Immune System

HIV pre-exposure prophylaxis: candidate selection and monitoring

Clinical Overview and When to Suspect PrEP Candidacy

— TDF/FTC (Truvada): daily oral, approved for all at-risk adults and adolescents ≥35 kg, including receptive vaginal exposure

— TAF/FTC (Descovy): daily oral, NOT approved for persons at risk via receptive vaginal sex (efficacy not established)

— Cabotegravir IM (Apretude): long-acting injectable every 2 months after loading doses; superior to oral in trials due to adherence

— Any patient who asks about PrEP — always offer regardless of risk disclosure

— Sexually active MSM or transgender women with inconsistent condom use, multiple partners, or recent STI

— Heterosexual adults with a partner of unknown or positive HIV status, especially serodifferent couples planning conception

— People who inject drugs (PWID) sharing equipment

— Recent bacterial STI (syphilis, gonorrhea, chlamydia) in the past 6 months

— Commercial sex workers, history of transactional sex

— Repeat users of nPEP (non-occupational post-exposure prophylaxis)

HIV pre-exposure prophylaxis (PrEP) is daily or on-demand antiretroviral therapy given to HIV-negative individuals at substantial risk of acquiring HIV, reducing sexual transmission by ~99% with consistent adherence and injection-related transmission by ~74%.

USPSTF Grade A recommendation (2023): clinicians should prescribe PrEP to persons at increased risk of HIV acquisition. ACA mandates coverage without cost-sharing, including the medication, labs, and clinic visits.

Three FDA-approved regimens:

When to suspect a PrEP candidate in primary care:

Step 3 management: PrEP is an outpatient longitudinal responsibility. The family physician should normalize sexual history-taking using the 5 P's (Partners, Practices, Protection, Past STIs, Pregnancy) at routine visits and proactively offer PrEP — not wait for the patient to ask.

Board pearl: Universal opt-out HIV screening (ages 13–64) is the gateway that surfaces PrEP candidates; the encounter that diagnoses an STI is the moment to discuss PrEP.

Presentation Patterns and Key History

— Partners: number in last 6 months, gender of partners, HIV status of partners (positive, negative, unknown), partner on ART with undetectable viral load (U=U)

— Practices: receptive vs insertive anal, vaginal, oral; condom use frequency; group sex; chemsex

— Protection from STIs: condoms, prior PrEP, doxy-PEP eligibility

— Past STIs: syphilis, GC/CT (especially rectal/pharyngeal), HSV, HPV, hepatitis

— Pregnancy intention: conception planning in serodifferent couples is a strong PrEP indication

— Injection drug use, equipment sharing, supervised consumption site access

— Methamphetamine, GHB, poppers (associated with condomless anal sex)

— Alcohol use that impairs protective decisions

— Renal disease (CrCl threshold), bone health, hepatitis B status (TDF/TAF treats HBV — stopping risks flare)

— Pregnancy status and breastfeeding plans

— Concurrent nephrotoxins (NSAIDs, aminoglycosides)

PrEP encounters are anticipatory, not symptom-driven. The "presentation" is a patient requesting PrEP, presenting after a high-risk exposure, completing nPEP, or screening positive for a bacterial STI.

Essential sexual history elements (5 P's expanded):

Substance use history:

Screen for acute HIV symptoms in the last 4 weeks before starting: fever, pharyngitis, rash, lymphadenopathy, myalgia, mouth ulcers — acute retroviral syndrome must be excluded because starting PrEP during acute HIV leads to resistance.

Medication and medical history:

Key distinction: A patient on TasP/U=U (the HIV+ partner has sustained undetectable viral load ≥6 months on ART) has effectively zero sexual transmission risk — PrEP is optional, not mandatory, and shared decision-making applies. But if adherence to the partner's ART is uncertain, offer PrEP.

Board pearl: A patient presenting for their third course of nPEP in a year should be transitioned to PrEP — recurrent nPEP is itself an indication.

Physical Exam Findings and Risk Assessment

— Vital signs and BMI: baseline for monitoring TDF-related weight changes (TAF actually associated with mild weight gain)

— Skin: rash suggestive of acute HIV, secondary syphilis (palms/soles), Kaposi sarcoma lesions

— Oropharynx: thrush (suggests immunocompromise — defer PrEP, work up for HIV), pharyngeal exudate, mucosal ulcers (HSV, syphilitic chancre)

— Lymph nodes: generalized lymphadenopathy raises concern for acute or established HIV

— Anogenital exam: condylomata, ulcers (HSV, syphilis, chancroid, LGV), discharge, proctitis findings

— Injection sites: track marks, abscesses, cellulitis in PWID

— HIRI-MSM score (HIV Incidence Risk Index for MSM): score ≥10 suggests substantial benefit from PrEP

— CDC indicators: any condomless anal/vaginal sex in past 6 months with partner of unknown/positive status, bacterial STI in past 6 months, or ongoing injection-equipment sharing

PrEP candidates are usually asymptomatic; the exam is a baseline and surveillance exam, not diagnostic.

Targeted physical exam at PrEP initiation:

Cardiopulmonary and abdominal exam are typically unremarkable but should be documented as part of annual preventive care.

