Immune System

HIV: starting antiretroviral therapy and adherence

Clinical Overview and When to Suspect HIV Requiring ART Initiation

— Rationale: START and TEMPRANO trials showed mortality and AIDS-event reduction; HPTN 052 and PARTNER/PARTNER2 established U=U (undetectable = untransmittable).

— Acute retroviral syndrome: fever, pharyngitis, mononucleosis-like rash, lymphadenopathy, mucocutaneous ulcers 2–4 weeks after exposure

— Recurrent shingles, thrush, seborrheic dermatitis, unexplained weight loss, chronic diarrhea

— AIDS-defining illness: PCP, esophageal candidiasis, cryptococcal meningitis, KS, CMV retinitis, PML, disseminated MAC, cerebral toxoplasmosis

— Risk-based: MSM, transgender women, injection drug use, sex workers, partners of PWH, incarcerated, hepatitis B/C, recurrent STIs

Board pearl: ART is started the same day as diagnosis in the outpatient clinic; you do not wait for CD4 count, genotype, or HLA-B*5701 to return before initiating an INSTI-based regimen — only later tailor if resistance or hypersensitivity risk emerges. The exceptions where you delay or sequence carefully are suspected cryptococcal meningitis and TB meningitis, where immediate ART risks fatal IRIS.

HIV infection is a chronic retroviral disease where untreated viremia drives progressive CD4+ T-cell depletion, opportunistic infections, and non-AIDS comorbidities (cardiovascular, renal, hepatic, malignancy).

Current paradigm: universal antiretroviral therapy (ART) for all persons with HIV regardless of CD4 count, ideally started the same day as diagnosis ("rapid start") once acute concerns are excluded.

When to suspect new HIV warranting workup and ART:

USPSTF: screen all persons aged 15–65 at least once; pregnant patients each pregnancy; high-risk individuals annually or more.

Pre-ART baseline must occur but should not delay therapy: HIV RNA, CD4, genotype resistance test, HLA-B*5701 (if abacavir considered), HBV/HCV serologies, CMC, CMP, lipids, A1c, urinalysis, pregnancy test, STI panel, tuberculin test/IGRA.

Presentation Patterns and Key History

— Fever (>90%), fatigue, pharyngitis, generalized lymphadenopathy, maculopapular trunk rash, painful mucocutaneous ulcers, myalgia, headache, aseptic meningitis

— Often mistaken for mononucleosis; EBV/CMV-negative mono-like illness should prompt HIV RNA testing (4th-gen Ag/Ab combo may still be negative in earliest window)

— Constitutional: weight loss, night sweats, low-grade fever

— Dermatologic: seborrheic dermatitis, eosinophilic folliculitis, recurrent zoster (especially multidermatomal or in young adults), molluscum, KS (violaceous palatal/skin plaques)

— Mucosal: oral thrush, hairy leukoplakia, recurrent aphthous ulcers, chronic perianal HSV

— Pulmonary: subacute dyspnea with hypoxia (PCP), chronic cough (TB)

— Neuro: cognitive slowing (HAND), focal deficits (toxoplasmosis, PML, CNS lymphoma), cryptococcal headache

— Hematologic: cytopenias, ITP

— Likely date and route of acquisition; partner notification context

— Prior HIV testing history, any prior ART exposure (including PrEP — relevant for INSTI resistance), PEP courses

— Sexual practices, current partners, partner serostatus and viral load

— Substance use including methamphetamine (adherence barrier), alcohol, IDU, shared equipment

— Mental health: depression, anxiety, trauma, housing instability, food insecurity, intimate partner violence

— Insurance, Ryan White eligibility, ADAP enrollment

— Reproductive plans and contraception

— Concomitant medications (PPIs, antacids, anticonvulsants, rifamycins, statins) — DDI screening

— Vaccination history (HBV, HAV, HPV, pneumococcal, influenza, COVID, mpox)

Step 3 management: A young patient with "EBV-negative mononucleosis" plus a rash and oral ulcers gets HIV RNA viral load plus a 4th-generation Ag/Ab assay — antibody alone may miss the window period. Treat as acute HIV and initiate ART promptly.

Acute (primary) HIV — 2–4 weeks post-exposure:

Established chronic HIV — variable, often clinically silent for years; may present with:

Critical history elements at intake:

Physical Exam Findings and Functional Assessment

— Seborrheic dermatitis of nasolabial folds, scalp, eyebrows

— Kaposi sarcoma: violaceous, non-blanching papules/plaques on palate, trunk, lower extremities

— Molluscum on face (especially giant/atypical → think advanced HIV or disseminated cryptococcus mimic)

— Pruritic papular eruption, eosinophilic folliculitis

— Herpes zoster scars, perianal/genital HSV ulcers

— Oral thrush (pseudomembranous, erythematous, or angular cheilitis), oral hairy leukoplakia on lateral tongue (EBV-driven, non-scrapable)

Key distinction: Oral thrush scrapes off leaving an erythematous base; oral hairy leukoplakia does not scrape off and sits on the lateral tongue — both predict more advanced HIV but only thrush is an AIDS-defining infection when esophageal. Hairy leukoplakia (EBV) flags immunosuppression but is not by itself AIDS-defining.

