Appendix B: A Summary Discussion of Characteristics of Antiretroviral Agents Used for Nonoccupational Postexposure Prophylaxis

Recommendations and Reports / May 8, 2025 / 74(1);48–56

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nPEP Efficacy for HIV Prevention

No randomized, placebo-controlled clinical trial evaluating the efficacy of nonoccupational postexposure prophylaxis (nPEP) for HIV prevention has been performed. However, data relevant to nPEP guidelines are available from multiple prospective, open-label randomized and nonrandomized experimental studies, longitudinal and observational cohort studies, and case studies of nPEP use. The 2025 nPEP guideline update adds evidence from January 2015 to January 2024. A systematic literature review was conducted according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) reporting guidelines. Literature searches were performed in Medline, Embase, PsycINFO, Cochrane Library, CINAHL, and Scopus databases. Search terms included “HIV post exposure prophylaxis,” “post-exposure prophylaxis,” “nPEP,” “nonoccupational postexposure or post-exposure prophylaxis,” “HIV postexposure or post-exposure prophylaxis,” “post exposure or post-exposure prevention,” “non-occupational,” “non-PEP,” “NOPEP,” “PEP,” “post-exposure prophylaxis after sexual exposure,” and “PEPSE.” Duplicates were identified and removed using the Endnote automated “find duplicates” function with preferences set to match on title, author, and year. Additional deduplication occurred during the review and categorization process. Studies included in this literature review were published in peer-reviewed journals or in CDC’s Morbidity and Mortality Weekly Report. The nPEP guideline update team defined key outcomes relevant to the nPEP topic areas. Exclusion criteria included no full-text available; non-human study; not relevant to HIV PEP; publication withdrawn or otherwise inaccessible; commentary or otherwise non–peer-reviewed studies except relevant conference abstracts; study protocol with no data; studies outside of the United States; nPEP epidemiology before 2018 (e.g., nPEP awareness and use); only about oPEP unless specifically on medications, regimens, adherence, outcomes, or side effects; and prevention of perinatal or mother-to-child transmission only. New evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework.

Alongside the systematic literature review, the nPEP work group also considered evidence from clinical trials and observational studies that used antiretroviral therapy (ART) for the purpose of HIV treatment to enhance understanding of the HIV current standards of care, which are not reflected in the GRADE tables but are discussed here. These ART agents include the nucleoside and nucleotide reverse-transcriptase inhibitors (NRTIs), nonnucleoside reverse-transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), a fusion inhibitor (FI), chemokine (C-C motif) receptor 5 (CCR5) antagonists (entry inhibitors), and postattachment inhibitors. Only ART agents approved by the Food and Drug Administration (FDA) for treatment of HIV infection were reviewed or included in these guidelines, although none of these agents has an FDA-approved indication for administration as nPEP. Newer data discussed in this report continue to support the assertion that nPEP initiated soon after exposure and continued for 28 days with sufficient medication adherence can reduce the risk for acquiring HIV infection after nonoccupational exposures. In many studies, HIV seroconversions have most commonly been attributed to ongoing risk behavior after completion of the nPEP course (1–9). However, certain studies have suggested that delayed initiation of nPEP, low adherence, and early primary HIV infection at the time of nPEP initiation as risks for HIV acquisition (1,3,10).

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nPEP Studies by Regimen

INSTI-Based Regimens

Bictegravir (BIC). Two prospective, nonrandomized open-label trials have evaluated BIC, emtricitabine (FTC), and tenofovir alafenamide (TAF) as once daily nPEP for 28 days (n = 164) (11,12). Both studies noted high completion rates (90% and 96%) by self-report with zero seroconversions (11,12). When comparing regimen completion rates to PEP regimens from earlier clinical trials, including 1) zidovudine (AZT)/lamivudine (3TC) plus a PI, 2) twice daily raltegravir (RAL) plus tenofovir disoproxil fumarate (TDF)/FTC, and 3) co-formulated elvitegravir (EVG)/cobicistat (c)/TDF/FTC, BIC/FTC/TAF, had significantly higher completion rates than the other regimens (38.8%, 57.0%, and 71.0%, respectively [p<0.05]) (11). In addition, BIC/FTC/TAF was less likely to be associated with side effects than historical studies, including RAL- and EVG-based regimens (11).

