Safety and Tolerability of Once Daily Coformulated Bictegravir, Emtricitabine, and Tenofovir Alafenamide for Postexposure Prophylaxis After Sexual Exposure

Discussion

Although advances in HIV treatment with HAART and prevention with PrEP have attenuated the spread of HIV globally, in 2020, there were more than 1.5 million new HIV infections.^[23] Most of these infections occurred in settings where individuals were unaware of their exposure, so no acute response was undertaken. However, in some circumstances, sudden disclosure of a partner's serostatus, or after sexual assault or occupational exposure, individuals often want to take action to protect themselves from becoming HIV-positive. Despite the absence of randomized controlled clinical trial data proving the efficacy of the use of antiretrovirals for PEP, the practice has become widely accepted by normative bodies and clinical practices globally over more than 2 decades, based on simian retroviral challenge experiments,^[2–4,24] a post-hoc analysis of a health care worker series,^[5] and open-label registries.^[7,8,25] Animal studies have suggested that the highest levels of protection are achieved if the medication is first administered as close to the time of exposure as possible, and the regimen is continued for an extended period of time. Simian challenge models and post-hoc analysis of human data have resulted in guidelines that recommend the initiation of treatment within 72 hours after an exposure, preferably for as soon as possible, and a 28-day course duration;^[21] however, the evidence base to support these recommendations is limited. Because of the relative inefficiency of HIV transmission, and because the use of PEP after an acute exposure is generally a one-time event (recurrent risks would warrant PrEP), many questions remain regarding optimal PEP practices, including how quickly must medication be initiated to be effective, the duration of treatment that provides optimal protection, and the preferred medication regimens.

When antiretrovirals were first demonstrated to be effective for the treatment of HIV disease more than 30 years ago, there were a limited number of available medications to become repurposed for PEP. The first regimens consisted of zidovudine, initially by itself, and then with other nucleoside reverse transcriptase inhibitors (NRTI). These regimens were frequently poorly tolerated, and completion rates were suboptimal.^[26] The advent of protease inhibitors in 1995 provided added potential efficacy, but tolerability issues remained a problem, and drug–drug interactions in pharmacologically boosted protease inhibitors added further complications and complexities.^[27] Other third agents presented clinical challenges, central nervous system side effects with efavirenz, and unacceptable levels of hepatotoxicity with nevirapine.^[28,29] One cost effectiveness modeling analysis suggested that 2 drug regimens may be preferable in many cases because of increased tolerability, except in settings where the source of potential transmission was known to have uncontrolled plasma viremia and/or likely NRTI resistance.^[30] The use of non-nucleoside reverse transcriptase medications coformulated with tenofovir and FTC has also been evaluated. Foster et al^[31] found that the single tablet, fixed-dose combination of rilpivirine and TDF/FTC was safe and well-tolerated when used for PEP, with a 92% completion rate and only one discontinuation because of side effects among 100 users. One clinical consideration with the use of this regimen for PEP are concerns about drug–drug interactions.^[32]

The advent of integrase strand transfer inhibitors created new possibilities to construct effective 3-drug PEP regimens, given their excellent tolerability and potency, particularly when coupled with tenofovir and FTC, compared with zidovudine-containing regimens.^[33] Combinations of NRTIs and raltegravir for PEP demonstrated a high level of safety and tolerability, but regimen completion was suboptimal, because many participants discontinued the medication prematurely or did not remember to take the second dose of raltegravir in the twice daily regimen.^[11,34–36] The fixed-drug single-pill coformulation of elvitegravir, cobicistat, FTC, and TDF allowed for the use of a single daily pill for PEP, but seemed to have higher rates of gastrointestinal symptoms and fatigue than raltegravir-based regimens, which may have led to product discontinuation.^[12,37,38] A subsequent study found that the fixed dose combination of elvitegravir, cobicistat, FTC and TAF was well-tolerated,^[39] but the use of the pharmacological booster has raised concerns about drug-drug interactions. Dolutegravir in combination with tenofovir plus lamivudine or FTC administered as coformulated medication has been studied as PEP and found to be safe and well-tolerated.^[40,41] An Australian study found that 90% of participants reported they completed the regimen as prescribed, and only 1 participant discontinued the medication because of an adverse event (headache).^[40] Although the regimen can be taken once daily, the combination entails taking 2 pills, which could be a disincentive for optimal adherence for some patients.