Mental health screen: PHQ-9, GAD-7, and intimate partner violence (IPV) screening — IPV can limit a patient's ability to negotiate condom use or take daily medication, making long-acting injectable cabotegravir preferred.

Risk-assessment frameworks:

Step 3 management: If exam reveals features of acute retroviral syndrome (fever + rash + pharyngitis + lymphadenopathy), DO NOT start oral PrEP — order HIV RNA (viral load) plus 4th-gen Ag/Ab; starting tenofovir-based PrEP during seroconversion can select for M184V resistance and compromise future treatment.

Board pearl: Document a chaperoned anogenital exam when clinically indicated and offer self-collected swabs as an alternative to improve uptake among patients with prior trauma.

Diagnostic Workup — Baseline Labs Before Starting PrEP

— HIV testing: 4th-generation HIV-1/2 Ag/Ab immunoassay PLUS HIV-1 RNA (viral load) if any exposure within the prior 4 weeks or any acute retroviral symptoms. RNA testing detects window-period infections that antigen/antibody may miss.

— Hepatitis B: HBsAg, anti-HBs, anti-HBc. TDF and TAF are active against HBV — if HBsAg positive, PrEP doubles as HBV treatment and must NOT be stopped abruptly (risk of fulminant flare). Vaccinate non-immune patients.

— Hepatitis C: anti-HCV with reflex RNA — high coinfection rates in PWID and MSM with rectal STIs.

— Renal function: serum creatinine with estimated CrCl (Cockcroft-Gault). Thresholds:

▪ Oral TDF/FTC: CrCl ≥60 mL/min

▪ Oral TAF/FTC: CrCl ≥30 mL/min

▪ Injectable cabotegravir: no renal cutoff (not nephrotoxic)

— STI screening at three sites: urine (or vaginal) NAAT, pharyngeal, and rectal swabs for gonorrhea and chlamydia; serum RPR or treponemal test for syphilis

— Pregnancy test in persons of childbearing potential

— Lipid panel and fasting glucose/HbA1c if starting TAF (associated with modest weight, lipid, and glucose changes)

Mandatory baseline panel (results needed before first dose, ideally within 7 days):

Bone health: baseline DEXA is NOT routinely required, but consider in patients >50 or with risk factors before TDF.

Document hepatitis A and HPV vaccination status; offer mpox vaccine to MSM/transgender PrEP candidates.

Step 3 management: If HIV Ag/Ab is reactive or HIV RNA detectable, STOP — refer to HIV specialty care for confirmatory testing and ART initiation; do not prescribe PrEP alone (functional monotherapy → resistance).

CCS pearl: Order "HIV 1/2 Ag/Ab, HIV-1 RNA, HBsAg, anti-HBs, anti-HBc, anti-HCV, CMP, urine pregnancy, GC/CT NAAT (urine + pharyngeal + rectal), RPR" as your PrEP-initiation bundle.

Diagnostic Workup — Advanced and Confirmatory Considerations

— Reflex differentiation assay (HIV-1/2 antibody differentiation) per CDC algorithm

— If differentiation indeterminate or negative, perform HIV-1 RNA quantitative — detectable RNA = acute HIV; undetectable = likely false positive

— Hold PrEP, link to HIV care within 7 days, obtain genotype and CD4 count

— Window period: HIV RNA detectable ~10 days post-exposure; p24 antigen ~14–18 days; antibody ~3–4 weeks (4th-gen ~18 days)

— A patient who took nPEP in the past 4 weeks may have masked seroconversion — repeat HIV testing 4 and 12 weeks after nPEP completion before declaring negative and starting PrEP

— Repeat Cr, calculate Cockcroft-Gault (preferred for tenofovir dosing — uses actual body weight)

— Urinalysis for proteinuria/glucosuria (tenofovir-associated proximal tubulopathy / Fanconi syndrome)

— Consider urine protein:creatinine ratio if proteinuria on dipstick

— Isolated anti-HBc positive: check HBV DNA to exclude occult infection before deciding regimen and counsel on flare risk if PrEP is discontinued

— HBsAg positive: coordinate with hepatology; PrEP becomes dual-purpose therapy; never stop abruptly

When baseline 4th-generation HIV Ag/Ab is reactive:

Acute HIV detection nuances:

Drug-resistance surveillance: not routine before PrEP initiation, but obtain HIV genotype if PrEP is started and a confirmed seroconversion later occurs.

Renal evaluation if borderline CrCl:

Hepatitis B nuances:

Bone density: consider DEXA in patients with osteoporosis risk factors before TDF; TAF or cabotegravir preferred if bone disease established.

Key distinction: Oral TDF/FTC = renal and bone toxicity concerns; TAF/FTC = better renal/bone profile but worse metabolic profile (weight, lipids) and not approved for receptive vaginal sex; cabotegravir IM = best for adherence challenges but requires q2-month clinic visits and has an injection-site reaction profile plus a long pharmacologic tail.

Board pearl: Detectable HIV RNA with negative Ag/Ab = acute HIV (Fiebig stage I–II) — highest transmissibility window; urgent linkage to ART, contact tracing, and partner notification.