General: assess weight trajectory, BMI, wasting (temporal, thenar), performance status. Document vitals including orthostatics if diarrhea/wasting.

Skin and mucosa (often the highest-yield exam in outpatient HIV):

Lymph nodes: generalized non-tender lymphadenopathy common; rapidly enlarging, asymmetric, or fixed node → biopsy for lymphoma or TB.

HEENT: funduscopy for CMV retinitis ("pizza pie" hemorrhages/exudates) when CD4 <50; cotton-wool spots are nonspecific HIV retinopathy.

Pulmonary: often normal; tachypnea and exertional desaturation suggest PCP.

Abdominal: hepatosplenomegaly (MAC, lymphoma, coinfection HBV/HCV).

Neurologic: mini-cog or MoCA for HAND screening; focal deficits → CNS imaging; meningismus → LP.

Genitourinary/anorectal: STI exam, anal exam for warts and dysplasia (especially MSM, women with cervical HPV history), Pap and anal cytology per local protocol.

Psychiatric: PHQ-9, GAD-7, substance use screening (AUDIT-C, NIDA) — adherence predictors.

Diagnostic Workup — Initial Labs and Confirmatory HIV Testing

— Step 1: 4th-generation HIV-1/2 Ag/Ab combination immunoassay (detects p24 antigen + antibodies; positive ~2–4 weeks post-exposure)

— Step 2 if reactive: HIV-1/HIV-2 antibody differentiation assay (Geenius)

— Step 3 if differentiation indeterminate/negative: HIV-1 RNA (NAAT) — distinguishes acute infection from false positive

— HIV RNA: detectable ~10–14 days

— p24 antigen: ~14–21 days

— IgM/IgG antibody: 3–4 weeks (rarely up to 12)

— CD4 count and percentage — staging, OI prophylaxis decisions

— HIV-1 RNA quantitative viral load — baseline and treatment monitoring

— HIV genotype resistance testing (RT/protease ± integrase if PrEP failure or transmitted INSTI resistance suspected)

— HLA-B*5701 if abacavir is contemplated (skip if using TAF/TDF-based regimen)

— Tropism assay only if maraviroc considered (rare first-line)

— CBC, CMP including AST/ALT, fasting lipids, A1c, urinalysis with UPCR

— HBsAg, anti-HBs, anti-HBc, HCV Ab with reflex RNA, HAV IgG

— Syphilis (RPR or treponemal), gonorrhea/chlamydia NAAT (3-site for MSM), trichomonas

— TB: IGRA preferred over TST

— Toxoplasma IgG, CMV IgG, VZV IgG, measles/rubella titers

— Pregnancy test in persons who can become pregnant

— Cervical cytology; anal cytology where available

CCS pearl: On the CCS case, after a reactive 4th-gen assay in a new patient, your next two orders are HIV antibody differentiation assay and HIV-1 RNA viral load — not a Western blot (no longer recommended). Then schedule rapid-start ART clinic visit within 7 days.

Diagnostic algorithm (CDC 2014):

Window periods:

Acute HIV diagnosis: reactive Ag/Ab + negative/indeterminate antibody differentiation + positive HIV RNA (typically >10,000 copies/mL, often >100,000).

Baseline labs to draw with diagnosis (do not delay ART):

Diagnostic Workup — Advanced and Pre-Treatment Staging Studies

— Genotype for reverse transcriptase and protease in all newly diagnosed (transmitted NNRTI resistance ~10% in US — another reason INSTIs are first-line)

— Integrase genotype if exposure to INSTI (failed PrEP with cabotegravir LA, prior INSTI use, perinatal exposure, or virologic failure on INSTI)

— If viral load <500–1000 copies/mL, genotype may not amplify — start ART empirically and reassess

— CD4 <200: PCP risk — start TMP-SMX prophylaxis; check CXR

— CD4 <100 with positive Toxoplasma IgG and no TMP-SMX: add toxo prophylaxis (TMP-SMX covers both)

— CD4 <50: screen for cryptococcal antigen (CrAg) in serum if prevalence high or symptoms; ophthalmology referral for CMV; consider MAC prophylaxis only if not starting effective ART (no longer routine if ART started)

— Symptomatic patients: induced sputum/BAL for PCP, blood cultures for MAC, LP for cryptococcal meningitis, brain MRI for ring-enhancing lesions

— HBV coinfection: HBeAg, HBV DNA, FibroScan or APRI — choose ART regimen with tenofovir (TDF or TAF) + emtricitabine/lamivudine to dually treat

— HCV coinfection: quantitative RNA, genotype, fibrosis assessment; plan DAA therapy with attention to DDIs

— Renal: eGFR, urine protein/Cr — informs TDF vs TAF

— Bone: DEXA in older patients, postmenopausal women, long-term steroid users

— Cardiovascular: ASCVD risk calculation; consider statin per REPRIEVE if 40–75 with low-to-intermediate ASCVD risk

Board pearl: Patients with HIV/HBV coinfection must receive an ART regimen containing two agents active against HBV (TDF or TAF plus FTC/3TC). Stopping these abruptly causes severe HBV flare with hepatic decompensation.

Resistance testing before ART (always):

Opportunistic infection screening when CD4 is low:

Comorbid disease staging:

Pregnancy: confirm with quantitative β-hCG; HIV RNA, CD4, genotype same as nonpregnant.

