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Hybrid stochastic framework predicts efficacy of prophylaxis against HIV: An example with different dolutegravir prophylaxis schemes.

ABSTRACT: To achieve the 90-90-90 goals set by UNAIDS, the number of new HIV infections needs to decrease to approximately 500,000 by 2020. One of the 'five pillars' to achieve this goal is pre-exposure prophylaxis (PrEP). Truvada (emtricitabine-tenofovir) is currently the only medication approved for PrEP. Despite its advantages, Truvada is costly and requires individuals to adhere to the once-daily regimen. To improve PrEP, many next-generation regimen, including long-acting formulations, are currently investigated. However, pre-clinical testing may not guide candidate selection, since it often fails to translate into clinical efficacy. On the other hand, quantifying prophylactic efficacy in the clinic is ethically problematic and requires to conduct long (years) and large (N>1000 individuals) trials, precluding systematic evaluation of candidates and deployment strategies. To prioritize- and help design PrEP regimen, tools are urgently needed that integrate pharmacological-, viral- and host factors determining prophylactic efficacy. Integrating the aforementioned factors, we developed an efficient and exact stochastic simulation approach to predict prophylactic efficacy, as an example for dolutegravir (DTG). Combining the population pharmacokinetics of DTG with the stochastic framework, we predicted that plasma concentrations of 145.18 and 722.23nM prevent 50- and 90% sexual transmissions respectively. We then predicted the reduction in HIV infection when DTG was used in PrEP, PrEP 'on demand' and post-exposure prophylaxis (PEP) before/after virus exposure. Once daily PrEP with 50mg oral DTG prevented 99-100% infections, and 85% of infections when 50% of dosing events were missed. PrEP 'on demand' prevented 79-84% infections and PEP >80% when initiated within 6 hours after virus exposure and continued for as long as possible. While the simulation framework can easily be adapted to other PrEP candidates, our simulations indicated that oral 50mg DTG is non-inferior to Truvada. Moreover, the predicted 90% preventive concentrations can guide release kinetics of currently developed DTG nano-formulations.

SUBMITTER: Duwal S

PROVIDER: S-EPMC6001963 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundChildhood obesity is high on the policy agenda of wealthier nations, and many interventions have been developed to address it. This work describes an overview of schemes for obese and overweight children and young people in England, and the 'mapping' approach we used.MethodsOur search strategy, inclusion criteria and coding frame had to be suitable for describing a potentially large number of schemes within a short timeframe. Data were collected from key informants, scheme publicity and reports, and via a web-survey. To be included, schemes had to be based in England, follow a structured programme lasting at least two weeks, promote healthy weight, and be delivered exclusively to overweight and/or obese children and young people (age range 4-18). Data were entered into a coding frame recording similar information for each scheme, including any underpinning research evidence, evaluation or monitoring reports. Priority questions were identified in consultation with colleagues from the Department of Health and the Cross Government Obesity Unit.ResultsFifty-one schemes were identified. Some operated in multiple areas, and by using estimates of the number of schemes provided by multi-site scheme leads, we found that between 314 and 375 local programmes were running at any time. Uncertainty is largely due to the largest scheme provider undergoing rapid expansion at the time of the mapping exercise and therefore able to provide only an estimate of the number of programmes running. Many schemes were similar in their approach, had been recently established and were following NICE guidelines on interventions to promote healthy weight. Rigorous evaluation was rare.ConclusionsOur methods enabled us to produce a rapid overview of service activity across a wide geographic area and a range of organisations and sectors. In order to develop the evidence base for childhood obesity interventions, rigorous evaluation of these schemes is required. This overview can serve as a starting point for evaluations of interventions to address obesity. More generally, a rapid and systematic approach of this type is transferable to other types of service activity in health and social care, and may be a tool to inform public health planning.

Project description:INTRODUCTION:The unexpected identification of a neural tube defect (NTD) safety signal with preconception dolutegravir (DTG) exposure in the Botswana Tsepamo birth outcomes study brought into sharp focus the need for reliable data on use of new antiretrovirals in pregnancy, improved pharmacovigilance systems to evaluate safety of new drugs being introduced into populations including women of reproductive potential, and balanced risk-benefit messaging when a safety signal is identified. DISCUSSION:The Tsepamo study NTD safety signal and accompanying regulatory responses led to uncertainty about the most appropriate approach to DTG use among women of reproductive potential, affecting global DTG roll-out plans, and limiting DTG use in adolescent girls and women. It also revealed a tension between a public health approach to antiretroviral treatment (ART) and individual choice, and highlighted difficulties interpreting and messaging an unexpected safety signal with uncertainty about risk. This difficulty was compounded by the lack of high-quality data on pregnancy outcomes from women receiving ART outside the Tsepamo surveillance sites and countries other than Botswana, resulting in a prolonged period of uncertainty while data on additional exposures are evaluated to refute or confirm the initial safety signal. We discuss principles for evaluating and introducing new drugs in the general population that would ensure collection of appropriate data to inform drug safety in adolescent girls and women of reproductive potential and minimize confusion about drug use in this population when a safety signal is identified. CONCLUSIONS:The response to a signal suggesting a possible safety risk for a drug used in pregnancy or among women who may become pregnant needs to be rapid and comprehensive. It requires the existence of appropriately designed surveillance systems with broad population coverage; data analyses that examine risk-benefit trade-offs in a variety of contexts; guidance to transform this risk-benefit balance into effective and agreed-upon policy; involvement of the affected community and other key stakeholders; and a communication plan for all levels of knowledge and complexity. Implementation of this proposed framework for responding to safety signals is needed to ensure that any drug used in pregnancy can be rapidly and appropriately evaluated should a serious safety alert arise.

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Hybrid stochastic framework predicts efficacy of prophylaxis against HIV: An example with different dolutegravir prophylaxis schemes.

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