About this Research Topic
Since its discovery more than 30 years ago, human immunodeficiency virus (HIV) infection continues to be one of our greatest health challenges. Antiretroviral combination therapy can effectively suppress virus replication and prevent immunodeficiency. However, HIV can persist in cellular and anatomical reservoirs for decades, precluding its clearance within the infected individual. While therapies are being developed to clear this reservoir, a cure remains elusive to date.
Another strategy to eliminate the virus and reduce its devastation to human health is to prevent its transmission. This goal can be achieved by vaccination, a strategy that has been successful in eliminating other viral infections (smallpox, rinderpest). The development of a broadly effective vaccine against HIV, however, poses enormous challenges that have yet to be overcome. In view of the unavailability of vaccines and options to cure HIV infected individuals, attention has been turned on repurposing antiretroviral treatment to prevent HIV transmission.
Two general methods have been suggested:
(i) ‘Treatment as Prevention’ (TasP) reduces the contagiousness of infected individuals by suppressing their viremia. However, infection needs to be diagnosed early enough and treatment initiated immediately for this strategy to be epidemiologically effective, i.e. prevent enough putative transmission events.
(ii) Pre-exposure prophylaxis (PrEP), akin to vaccination, is applied to the uninfected individual at risk. During the early events following exposure to HIV, the virus can still be cleared. PrEP inhibits virus replication which reduces the probability of establishing a productive infection. Unlike vaccination, PrEP does not induce an immunization reaction, and is therefore only efficient when the concentrations of antiretroviral drugs are above the threshold required for protection. This poses particular demands on the pharmacokinetics of PrEP, its administration schemes and the willingness of PrEP users to adhere to them.
The first PrEP regimen (Truvada: oral once daily emtricitabine + tenofovir disoproxil fumarate) was approved by the FDA in 2012, While it is generally safe, there are major pharmacological shortcomings of this regimen (i.e, the need for once-daily dosing) that may be overcome by next-generation PrEP regimen. Currently, next-generation PrEP compounds and novel dosing approaches are under investigation, including event-driven dosing, topically applied PrEP and some ‘long-acting formulations’ that may reduce variability arising from medication non-adherence. Yet still, pharmacological factors ultimately determining PrEP efficacy in different risk groups are incompletely understood. Such knowledge can significantly improve prioritization of PrEP candidates and dosing regimen to be advanced into human trials.
This Research Topic (Frontiers Special Issue) is devoted to pharmacokinetics (drug concentration time profile) and pharmacodynamics (concentration-response) of PrEP to help understand clinical variability in PrEP effectiveness, translating animal models and planning and evaluating clinical trials with PrEP. The focus will be on pre-clinical and clinical data, as well as mathematical models that integrate the various factors determining PrEP effectiveness.
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