Dolutegravir (DTG). Three studies (two cohort and one open-label single arm trial) have evaluated DTG-based regimens, including in combination with TDF/FTC and abacavir (ABC)/3TC as PEP (n = 1,134) (13–15). No studies compared BIC with DTG-based regimens. Studies containing DTG noted zero HIV seroconversions. Among studies reporting individual completion rates for DTG-based regimens, completion rates ranged from 64% to 94% (13–15). Rates of self-reported adherence to PEP were up to 98% (13–15). Premature PEP cessation due to adverse events was rare (13–15).

Elvitegravir (EVG). Six studies have examined regimens containing EVG as PEP (n = 2,351) (2,6,9,13,16–18). In three studies, no seroconversions were noted among participants who were administered EVG-based regimens (9,13,16). In a fourth study, one seroconversion occurred in the EVG/cobicistat (c)/TDF/3TC arm at day 90 in a person with multiple high-risk exposures to HIV before and after starting PEP (6). One study did not report HIV follow-up testing and one study reported a person who acquired HIV as a possible nPEP failure, but the nPEP regimen was not specified (9,18). Completion rates for EVG-based regimens ranged from 44% to 92% (6,9,13,16–18). In studies with comparison with other regimens, completion and adherence rates were higher for EVG-based regimens (including with TAF) than for those consisting of NNRTI plus two NRTIs (89% [CI = 88%–90%; n= 2,786]) or PI plus two NRTIs (80% [CI = 79%–81%; n = 12,903]) (6,13). Mixed evidence exists comparing EVG with other INSTIs for PEP. However, a separate study suggested RAL/TDF/FTC has higher rates of completion up to 96% (CI = 94%–98% [n = 866]), with EVG-based regimens being similar to DTG plus TDF/FTC (87% [CI = 84%–90%; n = 704]) (13,16). Most adverse events were mild and did not result in nPEP discontinuation (6,13,16). Adverse events were less frequent than in comparator groups (e.g., lopinavir and ritonavir [LPV/r]) (6,9,13,16–18).

Raltegravir (RAL). Fourteen studies examined adherence, tolerability, or efficacy of RAL-based regimens for PEP (n = 3,101) (3–5,7,13,19–27). Multiple studies reported HIV seroconversions. One seroconversion occurred in a patient reported to be on RAL at day 90 with known multiple potential sexual risk exposures before and after receiving nPEP (4). Three studies reported at least one seroconversion; however, the PEP regimen was not specified, and all but one seroconversion across all these studies occurred in persons who had continued subsequent high-risk behaviors (5–7). Another study had three HIV acquisitions in persons receiving RAL-based PEP but was not significantly different from compared regimens in multivariate regression (3). Six studies reported no seroconversions (7), and three studies did not report the number of seroconversions (3,4,20–27).

The completion rates of RAL-based regimens ranged from 32% to 96% (3–5,7,13,19–27). In studies comparing the completion rates of multiple regimens, RAL-based regimens had higher rates than older regimens (e.g., LPV/r) (4). However, commonly reported issues with adherence that required a regimen modification included failure to consistently take the second daily dose of RAL (19). Multiple studies reported discontinuations due to adverse events, but these events occurred less frequently than with older recommended regimens, suggesting better tolerability of RAL (4,21,23).

Long-Acting Injectables

Cabotegravir (CAB), a newer INSTI, is available co-packaged with rilpivirine (RPV), or separately for use as HIV pre-exposure prophylaxis (PrEP). CAB-RPV is available as extended-release injectable suspension administered intramuscularly (IM) as HIV treatment once every 4–8 weeks. The literature review did not reveal any studies examining the prescription of IM-administered long-acting cabotegravir-based ART regimens (i.e., CAB-RPV) as an alternative PEP regimen among any population, including in health care personnel with an occupational exposure to HIV or with nonoccupational exposures to HIV. A recent animal study indicated that PEP with long-acting CAB-RPV was partially effective and demonstrated late breakthrough infections, highlighting the limitations of this regimen for PEP (27). Due to the lack of data on safety, tolerability, and efficacy in a PEP setting, CAB-RPV was not included in the list of preferred or alternative regimens in this guideline update.

