HIV Infection: Prevention
Clinical Snapshot
Pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) use antiretroviral drugs to prevent HIV acquisition in an HIV-negative person, rather than to treat established infection — the subject of a separate chapter. PrEP is taken before an exposure and continued through an ongoing period of risk; PEP is a short course started after a specific exposure, and is further described by setting as occupational PEP (a workplace exposure, e.g. a needlestick) or non-occupational PEP (nPEP, following a sexual exposure or shared injection equipment) — current Canadian guidance uses largely the same drug regimens and timelines for both settings. Every prophylaxis decision rests on two inputs: the type of exposure and the likelihood that the source person has transmissible HIV infection.[1] Because starting or continuing PrEP during an undiagnosed acute HIV infection can select for drug-resistant virus, confirming a current negative HIV status is a precondition for every strategy in this chapter, not an afterthought.
Recognize the Condition
PrEP, PEP, and nPEP at a glance
| PrEP | Occupational PEP | Non-occupational PEP (nPEP) | |
|---|---|---|---|
| When it is used | Before, and throughout, an ongoing period of HIV risk | After a workplace exposure (e.g. needlestick, mucous-membrane splash) | After a single sexual exposure or episode of shared injection equipment |
| Timing to start | Elective; started whenever risk is identified | As soon as possible, ideally within hours, no later than 72 hours | As soon as possible, ideally within 24 hours, no later than 72 hours |
| Course length | Ongoing, reassessed at least every 3 months | 28 days | 28 days |
Recognizing acute HIV seroconversion
Acute retroviral syndrome can occur in anyone with a recent HIV exposure, including a patient already taking PrEP who acquired HIV despite it, or a patient who was in the undiagnosed window when PrEP was started. It is nonspecific and easy to mistake for a viral upper respiratory illness or mononucleosis, so ask about it directly in anyone being considered for, or already using, PrEP or PEP/nPEP.
- Fever
- Rash
- Sore throat (pharyngitis)
- Oral ulcers
- Fatigue and malaise
- Night sweats
- Myalgia and arthralgia (muscle and joint pain)
- Lymphadenopathy (swollen lymph nodes)
- Loss of appetite
Recognizing a qualifying exposure for PEP/nPEP
| Relative risk | Exposure type |
|---|---|
| Higher risk | Receptive anal intercourse; sharing injection drug-use equipment (needles, syringes, or other paraphernalia) |
| Moderate risk | Insertive anal intercourse; receptive vaginal/front-hole intercourse; insertive vaginal/front-hole intercourse |
| Low or negligible risk | Receptive or insertive oral sex; oral-anal contact; sharing sex toys; blood contact with non-intact (compromised) skin |
These tiers describe the exposure act itself and are combined with the source person's HIV risk category (see Assessment & Diagnosis) to decide whether PEP/nPEP is indicated.[1]
Risk Factors
- Anyone who requests PrEP should be offered it, regardless of whether specific risk factors are elicited — self-assessed risk is a sufficient indication on its own, since a targeted risk-factor checklist can underestimate a person's actual risk.[1]
- Clinicians should raise PrEP with every sexually active patient at least once, since at-risk individuals are often missed when screening relies only on a patient volunteering risk information.[2]
- Condomless anal intercourse in the past 6 months in a man who has sex with men or a transgender woman, together with any of: infectious syphilis or a rectal bacterial STI, recurrent use of nPEP, or an ongoing sexual relationship with a partner who has HIV infection with a substantial risk of transmissible virus.
- Condomless vaginal/front-hole or anal intercourse with a partner known to have HIV infection with a substantial or low-but-nonzero (not negligible) risk of transmissible virus, in a person having heterosexual sex.
- Sharing injection drug-use equipment with a person who has a non-negligible risk of HIV infection, or otherwise meeting the sexual-risk criteria above.
- A sexually transmitted infection diagnosed within the past 6-12 months.
- Recurrent nPEP use — this specifically signals ongoing risk and should prompt a PrEP discussion rather than repeated PEP courses.
- Transgender individuals face a disproportionately increased HIV risk driven by intersecting social and structural factors and should be assessed for PrEP based on individual risk rather than a single behavioural checkbox.
- Adolescents with any of the above risk factors may also be candidates for PrEP, with more frequent follow-up to support adherence.
