three randomized controlled trials, suggest that micronized progesterone may prevent postpartum return to cocaine and nicotine use by reducing cravings. The primary objective of this study is to assess feasibility of enrollment and randomization of postpartum individuals with MUD to micronized progesterone to prevent return to MU. The secondary objectives are to evaluate safety, establish a preliminary estimate of efficacy, and characterize the association between allopregnanolone levels and methamphetamine cravings. This is a pilot double-blind placebo randomized controlled trial. We plan to enroll 40 postpartum individuals with MUD over 24-months. Individuals, stratified by opioid use disorder (OUD), are randomized 1:1-400mg oral micronized progesterone daily or placebo and attend weekly study sessions for 12 weeks. Feasibility is measured by achieving 80% of enrollment goal. Safety is evaluated by side effect frequency, mental health status changes, lactation and medical complications. Efficacy is assessed by comparing proportion of participants with return to MU and time to return to MU based on self-report or urine testing between treatment and control groups. Salivary allopregnanolone levels and methamphetamine cravings are compared between the groups. Study results will provide a first critical step towards potential intervention for prevention of return to MU among postpartum individuals. Completion of this trial will set the stage for a large-scale efficacy trial.

IPECAD Modeling Workshop 2023 Cross-Comparison Challenge on Cost-Effectiveness Models in Alzheimer’s Disease

ObjectivesDecision-analytic models assessing the value of emerging Alzheimer’s disease (AD) treatments are challenged by limited evidence on short-term trial outcomes and uncertainty in extrapolating long-term patient-relevant outcomes. To improve understanding and foster transparency and credibility in modeling methods, we cross-compared AD decision models in a hypothetical context of disease-modifying treatment for mild cognitive impairment (MCI) due to AD. MethodsA benchmark scenario (US setting) was used with target population MCI due to AD and a set of synthetically generated hypothetical trial efficacy estimates. Treatment costs were excluded. Model predictions (10-year horizon) were assessed and discussed during a 2-day workshop. ResultsNine modeling groups provided model predictions. Implementation of treatment effectiveness varied across models based on trial efficacy outcome selection (clinical dementia rating – sum of boxes, clinical dementia rating – global, mini-mental state examination, functional activities questionnaire) and analysis method (observed severity transitions, change from baseline, progression hazard ratio, or calibration to these). Predicted mean time in MCI ranged from 2.6 to 5.2 years for control strategy and from 0.1 to 1.0 years for difference between intervention and control strategies. Predicted quality-adjusted life-year gains ranged from 0.0 to 0.6 and incremental costs (excluding treatment costs) from −US$66 897 to US$11 896. ConclusionsTrial data can be implemented in different ways across health-economic models leading to large variation in model predictions. We recommend (1) addressing the choice of outcome measure and treatment effectiveness assumptions in sensitivity analysis, (2) a standardized reporting table for model predictions, and (3) exploring the use of registries for future AD treatments measuring long-term disease progression to reduce uncertainty of extrapolating short-term trial results by health-economic models.

Genotyping methods to distinguish Plasmodium falciparum recrudescence from new infection for the assessment of antimalarial drug efficacy: an observational, single-centre, comparison study

