Beyond Undetectable: Modeling the Clinical Benefit of Improved Antiretroviral Adherence in Persons With Human Immunodeficiency Virus With Virologic Suppression.

Background: Incomplete antiretroviral therapy (ART) adherence has been linked to deleterious immunologic, inflammatory, and clinical consequences, even among virally suppressed (<50 copies/mL) persons with human immunodeficiency virus (PWH). The impact of improving adherence in the risk of severe non-AIDS events (SNAEs) and death in this population is unknown. Methods: We estimated the reduction in the risk of SNAEs or death resulting from an increase in ART adherence by (1) applying existing data on the association between adherence with high residual inflammation/coagulopathy in virally suppressed PWH, and (2) using a Cox proportional hazards model derived from changes in plasma interleukin 6 (IL-6) and D-dimer from 3 randomized clinical trials. Comparatively, assuming 100% ART adherence in a PWH who achieves viral suppression, we estimated the number of persons in whom a decrease in adherence to <100% would need to be observed for an additional SNAE or death event to occur during 3- and 5-year follow-up. Results: Increasing ART adherence to 100% in PWH who are suppressed on ART despite imperfect adherence translated into a 6%-37% reduction in the risk of SNAEs or death. Comparatively, based on an anticipated 12% increase in IL-6, 254 and 165 PWH would need to decrease their adherence from 100% to <100% for an additional event to occur over 3- and 5-year follow-up, respectively. Conclusions: Modest gains in ART adherence could have clinical benefits beyond virologic suppression. Increasing ART adherence (eg, via an intervention or switch to long-acting ART) in PWH who remain virally suppressed despite incomplete adherence should be evaluated.

Corrigendum: Translating the observed differences in interleukin-6 levels between some antiretroviral regimens into potential long-term risk of serious non-AIDS events: A modeling study.

[This corrects the article DOI: 10.3389/fimmu.2022.976564.].

Translating the observed differences in interleukin-6 levels between some antiretroviral regimens into potential long-term risk of serious non-AIDS events: A modeling study.

Introduction: Variable levels of systemic inflammation are observed in people with HIV (PWH), but the clinical significance of differences among antiretroviral therapy (ART) regimens on associated levels of inflammatory markers is unclear. Based on data from previous epidemiologic studies that defined the predicted change in risk of serious non-AIDS events (SNAEs)/death by changes in interleukin-6 (IL-6) and D-dimer, we modeled the effects of differences in these markers between specific ART regimens on the long-term risk of clinical outcomes. Methods: We used a Markov model to compare the risk of SNAEs/death with differences in IL-6 and D-dimer levels associated with remaining on specific three-drug regimens versus switching to specific two-drug ART regimens over 5 years of treatment. We used IL-6 and D-dimer data based on trajectories over time from the randomized TANGO and observational AIR studies. Age at model entry was set at 39 years. The primary endpoint was the number needed to treat for one additional SNAE/death. Results: Over 144 weeks, PWH on one of the three-drug regimens studied were predicted to spend 22% more time in the low IL-6 quartile and 13% less time in the high IL-6 quartile compared with those on one of the two-drug regimens. Over 144 weeks, the predicted mean number of SNAEs/deaths per 100 PWH was 5.6 for a three-drug regimen associated with lower IL-6 levels versus 6.8 for a two-drug regimen associated with higher IL-6 levels. The number needed to treat for one additional SNAE/death among PWH receiving a two-drug versus three-drug regimen for 240 weeks was 43. Approximately 2,900 participants would be required for a 240-week clinical study to evaluate the accuracy of the model. Conclusions: Our Markov model suggests that higher IL-6 levels associated with switching from specific three- to two- drug ART regimens may be associated with an increase in the risk of SNAEs/death. Clinical studies are warranted to confirm or refute these results.

Into the wild-WAMBAM goes to Canada.

The sixth Wild Animal Models Bi-Annual Meeting was held in July 2017 in Québec, with 42 participants. This report documents the evolution of questions asked and approaches used in evolutionary quantitative genetic studies of wild populations in recent decades, and how these questions and approaches were represented at the recent meeting. We explore how ideas from previous meetings in this series have developed to their present states, and consider how the format of the meetings may be particularly useful at fostering the rapid development and proliferation of ideas and approaches.

Individual variation in reproductive behaviour is linked to temporal heterogeneity in predation risk.

Variation in predation risk is a major driver of ecological and evolutionary change, and, in turn, of geographical variation in behaviour. While predation risk is rarely constant in natural populations, the extent to which variation in predation risk shapes individual behaviour in wild populations remains unclear. Here, we investigated individual differences in reproductive behaviour in 16 Trinidadian guppy populations and related it to the observed variation in predator biomass each population experienced. Our results show that high heterogeneity in predator biomass is linked to individual behavioural diversification. Increased within-population heterogeneity in predator biomass is also associated with behavioural polymorphism. Some individuals adjust the frequency of consensual mating behaviour in response to differences in sex ratio context, while others display constantly at elevated frequencies. This pattern is analogous to a 'live fast, die young' pace-of-life syndrome. Notably, both high and low mean differences in predator biomass led to a homogenization of individual frequency of consensual mating displays. Overall, our results demonstrate that individual behavioural variation is associated with heterogeneity in predator biomass, but not necessarily with changes in mean values of predator biomass. We suggest that heterogeneity in predator biomass is an informative predictor of adaptive responses to changes in biotic conditions.

Maternal response to environmental unpredictability.

Mothers are expected to use environmental cues to modify maternal investment to optimize their fitness. However, when the environment varies unpredictably, cues may not be an accurate proxy of future conditions. Under such circumstances, selection favors a diversifying maternal investment strategy. While there is evidence that the environment is becoming more uncertain, the extent to which mothers are able to respond to this unpredictability is generally unknown. In this study, we test the hypothesis that Daphnia magna increase the variance in maternal investment in response to unpredictable variation in temperature consistent with global change predictions. We detected significant variability across temperature treatments in brood size, neonate size at birth, and time between broods. The estimated variability within-brood size was higher (albeit not statistically significant) in mothers reared in unpredictable temperature conditions. We also detected a cross-generational effect with the temperature history of mothers modulating the phenotypic response of F1's. Notably, our results diverged from the prediction that increased variability poses a greater risk to organisms than changes in mean temperature. Increased unpredictability in temperature had negligible effects on fitness-correlated traits. Mothers in the unpredictable treatment, survived as long, and produced as many F1's during lifetime as those produced in the most fecund treatment. Further, increased unpredictability in temperature did not affect the probability of survival of F1's. Collectively, we provide evidence that daphnia respond effectively to thermal unpredictability. But rather than increasing the variance in maternal investment, daphnia respond to uncertainty by being a jack of all temperatures, master of none. Importantly, our study highlights the essential need to examine changes in variances rather than merely on means, when investigating maternal responses.