Red Flags & Refer
Confirming the absence of current or very recent HIV infection is a precondition for starting or continuing any strategy in this chapter — treating an undiagnosed infection with PrEP alone, or continuing PrEP through a new seroconversion, risks selecting for drug-resistant virus.
- Do not start or continue PrEP if the patient has signs or symptoms of acute HIV seroconversion (see Recognize the Condition) — assess for acute infection first (repeat HIV testing in 7-21 days, or an HIV RNA nucleic acid test if available) and defer PrEP until results return.
- A positive or indeterminate HIV test at any point while on PrEP or PEP/nPEP — stop the regimen immediately and refer urgently for confirmatory testing and HIV treatment, since a 1- or 2-drug prophylactic regimen is inadequate treatment for established infection and risks resistance if continued.
- Significant renal impairment (creatinine clearance under 30 mL/min) — PrEP should not be used; tenofovir disoproxil fumarate-containing PrEP specifically should not be given at a creatinine clearance under 60 mL/min.
- A PEP/nPEP candidate presenting beyond the 72-hour window — do not simply decline; reassess exposure severity and elapsed time, since an exceptionally high-risk exposure may still warrant expert consultation on late initiation, and the visit should still include risk-reduction counselling, baseline testing, and follow-up regardless of the PEP decision.
- Suspected non-consensual exposure (sexual assault) — offer sexual assault support services in addition to the standard nPEP assessment.
- Known or suspected drug-resistant virus in the source person — obtain expert guidance on regimen selection rather than using a standard first-line PEP/nPEP regimen.
- Severe hypersensitivity, suspected hepatotoxicity, or a severe skin reaction on any PrEP or PEP/nPEP agent — stop the implicated drug and refer for urgent assessment.
Assessment & Diagnosis
Categorizing the source person's HIV risk
Whether PEP/nPEP is indicated, and whether PrEP should be offered, both depend on how likely the source partner is to have transmissible HIV infection.[1]
| Category | Examples |
|---|---|
| Substantial risk | Confirmed HIV-positive with a detectable viral load; or HIV status unknown but from a population with disproportionately high HIV prevalence (e.g. men who have sex with men, people who inject drugs). |
| Low but nonzero risk | Confirmed HIV-positive with a viral load believed to be suppressed, with a concurrent sexually transmitted infection present at the time of exposure. |
| Negligible or none | Confirmed HIV-negative; confirmed HIV-positive with a suppressed viral load and no concurrent STI; or HIV status unknown, general population. |
PrEP candidacy assessment
History: sexual history, including gender identity, sexual orientation, sexual behaviours and anatomy, drug use, number/type of partners, and condom use; substance use, including methamphetamine or other drug use during sex; STI history within the past 6-12 months; and prior nPEP use.
Physical exam: screen for signs or symptoms of acute HIV infection (see Recognize the Condition) and for signs of any STI.
Baseline labs: an HIV test — a 4th-generation combination antibody/antigen assay is preferred — confirmed negative shortly before starting; syphilis serology; chlamydia and gonorrhea screening by urine NAAT plus throat and rectal swabs as indicated by exposure sites; hepatitis A, B, and C serologies, with vaccination offered against hepatitis A and B if nonimmune; renal function (serum creatinine/creatinine clearance) and urinalysis; and a pregnancy test for anyone of childbearing potential.
Hepatitis B or C infection is not a contraindication to PrEP, but liver function should be monitored for hepatitis B reactivation if emtricitabine/tenofovir DF or emtricitabine/tenofovir AF (both active against hepatitis B) is later discontinued — neither is active against hepatitis C.
PEP/nPEP assessment
Assess exposure timing (indicated within 72 hours) and exposure type (see Recognize the Condition); for nPEP, distinguish consensual from non-consensual exposure and offer sexual assault support services when applicable. Where possible, assess the source person's HIV status without delaying PEP/nPEP initiation — if the source is later confirmed HIV-negative, PEP/nPEP can be stopped and no further HIV follow-up testing of the exposed person is required. If the source has known HIV infection and consents to disclosure, obtain a viral load and resistance history to guide regimen selection.
Baseline labs for the exposed person: an HIV test (4th-generation combination assay, plus a point-of-care test if available); hepatitis B serology (surface antigen, surface antibody, core antibody), hepatitis C antibody, and alanine aminotransferase; a pregnancy test where appropriate; and renal function with a complete blood count if PEP/nPEP is being considered.