Distinguishing Plasmodium falciparum recrudescence from new infections is crucial for the assessment of antimalarial drug efficacy against Pfalciparum. We aimed to compare the efficacy of different genotyping methods to assess their effect on drug efficacy estimates, particularly in patients from high-transmission settings with polyclonal infections. In this head-to-head comparison study, we compared five different genotyping methods currently used: fast capillary electrophoresis (F-CE) using msp1, msp2, and glurp; high-resolution capillary electrophoresis (H-CE) using msp1, msp2, and glurp; H-CE using microsatellites; targeted amplicon deep sequencing (TADS) using single nucleotide polymorphism (SNP)-rich markers; and high-resolution melting (HRM) analysis using msp1 and msp2. We assessed their sensitivity in detecting minority clones in polyclonal infections, their reproducibility, and the genetic diversity of the markers used. Our study used four well characterised Pfalciparum laboratory strains mixed in varying ratios, and 20paired samples collected from an in-vivo clinical trial. The experiments were performed at the Swiss Tropical and Public Health Institute in Basel, Switzerland between May 5, 2020, and Aug 23,2021. H-CE using msp1 and msp2 and TADS revealed the highest sensitivity in detecting minority clones (up to ratios of 1:100 for H-CE and 50:1:1:1 for TADS in the FCB1:HB3 and 3D7:K1:HB3:FCB1 laboratory strain mixtures, respectively), highest reproducibility (intra-assay: 99% and 91% for H-CE and TADS, respectively; inter-assay: 98% and 92% for H-CE and TADS, respectively), and highest genetic diversity in the used markers (up to 36and32unique genotypes in 20paired samples for H-CE using msp2 and TADS using cpmp, respectively). Microsatellites assessed by H-CE had a lower genetic diversity compared with msp1, msp2, and glurp assessed by H-CE and the SNP-rich markers assessed by TADS, with a maximum of 13unique genotypes, and some genotypes having allelic frequencies larger than 30%.Markers used by TADS gave the most consistent results in distinguishing recrudescence from new infection across all methods (in 18of 20pairs of samples vs 15of 20pairs for H-CE). WHO currently recommends replacing glurp with microsatellites. However, in this study, the replacement of glurp with microsatellites did not change the genotyping outcome, probably due to the lower genetic diversity of microsatellites. More studies with large sample sizes are required to identify the most suitablemicrosatellites that could replace glurp. Our study indicates that TADS should be considered the gold standardfor genotyping to distinguish recrudescence from new infection, and that it should be used to validate other methods. Swiss Tropical and Public Health Institute.

Estimation of efficacy of a home monitoring and communication platform to prevent frailty among older adults in Sweden- a pilot study with a randomized controlled trial design

BackgroundThe aging population of the world is increasing. Aging leads to risks for frailty and other chronic diseases and health systems must focus more on prevention to guarantee healthy aging. The primary objective was to estimate the efficacy of the POSITIVE-(The Maintaining and imPrOving the intrinSIc capaciTy Involving Primary Care and caregiVErs) system in improving frailty during a 6-month follow-up period. MethodA randomized controlled, assessor-blinded pilot study (RCT) with 50 individual < 70 years, pre-frail or frail was recruited from a primary care center in Stockholm Region. All participants received a drug review, nutritional recommendations, and a Vivifrail physical exercise program. In addition, the intervention group received POSITIVE including a tablet, an application, and portable measurement devices. The intervention group was monitored remotely by a primary care nurse at the primary health care centre during a six-month follow-up period. ResultsAt baseline there was a significance between the groups regarding the FTS-5 scale, and significantly more obese participants in the intervention group. The drug reviews showed that three of 43 participants got a review and new diseases were discovered. The test of interactions showed a tendency for significant differences over time between the groups in frailty measured by Fried Frailty Phenotype's and FTS-5 scales. ConclusionFrailty status over time in the intervention group not differed significantly from the controls. Including individuals to the project even through a pandemic showing that the design is possible for future studies to show effects of new ways of preventing frailty at home. Trial RegistrationClinicalTrials.gov. Registration number: NCT04592146. October 19, 2020. https://clinicaltrials.gov/ct2/show/NCT04592146?term=positive&draw=2&rank=7

A Bayesian pharmacokinetics integrated phase I-II design to optimize dose-schedule regimes.