Risk Stratification and Regimen Selection Logic

— Step 1: Confirm HIV-negative status with no acute symptoms and adequate window-period coverage

— Step 2: Assess adherence likelihood, route-of-exposure, renal function, HBV status, pregnancy plans

— Step 3: Match patient to regimen via shared decision-making

— TDF/FTC daily: first-line for most adults and adolescents ≥35 kg; only oral option for receptive vaginal exposure and for PWID; cheapest (generic); preferred in pregnancy

— TAF/FTC daily: for cisgender MSM and transgender women at risk via anal sex; choose when renal disease (CrCl 30–59), osteoporosis, or TDF intolerance is present; NOT for vaginal-receptive exposure or PWID

— Cabotegravir IM: choose when oral adherence is poor, pill fatigue, privacy concerns (e.g., living with unaware family), IPV, or patient preference; loading at month 0 and 1, then every 2 months

— Anal exposure: ~7 days of daily TDF/FTC or TAF/FTC

— Vaginal/injection exposure: ~21 days

— Cabotegravir: protective from first injection (after loading)

Decision tree once a candidate is identified and baseline labs are clean:

Regimen-selection matrix:

On-demand "2-1-1" dosing (TDF/FTC only): 2 pills 2–24 hours before sex, 1 pill 24 h after, 1 pill 48 h after. CDC considers this off-label but IAS-USA and WHO endorse it for cisgender MSM with infrequent, planned exposures. NOT for receptive vaginal sex, PWID, chronic HBV, or transgender women on feminizing hormones.

Time-to-protection:

Step 3 management: A 24-year-old MSM with multiple partners and a history of missed primary-care appointments asking about PrEP — recommend cabotegravir IM to maximize adherence; back up with condoms during the 7-day lead time after starting any oral regimen.

Board pearl: "2-1-1" is the only dosing strategy with prospective RCT evidence (IPERGAY) for event-driven PrEP — confined to cisgender MSM.

Pharmacotherapy — First-Line Regimens in Depth

— One tablet PO daily, with or without food

— Mechanism: nucleotide/nucleoside reverse transcriptase inhibitors blocking HIV reverse transcriptase

— Adverse effects: nausea/GI upset (often transient first month — "start-up syndrome"), modest creatinine rise (~0.1 mg/dL via tubular secretion inhibition, not true GFR loss), proximal tubulopathy, decreased BMD (~1–2%), rare lactic acidosis

— Interactions: NSAIDs (additive nephrotoxicity), aminoglycosides, high-dose acyclovir; ledipasvir/sofosbuvir raises tenofovir levels

— One tablet PO daily

— Prodrug delivers tenofovir intracellularly with lower plasma levels → less renal and bone toxicity

— Adverse effects: weight gain (~1–2 kg), modest LDL/triglyceride rise, hyperglycemia

— Avoid with strong CYP3A/P-gp inducers (rifampin, carbamazepine, phenytoin, St. John's wort)

— Integrase strand-transfer inhibitor

— Optional oral lead-in (cabotegravir 30 mg PO daily × 4 weeks) to assess tolerability, then 600 mg IM gluteal at month 0 and month 1, then every 2 months

— Adverse effects: injection-site reactions (~80%, usually mild), hepatotoxicity, depression, weight gain

— Pharmacologic tail: detectable drug for 12+ months after last injection — if HIV acquired during the tail, risk of INSTI resistance; bridge with oral PrEP if discontinuing

TDF/FTC (tenofovir disoproxil fumarate 300 mg / emtricitabine 200 mg):

TAF/FTC (tenofovir alafenamide 25 mg / emtricitabine 200 mg):

Cabotegravir long-acting IM:

Step 3 management: A patient on TDF/FTC PrEP whose Cr rises from 0.9 to 1.3 mg/dL (CrCl drops to 55) → switch to TAF/FTC if eligible (MSM/transgender women) or cabotegravir; recheck Cr in 4 weeks.

Key distinction: "Truvada" = TDF/FTC; "Descovy" = TAF/FTC — the brand-name swap is a frequent stem trap. Generic TDF/FTC is now first-line in most coverage formularies.

Board pearl: Doxycycline PEP (doxy-PEP) 200 mg within 72 h after condomless sex reduces bacterial STIs in MSM/transgender women on PrEP — offer concurrently per 2024 CDC guidance.

Expanded Pharmacology — Adherence, Side-Effect Management, and Counseling

— Daily phone alarms, pill organizers, linking to existing daily habits (tooth brushing)

— Text-message reminders and patient navigators improve persistence

— Pharmacy auto-refill and 90-day supply when allowed

— Long-acting injectable cabotegravir for patients with documented adherence struggles

— GI upset / nausea in first month: reassure (resolves in ~80% by week 4), take with food, antiemetic PRN

— Headache: acetaminophen, hydration; avoid chronic NSAIDs with TDF

— Creatinine bump: expect ~0.1–0.15 mg/dL rise from tubular secretion; concerning if >25% from baseline or new proteinuria/glucosuria

— Bone pain or fragility fracture on TDF: switch to TAF; consider DEXA

— TAF weight gain: counseling on diet/exercise; check lipids and A1c annually

— Cabotegravir injection-site nodules: warm compress, rotate sites, NSAID short course