Do not delay initiation of PEP/nPEP while awaiting any test result.
When prophylaxis is not indicated
PrEP is not indicated when both the exposure type and the source person's risk category are negligible or none. PEP/nPEP is not indicated after a low-risk exposure, or when the source meets the U=U criteria above.
Treatment Targets
- Prevent HIV acquisition in an HIV-negative individual with ongoing or recent exposure risk.
- Avoid initiating or continuing prophylaxis in someone with undiagnosed acute or established HIV infection, which risks selecting drug-resistant virus.
- Achieve and sustain the level of adherence the chosen regimen needs for its protective effect.
- Identify and treat any coexisting STI, and offer hepatitis A/B vaccination where indicated.
- Transition anyone with recurrent PEP/nPEP need onto PrEP without a gap in protection.
Choose Initial Treatment
PrEP initiation
1st line daily oral emtricitabine 200 mg / tenofovir disoproxil fumarate 300 mg, once a negative HIV test and adequate renal function (creatinine clearance at least 60 mL/min) are confirmed — it is the most broadly evidence-supported option across anatomies and exposure types.[1]
On-demand ("2-1-1") dosing of the same emtricitabine/tenofovir DF tablet is an alternative for cisgender and transgender men, and transgender women, having planned, predictable receptive or insertive anal intercourse — it is not recommended for anyone whose risk is from receptive vaginal/front-hole intercourse, given insufficient evidence of efficacy in that population.[4]
Daily oral emtricitabine 200 mg / tenofovir alafenamide 25 mg is an alternative where renal or bone concerns favour it, down to a creatinine clearance of 30 mL/min — current product labelling does not support its use for PrEP against risk from receptive vaginal/front-hole intercourse, since this population was not included in the trial establishing its efficacy, and it should not be used on an on-demand schedule.[5]
Long-acting injectable cabotegravir is a preferred option for a patient who prefers, or would adhere better with, an injectable over a daily pill — it outperformed daily oral emtricitabine/tenofovir DF in randomized trials in both men who have sex with men/transgender women and cisgender women.[6][7]
Long-acting injectable lenacapavir is Health Canada-authorized for PrEP as of 2026 (brand name Yeytuo); use it per current product labelling, since incorporation into a fully updated Canadian clinical guideline is still pending — see Special Populations and Drug Tables for its specific testing and dosing requirements, including a testing caveat unique to this agent.[8]
PEP and nPEP initiation
Offer PEP/nPEP to any HIV-negative person presenting within 72 hours of a higher- or moderate-risk exposure where the source person has a non-negligible risk of transmissible HIV — start as soon as possible, ideally within hours for an occupational exposure and within 24 hours for a non-occupational exposure, since protective benefit is time-dependent and falls off the longer initiation is delayed.[1][9]
Preferred PEP/nPEP regimen a single daily tablet of bictegravir/emtricitabine/tenofovir alafenamide, or dolutegravir 50 mg once daily plus emtricitabine/tenofovir DF (or emtricitabine/tenofovir AF) once daily — either is appropriate first-line, for occupational and non-occupational exposures alike.[1][9]
Alternative 3rd agent raltegravir, or ritonavir-boosted darunavir — favour ritonavir-boosted darunavir specifically when the source person's virus is known or suspected to be drug-resistant; it is generally well tolerated but carries a high drug-interaction burden and must be taken with food.
PEP/nPEP is prescribed for a full 28-day course; do not prescribe an initial supply beyond that, and do not routinely extend it. Do not delay the first dose to await source-person or baseline test results.
Non-Pharmacologic Treatment
- Offer HIV/STI prevention counselling, condoms, and regular testing to every individual, regardless of which prophylactic strategy is chosen — PrEP and PEP/nPEP protect against HIV only, not other STIs or pregnancy.
- Regular STI testing is specifically recommended for anyone on PrEP, since an increased rate of other STIs has been observed among some PrEP users.
- Offer proven harm-reduction services to people who inject drugs, including access to sterile needles, syringes, and other injection equipment, and opioid agonist therapy.
- Screen for and address comorbid mental health and substance use concerns, and unstable housing, food, or financial insecurity, as part of a comprehensive prevention strategy — these barriers strongly affect adherence and follow-up.
- For nPEP following a non-consensual exposure, offer sexual assault support services alongside the standard medical assessment.