Risk Stratification and ART Initiation Logic

— Goal: start ART within 7 days of diagnosis, ideally same day, once acute OIs ruled out

— Benefits: faster viral suppression, higher retention in care, improved transmission prevention (U=U)

— Safe even before genotype, CD4, and HLA-B*5701 results return — use INSTI-based regimen with a high genetic barrier (bictegravir or dolutegravir) plus TAF/FTC or TDF/FTC

— Cryptococcal meningitis: delay ART 4–6 weeks after antifungal initiation (IRIS mortality risk)

— TB meningitis: delay ART ~8 weeks after starting TB therapy

— Pulmonary or other non-CNS TB with CD4 <50: start ART within 2 weeks of TB therapy; CD4 ≥50, within 8 weeks

— Severe OIs without specific delay (PCP, toxo): start ART within 2 weeks

— Lifelong adherence expectation; >95% adherence ideal for older regimens, but modern INSTI regimens forgive lapses better

— U=U education: undetectable viral load for ≥6 months means no sexual transmission

— Side-effect anticipatory guidance: weight gain (INSTI/TAF), insomnia/vivid dreams (dolutegravir, efavirenz), GI upset

— Drug–drug interactions: polyvalent cations (Mg, Al, Ca, Fe) chelate INSTIs — separate dosing; PPIs reduce rilpivirine and atazanavir absorption

— Cost, insurance, ADAP/Ryan White linkage

Step 3 management: New diagnosis in a 28-year-old without symptoms of OI → draw baseline labs and start bictegravir/TAF/FTC the same visit. Do not wait for genotype.

Universal ART is recommended for everyone with HIV, regardless of CD4, viral load, or symptom status (DHHS, IAS-USA, WHO).

Rapid initiation ("rapid start" or "test-and-treat"):

When to delay or modify timing:

Pre-treatment counseling checklist:

Adherence support tools: pill organizers, phone reminders, single-tablet regimens (STRs), long-acting injectable cabotegravir/rilpivirine for select virologically suppressed patients.

Pharmacotherapy — First-Line ART Regimens

— Bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) — single tablet, no HLA testing, no boosting, minimal DDIs

— Dolutegravir + (TAF or TDF)/FTC or DTG + 3TC (Dovato; not if HBV coinfected, HIV RNA >500,000, or genotype unavailable)

— Dolutegravir/abacavir/lamivudine (Triumeq) — requires negative HLA-B*5701

— INSTIs (preferred): bictegravir, dolutegravir, raltegravir, elvitegravir/cobicistat, cabotegravir (LA)

— NNRTIs: doravirine, rilpivirine, efavirenz (less favored)

— Boosted PIs: darunavir/cobicistat or /ritonavir — used for resistance, pregnancy in some scenarios, or adherence concerns (higher genetic barrier)

— TAF: lower bone/renal toxicity than TDF; more weight gain and lipid increase

— TDF: preferred if untreated HBV with high VL, simpler, also dual HBV activity; avoid eGFR <60

— Abacavir: avoid if HLA-B*5701 positive (severe hypersensitivity); concern for increased CV events in some cohorts

— 3TC/FTC: interchangeable; both active against HBV

— INSTIs: weight gain, insomnia (DTG), rare hepatotoxicity, neural tube defect signal with DTG at conception was downgraded — DTG now safe in pregnancy and at conception per updated Tsepamo data

— TDF: nephrotoxicity (Fanconi), bone loss

— TAF: weight, lipids

— Efavirenz: CNS effects, suicidality, QT, teratogenicity historically (now considered acceptable)

— Rilpivirine: requires food, acid for absorption — contraindicated with PPIs

— Polyvalent cations (Ca, Mg, Al, Fe): separate from INSTIs (2 hrs before or 6 hrs after)

— Rifampin lowers INSTI/PI levels → double DTG dose or switch to rifabutin

— Statins: avoid simvastatin/lovastatin with boosted PIs; rosuvastatin/atorvastatin dose-limited

Board pearl: The default answer for "best initial ART regimen" on Step 3 is bictegravir/TAF/FTC as a single daily tablet — no HLA-B*5701 testing required, no boosting, robust resistance barrier.

Backbone: 2 NRTIs + 1 anchor agent (INSTI preferred).

DHHS preferred initial regimens for most people with HIV:

Anchor drug classes:

Key NRTIs:

Critical adverse effects and monitoring:

Drug interactions to memorize:

Long-Acting and Alternative Regimens; Switch Strategies

— FDA-approved for adults virologically suppressed (<50 copies/mL) on oral ART for ≥3 months, no resistance to either agent, no HBV coinfection

— Dosed every 1 or 2 months IM gluteal; optional oral lead-in

— Ideal for adherence challenges, pill fatigue; requires reliable clinic follow-up because missed doses risk resistance

— Contraindications: chronic HBV (no HBV activity), severe hepatic impairment, concomitant rifamycins/anticonvulsants

— DTG/3TC (Dovato): approved for treatment-naive (with caveats above) and switch

— DTG + RPV (Juluca): switch only, for virologically suppressed patients without resistance, no HBV

— Use when adherence is uncertain (highest genetic barrier), suspected transmitted resistance pending genotype, or pregnancy with late presentation

