Step 2 CK · Internal Medicine · Infectious Disease

HIV & Opportunistic Infections

Name: HIV & Opportunistic Infections
Creator: Veli Bakalov, MD

The CD4 staircase of opportunistic infections and when to start ART

Infectious Disease·HIV & Sexually Transmitted Infections·4 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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High-yield

Screen everyone 15–65 with a 4th-generation HIV-1/2 Ag/Ab immunoassay (p24 + antibody), confirm with an antibody differentiation assay, and use HIV RNA for discordant results or suspected acute infection.
Acute retroviral syndrome (2–4 weeks after exposure): fever, pharyngitis, lymphadenopathy, rash, mucocutaneous ulcers, negative Monospot → HIV RNA, since antibodies may still be negative.
Start ART in everyone regardless of CD4 (tenofovir + emtricitabine + dolutegravir or bictegravir); viral load tracks response (undetectable = untransmittable), CD4 tracks OI risk.
Opportunistic infections by CD4: <500 thrush, zoster, Kaposi; <200 PCP; <100 Toxoplasma and Cryptococcus; <50 MAC and CMV retinitis.
PCP (dry cough, hypoxia, high LDH, bilateral interstitial infiltrates) → TMP-SMX, adding steroids if PaO2 <70 mmHg or A-a gradient ≥35.
Brain lesions: multiple ring-enhancing = toxoplasmosis (sulfadiazine + pyrimethamine); single periventricular ring-enhancing = EBV primary CNS lymphoma; non-enhancing white matter = PML (JC virus).
Prophylaxis: TMP-SMX at CD4 <200 (PCP) and <100 if Toxoplasma IgG-positive; azithromycin at <50 for MAC if not on ART; stop once ART restores CD4.
Odynophagia: empiric fluconazole for Candida (AIDS-defining); endoscopy with biopsy if no response (CMV = large linear ulcers, HSV = small punched-out ulcers).
IRIS = paradoxical worsening of TB, MAC, or Cryptococcus weeks after ART → continue ART; PrEP = daily oral tenofovir/emtricitabine or injectable cabotegravir or lenacapavir; PEP = 3-drug ART within 72 hours for 28 days.

Diagnosis and acute HIV

Screen with a 4th-generation test. USPSTF recommends screening everyone aged 15–65, plus every pregnancy and anyone at ongoing risk. The screen is a 4th-generation HIV-1/2 antigen/antibody combination immunoassay, which detects p24 antigen plus antibody and so turns positive earlier than antibody-only tests. Confirm a reactive result with an HIV-1/HIV-2 antibody differentiation assay, and use HIV RNA (viral load) when results are discordant or acute infection is suspected.

4th-gen Ag/Ab immunoassayp24 + antibody screen
HIV-1/2 antibody differentiationConfirms and types
HIV-1 RNA if discordantCatches acute infection
CD4 + viral load baselineStage and monitor

HIV testing algorithm

Acute retroviral syndrome mimics mono. Two to four weeks after exposure, patients develop fever, lymphadenopathy, pharyngitis, a maculopapular rash, myalgias, and mucocutaneous ulcers. Viral load is very high but antibody tests may still be negative, so order HIV RNA.

A mono-like illness with a rash and a negative Monospot should trigger HIV RNA testing.

Antiretroviral therapy and monitoring

Start ART immediately, in everyone. Begin antiretroviral therapy in ALL patients regardless of CD4 count, ideally at diagnosis. Standard initial regimens pair two NRTIs (tenofovir + emtricitabine) with an integrase strand-transfer inhibitor (dolutegravir or bictegravir). Baseline studies include resistance genotyping and hepatitis B serology, because tenofovir and emtricitabine also suppress HBV and stopping them can trigger a flare.

Viral load tracks response, CD4 tracks risk. Viral load measures treatment response; the goal is undetectable, expected within months of effective ART, and undetectable equals untransmittable (U=U). CD4 count gauges immune status and opportunistic-infection risk and sets the prophylaxis plan.

The main exception to "start now" is cryptococcal meningitis, where ART is deferred several weeks after antifungal therapy begins because early ART raises the risk of fatal IRIS.