PI-Based Regimens

Twelve reports examined adherence, tolerability, or efficacy of PI-based regimens, including lopinavir (LPV)- or darunavir (DRV)-based regimens (n = 14,398) (10,13,20,28–40). In studies reporting seroconversions, 18 occurred; at least nine were considered nPEP failures (10,13,30,32). No reports of HIV acquisition were among persons completing LPV-based PEP; two HIV acquisitions were among persons who stopped LPV-based PEP early during the course. PI-based regimens have among the lowest completion rates, ranging from 42% to 80% (10,13,20,28–40). In studies that compared different regimens, PI plus two NRTIs had lower completion rates than INSTI- and NNRTI-based regimens, with atazanavir and ritonavir (ATV/r) and nelfinavir (NFV) among the lowest (13). Adverse events were significantly higher with PI-based regimens than with INSTI-based regimens (p<0.05) (20). Early discontinuation is not uncommon (13,20,28–32). Case reports exist of LPV/r discontinuation due to serious adverse events (suspected acute interstitial nephritis and drug interaction with dihydroergotamine) (35,37,40). An observational study of DRV/r plus TDF/FTC with self-reported questionnaires (n = 51) demonstrated a discontinuation rate of 47% with six cases of discontinuation (12%) being treatment related (33). PI-based regimens containing AZT have an increased risk for drug discontinuation (relative risk = 9.33 [95% CI = 1.34–65.23]) due to adverse effects of medication related to gastrointestinal complications (29).

A 2015 systematic review of nPEP regimens that included 25 studies found that of 10 studies with 1,755 initiations, nPEP completion rates were highest for DRV/r plus TDF/FTC (94% [CI = 90%–98%]), then LPV/r plus TDF/FTC (71% [CI = 44%–97%]), and lowest for LPV/r plus AZT/3TC (59%) (8). The discontinuations due to drug reactions were highest for ATV/r plus AZT/3TC (21%). nPEP failure as determined by HIV seroconversion was rare and could not be compared across regimens because of the paucity of events and different protocols for longer-term monitoring after nPEP provision (8).

NNRTI-Based Regimens

Seven studies examined adherence, tolerability, or efficacy of NNRTI-based regimens as PEP (n = 3,580) (13,41–46). Overall, NNRTI-based regimens containing RPV had high completion rates, ranging from 81% to 92% (95% CI = 85%–96%) (13,42,45). A multicenter, open-label, nonrandomized trial of 100 men who have sex with men who received RPV/TDF/FTC once daily for 28 days demonstrated overall high adherence of >90% by self-report in 90% of persons despite frequent experiences of one or more clinical adverse events (88%) (42). Overall, few premature discontinuations of RPV due to adverse events were observed, mainly due to gastrointestinal intolerance (41,45,46). NNRTI regimens containing efavirenz (EFV) had lower completion rates (69%–71%) with lower tolerability (43,44). One cohort study found EFV as a significant factor associated with PEP noncompletion (OR = 37.8 [CI = 4.2–342.3; p<0.01]), with at least 10 persons discontinuing prematurely due to severe dizziness (43). Despite this, in the seven studies examining NNRTI-based regimens, zero seroconversions occurred (13,41–46).

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Potential Risks Associated with nPEP

Concerns regarding potential risks associated with nPEP as a clinical HIV prevention intervention include the occurrence of serious adverse effects from the short-term use of ART medications by otherwise healthy persons without HIV infection. Another concern is potential selection for drug-resistant strains of virus among those who acquire HIV despite nPEP use (particularly if medication adherence is inconsistent during the 28-day course or if the source transmits resistant virus).

ART Side Effects and Toxicity

INSTI-Based Regimens. All INSTIs are typically well tolerated (47). Insomnia, depression, and suicidal ideation, primarily in patients with a history of psychiatric illnesses, have been reported rarely in patients receiving INSTI-based regimens (47). In addition, initiation of INSTI-based regimens has been associated with greater weight gain than with NNRTI- or PI-based regimens, although this generally is observed with longer therapy than required for nPEP.

Fifteen studies have reported on the tolerability, side effects, and toxicity of INSTI-based regimens for use as nPEP. Reported side effects of BIC and DTG were mostly mild or self-limiting and did not result in nPEP discontinuation (11–13,48). The most common side effects of BIC- and DTG-based regimens include fatigue, headache, nausea or vomiting, and diarrhea. The most commonly reported adverse reactions of moderate-to-severe intensity to DTG-based regimens were insomnia and headache. Adverse events to DTG resulting in study drug discontinuation were rare but have been reported (headache [1%]) (14). Abnormal laboratory values, including elevated creatinine and liver transaminases, were observed rarely for BIC- and DTG-based regimens and resolved after PEP regimen completion (11,12,48). In an open-label, nonrandomized phase IV trial of 52 persons, BIC/FTC/TAF was less likely to be associated with any symptom compared with historical regimens containing AZT/3TC/PI (11). BIC/FTC/TAF also was less likely to be associated with diarrhea, loose stools, or headache than AZT/3TC/PI, RAL/FTC/TDF, and EVG/c/FTC/TDF; less likely to be associated with fatigue than EVG/c; and less likely to be associated with dizziness than RAL (11). Nonrandomized trials of EVG/c reported higher frequency of mild adverse events with nPEP use than observed in persons with HIV infection, most commonly abdominal discomfort, bloating, diarrhea, fatigue, nausea, vomiting, headache, or dizziness (6,16,49). These adverse events occur less frequently than with PI-based regimens (e.g., LPV/r) (6,9,13,16–18).

