4th-Gen HIV Testing Algorithm
Screen with 4th-generation HIV-1/2 Ag/Ab immunoassay (detects p24 capsid antigen + antibodies); confirm with HIV-1/HIV-2 antibody differentiation + HIV RNA PCR.
CD4 < 200: PJP Pneumonia
Pneumocystis jirovecii: diffuse ground-glass infiltrates, elevated LDH & β-D-glucan, GMS silver stain; Rx: TMP-SMX + Prednisone if PaO2 < 70 or A-a ≥ 35.
CD4 < 100: Toxo vs. CNS Lymphoma
Toxoplasma gondii = multiple ring-enhancing lesions in basal ganglia (Rx: Pyrimethamine + Sulfadiazine + Leucovorin); Primary CNS Lymphoma = solitary periventricular lesion + CSF EBV PCR+.
CD4 < 100: Cryptococcal Meningitis
Cryptococcus neoformans: subacute headache/meningismus + severely elevated LP opening pressure + CrAg / India ink / mucicarmine; Rx: Amphotericin B + Flucytosine → Fluconazole.
CD4 < 50: CMV vs. MAC
CMV (owl's-eye inclusions; retinitis, linear esophageal ulcers, colitis; Rx: Ganciclovir/Valganciclovir); MAC (fever, night sweats, pancytopenia, high ALP; Rx: Clarithromycin/Azithromycin + Ethambutol).
Kaposi Sarcoma vs. Bacillary Angiomatosis
Both cause violaceous vascular skin papules in AIDS! Kaposi = HHV-8 (spindle cells + lymphocytic infiltrate); Bacillary angiomatosis = Bartonella henselae (cat scratch, neutrophilic infiltrate; Rx: Doxycycline).
First-Line ART & Key Toxicities
Standard initial ART = INSTI (Bictegravir or Dolutegravir) + 2 NRTIs (Tenofovir + Emtricitabine); Abacavir requires HLA-B*5701 test; Tenofovir TDF = Fanconi proximal RTA.
Cryptococcal / TB IRIS Timing
Delay starting ART for 4–6 weeks after initiating antifungal therapy for Cryptococcal meningitis (and 2 weeks in severe TB meningitis) to prevent fatal intracranial IRIS!
Opportunistic Infections by CD4 Nadir & Management Guidelines
In patients living with Human Immunodeficiency Virus (HIV-1, an enveloped diploid ssRNA lentivirus that binds CD4 and CCR5/CXCR4 coreceptors on helper T lymphocytes, macrophages, and microglia), the absolute CD4+ T-lymphocyte count is the single strongest predictor of opportunistic infection (OI) susceptibility. Memorizing the three canonical CD4 thresholds (<200, <100, and <50 cells/mm3) governs both clinical diagnosis of AIDS-defining illnesses and antimicrobial prophylaxis.
| CD4 Cell Count Threshold | Opportunistic Pathogen & Disease | Classic Clinical Presentation & Diagnostics | First-Line Treatment & Prophylaxis |
|---|---|---|---|
| CD4 < 200 / μL | Pneumocystis jirovecii (PJP) | Subacute exertional dyspnea, dry cough, hypoxemia disproportionate to exam; bilateral perihilar ground-glass infiltrates; ↑ LDH | High-dose TMP-SMX (IV/PO) × 21 days; add prednisone if PaO2 < 70 mmHg or A-a gradient ≥ 35; Prophylaxis: TMP-SMX 1 DS daily |
| CD4 < 100 / μL | Toxoplasma gondii | Headache, focal neurologic deficits, seizures; Brain MRI: multiple ring-enhancing lesions with surrounding vasogenic edema in basal ganglia | Sulfadiazine + Pyrimethamine + Leucovorin; Prophylaxis: TMP-SMX 1 DS daily (covers both PJP and Toxoplasma) |
| CD4 < 100 / μL | Cryptococcus neoformans | Subacute meningoencephalitis, fever, elevated ICP; India ink / cryptococcal antigen (CrAg) in CSF; Sabouraud agar growth | Induction: Liposomal Amphotericin B + Flucytosine × ≥ 2 weeks → Consolidation: Fluconazole; serial lumbar punctures to relieve ICP |
| CD4 < 50 / μL | Mycobacterium avium complex (MAC) | Fever, night sweats, severe weight loss, chronic watery diarrhea, hepatosplenomegaly; elevated alkaline phosphatase; acid-fast bacilli on blood culture | Clarithromycin + Ethambutol ± Rifabutin; Primary prophylaxis: Azithromycin 1200 mg weekly (only if suppressive ART delayed) |
| CD4 < 50 / μL | Cytomegalovirus (CMV) Retinitis | Painless visual blurring, floaters, scotomas; Funduscopy: 'ketchup and cottage cheese' (perivascular retinal hemorrhages + white necrotic exudates) | IV Ganciclovir / Valganciclovir or intravitreal Foscarnet; routine ophthalmologic monitoring to avoid permanent blindness |
Interactive 2K Master Atlas Plate
CD4 <200 Tier: Pneumocystis jirovecii Pneumonia (GMS Stain, Steroid PaO2 <70 Cutoff & TMP-SMX) & Cryptococcal Meningitis