- Counsel on secondary-transmission precautions during PEP/nPEP, and until the 3-month HIV test is confirmed negative: barrier contraception, avoiding blood or tissue donation, and deferring pregnancy or breastfeeding where feasible.
- Build adherence support proactively into every visit — reminder tools, pharmacist-led follow-up, and addressing drug coverage or access barriers — since the protective effect of every PrEP option is directly tied to how consistently it is taken or received on schedule.[2]
Special Populations
Pregnancy
For PrEP, emtricitabine/tenofovir DF has the most pregnancy safety data and is the preferred agent if PrEP is used in pregnancy, with no dose adjustment required. For PEP/nPEP, preferred regimens in pregnancy are emtricitabine/tenofovir DF plus dolutegravir 50 mg once daily, or plus raltegravir 400 mg twice daily (the standard, not the once-daily high-dose, formulation, given a lack of pregnancy data for the high-dose tablet), or plus ritonavir-boosted darunavir 800/100 mg once daily — once-daily darunavir/ritonavir dosing is considered adequate specifically for the lower, prophylactic viral burden of PEP/nPEP, even though twice-daily dosing is used to treat established HIV infection in pregnancy. Lamivudine/zidovudine may substitute for emtricitabine/tenofovir DF in pregnancy. Avoid elvitegravir/cobicistat-containing regimens in pregnancy given the risk of subtherapeutic levels as pregnancy progresses.
Breastfeeding
PrEP may be used while breastfeeding where the benefit — avoiding maternal HIV acquisition, which carries a very high risk of transmission to the infant if acquired during lactation — outweighs the risk; emtricitabine and tenofovir DF are both transferred into breast milk at low-to-moderate levels. For PEP/nPEP, weigh the same risk-benefit through shared decision-making; pausing breastfeeding is sometimes advised specifically when a higher-risk exposure requires nPEP.
Pediatrics and adolescents
Daily oral PrEP, cabotegravir, and lenacapavir are all authorized from 12 years of age and a minimum body weight of 35 kg — the same dual age-and-weight threshold applies across all three, not just the injectables. On-demand dosing is not established in adolescents; use daily dosing in this age group. Adolescents may need more frequent follow-up visits to support adherence than adults.
Renal impairment
PrEP should not be used at a creatinine clearance under 30 mL/min. Emtricitabine/tenofovir DF should not be used at a creatinine clearance under 60 mL/min; emtricitabine/tenofovir AF may be used down to 30 mL/min, a practical advantage in mild-to-moderate renal impairment. Cabotegravir and lenacapavir require no dose adjustment for renal impairment.
Hepatitis B or C coinfection
Neither is a contraindication to PrEP. Because emtricitabine/tenofovir DF and emtricitabine/tenofovir AF are both active against hepatitis B, stopping either requires monitoring for a hepatitis B flare; neither drug is active against hepatitis C.
People who inject drugs
PrEP is indicated per the sexual- or equipment-sharing risk criteria above; combine PrEP with harm-reduction services rather than treating them as alternatives to each other.
Transgender individuals
Elicit the patient's own anatomy and their partners' anatomy directly and non-judgmentally to select an appropriate regimen — PrEP drug concentrations and adherence requirements differ meaningfully between rectal and vaginal/front-hole tissue, so regimen and dosing-schedule choice (for example, avoiding on-demand dosing or emtricitabine/tenofovir AF for vaginal/front-hole-only risk) must reflect the individual's actual anatomy and exposure type, not an assumption based on gender identity.[10]
Monitoring & Follow-Up
PrEP
Consider a tolerability/adherence check at 30 days, then formal reassessment at least every 3 months while on daily oral or on-demand PrEP: an HIV test, renal function (serum creatinine at 30 days, then every 3 months while on a tenofovir DF-containing regimen), an STI screen (syphilis, chlamydia, gonorrhea), and a pregnancy test where appropriate; repeat hepatitis C antibody (and a hepatitis B screen if nonimmune) annually. Do not issue a PrEP prescription beyond a 90-day supply without reconfirming a negative HIV status first.
For cabotegravir, confirm a negative HIV test before every injection and maintain the every-2-month injection schedule (a window of about 7 days on either side is acceptable). For lenacapavir, confirm a negative HIV test using a method sensitive enough to detect very recent infection before every dose, and maintain the every-26-week injection schedule.