The schedule of administering a drug has profound impact on the toxicity and efficacy profiles of the drug through changing its pharmacokinetics (PK). PK is an innate and indispensable component of the dose-schedule optimization. Motivated by this, we propose a Bayesian PK integrated dose-schedule finding (PKIDS) design to identify the optimal dose-schedule regime by integrating PK, toxicity, and efficacy data. Based on the causal pathway that dose and schedule affect PK, which in turn affects efficacy and toxicity, we jointly model the three endpoints by first specifying a Bayesian hierarchical model for the marginal distribution of the longitudinal dose-concentration process. Conditional on the drug concentration in plasma, we jointly model toxicity and efficacy as a function of the concentration. We quantify the risk-benefit of regimes using utility-continuously updating the estimates of PK, toxicity, and efficacy based on interim data-and make adaptive decisions to assign new patients to appropriate dose-schedule regimes via adaptive randomization. The simulation study shows that the PKIDS design has desirable operating characteristics.

Efficacy and safety of antidepressants for pain in older adults: A systematic review and meta-analysis.

In many countries, pain is the most common indication for use of antidepressants in older adults. We reviewed the evidence from randomized controlled trials on the efficacy and safety of antidepressants, compared to all alternatives for pain in older adults (aged ≥65 years). Trials published from inception to 1 February 2024, were retrieved from 13 databases. Two independent reviewers extracted data on study and participant characteristics, primary efficacy (pain scores, converted to 0-100 scale) and harms. Estimates for efficacy were pooled using a random effects model and reported as difference in means and 95% CI. Quality of included trials was assessed using the Cochrane risk of bias tool. Fifteen studies (n = 1369 participants) met the inclusion criteria. The most frequently studied antidepressants were duloxetine and amitriptyline (6/15 studies each). Pain related to knee osteoarthritis was the most studied (6/15 studies). For knee osteoarthritis, antidepressants did not provide a statistically significant effect for the immediate term (0-2weeks), (-5.6, 95% confidence interval [CI]: -11.5 to 0.3), but duloxetine provided a statistically significant, albeit a very small effect in the intermediate term, (≥6weeks and <12 months), (-9.1, 95% CI: -11.8 to -6.4). Almost half (7/15) of the studies reported increased withdrawal of participants in the antidepressant treatment group vs. the comparator group due to adverse events. For most chronic painful conditions, the benefits and harms of antidepressant medicines are unclear. This evidence is predominantly from trials with sample sizes of <100, have disclosed industry ties and classified as having unclear or high risk of bias.

The impact of trial inclusion criteria on outcomes in DLBCL patients treated with R-CHOP in the first line: a Danish nationwide study

Up to 50% of diffuse large B-cell lymphoma (DLBCL) patients are ineligible for participation in clinical trials. Ineligible patients have inferior outcomes, but less is known about the impact of commonly used organ-function-based inclusion criteria on drug efficacy estimates. Data on DLBCL patients treated with CHOP+/-rituximab were retrieved from the Danish Lymphoma Registry. Trial inclusion criteria were extracted from four international DLBCL trials (REMoDL-B, GOYA, POLARIX, and HOVON-84). Differences in overall survival (OS) and 5-year restricted mean survival differences (5 y-RMSDs) between trial eligible and ineligible patients were computed. The effectiveness of adding rituximab to CHOP was quantified by the 5 y-RMSD between CHOP and R-CHOP-treated patients and the impact of individual trial criteria on estimated effectiveness was quantified by Shapley-values. In total, 4,083 R-CHOP-treated and 890 CHOP-treated DLBCL patients were included. Across the trials, 18.6-29.3% of the included R-CHOP-treated patients were deemed ineligible for trial based on organ function and performance status alone. Ineligible patients had significantly worse survival, with adjusted absolute differences in 5-year OS of 9-15%. The impact of individual criteria on the estimated effectiveness of adding rituximab to CHOP was small (Shapley-value range, −2.74-0.31). Using a smaller set of criteria derived from a data-driven approach, the number of eligible patients increased by 16-38% and the 5 y-RMSD increased by 0.7-3.1 months. In conclusion, OS among trial ineligible DLBCL patients is inferior as expected, but relaxing trial criteria would have increased the number of trial participants without making major changes in estimated efficacy for a hypothetical CHOP versus R-CHOP trial. This does not necessarily imply that trial findings based on selected patients are unreliable, as the estimated effectiveness of adding rituximab to CHOP was only slightly affected by omitting selected inclusion criteria.