— Rifampin and rifabutin reduce cabotegravir levels — contraindicated

— Anticonvulsants (phenytoin, carbamazepine, phenobarbital) reduce both TAF and cabotegravir

— Hormonal contraception: no significant interaction with TDF/FTC or TAF/FTC; cabotegravir safe with estrogen-containing contraceptives

— Gender-affirming hormones: no clinically significant interaction with PrEP

— Reinforce PrEP does NOT prevent other STIs or pregnancy — continue condoms and contraception

— Discuss U=U for partners living with HIV

— Offer mpox, HAV, HBV, HPV, and meningococcal B vaccines as indicated

— Naloxone prescription and harm-reduction referral for PWID

Adherence strategies (drives effectiveness more than regimen choice):

Managing common side effects:

Drug interactions to flag:

Counseling pillars at every visit:

CCS pearl: When a patient on PrEP develops new flank pain and proteinuria, "order urinalysis, urine protein:creatinine ratio, serum phosphate, glucose" — looking for Fanconi syndrome; switch regimen and recheck in 4 weeks.

Board pearl: Tenofovir-related Cr elevation usually reverses within 4–8 weeks of discontinuation; persistent rise warrants nephrology referral.

Special Populations — Elderly and Renal/Hepatic Impairment

— Increased baseline osteopenia/osteoporosis → favor TAF/FTC or cabotegravir over TDF

— Polypharmacy and age-related renal decline → check CrCl every 6 months instead of annually

— Cognitive considerations: assess pill-taking ability; injectable cabotegravir helpful

— Sexual history-taking is often skipped in older adults — deliberately ask about new partners after divorce/widowhood

— CrCl ≥60: any regimen

— CrCl 30–59: avoid TDF; use TAF/FTC (if MSM/transgender woman) or cabotegravir

— CrCl <30: avoid both oral options; cabotegravir is the only choice (no renal adjustment needed)

— Dialysis: data limited; cabotegravir preferred; consult ID

— Monitor Cr at baseline, 3 months, then every 6 months on TDF; annually on TAF; not required for cabotegravir

— TDF, TAF, FTC: no dose adjustment for Child-Pugh A or B; limited data for Child-Pugh C

— Cabotegravir: no adjustment for mild-moderate; not studied in severe hepatic impairment

— HBV coinfection: TDF/FTC or TAF/FTC are dual-acting; if PrEP is stopped, monitor LFTs and HBV DNA every 4 weeks for 6 months for flare; never abrupt discontinuation

— Decompensated cirrhosis: coordinate with hepatology

Older adults (≥50): HIV incidence is rising in this group due to underestimated risk; PrEP is appropriate and safe.

Renal impairment:

Hepatic impairment:

Step 3 management: A 62-year-old man newly divorced with a new male partner, baseline CrCl 52 mL/min and osteopenia on DEXA → TAF/FTC daily is preferred; recheck Cr in 3 months; offer mpox and shingles vaccines at the same visit.

Key distinction: A creatinine bump (small, stable, ≤25%) on TDF is pharmacologic and acceptable; a progressive rise or new proteinuria/glucosuria indicates tubulopathy requiring switch.

Board pearl: Cockcroft-Gault (not CKD-EPI) is the formula used for tenofovir dosing decisions on USMLE stems.

Special Populations — Pregnancy, Adolescents, and Transgender Patients

— HIV acquisition risk doubles during pregnancy and the postpartum period

— TDF/FTC daily is the preferred PrEP regimen in pregnancy and lactation — extensive safety data from HIV-treatment cohorts; CDC, ACOG, and DHHS endorse continuation or initiation

— TAF/FTC: emerging data suggest safety but less robust; acceptable if TDF not tolerated

— Cabotegravir: limited pregnancy data; not first-line but may continue if already established; counsel about long pharmacologic tail and unknown fetal effects

— Serodifferent couples planning conception: PrEP for the HIV-negative partner plus sustained undetectable viral load in the HIV-positive partner allows condomless conception

— FDA-approved for ≥35 kg

— Confidentiality laws vary by state — most allow minors to consent to STI/HIV services including PrEP without parental notification

— Bone density still accruing — favor TAF when receptive anal exposure is the route

— More frequent follow-up (monthly initially) to support adherence

— No clinically significant interaction between gender-affirming hormones and any PrEP regimen — reassure patients who fear "estrogen washout"

— Transgender women have among the highest HIV incidence rates; proactively offer PrEP

— TAF/FTC and cabotegravir are options; TDF/FTC also effective

— Use gender-affirming language; offer self-swab options for STI screening

— TDF/FTC daily is the only oral regimen with proven efficacy (Bangkok Tenofovir Study)

— Cabotegravir not yet specifically approved for IDU exposure but increasingly used

— Pair PrEP with syringe-service programs, naloxone, MOUD (buprenorphine, methadone)

Pregnancy and breastfeeding:

Adolescents:

Transgender and gender-diverse patients:

People who inject drugs:

Step 3 management: Pregnant patient at 14 weeks gestation with HIV-positive partner of unknown viral load → start TDF/FTC daily, continue through pregnancy and breastfeeding, and link partner to HIV care.