Discontinuing oral PrEP: protection decreases over the 7-10 days following the last dose; a patient with a long history of adherent daily use may need only about 2 further days of dosing after their last exposure, while others (e.g. people who inject drugs, or women, given tissue-specific pharmacokinetics) may reasonably continue for up to 28 days by extrapolation from PEP data. HIV testing at 8 weeks after discontinuation is reasonable, since drug levels on PrEP can delay antibody detection. Discontinuing an injectable (cabotegravir or lenacapavir) requires bridging to another effective PrEP method, generally starting within about 2 months of the last injection and continuing for up to a year, given how long detectable drug levels persist.
PEP and nPEP
Reassess within 72 hours to confirm tolerability and adjust the regimen if source-person test results have since become available. Follow-up HIV testing at 6 weeks and 3 months after exposure reflects current, shortened guidance built around more sensitive HIV assays; extend testing to 6 months specifically if hepatitis C was acquired from the same exposure, given a risk of delayed HIV seroconversion in that setting.[9] Hepatitis B and C serology are repeated per baseline results and exposure type. Repeat serum creatinine and a complete blood count at 2 weeks only if baseline results were abnormal or the patient is symptomatic — routine repeat toxicity labs are no longer required when baseline results are normal and the patient remains asymptomatic.[9] Anyone who has needed nPEP more than once should be assessed for, and offered, PrEP — ideally starting immediately after completing the current 28-day nPEP course to avoid a gap in protection.
Common Errors to Avoid
- Starting or continuing PrEP without a current, confirmed negative HIV test, or without repeating testing when acute infection is suspected — the single highest-stakes error in this chapter.
- Prescribing on-demand ("2-1-1") dosing or emtricitabine/tenofovir AF for a patient whose risk is from receptive vaginal/front-hole intercourse — neither is supported for this population.
- Issuing a PrEP prescription beyond a 90-day supply without reconfirming HIV-negative status first.
- Delaying PEP/nPEP initiation to await source-person testing or baseline labs — start promptly and adjust later if needed.
- Missing that a patient has repeatedly needed nPEP without ever being offered PrEP.
- Stopping emtricitabine/tenofovir DF or AF in a patient with hepatitis B coinfection without monitoring for a hepatitis flare.
- Continuing routine toxicity labs (e.g. fixed-interval repeat CBC/creatinine) for an asymptomatic PEP/nPEP patient whose baseline results were normal — this is no longer required.
- Treating a missed or late long-acting injectable PrEP dose as a minor scheduling issue rather than a genuine protection gap that needs bridging and reassessment.
- Forgetting that PrEP and PEP/nPEP protect against HIV only — condoms, STI testing, and contraception still need separate attention.
Clinical Decision Algorithm
Drug Tables
How to use this table: doses are adult doses and require patient-specific confirmation, including renal/hepatic adjustment. Pediatric dosing for PrEP and PEP/nPEP is authorized only from 12 years of age (and, for the injectables, a minimum body weight) — it is not established below that threshold and should not be extrapolated without specialist input. Select any drug name to open its complete Pharmasist Drug Database page.
Coformulated NRTI/NtRTI combinations (PrEP daily/on-demand backbone; PEP/nPEP backbone)
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Emtricitabine / tenofovir DF | Adults, daily PrEP or PEP/nPEP backbone: 200 mg/300 mg PO once daily Adults, on-demand PrEP (anal-intercourse risk only): 2 tablets 2-24 h before sex, then 1 tablet 24 h later, then 1 more tablet 24 h after that Adolescents (≥35 kg): Same as adult daily dose; on-demand dosing not established in this age group | Headache, nausea, diarrhea, flatulence; long-term renal toxicity and decreased bone mineral density | Avoid combining with other nephrotoxic drugs; review the full medication list for additional interactions | Not recommended if creatinine clearance is under 60 mL/min. Adolescents ≥35 kg: same dose as adults. Confirm HIV-negative status before starting and every 3 months while continuing. |