— Simplification (e.g., to STR), toxicity mitigation (TDF→TAF for renal/bone; off efavirenz for CNS), DDI management, or pregnancy

— Confirm full historical genotype review; do not switch to a regimen with lower barrier if archived resistance exists

— Monitor VL at 4–8 weeks post-switch

— Confirm with repeat VL; assess adherence and DDIs

— Send genotype while still on failing regimen (resistance mutations only detectable with selective pressure)

— Construct new regimen with ≥2 fully active drugs, ideally from new classes

— Consult HIV specialist for multidrug-resistant virus; options include lenacapavir, fostemsavir, ibalizumab

CCS pearl: Patient with rising VL on TDF/FTC/DTG → order adherence assessment + HIV genotype while still on regimen before changing. Switching prematurely loses the chance to detect resistance.

Long-acting injectable cabotegravir + rilpivirine (CAB/RPV):

Two-drug oral regimens:

Boosted PI-based regimens (darunavir/cobicistat or /ritonavir + 2 NRTIs):

Switching ART in suppressed patients:

Virologic failure management:

PrEP failure presenting as new HIV: suspect INSTI resistance if cabotegravir LA PrEP; use boosted PI-based regimen while awaiting genotype.

Special Populations — Elderly, Renal, and Hepatic Impairment

— Higher burden of polypharmacy, CV disease, frailty, cognitive impairment, bone loss

— Prefer BIC/TAF/FTC or DTG-based regimens; avoid efavirenz (cognitive/falls)

— Annual ASCVD risk; REPRIEVE supports pitavastatin 4 mg for primary prevention in PWH aged 40–75 with low-to-intermediate ASCVD risk (≥40% relative risk reduction in MACE)

— DEXA at age 50 (men) and at menopause (women); earlier if on TDF

— Vaccinations: pneumococcal (PCV20 or PCV15→PPSV23), shingles (RZV regardless of age once CD4 ≥200), HBV if non-immune, annual influenza, COVID, mpox, HPV through age 26 (consider through 45 with shared decision)

— TDF contraindicated if eGFR <60 (some say <50) and avoid if proteinuria; switch to TAF (safe down to eGFR ~30, dialysis with combination products)

— Dose-adjust raltegravir? No (renally safe)

— BIC/TAF/FTC: usable down to eGFR 30; on hemodialysis use the same daily tablet

— Avoid abacavir if hypersensitivity risk; otherwise renally fine

— Cobicistat and dolutegravir inhibit tubular creatinine secretion → benign ~0.1–0.2 mg/dL creatinine rise without true GFR change; cystatin C clarifies

— Child-Pugh C: avoid darunavir/cobicistat, rilpivirine, doravirine per labels

— DTG and BIC generally safe in mild-moderate hepatic impairment

— HBV coinfection: must use TDF/TAF + FTC/3TC; never withdraw without bridge

— HCV: treat with DAAs; watch DDIs (sofosbuvir/velpatasvir generally compatible with INSTIs; check before pairing with boosted PIs)

Key distinction: A rise in creatinine after starting DTG, BIC, or cobicistat without proteinuria or other tubular signs is an inhibition of tubular creatinine secretion, not true nephrotoxicity — do not stop the drug. Compare to TDF-induced Fanconi syndrome (proteinuria, glycosuria with normoglycemia, hypophosphatemia) which mandates switching to TAF.

Older adults with HIV (≥50):

Renal impairment:

Hepatic impairment:

Special Populations — Pregnancy, Pediatrics, and Reproductive Health

— Goal: maternal viral suppression to prevent perinatal transmission (<1% if VL undetectable at delivery)

— Start ART as soon as possible, regardless of trimester

— Preferred regimens: DTG + (TDF or TAF)/FTC is now preferred throughout pregnancy and at conception (updated Tsepamo data showed neural tube defect risk not significantly elevated)

— Alternatives: raltegravir + TDF/FTC (especially late presenters — rapid VL drop), darunavir/ritonavir-based for resistance or adherence concerns

— Avoid: cobicistat-boosted regimens (subtherapeutic levels in 2nd/3rd trimester), bictegravir (less data), oral cabotegravir/rilpivirine LA in pregnancy

— VL <1000 at 34–36 weeks: vaginal delivery acceptable, no IV zidovudine needed

— VL ≥1000 or unknown near delivery: scheduled C-section at 38 weeks + IV zidovudine intrapartum

— Avoid artificial rupture of membranes, fetal scalp electrodes, and operative vaginal delivery when VL detectable

— Low-risk (mother suppressed throughout): zidovudine x 4 weeks

— Higher-risk (late ART, detectable VL, acute maternal HIV): presumptive 3-drug therapy (ZDV + 3TC + NVP or RAL)

— No breastfeeding is still the US recommendation, but updated 2023 guidance supports shared decision-making if mother is virologically suppressed and chooses to breastfeed; formula remains preferred in resource-rich settings

— Test infant with HIV DNA/RNA PCR at 14–21 days, 1–2 months, 4–6 months

Board pearl: The 2023 update placed dolutegravir as preferred at conception and throughout pregnancy — the older "avoid DTG in first trimester" teaching is outdated.