Board pearl: PrEP in pregnancy is protective — withholding it is the safety risk, not providing it.

Complications and Adverse Outcomes

— Rare but documented (~1–2 per 1000 person-years on oral PrEP, lower on cabotegravir)

— Causes: non-adherence (most common), exposure to drug-resistant strain, acute HIV at initiation, or pharmacokinetic failure

— M184V/I resistance (FTC) is the typical mutation; K65R (tenofovir) less common; INSTI mutations can emerge on cabotegravir, especially during the long tail

— Diagnosis is harder on PrEP: serologic response may be blunted, "atypical seroconverter" — check HIV RNA when symptoms or risk warrant

— Tubulopathy / Fanconi syndrome with TDF: glucosuria, phosphaturia, proteinuria, hypophosphatemia, hypokalemia

— Acute kidney injury (rare) — usually reversible after discontinuation

— TDF associated with ~1–2% BMD decrease, mostly in first 6 months, plateaus thereafter

— Fragility fractures rare in PrEP populations but documented in older patients

— HBV flare on discontinuation in HBsAg+ patients — can be fulminant

— Cabotegravir-associated hepatotoxicity (rare, monitor ALT)

— TAF: weight gain, dyslipidemia, insulin resistance

— Cabotegravir: weight gain

— Depression and suicidality reported with cabotegravir (rare); screen at each visit

Breakthrough HIV infection on PrEP:

Renal complications:

Bone health:

Hepatic complications:

Metabolic:

Psychiatric:

Injection-related (cabotegravir): injection-site reactions, nodules, sterile abscess, rare anaphylaxis

Acute retroviral syndrome missed at initiation → resistance selection — the most catastrophic preventable complication.

CCS pearl: A patient on TDF/FTC PrEP with new fatigue, fever, and rash 6 weeks after initiation — order HIV-1 RNA (not just Ag/Ab) immediately; if positive, stop PrEP, send resistance genotype, and refer to HIV care urgently.

Board pearl: The combination of glucosuria with normal serum glucose in a patient on TDF is proximal tubulopathy until proven otherwise.

When to Escalate — Specialty Referral and Acute Issues

— Suspected or confirmed HIV seroconversion on PrEP — same-day or next-day referral, ideally within 7 days

— Confirmed drug-resistant HIV at baseline

— Complex drug-drug interactions (e.g., active TB requiring rifampin)

— Decompensated hepatitis B or C

— CrCl <30 mL/min when only oral options are available

— Progressive Cr rise (>25% from baseline) despite regimen switch

— New significant proteinuria or features of Fanconi syndrome

— Tubulopathy not resolving 8 weeks after stopping tenofovir

— HBsAg-positive patient initiating or discontinuing PrEP

— HCV RNA-positive patient needing DAA therapy

— Active substance use disorder; coordinate MOUD initiation

— IPV disclosure — link to advocacy and safety planning

— Patients <18, especially with confidentiality challenges

— Acute HIV with severe symptoms (meningitis, severe ARS) — admit

— Anaphylaxis to cabotegravir injection — discontinue, alternative regimen

— Severe lactic acidosis on tenofovir (very rare) — admit, stop drug

— Communicate PrEP status to OB, surgeons, ED clinicians to avoid inappropriate discontinuation

— Ensure pharmacy benefit navigation (Ready, Set, PrEP federal program for uninsured)

PrEP is primarily managed in primary care, family medicine, and community health settings. Escalate to HIV specialist / infectious disease when:

Refer to nephrology if:

Refer to hepatology:

Refer to mental health / addiction medicine:

Refer to adolescent medicine or pediatrics:

Emergency considerations:

Coordination of care:

Step 3 management: A PrEP patient newly diagnosed with active TB → coordinate with ID; rifampin interaction precludes cabotegravir and significantly lowers TAF; switch to TDF/FTC if continuing PrEP during anti-TB therapy.

Board pearl: Same-day initiation ("PrEP on demand from the clinic") is now standard — don't delay starting waiting for lab results in low-acuity, low-symptom patients with a recent negative HIV test.

Key Differentials — Conditions Confused with PrEP Indication

— Indicated AFTER a discrete high-risk exposure within the prior 72 hours

— Regimen: 28-day course of TDF/FTC + dolutegravir (or raltegravir)

— Transition to PrEP at completion if ongoing risk

— Key distinction: PEP is reactive and time-limited; PrEP is proactive and continuous. Confusing the two is a classic stem trap.