| Emtricitabine / tenofovir AF | Adults: 200 mg/25 mg PO once daily Adolescents (≥35 kg): Same as adult dose | Less renal/bone impact than tenofovir DF; weight gain reported when used for PrEP | Avoid combining with other nephrotoxic drugs | Not indicated for PrEP against receptive vaginal/front-hole intercourse risk. Not for on-demand dosing. Combination not recommended if creatinine clearance is under 30 mL/min. |
| Bictegravir / emtricitabine / tenofovir AF | Adults, PEP/nPEP: 1 tablet PO once daily × 28 days | Nausea, headache, diarrhea | Fewer interactions than a ritonavir- or cobicistat-boosted regimen; still review the full medication list | Single-tablet preferred PEP/nPEP regimen. Not authorized as a standalone PrEP product. |
Individual NRTIs/NtRTIs (PEP/nPEP alternative backbone components)
Used when the coformulated tablet above is not appropriate, e.g. for renal-impairment dose separation.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Lamivudine | Adults: 150 mg PO BID, or 300 mg PO once daily | Minimal toxicity; generally well tolerated | Low potential for drug interactions | Alternative backbone component with tenofovir DF when the coformulated tablet is not suitable. |
| Tenofovir DF | Adults: 300 mg PO once daily | Headache, nausea, diarrhea, flatulence; renal toxicity, decreased bone mineral density with long-term use | Avoid combining with other nephrotoxic drugs | Not recommended for PrEP if creatinine clearance is under 60 mL/min. Paired with lamivudine as an alternative backbone. |
| Zidovudine | Adults: 300 mg PO BID | Nausea, headache, malaise, fatigue, rash, myositis, anemia, leukopenia, hepatic steatosis | Additive hemotoxicity with other bone-marrow-suppressing drugs; numerous other interactions -- consult a drug interaction resource | Component of lamivudine/zidovudine; may be given separately from lamivudine when renal impairment requires individualized dosing. |
| Lamivudine / zidovudine | Adults: 150 mg/300 mg PO BID | As for the individual components | As for the individual components | Alternative PEP/nPEP backbone to emtricitabine/tenofovir DF, e.g. in significant renal impairment; components may be dosed separately if renal adjustment is needed. |
Long-acting injectable PrEP
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Cabotegravir | Optional oral lead-in: 30 mg PO once daily for ≥28 days Initiation injections: 600 mg IM ×2, one month apart Maintenance injections: 600 mg IM every 2 months | Injection site reactions (pain, swelling, nodules), headache, fatigue, diarrhea; rare hepatotoxicity, severe hypersensitivity, or mood changes including depression | Contraindicated with strong UGT1A1/UGT1A9 inducers (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine); separate oral antacids by several hours | A documented negative HIV test is required before starting and before every injection. No dose adjustment needed for renal or hepatic impairment (not studied in severe hepatic impairment). Authorized from 12 years of age and 35 kg body weight. |
| Lenacapavir (PrEP) | Oral lead-in: 600 mg PO on Day 1 and again on Day 2 Initiation injection: 927 mg SC (2 injections) on Day 1 Maintenance injections: 927 mg SC (2 injections) every 26 weeks | Injection site reactions (pain, swelling, nodules) very common and can persist for weeks; headache, nausea, fatigue, diarrhea | Contraindicated with strong CYP3A inducers (rifampin, rifapentine, carbamazepine, phenytoin, St. John's wort) | Use a testing method sensitive enough to detect very recent infection before every dose, given a delayed-antibody-detection concern specific to this drug class. Detectable drug levels persist for a year or longer after the last dose -- bridge to another PrEP method on discontinuation. Authorized from 12 years of age and 35 kg body weight. |
Integrase inhibitors (PEP/nPEP 3rd agent)
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Dolutegravir | Adults: 50 mg PO once daily × 28 days | Early, benign increase in serum creatinine; insomnia and other CNS effects (headache, fatigue, depression) | Separate from polyvalent-cation products (antacids, iron, calcium, magnesium, sucralfate) by 2 h before or 6 h after; significantly increases metformin levels | Preferred PEP/nPEP 3rd agent alongside emtricitabine/tenofovir DF or AF. |
| Raltegravir | Adults, standard tablet: 400 mg PO BID × 28 days Adults, high-dose tablet: 1200 mg (2 × 600 mg) PO once daily × 28 days | Generally well tolerated; infrequent insomnia/CNS effects; rare severe skin or hypersensitivity reactions | Not a CYP inhibitor/inducer; rifampin lowers levels (increase raltegravir dose if coadministered); avoid aluminum/magnesium antacids with any strength, and calcium antacids with the high-dose formulation | Alternative 3rd agent, e.g. when dolutegravir/bictegravir is unavailable or not tolerated. |