Drug-resistant tuberculosis treatments, the case for a phase III platform trial.

Most phase III trials in drug-resistant tuberculosis have either been underpowered to quantify differences in microbiological endpoints or have taken up to a decade to complete. Composite primary endpoints, dominated by differences in treatment discontinuation and regimen changes, may mask important differences in treatment failure and relapse. Although new regimens for drug-resistant tuberculosis appear very effective, resistance to new drugs is emerging rapidly. There is a need for shorter, safer and more tolerable regimens, including those active against bedaquiline-resistant tuberculosis. Transitioning from multiple regimen A versus regimen B trials to a single large phase III platform trial would accelerate the acquisition of robust estimates of relative efficacy and safety. Further efficiencies could be achieved by adopting modern adaptive platform designs. Collaboration among trialists, affected community representatives, funders and regulators is essential for developing such a phase III platform trial for drug-resistant tuberculosis treatment regimens.

Efficacy and safety of therapeutic vaccines for the treatment of chronic hepatitis B: A systematic review and meta-analysis of randomized controlled trials update.

Most people diagnosed with chronic hepatitis B (CHB) need treatment to help reduce the risk of liver disease and limit disease transmission. Therapeutic vaccine (TV) candidates have been under study for their clinical effects on inducing HBV-specific host immune responses. This review aimed to systematically synthesize updated evidence on the efficacy and safety of TVs in patients with CHB. This systematic review was performed by searching different databases from January to February 2021. Completed randomized controlled trials that reported TVs' efficacy and/or safety for treating CHB compared with the standard of care (SOC) or placebo were included. Efficacy and safety estimates were reported as the logarithm of the odds ratio and risk differences, respectively. I2 > 50% was considered significant heterogeneity. Significant publication bias was considered when Egger's test P value < .10. The risk of bias was assessed using the Cochrane Risk of Bias tool. The GRADE methodology was used to assess the certainty of the evidence for each outcome. Twenty-four articles with 2889 pooled samples were included. TVs made a significant difference in hepatitis B envelope antigen (HBeAg) SC (log OR = 0.76, P = .01) and (log OR = 0.40, P = .03) compared to placebo and combination therapy, respectively. HBeAg SC was significantly affected by TVs at the end of follow up (log OR = 0.49, P = .01), with significant HBsAg mean difference (MD = -0.62, P = .00). At the end of treatment, the TVs had no significant effect on HBV DNA negativity over the SOC (log OR = 0.62, P = .09) or placebo (log OR = -0.07, P = .91). TVs do not significantly affect the risk of serious adverse events (RD 0.02, 95% CI 0.00-0.04). In patients with CHB, TVs had significant effects on HBeAg SC compared to the SOC or placebo. There was no significant difference between serious adverse events. TVs are promising treatment strategy to overcome CHB.

The use of controlled human infection models to identify correlates of protection for invasive Salmonella vaccines.

Controlled human infection model (CHIM) studies, which involve deliberate exposure of healthy human volunteers to an infectious agent, are recognised as important tools to advance vaccine development. These studies not only facilitate estimates of vaccine efficacy, but also offer an experimental approach to study disease pathogenesis and profile vaccine immunogenicity in a controlled environment, allowing correlation with clinical outcomes. Consequently, the data from CHIMs can be used to identify immunological correlates of protection (CoP), which can help accelerate vaccine development. In the case of invasive Salmonella infections, vaccination offers a potential instrument to prevent disease. Invasive Salmonella disease, caused by the enteric fever pathogens Salmonella enterica serovar Typhi (S. Typhi) and S. Paratyphi A, B and C, and nontyphoidal Salmonella (iNTS), remains a significant cause of mortality and morbidity in low- and middle-income countries, resulting in over 200,000 deaths and the loss of 15 million DALYs annually. CHIM studies have contributed to the understanding of S. Typhi infection and provided invaluable insight into the development of vaccines and CoP following vaccination against S. Typhi. However, CoP are less well understood for S. Paratyphi A and iNTS. This brief review focuses on the contribution of vaccine-CHIM trials to our understanding of the immune mechanisms associated with protection following vaccines against invasive Salmonella pathogens, particularly in relation to CoP.