— Healthcare workers after needlestick or mucosal exposure

— Same regimen as nPEP; source patient testing drives duration

— Not "PrEP" — different counseling and follow-up algorithm

— Applies to the HIV-positive partner; sustained viral suppression eliminates sexual transmission

— Does NOT replace PrEP if partner adherence uncertain or relationship not monogamous

— EBV mononucleosis, CMV, acute toxoplasmosis, secondary syphilis, drug rash, viral hepatitis, primary HSV

— All can present with fever, rash, lymphadenopathy, pharyngitis

— Always include HIV RNA in the workup of any acute mononucleosis-like syndrome in a sexually active adult

— Frequently confused with PrEP encounters; address both at the same visit but recognize they are independent decisions

— PrEP for HIV-negative partner + ART with U=U for HIV-positive partner + timed intercourse during ovulation = current standard

— Alternative: sperm washing with IUI/IVF (less commonly required now)

Within the HIV-prevention space, several scenarios mimic but differ from PrEP indications:

Post-exposure prophylaxis (PEP / nPEP):

Occupational PEP:

Treatment as Prevention (TasP / U=U):

Acute HIV mimics:

Long-acting reversible contraception requests:

Pre-conception counseling in serodifferent couples:

Board pearl: "72 hours" in a stem = PEP, not PrEP. "Ongoing risk over months" = PrEP.

Key Differentials — Other-Category Conditions to Distinguish

— Diffuse maculopapular rash including palms and soles, condyloma lata, mucous patches, lymphadenopathy, fever

— RPR with treponemal confirmation; treat with benzathine penicillin G 2.4 million units IM

— Coinfection rates high — always screen at PrEP visits

— Triad of polyarthralgia, tenosynovitis, dermatitis (pustular/hemorrhagic) in sexually active adult

— Blood, joint, mucosal cultures; ceftriaxone IV

— Reservoir often pharyngeal/rectal — test all three sites

— RUQ pain, jaundice, elevated transaminases >1000 U/L in B

— Surface antigen, anti-HCV with reflex RNA

— Painful anogenital lesions evolving through stages, lymphadenopathy, fever, proctitis

— PCR of lesion swab; vaccinate eligible PrEP patients (Jynneos)

— Painful vesicles/ulcers; PCR or culture; valacyclovir

— C. trachomatis serovars L1–L3; severe proctitis, inguinal buboes in MSM

— Doxycycline 100 mg BID × 21 days

— Heterophile-positive, atypical lymphocytes; supportive care

Conditions outside the HIV-prevention category that overlap clinically with PrEP encounters:

Syphilis (especially secondary):

Disseminated gonorrhea:

Acute hepatitis B or C:

Mpox:

HSV proctitis or genital ulcers:

Lymphogranuloma venereum (LGV):

EBV mononucleosis:

Adverse drug reactions (DRESS, SJS): rule out with any new rash after PrEP initiation; rare with current regimens.

Anxiety disorder / PrEP-stigma somatization: occasional patients attribute unrelated symptoms to PrEP — validate concerns, evaluate, but don't discontinue prematurely.

Step 3 management: A PrEP patient presents with painful proctitis and inguinal lymphadenopathy → rectal NAAT for GC/CT with LGV reflex, HSV PCR, mpox PCR, RPR — empiric doxycycline 100 mg BID while awaiting results.

Board pearl: Three-site STI testing (urethral/vaginal, pharyngeal, rectal) catches >70% of asymptomatic infections that single-site urine NAAT misses.

Long-Term Plan — Continuation, Discontinuation, and Secondary Prevention

— Reassess ongoing indication at each visit — life changes (monogamy, abstinence, partner becomes virally suppressed) may alter need

— Reinforce U=U for partners

— Discuss "PrEP holidays" for planned low-risk intervals (e.g., long travel without partners), with structured restart

— Sustained low/no risk (mutually monogamous with HIV-negative partner)

— Pregnancy desire achieved with ART-suppressed partner (decision is patient-driven)

— Intolerable adverse effects after attempts at regimen switch

— Patient choice

— Oral PrEP: continue for at least 2 days after last exposure for anal sex (MSM), or 7 days for vaginal/PWID exposure, then stop

— Cabotegravir: requires bridge with daily oral PrEP for up to 12 months after last injection due to pharmacologic tail — without bridging, subtherapeutic levels select resistance if HIV acquired

— HBsAg-positive: never abruptly stop tenofovir — transition to alternative HBV therapy (entecavir) and monitor for flare

— Doxy-PEP: doxycycline 200 mg within 72 h post-sex for MSM/transgender women with recent bacterial STI — reduces syphilis, chlamydia, and (partially) gonorrhea

— Vaccinations: HBV, HAV, HPV (through age 26, shared decision through 45), mpox, meningococcal, COVID, influenza

— Naloxone, MOUD, harm-reduction supplies for PWID

— Condoms remain first-line for non-HIV STI and pregnancy prevention

— Mental health, IPV resources, substance use treatment

PrEP is a longitudinal commitment, not a finite course. The "discharge plan" is sustained follow-up.

Continuation strategy:

Discontinuation indications:

Safe discontinuation protocol:

Secondary prevention adjuncts:

CCS pearl: A patient stopping cabotegravir who declines oral bridging — document shared decision, schedule HIV RNA testing at 1, 3, 6, 9, and 12 months to catch a tail-period seroconversion early.

Board pearl: "2-2-7" rule of thumb for stopping oral PrEP: continue 2 days after last anal exposure, 7 days after last vaginal or injection exposure.