Pregnancy with HIV:

Delivery management:

Infant management:

Contraception: most methods compatible; efavirenz and some PIs reduce hormonal contraception efficacy modestly — IUDs and DMPA reliable.

Conception planning: sustained undetectable VL = no sexual transmission; PrEP for negative partner optional.

Complications and Adverse Outcomes

— Paradoxical worsening of a known infection or unmasking of subclinical infection 2–12 weeks after ART start as CD4 rebounds

— Highest risk with CD4 <50 and active or recent OI

— Common culprits: TB, MAC, cryptococcus, CMV, PML, HBV/HCV

— Management: continue ART in most cases, treat underlying infection, add corticosteroids for severe TB-IRIS or symptomatic CNS IRIS

— Exception: cryptococcal meningitis IRIS can be fatal — hence the 4–6 week delay in starting ART after antifungal initiation

— Weight gain and metabolic syndrome — INSTIs (especially DTG, BIC) + TAF; monitor BMI, A1c, lipids annually

— Renal: TDF tubulopathy (Fanconi), kidney stones with atazanavir

— Bone: TDF-associated osteopenia; consider DEXA

— Hepatic: NVP hypersensitivity hepatitis (women with CD4 >250, men >400 — avoid); rare DTG/BIC transaminitis

— Neuropsychiatric: efavirenz (depression, suicidality, vivid dreams), dolutegravir (insomnia, headache)

— Hypersensitivity: abacavir (HLA-B*5701), NVP (Stevens-Johnson)

— Lipodystrophy: older PIs and stavudine — rare with modern regimens

— Accelerated atherosclerosis, increased MI risk

— Chronic kidney disease (HIVAN — collapsing FSGS in untreated, especially in patients of African descent)

— Non-AIDS malignancies (anal, lung, HCC, Hodgkin lymphoma)

— HAND (HIV-associated neurocognitive disorder)

— Frailty, osteoporosis, hypogonadism

Step 3 management: A patient with CD4 30 starts ART, and 3 weeks later develops fever and worsening lymphadenopathy. Suspect IRIS (often unmasking MAC or TB) — continue ART, obtain mycobacterial blood cultures, treat the OI, add steroids if severe.

Immune reconstitution inflammatory syndrome (IRIS):

ART-class–specific complications:

Non-AIDS complications of chronic HIV (even when suppressed):

Treatment failure: virologic (VL >200 confirmed), immunologic (failure to gain CD4), clinical (new OI on ART).

When to Escalate Care — ICU, Consult, and Inpatient Triage

— Suspected or confirmed transmitted drug resistance

— Virologic failure with resistance mutations

— Multidrug-resistant HIV (need for lenacapavir, fostemsavir, ibalizumab)

— Pregnancy (co-manage with maternal-fetal medicine)

— Pediatric HIV

— Active opportunistic infection requiring specialized therapy

— Coinfection management (HBV, HCV, TB)

— Long-acting injectable program enrollment

— Active OI requiring IV therapy: severe PCP (PaO₂ <70 or A-a gradient >35), cryptococcal meningitis (induction amphotericin + flucytosine), CMV retinitis with vision threat, disseminated MAC, severe toxoplasmosis

— Severe IRIS with end-organ compromise

— New AIDS-defining malignancy needing workup (CNS lymphoma)

— Acute renal failure on TDF, severe hepatotoxicity

— Acute HIV with severe meningoencephalitis

— Respiratory failure from PCP (intubation, often with adjunctive steroids when PaO₂ <70 mmHg or A-a >35)

— Septic shock from bacterial pneumonia, MAC, salmonella bacteremia

— Status epilepticus from CNS OI

— Hemodynamic instability from adrenal insufficiency (CMV adrenalitis) or massive GI bleed (KS, lymphoma)

— Inpatients newly diagnosed should ideally start ART before discharge if no contraindication, with scheduled outpatient HIV clinic visit within 7–14 days

— Confirm medication coverage (Ryan White, ADAP, 340B pharmacy) before discharge to prevent treatment interruption

— Pharmacist-led discharge medication reconciliation reduces DDI errors

CCS pearl: Hospitalized patient with PCP and new HIV diagnosis: start TMP-SMX (+ steroids if severe), initiate ART within 2 weeks of OI therapy, and arrange HIV clinic follow-up within 7 days of discharge — do not let them leave without a confirmed appointment.

Outpatient HIV care is the default; most ART initiations happen in clinic.

ID/HIV specialist consultation indications:

Inpatient admission indications:

ICU criteria:

Care transitions:

Key Differentials — Same-Category (Other Viral and Immunodeficiency Mimics)

— EBV mononucleosis: heterophile-positive, exudative pharyngitis, prominent posterior cervical lymphadenopathy, splenomegaly; atypical lymphocytes prominent

— CMV mononucleosis: heterophile-negative, more hepatitis-predominant, less pharyngitis

— Acute toxoplasmosis: lymphadenopathy with low-grade illness, contact with cats/raw meat

— Secondary syphilis: palmoplantar maculopapular rash, condyloma lata, generalized lymphadenopathy — always co-test for HIV

— Acute viral hepatitis A/B/C: jaundice, transaminitis; HBV/HCV share risk factors with HIV — co-test