When the CD4+ count falls below 200 cells/mm3, initiate primary prophylaxis against Pneumocystis jirovecii Pneumonia (PJP, formerly PCP) using oral Trimethoprim-Sulfamethoxazole (TMP-SMX, Bactrim) (alternatives for sulfa allergy or G6PD deficiency: Dapsone [check G6PD first!], Atovaquone, or Inhaled Pentamidine). PJP is an atypical yeast-like fungus presenting subacutely over weeks with progressive exertional dyspnea, fever, non-productive ('dry') cough, hypoxia that desaturates markedly with ambulation, elevated serum LDH and 1,3-β-D-glucan, and bilateral diffuse symmetric ground-glass ('bat-wing') interstitial infiltrates on chest radiograph/CT (can also form upper-lobe pneumatoceles precipitating spontaneous pneumothorax!). Definitive diagnosis requires bronchoalveolar lavage (BAL) or induced sputum stained with Gomori Methenamine Silver (GMS) showing disc-shaped ('crushed ping-pong ball') yeast cysts. First-line treatment for PJP is high-dose IV/PO TMP-SMX for 21 days. CRITICAL BOARD RULE FOR ADJUNCTIVE STEROIDS IN PJP: Administer Systemic Corticosteroids (Prednisone taper) alongside TMP-SMX whenever the patient has severe PJP defined by room-air arterial PaO2 <70 mmHg OR an Alveolar-arterial (A-a) oxygen gradient ≥35 mmHg (or SpO2 <92%), because antibiotic-induced fungal lysis triggers fatal alveolar inflammation! Below CD4 100–150 cells/mm3, Cryptococcus neoformans (heavily encapsulated yeast inhaled from pigeon droppings) causes subacute meningoencephalitis (headache, fever, cranial nerve palsies, extreme opening pressure >250–400 mmH2O requiring serial therapeutic lumbar punctures!) diagnosed by CSF Cryptococcal Antigen (CrAg), India Ink stain (clear halo around budding yeast), or Mucicarmine stain. Treat Cryptococcal meningitis with 3 phases: (1) Induction with Liposomal Amphotericin B + Flucytosine for 2 weeks → (2) Consolidation with Fluconazole (8 weeks) → (3) Maintenance with Fluconazole (1 year)—and delay starting Antiretroviral Therapy (ART) for 4 to 6 weeks in Cryptococcal Meningitis to prevent fatal CNS Immune Reconstitution Inflammatory Syndrome (IRIS)!
CD4 <100 (Toxoplasma Ring-Enhancing vs. CNS Lymphoma EBV) & CD4 <50 (MAC, CMV Retinitis & Cryptosporidium)
At a CD4+ count below 100 cells/mm3 (and positive Toxoplasma IgG serology), initiate primary prophylaxis with TMP-SMX against Cerebral Toxoplasmosis (Toxoplasma gondii reactivation from cat feces/undercooked meat). On Brain MRI, boards routinely ask you to distinguish the two causes of Ring-Enhancing Brain Lesions in AIDS: Cerebral Toxoplasmosis typically presents with MULTIPLE subcortical/basal ganglia ring-enhancing lesions, whereas Primary CNS Lymphoma (a diffuse large B-cell lymphoma uniformly driven by Epstein-Barr Virus [EBV]) typically presents as a SOLITARY periventricular/corpus callosum ring-enhancing lesion with positive CSF EBV PCR (if empiric Pyrimethamine + Sulfadiazine + Leucovorin for 2 weeks fails to shrink the lesions, perform stereotactic brain biopsy for CNS lymphoma!). Other CD4 <100 OIs include Esophageal Candidiasis (odynophagia + oral thrush; treat with Oral/IV Fluconazole, NOT nystatin swish-and-swallow; if odynophagia fails to improve, perform EGD to distinguish CMV Esophagitis [single large linear deep ulcer + intranuclear 'owl's-eye' inclusions → Ganciclovir] from HSV Esophagitis [multiple small punched-out vesicles/ulcers + multinucleated giant cells → Acyclovir]) and Bacillary Angiomatosis (Bartonella henselae from cat scratches causing friable vascular papules that mimic Kaposi sarcoma [HHV-8], but show neutrophilic infiltrate and Warthin-Starry stain bacilli → treat with Doxycycline or Azithromycin). Finally, when CD4 drops below 50 cells/mm3, watch for Disseminated Mycobacterium avium complex (MAC) (fever, drenching night sweats, weight loss, hepatosplenomegaly, pancytopenia, high alkaline phosphatase → treat with Clarithromycin/Azithromycin + Ethambutol; note that primary MAC prophylaxis is no longer recommended if ART is initiated immediately!) and Cytomegalovirus (CMV) Retinitis (painless blurred vision/floaters with perivascular retinal hemorrhages and fluffy white exudates—'pizza-pie / cottage-cheese and ketchup' retinopathy → treat with Valganciclovir / Ganciclovir).