Role of the dengue vaccine TAK-003 in an outbreak response: Modeling the Sri Lanka experience.

Outbreaks of dengue can overburden hospital systems, drastically reducing capacity for other care. The 2017 dengue serotype 2 (DENV-2) outbreak in Sri Lanka coincided with vaccination in an ongoing phase 3 efficacy trial of a tetravalent dengue vaccine, TAK-003 (NCT02747927). Here, we present data on the efficacy of TAK-003 following two doses of the vaccine administered 3 months apart in participants aged 4-16 years in Sri Lanka. In addition, we have used the 2017 outbreak dynamics to model the potential impact of TAK-003 on virologically confirmed dengue (VCD) cases and hospitalizations during an outbreak situation. Modeling was performed using an age-structured, host-vector, spatial and stochastic transmission model, assuming 65% vaccine coverage and 30 days until initiation of vaccination. Efficacy of TAK-003 against VCD and hospitalized VCD cases was based on data against DENV-2 from the first year of the phase 3 trial. Vaccine efficacy and safety findings in Sri Lanka were in line with those of the overall trial population. The efficacy estimates in Sri Lanka up to the first 12 months after the second dose of TAK-003 were 94.7% and 95.7% against VCD and hospitalized VCD cases, respectively. Modeling of the trial data over an extended geographic area showed a substantial reduction in cases and a flattening of outbreak curves from TAK-003 use. The baseline vaccination scenario (initiation at 30 days, 65% target coverage, vaccine effective at 14 days, 70% hospitalization rate, VE of 95% for VCD and 97% for hospitalized VCD, and 47% for asymptomatic) resulted in a 69.1% reduction in VCD cases and 72.7% reduction in VCD hospitalizations compared with no vaccination. An extreme high scenario (vaccination initiated at Day 15, 80% coverage rate, baseline VE) resulted in 80.3% and 82.3% reduction in VCD and VCD hospitalizations, respectively. Vaccine performance, speed of vaccination campaign initiation, and vaccine coverage were key drivers in reducing VCD cases and hospitalizations. Overall, the study and modeling results indicate that TAK-003 has the potential of meaningful utility in dengue outbreaks in endemic areas.

Efficacy of the Dapivirine Vaginal Ring Accounting for Imperfect Adherence.

Product adherence is critical to obtaining objective estimates of efficacy of pre-exposure prophylactic interventions against HIV-1 infection. With imperfect adherence, intention-to-treat analyses assess the collective effects of complete, sub-optimal and non-adherence, providing a biased and attenuated estimate of the averagecausal effect of an intervention. Using data from the MTN-020/ASPIRE phase III trial evaluating HIV-1 efficacy of the dapivirine vaginal ring, we conducted per-protocol, and adherence-adjusted causal inference analyses using principal stratification and marginal structural models. We constructed two adherence cut offs of ≥ 0.9mg (low cutoff) and > 4.0mg (high cutoff) that represent drug released from the ring over a 28-day period. The HIV-1 efficacy estimate (95% CI) was 30.8% (3.6%, 50.3%) (P = 0.03) from the per-protocol analysis, and 53.6% (16.5%, 74.3%) (P = 0.01) among the highest predicted adherers from principal stratification analyses using the low cutoff. Marginal structural models produced efficacy estimates (95% CIs)ranging from 48.8 (21.8, 66.4) (P = 0.0019) to 56.5% (32.8%, 71.9%) (P = 0.0002). Application of adherence-adjusted causal inference methods are useful in interpreting HIV-1 efficacy in secondary analyses of PrEP clinical trials.