Although rare, side effects can occur with RAL for nPEP and include gastrointestinal discomfort, nausea, dizziness, and headache (3,4,21–25,50). Rare cases of skeletal muscle toxicity, thrombocytopenia, and severe systemic cutaneous reactions resembling Stevens-Johnson syndrome also have been reported (51–54). Side effects of RAL occur less frequently compared with LPV/r or ATV (21,22,24,25). Abnormal laboratory values observed include elevated creatinine and liver transaminases (23).

Extrapolating data from HIV treatment trials, multiple comparisons of boosted PI- and INSTI-based regimens used as HIV treatment revealed that the INSTI-based regimens were better tolerated and resulted in fewer treatment discontinuations (47,55–57). Compared with boosted PI-based regimens and NNRTI-based regimens, INSTI-based regimens were more likely to have viral suppression and are among the most effective agents in suppressing HIV viral load (55,58–61).

Among the INSTI-based regimens, BIC- and DTG-based regimens have a higher barrier to resistance, lower pill burden, and higher completion rates than the first-generation INSTI-based regimens that contain EVG or RAL (47,62,63). EVG-based regimens also contain cobicistat, a strong cytochrome P450 inhibitor, which increases the potential risk for drug–drug interactions (47).

Transmitted and treatment-emergent resistance has been reported rarely with DTG- or BIC-based treatment regimens (64–67). Data from two randomized trials demonstrated that, in terms of virologic efficacy, DTG plus 3TC was noninferior to a 3-drug regimen of DTG plus TDF/FTC (68,69). No treatment-emergent resistance was observed in either the 2-drug or the 3-drug group (68,69). HIV treatment clinical trials have demonstrated BIC-based regimens to be noninferior to DTG-based regimens (70,71).

PI-Based Regimens

Multiple side effects appear to be class-specific, whereas others are agent-specific. PI class-specific side effects include metabolic complications (e.g., insulin resistance, diabetes, dyslipidemia, and lipodystrophy) and other adverse reactions (e.g., hepatotoxicity) (72–75). However, the propensity to cause side effects differs by PI and pharmacokinetic (PK)-enhancing agent. Most drug–drug interactions with PIs arise from the pharmacological boosting agents, ritonavir and cobicistat.

Five studies examined adherence and tolerability of PI-based nPEP regimens (20,28,29,32,34,76). Multiple observational and randomized, noninferiority studies have suggested improved tolerability, lower adverse events overall, and fewer moderate-to-severe events for boosted DRV than boosted LPV and ATV, due in part to hyperbilirubinemia associated with ATV (28). Commonly reported side effects of DRV/r include fatigue, nausea, diarrhea, loss of appetite, and headache; studies comparing DRV/r with INSTIs revealed significantly less side effects for INSTIs (p<0.0001) (20,28,76). Other reactions observed with DRV/r include skin rash, which is usually mild-to-moderate in severity and self-limited, and elevated liver transaminases. Case reports of TDF-induced Fanconi’s syndrome are described in the nPEP literature, one in combination with DRV/r (39). ATV and cobicistat (ATV/c) and ATV/r can cause fatigue and gastrointestinal side effects, including diarrhea (32). Nephrolithiasis, nephrotoxicity, and cholelithiasis have been reported for ATV used in treatment regimens (77–81). Adverse events also have been reported with LPV/r for nPEP, including nausea, vomiting, diarrhea, fatigue, headache, acute kidney injury, and ergotism with acute limb ischemia (34–37).

In studies for the treatment of HIV infection, large observational cohorts demonstrated an association between certain PIs (DRV/r, LPV/r) and an increased risk for cardiovascular events; however, this association was not observed with ATV (82–85). Further study is needed to determine the clinical significance of this finding for nPEP with a 28-day course. Boosted ATV, like boosted DRV, has relatively few metabolic adverse effects compared with older boosted-PI regimens; however, ATV/r had a higher rate of adverse effect–associated drug discontinuation rate than DRV/r and RAL in a randomized clinical trial (55). Certain studies have demonstrated that unsuspected drug–drug interactions were more common among persons with HIV infection taking PIs compared with NNRTIs or NRTIs (86).