— Disseminated gonococcal infection: rash, tenosynovitis, fever

— Drug reaction (DRESS): eosinophilia, organ involvement

— Common variable immunodeficiency (CVID): recurrent sinopulmonary infections, low immunoglobulins, normal CD4 count

— Idiopathic CD4 lymphocytopenia: persistently low CD4 (<300) with HIV testing negative on multiple modalities including RNA — rare but exam-classic

— HTLV-1 infection: tropical spastic paraparesis, adult T-cell leukemia; shares transmission routes

— Chronic active EBV: atypical, often Asian populations

— HIV RNA viral load distinguishes acute HIV from EBV/CMV mononucleosis (HIV RNA typically >100,000)

— 4th-gen Ag/Ab plus differentiation assay confirms HIV

— Quantitative immunoglobulins distinguish CVID

Key distinction: A heterophile-negative mononucleosis-like syndrome in a sexually active adult must have HIV RNA ordered — not just a repeat monospot. Acute HIV is the must-not-miss differential because rapid ART initiation transforms outcomes and prevents onward transmission.

Acute HIV mimics (the mononucleosis-like syndrome):

Chronic HIV mimics (immunosuppression and constitutional symptoms):

Distinguishing tools:

Key Differentials — Other-Category Mimics of Advanced HIV Presentations

— PCP (CD4 <200): bilateral diffuse interstitial; elevated LDH, β-D-glucan

— Bacterial pneumonia: focal consolidation, rapid onset — most common pulmonary infection in HIV at any CD4

— TB: upper lobe cavitation if higher CD4; atypical/disseminated with miliary pattern if CD4 <200

— Fungal (cryptococcus, histoplasma, coccidioides): geographic exposure, miliary or nodular patterns

— Lymphoid interstitial pneumonitis, KS pulmonary involvement

— Toxoplasmosis: multiple lesions, positive serology, basal ganglia predilection — empiric trial of pyrimethamine-sulfadiazine

— Primary CNS lymphoma: usually single, periventricular, EBV-positive CSF, thallium SPECT uptake

— Tuberculoma, cryptococcoma, bacterial abscess

— PML (JC virus): non-enhancing white matter lesions, no mass effect

— Cryptosporidium, microsporidia, isospora, MAC, CMV colitis, C. difficile, lymphoma

— Workup: stool culture, O&P, AFB, cryptosporidium antigen, C. diff PCR; colonoscopy with biopsy if persistent

— Disseminated MAC (CD4 <50), TB, lymphoma, KS, adrenal insufficiency (CMV), thyroid disease

— HIV itself, parvovirus B19 (PRCA), ZDV, TMP-SMX, ganciclovir, marrow infiltration by lymphoma/MAC

Board pearl: Multiple ring-enhancing lesions in advanced HIV with positive Toxoplasma IgG → empiric pyrimethamine + sulfadiazine + leucovorin and reimage in 2 weeks; lack of response → biopsy for primary CNS lymphoma (often EBV-driven, single lesion classically but can be multiple).

Pulmonary infiltrates in immunocompromised host:

Ring-enhancing brain lesions:

Diarrhea in advanced HIV:

Weight loss and fevers:

Cytopenias:

Secondary Prevention, Discharge Plans, and Long-Term Care

— TMP-SMX if CD4 <200 (PCP) or <100 with toxo IgG positive — discontinue when CD4 >200 for 3 months on ART

— Azithromycin for MAC if CD4 <50 — no longer routinely required if patient is on effective ART (DHHS 2017 update); reserve for those not yet on ART

— Treat latent TB: 3HP, 4R, or 9 INH after ruling out active disease

— CrAg screening and preemptive fluconazole if CD4 <100 and CrAg positive without meningitis

— Inactivated: pneumococcal (PCV20 or PCV15→PPSV23), HBV (high-dose 4-dose series if non-immune), HAV, HPV (through 26, consider to 45), Tdap, influenza annually, COVID, mpox, RZV (shingles) once CD4 ≥200

— Live vaccines (MMR, varicella, yellow fever): only if CD4 ≥200 and stable; avoid LAIV

— Pitavastatin 4 mg daily per REPRIEVE for PWH aged 40–75 with low-intermediate ASCVD risk

— BP, lipid, A1c, weight monitoring

— Smoking cessation (highest single mortality lever in well-suppressed HIV)

— Cervical cytology annually for 3 years, then q3y if normal

— Anal cytology in MSM, women with HPV-related disease, transgender persons (HRA referral if abnormal)

— Standard mammography, colonoscopy, lung CT per general guidelines

— HCC surveillance with US q6mo if cirrhosis or chronic HBV

Step 3 management: Stable PWH on ART with CD4 250 returns for annual visit — order viral load, CD4, CMP, lipids, A1c, urinalysis with UPCR, STI screening per behavior, vaccinations review, pitavastatin if ASCVD criteria met, and cervical/anal cancer screening as indicated.

Lifelong ART is the cornerstone — never discontinue without specialist input.

Opportunistic infection prophylaxis:

Vaccinations:

Cardiovascular and metabolic prevention:

Cancer screening:

Mental health and substance use: integrated care; treat depression aggressively (adherence driver).

Partner services: assist with notification; expedited partner therapy for STIs where legal; PrEP for HIV-negative partners; treatment-as-prevention messaging.

