Chronic retroviral infection of CD4 T-cells leading to progressive immunodeficiency; managed with lifelong combination antiretroviral therapy.
Also known as: HIV, AIDS, human immunodeficiency virus, acquired immunodeficiency syndrome
Overview
Infection with HIV-1 or HIV-2, single-stranded RNA retroviruses that bind CD4 and CCR5/CXCR4 to infect helper T-cells, monocytes, and dendritic cells. AIDS is defined as HIV infection plus CD4 count <200 cells/uL or the presence of an AIDS-defining illness.
Epidemiology
Approximately 1.2 million people in the US live with HIV; roughly 13% are undiagnosed. New infections concentrated among men who have sex with men, injection drug users, and Black and Latino populations in the South. HIV-1 dominates worldwide; HIV-2 largely restricted to West Africa.
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Question 1Infectious DiseaseMedium
A 45-year-old man with HIV and a CD4 count of 320 cells/uL begins antiretroviral therapy (ART). Two weeks later he develops fever, new lymphadenopathy, and worsening of a previously diagnosed mycobacterial infection that had been improving on treatment. Which of the following is the most likely cause of his new findings?
AVirologic failure of ART
BImmune reconstitution inflammatory syndrome
CAcute retroviral syndrome
DAcute antiretroviral toxicity
EDrug-resistant mycobacterial infection
Reveal answer & full explanation
Correct answer: B — Immune reconstitution inflammatory syndrome
AVirologic failure of ART
BImmune reconstitution inflammatory syndrome✓
CAcute retroviral syndrome
DAcute antiretroviral toxicity
EDrug-resistant mycobacterial infection
Why Immune reconstitution inflammatory syndrome is correct
Immune reconstitution inflammatory syndrome (IRIS) is a paradoxical worsening or unmasking of an opportunistic infection (OI) as CD4 count rises and immune function recovers after antiretroviral therapy (ART) initiation
IRIS occurs in 10–25% of patients, typically within weeks to months of ART initiation
Paradoxical IRIS: a known OI worsens after ART is started
Unmasking IRIS: a previously subclinical OI presents clinically after ART is started
Here a treated mycobacterial infection that had been improving flares with fever and new lymphadenopathy 2 weeks after ART begins, the classic timing of paradoxical IRIS
Why the others are wrong
Virologic failure of ART — virologic failure occurs over months, not within 2 weeks, and does not explain worsening of an existing infection shortly after starting ART
Acute antiretroviral toxicity — drug toxicity typically manifests as side effects (e.g., nausea, hepatotoxicity), not fever with worsening of an OI
Drug-resistant mycobacterial infection — should be excluded with cultures and susceptibility testing, but resistance causes failure to improve or gradual progression on therapy, not an abrupt inflammatory flare with fever and new lymphadenopathy in an infection that had been improving until ART was started 2 weeks earlier
Acute retroviral syndrome — fever and lymphadenopathy are hallmark features, but acute retroviral syndrome is the mononucleosis-like illness of primary HIV infection, arising 2 to 4 weeks after exposure; this patient already has established HIV, and the syndrome would not explain flaring of a treated mycobacterial infection after ART is started
Additional high-yield points
Management of IRIS: continue ART, treat the underlying infection, and use corticosteroids for severe IRIS — especially tuberculosis (TB)-IRIS, supported by randomized prednisone trials (Meintjes 2010 for treatment of paradoxical TB-IRIS; PredART 2018 for prevention when ART is started at a CD4 count of 100 cells/uL or less)
Question 2Infectious DiseaseMedium
A 35-year-old male healthcare worker sustains a needlestick from a patient known to be HIV positive (viral load 50,000 copies/mL). Exposure occurred 2 hours ago. Which of the following is the most appropriate post-exposure prophylaxis?