Antiretroviral Pharmacology & Key Board Toxicities
Modern Antiretroviral Therapy (ART) is initiated immediately in all individuals diagnosed with HIV regardless of CD4 count (reducing viral load to undetectable [<20–50 copies/mL] and eliminating sexual transmission: U=U). First-line regimens combine a high-genetic-barrier Integrase Strand Transfer Inhibitor (INSTI: Biktarvy [bictegravir/TAF/emtricitabine] or dolutegravir-based regimens) with two Nucleoside Reverse Transcriptase Inhibitors (NRTIs).
| Drug Class | Representative Agents | Mechanism of Action | High-Yield Board Toxicity / Contraindication |
|---|---|---|---|
| NRTIs (Nucleoside Reverse Transcriptase Inhibitors) | Tenofovir (TDF vs TAF), Emtricitabine, Abacavir, Lamivudine, Zidovudine | Competitively inhibit reverse transcriptase; lack 3'-OH group causing chain termination | Abacavir: Fatal hypersensitivity in HLA-B*5701 positive; TDF: Fanconi nephropathy and bone demineralization (TAF has less renal/bone toxicity); Zidovudine: Macrocytic anemia and bone marrow suppression |
| NNRTIs (Non-Nucleoside) | Efavirenz, Rilpivirine, Nevirapine | Allosterically bind reverse transcriptase near active site; do not require phosphorylation | Efavirenz: Vivid nightmares, neuro-psychiatric disturbances, teratogenicity (neural tube defects); Nevirapine: Fulminant hepatotoxicity, SJS/TEN |
| INSTIs (Integrase Inhibitors) | Bictegravir, Dolutegravir, Raltegravir | Inhibit HIV integrase, blocking proviral DNA integration into host cellular chromosome | Dolutegravir / Bictegravir: Weight gain, insomnia; Raltegravir: Rhabdomyolysis and ↑ CK. Modern first-line backbone due to high resistance barrier |
| Protease Inhibitors (PIs) | Darunavir, Atazanavir, Ritonavir (booster) | Prevent cleavage of Gag-Pol polyprotein, producing immature, non-infectious virions | Metabolic syndrome: Hyperlipidemia, insulin resistance/lipodystrophy; Atazanavir: Indirect hyperbilirubinemia, nephrolithiasis; Ritonavir: Potent CYP3A4 inhibitor |
NRTI Backbone Toxicities: Abacavir HLA-B*5701 Hypersensitivity, Tenofovir (TDF vs. TAF) Fanconi Syndrome & Zidovudine
Every standard HIV regimen includes a dual-NRTI backbone (classically Tenofovir + Emtricitabine [FTC] or Lamivudine [3TC], which are also active against Hepatitis B Virus!), which act as nucleoside/nucleotide analogues lacking a 3'-hydroxyl group to cause competitive DNA chain termination of HIV reverse transcriptase (after intracellular phosphorylation by host kinases; note that Tenofovir is a pre-phosphorylated nucleotide). Memorize the signature board toxicities of individual NRTIs: (1) Abacavir (ABC) is strictly contraindicated in patients who carry the HLA-B*5701 allele; therefore, HLA-B*5701 genetic screening is MANDATORY before ever prescribing Abacavir to prevent a potentially fatal Type IV Abacavir Hypersensitivity Syndrome (fever, rash, GI distress, and respiratory symptoms within 6 weeks; re-challenge causes immediate anaphylactoid shock and death!). (2) Tenofovir Disoproxil Fumarate (TDF) causes proximal renal tubular toxicity (Type 2 Proximal RTA and Fanconi Syndrome: normoglycemic glycosuria, phosphaturia, aminoaciduria) and decreased Bone Mineral Density (osteopenia); switching to the newer prodrug Tenofovir Alafenamide (TAF) concentrates tenofovir inside lymphoid cells with 90% lower plasma exposure, markedly reducing renal and bone toxicity. (3) Zidovudine (AZT / ZDV) (historically used for intrapartum IV infusion during delivery when maternal HIV viral load is >1,000 copies/mL) causes severe Bone Marrow Suppression (macrocytic anemia and neutropenia) and mitochondrial myopathy. Class-wide, older NRTIs (especially stavudine/didanosine) inhibit human mitochondrial DNA polymerase-γ, causing hepatic steatosis, pancreatitis, peripheral neuropathy, and severe Lactic Acidosis.