Given the pro and con considerations regarding other PEP regimens, the current study of BIC/FTC/TAF was undertaken. The rationale for using the combination was that this coformulated medication can be administered as one pill once a day, is very active against HIV, and has very few drug interactions.^[13–15] Simian retroviral challenge studies have found that a single pre-exposure and single postexposure dose of this combination was highly protective.^[16] The current study found this regimen to be safe and well-tolerated with the best completion rates (over 90%) of any PEP regimen studied at our center. Although PEP-associated side effects of nausea/vomiting, diarrhea/loose stool, fatigue, and headache were occasionally noted, they were generally mild, and were less common than previously studied PEP regimens. These favorable characteristics suggest that this combination may have many reasons to be considered as a first-line PEP regimen. The tolerability of a PEP regimen is an important consideration, because noncompletion may be associated with subsequent HIV seroconversion^[42] and PEP may be a bridge to PrEP, for individuals who are likely to have recurrent HIV risks.^[43] Retention in PEP care after a favorable experience taking an antiretroviral regimen could increase the likelihood that a transition to chronic PrEP will be successful. Given that 2 of the 3 drugs used in oral PrEP regimens are present in BIC/FTC/TAF, it is reasonable to presume that people who tolerate the 3-drug regimen could readily transition to the 2-drug regimen for chronic PrEP. Given that simian studies suggest that BIC/FTC/TAF was protective when given as event-driven PEP/PrEP (ie, one dose before and after a retroviral challenge),^[16] it is also possible that this combination could become used as an on-demand PrEP regimen; but, this approach would require human studies.

Although the current study demonstrated excellent acceptability, tolerability, and safety of the combination of BIC/FTC/TAF, it had several limitations. The sample size was modest and the study was conducted at one center in one US city. Additional studies of more geographically and socio-demographically diverse populations will be important to assess the generalizability of the current findings. The study was an open-label, nonrandomized study which used historical controls as comparators. This was necessary, because HIV transmission is a high-consequence, low-probability event. The rates of HIV transmission after a single exposure to HIV are generally below 1%. Given that current practice would make the use of a placebo or nonintervention observational arm to be unethical and unacceptable, a randomized, controlled study of any new PEP regimen would have to enroll many thousands of individuals. Given that even busy PEP programs rarely enroll more than 100–200 persons per year, such a study would require sufficient resources to enroll at multiple centers. A contemporaneous cohort of patients who used PEP at the study site who did not participate in the BIC/FTC/TAF PEP study could have provided a better comparison, but these individuals would have had to consent to have their data reviewed and abstracted, and to be interviewed to assess adverse events, if their experiences on other PrEP regimens were to be comparable to those of patients who used the BIC/FTC/TAF regimen. Moreover, people who consent to participate in an experimental PEP trial, and those who choose standard-of-care may differ by sociodemographic and behavioral characteristics, confounding comparisons. Although the sample size for a trial comparing 2 or more active PEP regimens would be enormous, a more modest-sized trial comparing tolerability and regimen completion could be feasible and could help inform clinical practice. In the meantime, it will be important for other groups to undertake prospective cohort studies of their PEP experience with BIC/FTC/TAF, and to share their findings with colleagues through reports at international conferences and in the peer-reviewed literature, to obtain a more complete profile of this new PEP regimen. The role of normative bodies, such as the WHO and US Centers for disease control and prevention, will remain important as objective evaluators of accruing data, to inform guidelines and to disseminate best practices.

In conclusion, the fixed drug combination of BIC/FTC/TAF was found to be a safe, well-tolerated, and highly acceptable regimen when use for PEP after sexual exposure, generally with fewer adverse events and higher completion rates than other PEP regimens. Further studies are warranted to determine the robustness of these findings. This regimen should be considered for PEP if additional studies support these favorable findings.

J Acquir Immune Defic Syndr. 2022;90(1):27-32. © 2022 Lippincott Williams & Wilkins