Follow-Up, Monitoring Schedule, and Counseling

— Month 1 after initiation: HIV Ag/Ab (+ RNA if symptoms), Cr, adherence/side-effect check, STI testing if symptomatic

— Every 3 months thereafter:

▪ HIV Ag/Ab (4th-gen) — add RNA if any acute symptoms or recent high-risk exposure

▪ Pregnancy test (childbearing potential)

▪ Syphilis (RPR), GC/CT three-site NAAT, symptom review

▪ Adherence assessment, side-effect review

— Every 6 months: serum Cr (CrCl), urinalysis on TDF

— Annually: lipid panel and glucose on TAF; HCV antibody (high-risk groups); reassess HBV status if not immune

— Every 2 months at injection visits: HIV Ag/Ab plus HIV-1 RNA (recommended because of risk of LEVI — Long-acting Early Viral Inhibition delaying serologic detection)

— Same STI cadence as oral

— Reaffirm adherence importance and review missed doses

— Sexual history update — practices, partners, condom use

— Substance use review

— Mental health screen (PHQ-2/9 and IPV)

— Vaccination updates (mpox, COVID, flu, HPV)

— Discuss U=U, doxy-PEP eligibility, partner testing/PrEP

— Track HIV negativity, STI incidence, persistence on PrEP (a value-based care metric)

— Many systems use registries to flag overdue testing

Standard CDC follow-up cadence (oral PrEP):

Cabotegravir-specific monitoring:

Counseling at every visit:

Documentation and quality metrics:

Step 3 management: A patient 3 months into PrEP reports inconsistent dosing (4 pills/week) and recent condomless sex — counsel that 4 doses/week of TDF/FTC provides ~96% protection for anal sex but inadequate for vaginal sex; intensify adherence support or transition to cabotegravir.

Board pearl: The single most predictive lab on PrEP follow-up is HIV testing every 3 months — missing it risks treating an infected patient with PrEP monotherapy and selecting resistance.

Ethical, Legal, and Patient Safety Considerations

— Most US states allow minors to consent to STI/HIV testing and treatment without parental notification; PrEP coverage under "STI services" varies

— Insurance Explanation of Benefits (EOBs) mailed to policyholders can inadvertently disclose PrEP use — counsel adolescents and dependents about Title X clinics, confidential billing options, or self-pay

— Document discussion of efficacy, time-to-protection, side-effect profile (renal, bone, metabolic), need for ongoing HIV testing, resistance risk if HIV acquired, and alternatives (condoms, U=U partner ART)

— Special consent for off-label "2-1-1" dosing — document shared decision

— HIV diagnosis: reportable in all US states (named or coded depending on jurisdiction)

— Syphilis, gonorrhea, chlamydia, HBV, HCV: reportable

— Partner notification services available through state health departments; physicians may notify partners with patient consent or through public-health intermediaries

— Hospitalization or surgery may interrupt PrEP — inpatient teams often discontinue; document PrEP prominently on the home med list and educate the patient to advocate

— Insurance lapses interrupt continuity — use Ready, Set, PrEP (federal program) or 340B clinics

— Avoid documentation that could be used in custody disputes or immigration cases without patient awareness

— Use gender-affirming, non-judgmental language

— Disparities: Black and Latino MSM and transgender women have highest incidence but lowest PrEP uptake — proactively address structural barriers

— Telehealth PrEP expanding access in rural areas

— Starting PrEP during undiagnosed acute HIV selects resistance — careful baseline testing is both individual and population safety

Confidentiality and adolescents:

Informed consent:

Mandatory reporting:

Transition-of-care risks:

Stigma and discrimination:

Equity and access:

Drug resistance as a public-health harm:

Step 3 management: A 17-year-old requests PrEP and asks that his parents not be notified through insurance EOB — refer to a Title X-funded clinic or use a 340B confidential pathway; document the conversation and state minor-consent statute.

Board pearl: Universal opt-out HIV testing and routine PrEP discussion reduce stigma — frame PrEP like contraception or statins, not as risk-group-specific medicine.

High-Yield Associations and Rapid-Fire Facts

Efficacy: ~99% reduction in sexual HIV transmission with consistent oral PrEP; ~74% reduction for injection exposure; cabotegravir IM superior to oral in HPTN 083/084 (lower incidence due to adherence)

Time to protection: anal — 7 days oral; vaginal/IDU — 21 days oral; cabotegravir — from first injection (post loading)

USPSTF: Grade A recommendation (2023); ACA mandates zero cost-sharing for med, labs, visits

Window-period testing: 4th-gen Ag/Ab ~18 days; HIV RNA ~10 days; always add RNA for symptomatic or very recent exposures

HBsAg-positive PrEP patient: never stop abruptly — flare risk

Cabotegravir tail: drug detectable up to 12 months — bridge with oral PrEP at discontinuation

2-1-1 dosing: only for cisgender MSM; only TDF/FTC; not for vaginal sex, PWID, or HBV

Pregnancy: TDF/FTC preferred; continue through breastfeeding

Adolescents ≥35 kg: any oral regimen FDA-approved

Renal cutoffs: TDF ≥60 mL/min; TAF ≥30 mL/min; cabotegravir — no cutoff

Creatinine bump: ~0.1–0.15 mg/dL expected on tenofovir from tubular secretion inhibition — not true GFR loss

