Antiretroviral Drugs for HIV Postexposure Prophylaxis: The Evidence Behind the 2025 nPEP Guidelines

Nonoccupational postexposure prophylaxis (nPEP) — antiretroviral drugs taken after a possible HIV exposure outside work — has never been tested in a randomized, placebo-controlled trial. But open-label trials, cohort and observational studies and case reports all support the same conclusion: nPEP started soon after exposure and taken for 28 days with good adherence can reduce the risk of HIV. This appendix to CDC's 2025 nPEP guidelines summarizes the evidence by drug class.

How the review was done. A systematic review following PRISMA guidelines searched Medline, Embase, PsycINFO, Cochrane Library, CINAHL and Scopus for peer-reviewed U.S. studies (and MMWR reports) from January 2015 to January 2024; recommendations were graded with the GRADE framework. The work group also drew on HIV treatment trials to understand current standards of care. None of the drugs discussed has an FDA-approved indication for nPEP.

When nPEP fails, it's most often attributed to ongoing risk behavior after the course ends — though some studies point to late starts, poor adherence, and early HIV infection already present when nPEP began.

How each class has performed as nPEP

A 2015 systematic review found completion highest for darunavir/ritonavir plus TDF/FTC (94%), then lopinavir/ritonavir plus TDF/FTC (71%), and lowest for lopinavir/ritonavir plus AZT/3TC (59%); discontinuation for drug reactions was highest with atazanavir/ritonavir plus AZT/3TC (21%). A study of TDF regimens found them far more likely to be completed than AZT regimens (adjusted OR 2.80).

Long-acting injectable cabotegravir/rilpivirine was not included as a preferred or alternative regimen: no studies have looked at it as PEP, and an animal study found it only partly effective, with late breakthrough infections.

Risks of nPEP

The main concerns are serious side effects in otherwise healthy people taking antiretrovirals for a short time, and selecting for drug-resistant virus in anyone who acquires HIV despite nPEP — especially with inconsistent adherence, or if the source has resistant virus.

Integrase inhibitors (INSTIs)

• Generally well tolerated. Rarely, insomnia, depression and suicidal thoughts — mainly in people with a history of psychiatric illness. Weight gain is greater than with NNRTIs or PIs, but usually with longer use than a 28-day course.
• Bictegravir and dolutegravir: side effects mostly mild and self-limiting — fatigue, headache, nausea or vomiting, diarrhea; dolutegravir's moderate-to-severe ones were mainly insomnia and headache (stopping for headache, about 1%). Rare, reversible rises in creatinine and liver enzymes. In a 52-person trial, BIC/FTC/TAF caused fewer symptoms than older regimens.
• Elvitegravir/cobicistat: more frequent mild side effects — stomach discomfort, bloating, diarrhea, fatigue, nausea, headache, dizziness — though fewer than with PIs. Cobicistat strongly inhibits cytochrome P450, raising drug interaction risk.
• Raltegravir: occasional stomach upset, nausea, dizziness and headache; rare muscle toxicity, low platelets and severe Stevens-Johnson-like skin reactions.
• Bictegravir and dolutegravir have a higher barrier to resistance, fewer pills and better completion than the first-generation elvitegravir and raltegravir. In treatment trials, INSTIs were better tolerated and more often achieved viral suppression than boosted PIs or NNRTIs; resistance has been reported rarely with dolutegravir or bictegravir.

Protease inhibitors (PIs)

• Class effects include metabolic complications (insulin resistance, diabetes, abnormal lipids, lipodystrophy) and liver toxicity, varying by drug and booster. Most drug interactions come from the boosters ritonavir and cobicistat.
• Boosted darunavir is better tolerated than boosted lopinavir or atazanavir (partly because of atazanavir's raised bilirubin); its common side effects are fatigue, nausea, diarrhea, poor appetite and headache, sometimes rash or raised liver enzymes. INSTIs cause significantly fewer side effects.
• Atazanavir can cause kidney stones, kidney damage and gallstones; lopinavir/ritonavir has been linked in nPEP to acute kidney injury and ergotism with limb ischemia (a dihydroergotamine interaction).
• In one observational study of darunavir/ritonavir plus TDF/FTC (51 people), 47% stopped early, six for treatment-related reasons. PI regimens with AZT carry a much higher risk of stopping because of stomach side effects (relative risk 9.33).
• Some PIs (darunavir/ritonavir, lopinavir/ritonavir) were linked to more cardiovascular events in long-term HIV treatment; the relevance to a 28-day course is unknown.
• Despite more interaction potential, boosted darunavir shows excellent completion and tolerability; DRV/c/TAF/FTC is a single daily tablet that can be considered in some situations.

NNRTIs

• Efavirenz and rilpivirine can cause QTc prolongation, rash, and neurologic and psychiatric effects including depression.
• Rilpivirine/FTC/TDF: up to 88% had at least one side effect — fatigue, dizziness, nausea, stomach upset, headache, sleep problems — mostly mild, with few early stops.
• Efavirenz: central nervous system toxicity, liver problems (including fulminant hepatitis) and QT prolongation; avoided in severe liver disease and psychiatric illness. Doravirine and rilpivirine are better tolerated.
• NNRTI resistance is common in untreated patients, and first-generation drugs need only one mutation to fail. Doravirine matched efavirenz and darunavir/ritonavir in effectiveness with fewer metabolic effects and interactions.

NRTIs

• The class's hallmark toxicity is mitochondrial — neuropathy, myopathy, pancreatitis, fat loss, fatty liver, lactic acidosis — less common with newer drugs.
• Tenofovir can harm kidneys and bone, especially with a booster; TAF does so less than TDF, but may raise blood lipids. FTC and 3TC are well tolerated (3TC rarely causes pancreatitis, perhaps more in children).
• Abacavir is generally avoided — risk of hypersensitivity (HLA-B*5701 testing needed) and possible heart attack risk in coronary artery disease. AZT causes headache, malaise, poor appetite, nausea, vomiting, lactic acidosis and limb fat loss.

Boosters

Ritonavir and cobicistat strongly inhibit the CYP3A enzyme, so they can interact with many medicines. Cobicistat also raises measured serum creatinine without actually reducing kidney function; ritonavir can cause stomach upset, high lipids, a bitter aftertaste and malaise.

Sources

Based on "Appendix B: A Summary Discussion of Characteristics of Antiretroviral Agents Used for Nonoccupational Postexposure Prophylaxis," from CDC's 2025 update of the U.S. nPEP guidelines, MMWR Recommendations and Reports volume 74, number 1, Centers for Disease Control and Prevention; a work of the United States government in the public domain. This summary is for general information; clinical decisions should follow the full guideline.