Follow-Up, Monitoring, and Counseling Cadence

— Visit at 2–4 weeks to assess tolerance, adherence, side effects, and reinforce education

— Viral load and CD4 at 4–8 weeks: expect ~1-log drop by 4 weeks; undetectable (<50) by 24 weeks

— If VL not falling appropriately: assess adherence, DDIs, and consider resistance testing

— VL every 3–4 months during first 2 years; thereafter every 6 months if stable >2 years on therapy and adherent

— CD4 every 6 months until stably >300; can extend to annually or discontinue monitoring if CD4 consistently >500 for 2 years on suppressive ART (DHHS option)

— CMP, CBC, lipids, A1c, UA/UPCR annually

— STI screening every 3–6 months for those at risk

— DEXA, dental, ophthalmology per general adult guidance with HIV-specific timing

— Reinforce U=U: undetectable VL = no sexual transmission

— Adherence check: pill count, pharmacy refill data, self-report; identify barriers (mental health, substance use, housing, stigma)

— Sexual health, contraception, conception planning

— Vaccination updates

— Mental health screen (PHQ-9, GAD-7) at least annually

— Single-tablet regimens improve adherence

— Reminder apps, pill boxes, blister packs

— Directly observed therapy in select cases (incarceration, methamphetamine use disorder)

— Long-acting cabotegravir/rilpivirine IM for select suppressed patients with adherence challenges

— Address social determinants: Ryan White case management, ADAP, housing assistance

Board pearl: Goal is VL <50 copies/mL by 24 weeks. A persistent low-level viremia (50–200) is often not true failure but a "blip" — recheck before changing regimens. Confirmed VL >200 on two occasions = virologic failure → genotype while still on regimen.

After ART initiation:

Once virologically suppressed and stable:

Counseling each visit:

Adherence interventions:

Patient self-management red flags to teach: fever, weight loss, new neurologic symptoms, vision change, rash with mucosal involvement, jaundice.

Ethical, Legal, and Patient Safety Considerations

— US guidance: opt-out testing for ages 13–64 in healthcare settings; verbal consent sufficient; no separate written consent required federally (state laws vary, e.g., NY requires specific written or verbal consent)

— Disclosure of positive result must be in person when possible, with linkage to care arranged

— HIV status protected under HIPAA; many states have additional HIV-specific confidentiality statutes

— Records release requires explicit patient authorization, often a separate form

— All states mandate HIV case reporting to public health (named reporting)

— Partner notification services are typically performed by public health, preserving index patient anonymity

— A few states recognize a clinician's limited "duty to warn" identifiable partners at imminent risk; know your jurisdiction

— HIV criminalization laws still exist in many states (criminal exposure, transmission) — counsel patients about disclosure obligations

— Most states allow minors to consent independently to HIV testing and treatment without parental notification

— Maternal autonomy is preserved; ART strongly encouraged but cannot be coerced

— Most states require prenatal HIV testing with opt-out

— Medication interruption is the #1 preventable harm — confirm pharmacy access before discharge, use 90-day fills, coordinate with ADAP

— Avoid abrupt discontinuation of TDF/TAF + FTC/3TC in HBV-coinfected patients (severe hepatitis flare)

— Reconcile DDIs at every transition (especially rifamycins, anticonvulsants, PPIs, statins, hormonal therapy)

— Use single-tablet regimens when possible to reduce error

Step 3 management: A newly diagnosed patient asks you not to tell their partner. Respond by offering anonymous partner notification through public health, counseling on disclosure and U=U, and documenting the conversation — do not unilaterally breach confidentiality unless your jurisdiction's duty-to-warn statute compels it.

Informed consent for HIV testing:

Confidentiality:

Partner notification and duty to warn:

Adolescents and minors:

Pregnancy:

Patient safety / transitions of care:

U=U messaging is itself an ethical imperative: failure to communicate U=U has been recognized as a deficiency in HIV care.

High-Yield Associations and Rapid-Fire Clinical Facts

Board pearl: If the question asks "next best step" after a reactive 4th-gen test, the answer is HIV-1/2 antibody differentiation assay, not Western blot.

U=U = undetectable (<200, ideally <50) ≥6 months → zero sexual transmission risk (PARTNER, PARTNER2, Opposites Attract).

Preferred first-line ART: bictegravir/TAF/FTC or dolutegravir + (TAF/TDF)/FTC.

HLA-B*5701 required before abacavir.

TDF nephrotoxicity = proximal tubulopathy (Fanconi): hypophosphatemia, glycosuria with normoglycemia, proteinuria → switch to TAF.

Cobicistat, DTG, BIC cause benign creatinine bump (tubular secretion inhibition), not true GFR decline.

Rilpivirine needs acid and food — no PPIs.

Rifampin halves INSTI levels → double DTG dose or use rifabutin.

Polyvalent cations (Mg, Al, Ca, Fe) bind INSTIs — separate by hours.

Pregnancy preferred: DTG-based + TAF or TDF/FTC (DTG safe at conception per 2023 update).

HBV coinfection: ART must include TDF or TAF + FTC or 3TC; never stop abruptly.

Cryptococcal meningitis: delay ART 4–6 weeks; TB meningitis: delay 8 weeks; other OIs: start ART within 2 weeks.

PCP prophylaxis: TMP-SMX when CD4 <200; stop when CD4 >200 for 3 months.

