Isoniazid preventive therapy-related adverse events among Malawian adults on antiretroviral therapy: A cohort study

Adverse events may be a cause of observed poor completion of isoniazid preventive therapy (IPT) among people living with HIV in high tuberculosis burden areas. Data on IPT-related adverse events (AE) from sub-Saharan Africa are scarce. We report IPT-related AEs, associated clinical characteristics, and IPT discontinuations in adults who were stable on antiretroviral therapy (ART) when they initiated IPT. Cohort study nested within a randomized, controlled, clinical trial of cotrimoxazole and chloroquine prophylaxis in Malawians aged ≥ 18 years and virologically suppressed on ART. Eight hundred sixty-nine patients were followed for a median of 6 months after IPT initiation. IPT relatedness of AEs was determined retrospectively with the World Health Organization case-causality tool. Frailty survival regression modeling identified factors associated with time to first probably IPT-related AE. The overall IPT-related AE incidence rate was 1.1/person year of observation. IPT relatedness was mostly uncertain and few AEs were severe. Most common were liver and hematological toxicities. Higher age increased risk of a probably IPT-related AE (aHR = 1.02; 95% CI 1.00–1.06; P = .06) and higher weight reduced this risk (aHR = 0.98; 95% CI 0.96–1.00; P = .03). Of 869 patients, 114 (13%) discontinued IPT and 94/114 (82%) discontinuations occurred at the time of a possibly or probably IPT-related AE. We observed a high incidence of mostly mild IPT-related AEs among individuals who were stable on ART. More than 1 in 8 persons discontinued IPT. These findings inform strategies to improve implementation of IPT in adults on ART, including close monitoring of groups at higher risk of IPT-related AEs.     

Effectiveness and safety of tenofovir alafenamide in children and adolescents living with HIV: a systematic review

Introduction

Tenofovir alafenamide (TAF) is approved for paediatric use in fixed-dose combination tablets, but efficacy and safety data in children are limited. We conducted a systematic review on the efficacy/effectiveness and safety of TAF in infants, children and adolescents living with HIV.

Methods

We searched MEDLINE, Embase, the Cochrane Library, clinical trial registries, reference lists and relevant conferences to identify literature published January 2009–March 2021. We included clinical trials and observational studies assessing the efficacy/effectiveness or safety of TAF through ≥6 months of treatment in participants aged 0–19 years.

Results and discussion

Overall 3626 abstracts and 371 full papers were screened. Four single-arm, innovator-funded trials (341 participants) and a pooled analysis of those trials were identified. All four trials included treatment-experienced and virally suppressed children or adolescents. One trial also included treatment-naïve adolescents with baseline viral load >1000 copies/ml. The risk of bias was rated as low in one study and unclear in the other three owing to missing data on study design (all conference presentations). At 48 weeks, 92% (46/50) of treatment-naïve participants were virally suppressed (one trial). Among treatment-experienced participants with viral load at 48 weeks, 214 of 224 participants were virally suppressed. Across the studies, one grade 3/4 adverse event was considered drug-related (intermediate uveitis). There were three discontinuations for adverse events (grade 2 anxiety and insomnia, grade 1 iridocyclitis [drug-related] and grade 1 pulmonary tuberculosis [unrelated to treatment]). One accidental death occurred across the four studies. In the pooled analysis of 223 participants, the median change in bone mineral density z-score (height- and age-adjusted) from baseline to 48 weeks was −0.12 (interquartile range [IQR] −0.46, 0.17) to 0.05 (IQR not reported) for spine, and −0.09 (IQR −0.33, 0.07) to 0.09 (IQR not reported) for total body less head. Weight-for-age z-scores increased by 0.25 from baseline to 48 weeks.

Conclusions

Four single-arm trials were identified in this systematic review, with initial evidence suggesting good viral suppression and no obvious safety concerns in children and adolescents on TAF-containing regimens over 24–48 weeks. However, further comparative and longer-term safety data are needed in children and adolescents, including on weight and metabolic changes.     

A new modeling approach for quantifying expert opinion in the drug discovery process

Expert opinion plays an important role when choosing clusters of chemical compounds for further investigation. Often, the process by which the clusters are assigned to the experts for evaluation, the so‐called selection process, and the qualitative ratings given by the experts to the clusters (chosen/not chosen) need to be jointly modeled to avoid bias. This approach is referred to as the joint modeling approach. However, misspecifying the selection model may impact the estimation and inferences on parameters in the rating model, which are of most scientific interest. We propose to incorporate the selection process into the analysis by adding a new set of random effects to the rating model and, in this way, avoid the need to model it parametrically. This approach is referred to as the combined model approach. Through simulations, the performance of the combined and joint models was compared in terms of bias and confidence interval coverage. The estimates from the combined model were nearly unbiased, and the derived confidence intervals had coverage probability around 95% in all scenarios considered. In contrast, the estimates from the joint model were severely biased under some form of misspecification of the selection model, and fitting the model was often numerically challenging. The results show that the combined model may offer a safer alternative on which to base inferences when there are doubts about the validity of the selection model. Importantly, thanks to its greater numerical stability, the combined model may outperform the joint model even when the latter is correctly specified. Copyright © 2015 John Wiley & Sons, Ltd.     

Ignoring overdispersion in hierarchical loglinear models: Possible problems and solutions

Poisson data frequently exhibit overdispersion; and, for univariate models, many options exist to circumvent this problem. Nonetheless, in complex scenarios, for example, in longitudinal studies, accounting for overdispersion is a more challenging task. Recently, Molenberghs et.al, presented a model that accounts for overdispersion by combining two sets of random effects. However, introducing a new set of random effects implies additional distributional assumptions for intrinsically unobservable variables, which has not been considered before. Using the combined model as a framework, we explored the impact of ignoring overdispersion in complex longitudinal settings via simulations. Furthermore, we evaluated the effect of misspecifying the random-effects distribution on both the combined model and the classical Poisson hierarchical model. Our results indicate that even though inferences may be affected by ignored overdispersion, the combined model is a promising tool in this scenario.