HIV infection & opportunistic complications

Why HIV still belongs on every IM differential

Antiretroviral therapy transformed HIV from a near-uniformly fatal illness into a chronic, manageable condition with near-normal life expectancy when started early. Yet late presentations still occur — the patient with 'pneumonia' who has PCP, the young adult with a mono-like illness who has acute HIV seroconversion, or the inpatient with unexplained wasting and oral candidiasis. Early diagnosis and rapid ART initiation improve individual outcomes and prevent transmission. The clinician's job is to test, treat early, prevent OIs, and engage patients in lifelong care.

• About 1 in 7 people with HIV in the United States are unaware of their status — routine opt-out screening is recommended for everyone aged 13–64 at least once. [VERIFY prevalence]
• Late presenters (CD4 < 200 at diagnosis) account for a substantial fraction of new diagnoses and drive most opportunistic complications.
• U=U — sustained viral load suppression prevents sexual transmission; this is a powerful counseling and adherence tool.

Diagnosis: the 4th-generation test, acute HIV, and the window period

The laboratory 4th-generation HIV antigen/antibody combination test detects p24 antigen (appearing ~2 weeks after exposure) and HIV-1/2 antibodies (appearing ~3–8 weeks). It narrows the window period to about 2–6 weeks. Acute HIV — the syndrome of high-level viremia in the weeks after acquisition — is the period when antibody may still be negative but p24 antigen and HIV RNA are positive. When acute HIV is suspected and the Ag/Ab test is negative, send an HIV RNA (viral load), which will be very high (often >1 million copies/mL).

• 4th-generation Ag/Ab: preferred screening test; p24 Ag narrows the window to ~2–6 weeks.
• Acute HIV (seroconversion illness): fever, rash, pharyngitis, adenopathy, mucosal ulcers, arthralgia — mono-like; send HIV RNA if Ag/Ab is negative.
• Rapid point-of-care antibody tests have a longer window (~3–12 weeks); a negative rapid test does not exclude acute HIV.
• Confirm a reactive Ag/Ab with an HIV-1/HIV-2 differentiation immunoassay; acute infection may show a positive p24 with a partial antibody profile.

ART principles: START early, U=U, INSTI-first

The START trial established that immediate ART — regardless of CD4 count — reduces serious AIDS and non-AIDS events and mortality. Current guidelines recommend ART for everyone living with HIV on the day of diagnosis if the patient is ready. Sustained viral suppression to undetectable levels eliminates sexual transmission (HPTN 052; PARTNER/PARTNER2). First-line regimens are built around an integrase strand transfer inhibitor (INSTI) — bictegravir or dolutegravir — combined with two NRTIs, often as a single-tablet regimen.

• START (NEJM 2015): immediate ART reduced serious AIDS/non-AIDS events vs deferred therapy at CD4 ≤ 350 — treat everyone, immediately.
• U=U (PARTNER, PARTNER2): zero linked sexual transmissions when viral load is suppressed (<200 copies/mL) — a core counseling message.
• INSTI + 2 NRTIs is first-line: bictegravir (Biktarvy = BIC/FTC/TAF), dolutegravir (Triumeq = DTG/ABC/3TC; Dovato = DTG/3TC in selected patients). [VERIFY current DHHS preferred list]
• HLA-B*5701 screening before abacavir (hypersensitivity); HBV co-infection mandates a tenofovir-containing regimen (don't use Dovato/Triumeq without HBV coverage).

Opportunistic infections: the classic syndromes

OIs arise predominantly with CD4 < 200 cells/µL and remain the way many late presenters first come to medical attention. The pattern is recognizable: a dyspneic patient with a diffuse interstitial pneumonia and an elevated LDH has PCP until proven otherwise; a patient with headache, fever, and ring-enhancing brain lesions has cerebral toxoplasmosis; a patient with floaters and visual loss has CMV retinitis. Prophylaxis is effective and CD4-driven.

• PCP (Pneumocystis jirovecii): subacute dyspnea, dry cough, fever, diffuse bilateral infiltrates, elevated LDH, often pneumothorax risk; treat with TMP-SMX, add steroids if severe (PaO₂ < 70 mmHg or A-a gradient ≥ 45).
• Cerebral toxoplasmosis: multiple ring-enhancing lesions, seizures, headache; Toxo IgG usually positive; treat with pyrimethamine + sulfadiazine + leucovorin.
• CMV retinitis: floaters, scotomata, visual loss; urgent ophthalmology; treat with valganciclovir or ganciclovir/foscarnet.
• Disseminated Mycobacterium avium complex (MAC): fever, weight loss, anemia, hepatosplenomegaly at CD4 < 50; treat with azithromycin + ethambutol (± rifabutin).
• Cryptococcal meningitis: subacute headache, fever, meningismus; serum/CSF cryptococcal antigen; treat with liposomal amphotericin + flucytosine induction, then fluconazole consolidation (AIIRS/ACTA). [VERIFY current induction regimen]

Immune reconstitution inflammatory syndrome (IRIS)

IRIS is a paradoxical worsening of a known or subclinical opportunistic infection within weeks of ART initiation, driven by the recovering immune system's exaggerated response to microbial antigens. It occurs most often in patients with very low baseline CD4 counts and presents as worsening fever, adenopathy, infiltrates, or inflammation around a known OI (TB, MAC, CMV retinitis, cryptococcal meningitis, herpes). ART is generally continued; treat the underlying OI and, in severe IRIS, use short-course corticosteroids or NSAIDs. Distinguish IRIS from ART toxicity, drug resistance, and a new OI.