Protease inhibitors (PEP/nPEP alternative 3rd agent, e.g. known/suspected source drug resistance)
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Darunavir + ritonavir | Adults: 800 mg PO once daily with ritonavir 100 mg PO once daily × 28 days | Diarrhea, nausea, headache, rash (possible cross-sensitivity with sulfonamides) | High interaction burden via CYP3A -- review the full medication list before starting | Take with food. A reasonable 3rd-agent choice when the source person's virus is known or suspected to be drug-resistant. |
| Ritonavir (booster) | Adults: 100 mg PO once daily, with the boosted agent | GI upset, diarrhea, liver enzyme elevations | Potent CYP3A inhibitor -- high interaction burden; review the full medication list before starting | Used only as a low-dose booster with darunavir or atazanavir, never as a sole protease inhibitor. |
| Darunavir / cobicistat | Adults: 800 mg/150 mg PO once daily with food × 28 days | As for darunavir; early, benign increase in serum creatinine from cobicistat | Cobicistat is a potent CYP3A inhibitor -- high interaction burden | Single-tablet alternative to separate darunavir plus ritonavir; do not combine with ritonavir. |
| Atazanavir + ritonavir | Adults: 300 mg PO once daily with ritonavir 100 mg PO once daily × 28 days, with food | Benign hyperbilirubinemia/jaundice in genetically predisposed patients; less commonly kidney stones, rash | Absorption is acid-dependent -- separate from antacids/H2-blockers; contraindicated with proton pump inhibitors | Legacy alternative 3rd agent; less commonly used now that integrase-inhibitor-based regimens are preferred. |
| Lopinavir / ritonavir | Adults: 400 mg/100 mg PO BID (or 800 mg/200 mg PO once daily) with food × 28 days | GI intolerance (diarrhea, nausea) common; less well tolerated than other protease inhibitors | High interaction burden via CYP3A | Legacy alternative reserved for when other 3rd-agent options are unavailable or unsuitable. |
References
- Canadian guideline on HIV pre- and postexposure prophylaxis: 2025 update — CMAJ (Tan DHS, Hull MW, Onyegbule SO, et al.). CMAJ 2025;197(41):E1374-E1391
- Preexposure Prophylaxis for the Prevention of HIV Infection in the United States — 2021 Update: A Clinical Practice Guideline — US Public Health Service, Centers for Disease Control and Prevention. CDC Clinical Practice Guideline, 2021
- Viral suppression and HIV transmission in serodiscordant male couples: an international, prospective, observational, cohort study — Lancet HIV (Bavinton BR, Pinto AN, Phanuphak N, et al.). Lancet HIV 2018;5(8):e438-e447
- On-Demand Preexposure Prophylaxis in Men at High Risk for HIV-1 Infection — New England Journal of Medicine (Molina JM, Capitant C, Spire B, et al.). N Engl J Med 2015;373(23):2237-2246
- Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial — Lancet (Mayer KH, Molina JM, Thompson MA, et al.). Lancet 2020;396(10246):239-254
- Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women — New England Journal of Medicine (Landovitz RJ, Donnell D, Clement ME, et al.). N Engl J Med 2021;385(7):595-608
- Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial — Lancet (Delany-Moretlwe S, Hughes JP, Bock P, et al.). Lancet 2022;399(10337):1779-1789
- Clinical Recommendation for the Use of Injectable Lenacapavir as HIV Preexposure Prophylaxis — United States, 2025 — MMWR Morbidity and Mortality Weekly Report (Patel RR, Hoover KW, Lale A, et al.). MMWR Morb Mortal Wkly Rep 2025;74(35):541-549
- 2025 US Public Health Service Guidelines for the Management of Occupational Exposures to Human Immunodeficiency Virus and Recommendations for Post-exposure Prophylaxis in Healthcare Settings — Infection Control & Hospital Epidemiology (Kofman AD, Struble KA, Heneine W, et al.). Infect Control Hosp Epidemiol 2025;46(9):863-873
- A Translational Pharmacology Approach to Predicting Outcomes of Preexposure Prophylaxis Against HIV in Men and Women Using Tenofovir Disoproxil Fumarate With or Without Emtricitabine — Journal of Infectious Diseases (Cottrell ML, Yang KH, Prince HMA, et al.). J Infect Dis 2016;214(1):55-64
Professional reference only. Apply clinical judgment and verify patient-specific decisions against current authoritative guidance and product information.