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.