Network Meta-Analysis of Post-Exposure Prophylaxis Randomized Clinical Trials

I Fernández; E. deLazzari; A. Inciarte; V. Diaz-Brito; A. Milinkovic; A. Arenas-Pinto; F. Etcheverrry; F. García; L Leal


HIV Medicine. 2021;22(3):218-224. 

In This Article

Abstract and Introduction


Objectives: We performed a network meta-analysis of PEP randomized clinical trials to evaluate the best regimen.

Methods: After MEDLINE/Pubmed search, studies were included if: (1) were randomized, (2) comparing at least 2 PEP three-drug regimens and, (3) reported completion rates or discontinuation at 28 days. Five studies with 1105 PEP initiations were included and compared ritonavir-boosted lopinavir (LPV/r) vs. atazanavir (ATV) (one study), cobicistat-boosted elvitegravir (EVG/c) (one study), raltegravir (RAL) (one study) or maraviroc (MVC) (two studies). We estimated the probability of each treatment of being the best based on the evaluation of five outcomes: PEP non-completion at day 28, PEP discontinuation due to adverse events, PEP switching due to any cause, lost to follow-up and adverse events.

Results: Participants were mostly men who have sex with men (n = 832, 75%) with non-occupational exposure to HIV (89.86%). Four-hundred fifty-four (41%) participants failed to complete their PEP course for any reason. The Odds Ratio (OR) for PEP non-completion at day 28 in each antiretroviral compared to LPV/r was: ATV 0.95 (95% CI 0.58–1.56; EVG/c: OR 0.65 95% CI 0.30–1.37; RAL: OR 0.68 95% CI 0.41–1.13; and MVC: OR 0.69 95% CI 0.47–1.01. In addition, the rankogram showed that EVG/c had the highest probability of being the best treatment for the lowest rates in PEP non-completion at day 28, switching, lost to follow-up or adverse events and MVC for PEP discontinuations due to adverse events.

Conclusions: Our study shows the advantages of integrase inhibitors when used as PEP, particularly EVG as a Single-Tablet Regimen.


Post-exposure prophylaxis (PEP) is a well-known prevention strategy for people who have had a potential risk exposure to HIV. PEP generally consists of a combination of three antiretroviral drugs (ARVs) for 28 days. To maximize the desired preventive effect, PEP compliance seems essential. Toxicity and/or side effects leading to frequent drop-outs and loss to follow-up have been frequently described during this type of treatment. Higher rates of ARV toxicity and discontinuation have been reported as a result of the use of PEP regimens when compared with people living with HIV receiving treatment with the same ARV combination. Due to ethical constraints and sample size, PEP efficacy studies cannot be performed, and therefore its prescription is based on data from animal studies,[1] retrospective analysis of occupational PEP[2] and prophylaxis of maternal–fetal transmission.[3]

Previous PEP regimens consisted on zidovudine (AZT)/lamivudine (3TC) as the backbone and a third drug, preferably a protease inhibitor (PI). As tolerability was an issue with these nucleoside reverse transcriptase inhibitors (NRTIs), more recent PEP combinations are based on a backbone, including tenofovir (TDF)/emtricitabine (FTC). Until very recently the third recommended ARV was ritonavir-boosted lopinavir (LPV/r) or atazanavir (ATV)[4] with poor rates of PEP completion. Some studies have been conducted in the last decade searching for better tolerated regimens. Cohort single arm studies using as third drug an integrase inhibitor (INSTI),[5] the entry inhibitor maraviroc (MVC)[6] or the nonnucleoside transcriptase inhibitor (NNRTI) rilpivirine[7] have been reported, suggesting that these alternative regimens have better completion outcomes than PI. Updated guidelines (based on expert opinion) now recommend INSTIs as first-line treatment (e.g. in the UK, raltegravir; in the USA, raltegravir or dolutegravir), with boosted PIs as alternatives.[8,9]

Few randomized studies have been conducted searching for better tolerated regimens as a priority.[10–14] It is not known which is the best tolerated regimen and, therefore, the recommendations of guidelines are mainly based on expert opinions.[15] To evaluate which PEP regimen has the best completion rate, we performed a network meta-analysis (NMA) of five randomized clinical trials (RCTs) comparing different PEP regimens and reporting completion outcomes on 1105 PEP initiations.[10–14]