AZidovudine/lamivudine plus nevirapine for 28 days
BTenofovir/emtricitabine plus dolutegravir for 28 days
CTenofovir/emtricitabine plus darunavir/ritonavir for 28 days
DTenofovir/emtricitabine/efavirenz for 28 days
EAbacavir/lamivudine plus dolutegravir for 28 days
Reveal answer & full explanation
Correct answer: B — Tenofovir/emtricitabine plus dolutegravir for 28 days
AZidovudine/lamivudine plus nevirapine for 28 days
BTenofovir/emtricitabine plus dolutegravir for 28 days✓
CTenofovir/emtricitabine plus darunavir/ritonavir for 28 days
DTenofovir/emtricitabine/efavirenz for 28 days
EAbacavir/lamivudine plus dolutegravir for 28 days
Why Tenofovir/emtricitabine plus dolutegravir for 28 days is correct
HIV post-exposure prophylaxis (PEP) should start as soon as possible, ideally within 2 hours and no later than 72 hours post-exposure
Transmission risk from a needlestick of an HIV+ source is approximately 0.3% without PEP; PEP reduces transmission by approximately 80%
Preferred regimens (2025 US Public Health Service occupational PEP guideline): bictegravir/emtricitabine/tenofovir alafenamide, or dolutegravir plus tenofovir (TDF or TAF) plus emtricitabine or lamivudine, for 28 days; raltegravir-based regimens are no longer preferred
Why the others are wrong
Tenofovir/emtricitabine/efavirenz for 28 days — efavirenz-based regimens are no longer preferred due to neuropsychiatric side effects
Zidovudine/lamivudine plus nevirapine for 28 days — nevirapine is avoided for PEP because of hepatotoxicity
Tenofovir/emtricitabine plus darunavir/ritonavir for 28 days — darunavir/ritonavir is an alternative anchor but is not the preferred agent
Abacavir/lamivudine plus dolutegravir for 28 days — dolutegravir is a preferred anchor, which makes this familiar treatment regimen tempting, but abacavir requires HLA testing before the first dose to exclude carriers at risk of a potentially fatal hypersensitivity reaction, and waiting for that result delays a time-critical start, so abacavir is not used for routine PEP
Additional high-yield points
Follow-up HIV testing: 4th-generation antigen/antibody test at baseline, then final testing at 12 weeks with a laboratory antigen/antibody test plus an HIV nucleic acid test; interim testing at 4-6 weeks is added only if PEP started more than 24 hours after exposure or doses were missed, and 6-month testing is no longer recommended
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Multiple sex partners, condomless sex, concurrent STI (especially ulcerative — syphilis, HSV)
Injection drug use with shared needles
Vertical transmission (in utero, intrapartum, breastfeeding) — risk reduced from ~25% to <1% with maternal ART
Occupational needlestick (per-exposure risk ~0.3% for hollow-bore blood exposure)
Blood transfusion in regions without universal screening
Pathophysiology
Envelope gp120 binds CD4 and a coreceptor (CCR5 in early infection, CXCR4 later), allowing gp41-mediated fusion and viral entry. Reverse transcriptase produces proviral DNA that integrates into the host genome via integrase. Ongoing replication depletes CD4 cells, disrupts lymph node architecture, and causes chronic immune activation. Untreated, CD4 declines ~50-100 cells/uL/year; opportunistic infections appear as immunity fails.
Acute mononucleosis-like illness 2-4 weeks after high-risk exposure, often with a non-pruritic trunk rash, should prompt HIV RNA testing even if antibody screening is negative.
Differential diagnosis
Acute viral syndrome (EBV, CMV, acute hepatitis) — Acute retroviral syndrome mimics mononucleosis; obtain HIV RNA viral load (turns positive ~10 days) — antibody tests miss the window period
Secondary syphilis — Diffuse maculopapular rash including palms/soles, mucous patches, condyloma lata; RPR/VDRL plus treponemal test
Lymphoma — Persistent lymphadenopathy, B symptoms; biopsy required — HIV-associated lymphomas common at low CD4
Idiopathic CD4 lymphocytopenia — Low CD4 with negative HIV tests; rare diagnosis of exclusion
Tuberculosis — Coinfection extremely common worldwide; screen all newly diagnosed HIV with IGRA or TST and CXR
Diagnostic workup
Diagnostic criteria
CDC algorithm: reactive Ag/Ab combo assay confirmed by HIV-1/2 differentiation assay. Discordant or early-infection cases resolved with HIV RNA. AIDS = HIV plus CD4 <200 cells/uL or any stage-3 AIDS-defining condition.
CD4-stratified opportunistic infections and prophylaxis thresholds in HIV/AIDS.