• Risk: low baseline CD4, high baseline viral load, rapid ART start with a subclinical OI, and specific pathogens (TB, MAC, Crypto, CMV).
• Onset: typically within the first 4–8 weeks of ART, occasionally later.
• Management: continue ART, treat the OI, and use corticosteroids for severe or organ-threatening IRIS (e.g., IRIS with respiratory failure or CNS inflammation).
• Do not routinely delay ART for OI treatment in most cases — early ART reduces mortality (exceptions: cryptococcal meningitis and TB meningitis, where a short delay may be considered). [VERIFY timing recommendations]

ART toxicities & drug interactions every IM resident should know

Modern ART is well tolerated, but specific toxicities and interactions remain important. Tenofovir disoproxil fumarate (TDF) can cause nephrotoxicity and bone loss; tenofovir alafenamide (TAF) reduces these but can cause weight gain and lipid changes. Abacavir requires HLA-B*5701 screening (hypersensitivity). Dolutegravir and other INSTIs can cause weight gain and, rarely, neuropsychiatric symptoms. Efavirenz causes vivid dreams, depression, and is teratogenic in the first trimester. Ritonavir/cobicistat boosting creates major cytochrome P450 interactions — review all co-prescribed medications.

• Tenofovir (TDF): nephrotoxicity (Fanconi-like), bone demineralization — prefer TAF in kidney disease or osteoporosis.
• Abacavir: screen HLA-B*5701 — hypersensitivity (fever, rash, GI) can be fatal on rechallenge.
• INSTIs (BIC, DTG, RAL): generally well tolerated; weight gain and rare neuropsychiatric symptoms (insomnia, mood) reported.
• Efavirenz: CNS effects, depression, suicidality, teratogenicity — avoid in pregnancy planning.
• PIs (darunavir, atazanavir): hyperlipidemia, hyperglycemia, GI; atazanavir causes indirect hyperbilirubinemia.
• Pharmacokinetic boosters (ritonavir, cobicistat): potent CYP3A inhibition — check every new medication (statins, anticoagulants, steroids, PPIs).

Prevention: PrEP, PEP, U=U, and prevention of vertical transmission

HIV prevention is now as central as treatment. Pre-exposure prophylaxis (PrEP) with daily tenofovir-based therapy (TDF/FTC or TAF/FTC) is highly effective in high-risk individuals; long-acting injectable cabotegravir every 2 months is an alternative for those who prefer it. Post-exposure prophylaxis (PEP) is a 28-day regimen started within 72 hours of a high-risk exposure. Treatment as prevention (U=U) means that suppressed patients do not transmit HIV sexually. Perinatal transmission is preventable with maternal ART, planned delivery, and (when needed) neonatal prophylaxis.

• PrEP: daily oral TDF/FTC (Truvada) or TAF/FTC (Descovy) in high-risk individuals; long-acting cabotegravir every 2 months is an alternative. [VERIFY current CDC PrEP guidance]
• Test creatinine, HBV, and HIV before starting PrEP; follow every 3 months with HIV test, STI screen, and adherence counseling.
• PEP: TDF/FTC + raltegravir or dolutegravir for 28 days, started within 72 hours of exposure (sooner is better).
• Perinatal transmission: maternal viral suppression throughout pregnancy and delivery reduces transmission to <1%; planned C-section if viral load >1,000 near delivery; neonatal prophylaxis tailored to risk.

Guidelines

• DHHS Panel on Antiretroviral Guidelines for Adults and AdolescentsClinicalinfo.hiv.gov, current living guideline [VERIFY version]The U.S. standard-of-care ART guideline — preferred regimens, monitoring, OIs, pregnancy.
• CDC/NIH/IDSA OI Prevention and Treatment GuidelinesNIH Clinicalinfo, current living guideline [VERIFY version]CD4-driven prophylaxis and treatment of opportunistic infections in adults and adolescents.

Key trials

• START — Immediate versus deferred ART for HIV infectionINSIGHT START Study Group. N Engl J Med. 2015;373:795–807 [VERIFY volume/pages]Immediate ART reduces serious AIDS and non-AIDS events regardless of baseline CD4 — treat everyone.
• HPTN 052 — ART for prevention of HIV transmissionCohen MS, et al. N Engl J Med. 2011;365:493–505 and 2016 [VERIFY]Early ART reduced HIV transmission by 96% in serodiscordant couples — treatment as prevention.
• PARTNER and PARTNER2 — Sexual transmission when viral load is suppressedRodger AJ, et al. Lancet / JAMA. [VERIFY citations]Zero linked transmissions in serodiscordant couples when viral load was suppressed — U=U.
• iPrEx — Preexposure chemoprophylaxis for HIV in MSMGrant RM, et al. N Engl J Med. 2010;363:2587–2599 [VERIFY]Daily TDF/FTC reduced HIV acquisition by ~44% overall and ~92% among those with detectable drug levels.
• DISCOVER — TAF/FTC vs TDF/FTC for PrEPMayer KH, et al. Lancet. 2020 [VERIFY]TAF/FTC non-inferior to TDF/FTC for PrEP with better bone and renal markers.