Boosted-PI (PK-enhanced) regimens have greater potential for drug–drug interactions than other regimens. However, nPEP observational studies and treatment clinical trials have suggested boosted PI-based regimens (boosted DRV) have excellent completion rates and tolerability with low rates of transmitted and treatment-emergent resistance (87). DRV/c/TAF/FTC is available as a fixed-dose single tablet once-per-day regimen that can be considered in certain clinical situations.

NNRTI-Based Regimens

Although no explicit class-specific adverse events have been reported, two commonly used NNRTIs (EFV and RPV) can result in QTc prolongation, skin rash, and neurologic and psychiatric side effects, including depression. Seven studies examined adherence and tolerability of NNRTI-based regimens as nPEP (13,41–46). Multiple multicenter, nonrandomized studies of RPV/FTC/TDF reported high proportions (up to 88% of participants) of one or more clinical adverse events, including fatigue, dizziness, nausea, gastrointestinal intolerance, headache, and sleep disorders (41,42,45). Although most adverse events were mild and self-limited, few premature discontinuations occurred (41,42,45). Laboratory abnormalities included elevated creatinine (41,42). Doravirine (DOR) and RPV are generally better tolerated than EFV (88). EFV-based PEP regimens are associated with premature discontinuation, mostly due to severe dizziness (43). Side effects observed with EFV include central nervous system (CNS) toxicity, elevated hepatic transaminases (including fulminant hepatitis), and QT interval prolongation (43,89–92). Thus, EFV is avoided in persons with severe liver disease (Child-Pugh classes B and C) and psychiatric illness. Other side effects include rash and hyperlipidemia (43).

The major disadvantages of currently available NNRTIs are the prevalence of NNRTI-resistant viral strains in ART-naive patients and the drugs’ low barrier for the development of resistance. The first-generation NNRTIs (e.g., EFV and NVP) require only a single mutation to confer drug resistance (47). Despite this, EFV-based regimens have excellent virologic efficacy, although the relatively high rate of adverse events (e.g., CNS related) can lead to nPEP discontinuation (93,94). Two controlled trials compared RPV with EFV in treatment-naïve patients in combination with two NRTIs and demonstrated comparable proportions of viral suppression at 48 weeks with improved tolerability of RPV. Compared with EFV and DRV/r, DOR is noninferior with excellent virologic efficacy and has fewer metabolic adverse effects and less potential for drug–drug interactions (88,94,95).

NRTI-Containing Regimens

Although less common with newer NRTIs, a hallmark toxicity of the NRTI class is mitochondrial toxicity. This toxicity might manifest as peripheral neuropathy, myopathy, pancreatitis, lipoatrophy, hepatic steatosis, and lactic acidosis (96–100).

Five studies had TAF-containing regimens as nPEP (n = 479) (2,11–13,46). Among four studies reporting completion rates of various TAF-containing regimens, the completion rates ranged from 82% to 96% without any HIV seroconversions (2,11–13,46).

Tenofovir can lead to kidney and bone toxicities, especially when used with a PK booster; however, TAF is associated with less renal and bone toxicity compared with TDF because it achieves lower plasma tenofovir concentrations (101,102). TAF might be associated with higher blood lipid levels than TDF (103). Both FTC and 3TC have been well tolerated with no significant treatment-limiting adverse effects (104). Rarely, 3TC has been associated with pancreatitis; this risk might be higher in children (105,106).

Less commonly used NRTIs include ABC and AZT. ABC is generally avoided due to concerns for developing an ABC hypersensitivity reaction and the need for HLA-B5701 testing. In addition, ABC generally is avoided in persons with coronary artery disease due to possible risk for myocardial infarction (107,108). Adverse reactions reported with AZT include headache, malaise, anorexia, nausea, vomiting, lactic acidosis, and loss of limb fat. A study examining nPEP longitudinal trends suggested that TDF-containing regimens were associated with significantly higher completion rates than AZT-containing regimens (adjusted OR = 2.80 [95% CI = 1.69–4.63; p<0.001]) (106).

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PK Boosters

PK enhancement, or PK boosting, for ART regimens contains either cobicistat or ritonavir. Regimens with cobicistat and ritonavir, both potent CYP3A enzyme inhibitors, might lead to significant interactions with medications metabolized by this enzyme (47). Cobicistat also inhibits active tubular secretion of creatinine, resulting in increases in serum creatinine and reduction in estimated creatinine clearance, without reducing glomerular function (109,110). Adverse effects of ritonavir include gastrointestinal intolerance, hyperlipidemia, bitter aftertaste, and malaise, some of which are dose-related (47).

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