Interpretation of active-control randomised trials: the case for a new analytical perspective involving averted events.

Active-control trials, where an experimental treatment is compared with an established treatment, are performed when the inclusion of a placebo control group is deemed to be unethical. For time-to-event outcomes, the primary estimand is usually the rate ratio, or the closely-related hazard ratio, comparing the experimental group with the control group. In this article we describe major problems in the interpretation of this estimand, using examples from COVID-19 vaccine and HIV pre-exposure prophylaxis trials.

Confidence limits for the averted infections ratio estimated via the counterfactual placebo incidence rate.

Objectives: The averted infections ratio (AIR) is a novel measure for quantifying the preservation-of-effect in active-control non-inferiority clinical trials with a time-to-event outcome. In the main formulation, the AIR requires an estimate of the counterfactual placebo incidence rate. We describe two approaches for calculating confidence limits for the AIR given a point estimate of this parameter, a closed-form solution based on a Taylor series expansion (delta method) and an iterative method based on the profile-likelihood.

Using the adherence-efficacy relationship of emtricitabine and tenofovir disoproxil fumarate to calculate background hiv incidence: a secondary analysis of a randomized, controlled trial.

Introduction: Randomized trials of new agents for HIV pre-exposure prophylaxis (PrEP) compare against emtricitabine and tenofovir disoproxil fumarate (F/TDF), without a placebo group. We used the well-characterized adherence-efficacy relationship for F/TDF to back-calculate the (non-PrEP) counterfactual background HIV incidence (bHIV) in a randomized trial of a novel PrEP agent and estimate comparative efficacy (to counterfactual bHIV).

Methods: The DISCOVER trial (ClinicalTrials.

A Bayesian averted infection framework for PrEP trials with low numbers of HIV infections: application to the results of the DISCOVER trial.

Trials of candidate agents for HIV pre-exposure prophylaxis (PrEP) might randomly assign participants to be given a new PrEP agent or oral coformulated tenofovir disoproxil fumarate plus emtricitabine. This design presents unique challenges in interpretation. First, with two active arms, HIV incidence might be low.

Associations between baseline characteristics, CD4 cell count response and virological failure on first-line efavirenz + tenofovir + emtricitabine for HIV.

Objectives: The aim of this study was to investigate associations between baseline characteristics and CD4 cell count response on first-line antiretroviral therapy and risk of virological failure (VF) with or without drug resistance.

Methods: We conducted an analysis of UK Collaborative HIV Cohort data linked to the UK HIV Drug Resistance Database. Inclusion criteria were viral sequence showing no resistance prior to initiation of first-line efavirenz + tenofovir disoproxil fumarate + emtricitabine and virological suppression within 6 months.

No overall change in the rate of weight gain after switching to an integrase-inhibitor in virologically suppressed adults with HIV.

Objective: Excessive weight gain has been reported with integrase strand transfer inhibitors (INSTIs). We evaluated weight changes in virologically suppressed adults with HIV who switched from non-INSTI regimens to raltegravir (RAL)-containing or dolutegravir (DTG)-containing antiretroviral therapy.

Design: Retrospective single-centre cohort.

Estimation of delay to diagnosis and incidence in HIV using indirect evidence of infection dates.

Background: Minimisation of the delay to diagnosis is critical to achieving optimal outcomes for HIV patients and to limiting the potential for further onward infections. However, investigation of diagnosis delay is hampered by the fact that in most newly diagnosed patients the exact timing of infection cannot be determined and so inferences must be drawn from biomarker data.

Methods: We develop a Bayesian statistical model to evaluate delay-to-diagnosis distributions in HIV patients without known infection date, based on viral sequence genetic diversity and longitudinal viral load and CD4 count data.

The averted infections ratio: a novel measure of effectiveness of experimental HIV pre-exposure prophylaxis agents.

Tenofovir disoproxil fumarate combined with emtricitabine is a highly effective oral pre-exposure prophylaxis (PrEP) agent for preventing the acquisition of HIV. This effectiveness has consequences for the design and analysis of trials assessing experimental PrEP regimens, which now generally include an active-control tenofovir disoproxil fumarate plus emtricitabine group, rather than a placebo group, as a comparator. Herein, we describe major problems in the interpretation of the primary measure of effectiveness proposed for these trials, namely the ratio of HIV incidence in the experimental agent group to that in the active-control group.

Risk factors and outcomes for the Q151M and T69 insertion HIV-1 resistance mutations in historic UK data.

Background: The prevalence of HIV-1 resistance to antiretroviral therapies (ART) has declined in high-income countries over recent years, but drug resistance remains a substantial concern in many low and middle-income countries. The Q151M and T69 insertion (T69i) resistance mutations in the viral reverse transcriptase gene can reduce susceptibility to all nucleoside/tide analogue reverse transcriptase inhibitors, motivating the present study to investigate the risk factors and outcomes associated with these mutations.

Methods: We considered all data in the UK HIV Drug Resistance Database for blood samples obtained in the period 1997-2014.

Combined models for pre- and post-treatment longitudinal biomarker data: an application to CD4 counts in HIV-patients.

Background: There has been some debate in the literature as to whether baseline values of a measurement of interest at treatment initiation should be treated as an outcome variable as part of a model for longitudinal change or instead used as a predictive variable with respect to the response to treatment. We develop a new approach that involves a combined statistical model for all pre- and post-treatment observations of the biomarker of interest, in which the characteristics of response to treatment are treated as a function of the 'true' value of the biomarker at treatment initiation.

Methods: The modelling strategy developed is applied to a dataset of CD4 counts from patients in the UK Register of HIV Seroconverters (UKR) cohort who initiated highly active antiretroviral therapy (HAART).

Patterns of Second- and Third-Trimester Growth and Discordance in Twin Pregnancy: Analysis of the Southwest Thames Obstetric Research Collaborative (STORK) Multiple Pregnancy Cohort.

Introduction: This study investigates patterns of intertwin size discordance in dichorionic diamniotic (DCDA) and monochorionic diamniotic (MCDA) twin pregnancies.

Material And Methods: Ultrasound measurements of twin pregnancies, from 14 weeks to term, were collected by 9 hospitals over a 10-year period. This analysis considers the modelled and observed levels of discordance in abdominal circumference (AC) and estimated fetal weight (EFW) in relation to gestational age.

Fractional Brownian motion and multivariate-t models for longitudinal biomedical data, with application to CD4 counts in HIV-positive patients.

Longitudinal data are widely analysed using linear mixed models, with 'random slopes' models particularly common. However, when modelling, for example, longitudinal pre-treatment CD4 cell counts in HIV-positive patients, the incorporation of non-stationary stochastic processes such as Brownian motion has been shown to lead to a more biologically plausible model and a substantial improvement in model fit. In this article, we propose two further extensions.