Resistance on breakthrough: M184V (FTC) most common

Doxy-PEP: 200 mg within 72 h post-sex for MSM/TGW with recent bacterial STI — CDC 2024

Three-site STI testing: urethral/vaginal + pharyngeal + rectal — every 3 months

U=U: undetectable = untransmittable; sustained ART with VL <200 copies/mL eliminates sexual transmission

Vaccines bundled with PrEP visits: HAV, HBV, HPV, mpox, meningococcal B

Generic TDF/FTC: now <$30/month — cost no longer a barrier in most settings

Telehealth PrEP: permitted with lab-corp partnerships in most states

HIRI-MSM ≥10: substantial HIV-acquisition risk threshold

Same-day PrEP start: increasingly standard for low-acuity patients with negative point-of-care HIV test

Board pearl: If a stem mentions "negative HIV antibody but symptomatic with fever and rash 2 weeks after exposure" — order HIV-1 RNA; never start PrEP without ruling out acute HIV.

Board Question Stem Patterns

— 28-year-old MSM presents for routine visit, mentions multiple male partners, inconsistent condom use, recent rectal chlamydia. HIV Ag/Ab negative. Next step? → Initiate TDF/FTC or TAF/FTC daily PrEP after baseline labs (Cr, HBV, three-site STI, pregnancy if applicable)

— Patient requests PrEP. Reports fever, sore throat, rash, lymphadenopathy 10 days ago after condomless sex. HIV Ag/Ab today negative. Next step? → HIV-1 RNA viral load before considering PrEP; if positive, refer to ART, do NOT start PrEP alone

— Patient on TDF/FTC PrEP for 2 years, HBsAg-positive, decides to stop PrEP. Next step? → Do not stop abruptly; continue tenofovir or transition to entecavir; monitor LFTs and HBV DNA

— Patient on TDF/FTC × 18 months, Cr rises from 0.9 to 1.4 mg/dL with new glucosuria. Next step? → Stop TDF, evaluate for Fanconi syndrome, switch to TAF/FTC or cabotegravir

— College student on daily PrEP misses 50% of doses, multiple new partners. Next step? → Switch to cabotegravir long-acting IM every 2 months

— Pregnant patient at 12 weeks with HIV-positive partner not yet on ART. Next step? → Start TDF/FTC PrEP for patient AND link partner to HIV care

— Patient completed 28-day nPEP after assault, ongoing high-risk partner. Next step? → Transition directly to PrEP at completion, confirming HIV-negative status (and repeat HIV test at 3 months)

— MSM on TDF/FTC entering monogamous relationship with HIV-negative partner, wants to stop. Next step? → Continue PrEP at least 2 days after last anal exposure, confirm HIV-negative at stop, counsel on restart criteria

— 16-year-old requests PrEP, fears parental discovery via EOB. Next step? → Refer to Title X confidential clinic or use minor-consent pathway

Stem pattern 1 — The "asking patient":

Stem pattern 2 — The acute HIV trap:

Stem pattern 3 — The HBV coinfection:

Stem pattern 4 — The renal change:

Stem pattern 5 — The adherence-challenged patient:

Stem pattern 6 — The pregnancy scenario:

Stem pattern 7 — The PEP-to-PrEP transition:

Stem pattern 8 — The "stopping" scenario:

Stem pattern 9 — The adolescent confidentiality case:

Board pearl: When a stem includes recent symptoms compatible with acute HIV, the answer is always HIV RNA before PrEP — never start PrEP on Ag/Ab alone in that setting.

One-Line Recap

HIV PrEP is a USPSTF Grade-A, primary-care–delivered, lifelong-when-indicated intervention in which any HIV-negative person at substantial risk should be offered TDF/FTC, TAF/FTC, or long-acting cabotegravir after baseline screening (HIV Ag/Ab + RNA, HBV, HCV, renal function, three-site STI, pregnancy), with HIV and STI testing every 3 months, renal monitoring, and proactive transitions across pregnancy, adherence challenges, and discontinuation.

High-yield recap bullets:

Always exclude acute HIV before starting — HIV-1 RNA in any patient with recent exposure or ARS symptoms; missing this selects M184V resistance

Match the regimen to the patient: TDF/FTC for vaginal exposure, PWID, pregnancy, and as low-cost first line; TAF/FTC for renal/bone concerns in MSM/TGW; cabotegravir for adherence struggles, privacy needs, or pill fatigue

Monitor every 3 months: HIV Ag/Ab (+ RNA on cabotegravir or with symptoms), three-site STI, syphilis, pregnancy; renal every 6 months on TDF

Stop safely: 2 days post anal exposure / 7 days post vaginal or IDU exposure for oral; bridge cabotegravir with oral PrEP for up to 12 months because of pharmacologic tail; never abruptly discontinue tenofovir in HBsAg+ patients

Bundle prevention: doxy-PEP, HBV/HAV/HPV/mpox vaccination, contraception, naloxone/MOUD, mental health and IPV screening, and U=U messaging for partners

Step 3 management mindset: Treat PrEP like statins or contraception — universally offered, longitudinally managed, equity-centered, and integrated into the preventive care visit rather than reserved for specialty clinics.