MAC prophylaxis no longer routine if effective ART started; reserve for non-ART patients with CD4 <50.

RZV (shingrix) once CD4 ≥200.

Live vaccines only if CD4 ≥200; avoid LAIV.

Statin for primary prevention (REPRIEVE): pitavastatin 4 mg in PWH 40–75 with low-intermediate ASCVD risk.

Acute HIV = high VL (>100K) + reactive Ag/Ab + negative antibody differentiation.

PrEP-failure HIV → suspect INSTI resistance if on cabotegravir LA.

Long-acting CAB/RPV IM for suppressed adherent patients without HBV or rifamycin needs.

Window periods: RNA ~10 d, p24 ~14–21 d, antibody ~3–4 wk.

AIDS-defining CD4 cutoff: <200.

Board Question Stem Patterns

Key distinction: "Best initial regimen" in a treatment-naive adult is almost always bictegravir/TAF/FTC; modifications come from HBV (need TDF/TAF + FTC), pregnancy (DTG-based), renal failure (TAF favored), or TB therapy (DTG dose-adjusted with rifampin).

Stem 1 — Acute HIV: 24-yo MSM with 1 week of fever, sore throat, truncal rash, and oral ulcers 3 weeks after unprotected encounter. Heterophile negative. Best next test? → HIV RNA viral load (plus 4th-gen Ag/Ab). Best initial therapy once confirmed → bictegravir/TAF/FTC same day.

Stem 2 — Rapid start: Newly diagnosed asymptomatic 35-yo with CD4 480. What to do today? → Draw genotype, CD4, baseline labs, and start INSTI-based ART at this visit. Do not wait for results.

Stem 3 — Pregnancy: G2P1 at 10 weeks newly diagnosed HIV, VL 45,000. Best regimen? → Dolutegravir + TAF/FTC (updated guidance favors DTG throughout pregnancy).

Stem 4 — Cryptococcal meningitis + new HIV: Start amphotericin + flucytosine; delay ART 4–6 weeks to avoid IRIS.

Stem 5 — HBV coinfection: HIV + HBsAg positive. Regimen must contain TDF or TAF + FTC/3TC.

Stem 6 — Renal: PWH on TDF/FTC/DTG with new proteinuria, hypophosphatemia, glycosuria with normal glucose → TDF tubulopathy; switch TDF to TAF.

Stem 7 — Creatinine bump: New DTG-based regimen, Cr rose 0.15 mg/dL, no proteinuria → tubular secretion inhibition; continue regimen.

Stem 8 — IRIS: CD4 was 25, started ART 3 weeks ago, now fever and enlarging cervical nodes → continue ART, evaluate for MAC/TB, treat OI, consider steroids.

Stem 9 — Virologic failure: VL rebounds to 5,000 on long-term therapy → adherence assessment + genotype while still on regimen before switching.

Stem 10 — DDI: Patient starting rifampin for TB on DTG → double DTG to 50 mg BID or switch rifampin to rifabutin.

Stem 11 — Prophylaxis: CD4 180 with no symptoms → start TMP-SMX. CD4 rises to 250 sustained 3+ months → stop TMP-SMX.

Stem 12 — Vaccination: PWH, CD4 350, never had shingles vaccine → RZV (Shingrix) two doses.

Stem 13 — U=U counseling: Suppressed patient asks about condomless sex with negative partner → U=U: no sexual transmission risk; offer partner PrEP per preference.

Stem 14 — LA injectable eligibility: Suppressed >6 months, no resistance, no HBV, reliable follow-up → candidate for CAB/RPV IM.

One-Line Recap

Start ART the day of HIV diagnosis with an INSTI-based single-tablet regimen — preferably bictegravir/TAF/FTC or dolutegravir + TAF/FTC — for every person with HIV regardless of CD4, because durable viral suppression saves lives, prevents transmission (U=U), and reduces non-AIDS comorbidities.

Board pearl: When in doubt on the exam, the right answer for a newly diagnosed adult is "start bictegravir/TAF/FTC today and link to HIV clinic within 7 days" — the rest of the workup happens in parallel, not before.

Rapid start beats waiting: baseline labs (CD4, VL, genotype, HLA-B*5701, HBV/HCV, renal) are drawn at the initiating visit but do not delay ART; the only true delay is cryptococcal or TB meningitis (4–8 weeks) to avoid fatal IRIS.

Regimen tailoring rules: HBV coinfection → must include TDF/TAF + FTC/3TC; pregnancy → DTG + TAF/TDF/FTC (safe at conception per updated Tsepamo); renal disease → choose TAF over TDF; rifampin → double DTG; PPIs → avoid rilpivirine/atazanavir.

Monitor and prevent: VL at 4–8 weeks then q3–4 months, target undetectable by 24 weeks; TMP-SMX if CD4 <200; RZV when CD4 ≥200; pitavastatin per REPRIEVE for ASCVD primary prevention; annual STI, cervical/anal cytology, mental health screens.

Adherence is the regimen: address mental health, substance use, housing, insurance (Ryan White/ADAP); use single-tablet regimens; consider long-acting cabotegravir/rilpivirine IM for suppressed patients with pill fatigue; communicate U=U at every visit as both a clinical and ethical imperative.