Opportunistic infections by CD4 count

CD4 <500Thrush, zoster, Kaposi sarcoma
CD4 <200PCP: start TMP-SMX
CD4 <100Toxoplasma, Cryptococcus
CD4 <50MAC, CMV retinitis

Opportunistic infections as CD4 falls

The CD4 staircase

Infection	CD4	Clues	Treatment
Pneumocystis jirovecii (PCP)	<200	Dry cough, dyspnea, hypoxia, high LDH, bilateral interstitial infiltrates	TMP-SMX; steroids if PaO₂ <70 mmHg or A-a gradient ≥35
Toxoplasma gondii	<100	Multiple ring-enhancing brain lesions	Sulfadiazine + pyrimethamine
Cryptococcus neoformans	<100	Meningitis with high opening pressure; cryptococcal antigen or India ink	Amphotericin B + flucytosine, then fluconazole
Mycobacterium avium complex	<50	Disseminated: fever, weight loss, night sweats	Clarithromycin + ethambutol
CMV retinitis	<50	Floaters, painless visual loss	Ganciclovir or valganciclovir

Pneumocystis is the classic AIDS-defining pneumonia: subacute, with exertional hypoxia out of proportion to the exam. Corticosteroids reduce mortality in moderate to severe disease, defined by the PaO₂ or A-a gradient cutoffs above.

Cryptococcal meningitis presents subacutely with headache and fever; the high opening pressure is relieved with serial lumbar punctures.

CNS lesions and GI infections

Brain lesions in advanced HIV

Feature	Toxoplasmosis	Primary CNS lymphoma	PML
Cause	Toxoplasma gondii	EBV	JC virus
Imaging	Multiple ring-enhancing lesions	Single ring-enhancing periventricular lesion	Non-enhancing white-matter lesions
Approach	Empiric anti-Toxoplasma therapy	Biopsy if lesions fail to respond to Toxoplasma treatment	ART; no specific antiviral

Odynophagia: Candida, CMV, HSV. Candida esophagitis (white plaques) is the most common cause and is AIDS-defining; empiric fluconazole is both diagnostic and therapeutic. Persistent symptoms despite fluconazole prompt endoscopy with biopsy: CMV causes large linear ulcers (ganciclovir) and HSV small punched-out ulcers (acyclovir).

Diarrhea. Cryptosporidium causes chronic watery diarrhea in advanced disease; restoring immunity with ART is the key treatment.

Prophylaxis, IRIS, and prevention

<200TMP-SMX for PCP

<100TMP-SMX for Toxoplasma if IgG-positive

<50azithromycin for MAC if not on ART

The prophylaxis thresholds to memorize. TMP-SMX for PCP at CD4 <200 (or oropharyngeal candidiasis, or CD4 below 14%); TMP-SMX for Toxoplasma at CD4 <100 if seropositive; azithromycin for MAC at CD4 <50, now only when fully suppressive ART is not started promptly. Discontinue prophylaxis once ART restores CD4 above the thresholds. For sulfa allergy, dapsone (after checking G6PD) or atovaquone can cover PCP.

IRIS: getting worse after starting ART. As immunity recovers, it can paradoxically worsen a known infection or unmask a hidden one, classically TB, MAC, or Cryptococcus, surfacing weeks into ART as CD4 rises. Continue ART and treat the underlying infection, adding steroids in severe cases.

PrEP and PEP. Pre-exposure prophylaxis is daily oral tenofovir disoproxil/emtricitabine or tenofovir alafenamide/emtricitabine (the latter not for receptive vaginal sex), or injectable cabotegravir every 2 months or lenacapavir twice yearly, for high-risk HIV-negative people, with baseline and periodic HIV testing; confirm the person is HIV-negative before starting, because two drugs would undertreat an undiagnosed infection and breed resistance. Post-exposure prophylaxis after occupational or sexual exposure is a three-drug regimen (preferred: tenofovir/emtricitabine + dolutegravir, or bictegravir/emtricitabine/tenofovir alafenamide) started within 72 hours and continued for 28 days. Sooner is better, because efficacy falls as time passes.