Treatment
First-line
Initiate ART at diagnosis regardless of CD4 (START and TEMPRANO trials); exception: in cryptococcal meningitis, defer ART until 4-6 weeks after starting antifungal therapy to lower the risk of fatal IRIS
INSTI (HIV integrase inhibitor) — bictegravir or dolutegravir (raltegravir-based regimens are no longer recommended for initial therapy)
NRTI backbone — tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF) plus emtricitabine or lamivudine; abacavir/lamivudine only in certain clinical situations (HLA-B*5701 negative, no HBV; possible cardiovascular risk)
Single-tablet options: bictegravir/TAF/emtricitabine (Biktarvy); dolutegravir/lamivudine (Dovato) except with VL >500,000, HBV coinfection, or before genotype and HBV results are available. Dolutegravir/abacavir/lamivudine (Triumeq) is now reserved for certain clinical situations (DHHS 2024)
Long-acting injectable cabotegravir + rilpivirine IM every 1-2 months for virologically suppressed patients
Pre-exposure prophylaxis (PrEP)
Daily oral TDF/emtricitabine (Truvada) or TAF/emtricitabine (Descovy; not for receptive vaginal exposure)
Long-acting injectables: cabotegravir IM every 2 months (Apretude) or lenacapavir SC every 6 months (Yeztugo; FDA 2025, CDC 2025)
On-demand 2-1-1 TDF/FTC dosing for MSM in select settings
Repeat HIV testing every 3 months; STI and renal monitoring
Post-exposure prophylaxis (PEP)
Initiate within 72 hours of exposure; 28-day course
Preferred (USPHS 2025 occupational; CDC nPEP 2025): bictegravir/emtricitabine/TAF (Biktarvy), or dolutegravir + tenofovir (TDF or TAF) + emtricitabine or lamivudine; raltegravir is no longer preferred
Baseline HIV test; final testing at 12 weeks with a laboratory Ag/Ab immunoassay plus HIV RNA (NAT); add a 4-6 week test if PEP started >24 h after exposure or doses were missed
MAC (CD4 <50): historically azithromycin; current DHHS recommends deferral if ART started promptly
Latent TB: short rifamycin-based courses preferred — isoniazid + rifapentine weekly x 12 weeks (3HP) or isoniazid + rifampin daily x 3 months (3HR), checking ART drug interactions; isoniazid + B6 for 6-9 months is an alternative
Second-line / adjunct
Protease inhibitor (boosted) — darunavir/ritonavir or darunavir/cobicistat for resistance or pregnancy
NNRTI — doravirine, rilpivirine, efavirenz (efavirenz historically avoided in first trimester pregnancy planning)
AIDS-defining malignancies — Kaposi sarcoma, non-Hodgkin lymphoma, invasive cervical cancer
HIV-associated neurocognitive disorder (HAND)
Immune reconstitution inflammatory syndrome (IRIS): usually 2-12 weeks after starting ART as CD4 rises and viral load falls; paradoxical (a treated OI worsens) or unmasking (a subclinical OI such as MAC, TB, or cryptococcus appears); continue ART, treat the OI, and add NSAIDs for mild IRIS or corticosteroids for severe IRIS
Accelerated atherosclerosis, CKD (especially with TDF), osteoporosis, metabolic syndrome
PANCE pearls
Acute HIV: antibody-based tests can be negative in the window period — order HIV RNA viral load.
Pregnancy: dolutegravir is now preferred throughout pregnancy (early neural tube signal not confirmed). Preferred pregnancy regimens (Perinatal guidelines 2025): dolutegravir + (TDF or TAF) + (FTC or 3TC), or bictegravir/TAF/FTC.
U = U: undetectable equals untransmittable. Sustained viral suppression eliminates sexual transmission risk (PARTNER, PARTNER2, Opposites Attract trials).
Cryptococcal meningitis: measure opening pressure; if ≥25 cm H2O, serial therapeutic LPs to lower ICP improve survival. Induction is amphotericin B (liposomal preferred) plus flucytosine.
Vaccines in HIV: live vaccines (MMR, varicella, yellow fever) are contraindicated if CD4 <200 and may be given if CD4 ≥200; inactivated, toxoid, and recombinant vaccines (influenza, pneumococcal, hepatitis A/B, Tdap, recombinant zoster) are safe at any CD4.
References
DHHS 2024 — Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV (clinicalinfo.hiv.gov)
CDC/APHL 2014 — Centers for Disease Control and Prevention and Association of Public Health Laboratories. Laboratory Testing for the Diagnosis of HIV Infection: Updated Recommendations. June 27, 2014. stacks.cdc.gov/view/cdc/23447
START Trial — Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection (NEJM 2015)
PARTNER2 — Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (Rodger et al., Lancet 2019)
USPHS 2025 — Kofman AD, Struble KA, Heneine W, et al. 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. Infect Control Hosp Epidemiol 2025;46(9):863-873.
CDC nPEP 2025 — Tanner MR, O'Shea JG, Byrd KM, et al. Antiretroviral Postexposure Prophylaxis After Sexual, Injection Drug Use, or Other Nonoccupational Exposure to HIV — CDC Recommendations, United States, 2025. MMWR Recomm Rep 2025;74(1):1-56.
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