INSTIs (Dolutegravir/Bictegravir), Protease Inhibitors (Ritonavir CYP3A4 & Lipodystrophy), NNRTIs & Pre/Post-Exposure Prophylaxis
Understand the mechanisms and signature adverse effects of the remaining antiretroviral classes and prevention protocols: (1) Integrase Strand Transfer Inhibitors (INSTIs — '-tegravir': Bictegravir, Dolutegravir, Cabotegravir, Raltegravir, Elvitegravir) block HIV integrase from inserting viral cDNA into the host chromosome; they are the #1 first-line cornerstone of modern ART, with main side effects of weight gain, insomnia/headache, and benign inhibition of renal tubular OCT2 creatinine secretion (dolutegravir/bictegravir cause a mild, non-pathologic 0.1–0.2 mg/dL rise in serum creatinine without changing true GFR!), plus chelation by oral divalent cations (take 2 hours before or 6 hours after calcium/iron/magnesium antacids). (2) Protease Inhibitors (PIs — '-navir': Darunavir, Atazanavir, Lopinavir, Ritonavir) inhibit HIV-1 aspartate protease, preventing cleavage of the gag-pol polyprotein and producing immature, non-infectious virions. Because Ritonavir (and Cobicistat) is a potent CYP3A4 inhibitor, low-dose ritonavir is used as a pharmacokinetic 'booster' for other PIs. PI toxicities include hyperglycemia (insulin resistance), hypertriglyceridemia, lipodystrophy (Cushingoid 'buffalo hump' fat redistribution), unconjugated hyperbilirubinemia and radiolucent nephrolithiasis (Atazanavir and Indinavir). (3) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs: Efavirenz, Rilpivirine, Doravirine) bind an allosteric hydrophobic pocket on HIV-1 reverse transcriptase without requiring intracellular phosphorylation (ineffective against HIV-2!); Efavirenz causes vivid dreams, dizziness, depression, and suicidality. (4) Entry Inhibitors: Maraviroc blocks host CCR5 (requires tropism assay confirming R5-tropic HIV), while Enfuvirtide (T-20) binds viral gp41 to block membrane fusion. For HIV Post-Exposure Prophylaxis (PEP) after a high-risk needlestick or sexual assault, initiate a 3-drug regimen (Tenofovir/Emtricitabine + Dolutegravir or Raltegravir) within 72 hours (ideally <2 hours) for 28 days; for Pre-Exposure Prophylaxis (PrEP), prescribe daily oral Tenofovir/Emtricitabine (Truvada/Descovy) or long-acting IM Cabotegravir after confirming a negative 4th-generation HIV Ag/Ab screen!
HIV Virology, Structural Genes, Coreceptors & 4th-Generation Diagnostic Algorithm
Human Immunodeficiency Virus (HIV-1 and HIV-2) is an enveloped diploid (two identical copies) positive-sense single-stranded RNA retrovirus belonging to the Lentivirus genus. Its conical p24 capsid houses the viral RNA genome alongside three essential retroviral enzymes encoded by the pol gene: Reverse Transcriptase (RNA-dependent DNA polymerase that synthesizes dsDNA in the host cytoplasm, lacking 3'→5' proofreading exonuclease activity and generating extreme antigenic variation), Integrase (inserts proviral dsDNA into host chromosomes), and Protease (cleaves gag-pol polyproteins during virion maturation so infectious particles can bud).
| CD4+ T-Cell Threshold | Signature Opportunistic Pathogen(s) | Classic Clinical Syndrome | Primary Prophylaxis Regimen | Discontinuation Criteria (on ART) |
|---|---|---|---|---|
| CD4 < 500 cells/μL | Candida albicans, EBV, HHV-8, HPV, M. tuberculosis | Oral thrush (scrapable), Oral hairy leukoplakia (EBV, lateral tongue, unscrapable), Kaposi sarcoma, TB | None (treat latent TB if IGRA/PPD ≥ 5 mm with INH/Rifapentine) | Initiate universal Antiretroviral Therapy (ART) immediately at any CD4 count |
| CD4 < 200 cells/μL | Pneumocystis jirovecii (PJP), Histoplasma capsulatum, Coccidioides, Cryptosporidium | Subacute hypoxia, dry cough, diffuse ground-glass infiltrates; chronic watery diarrhea | TMP-SMX (1st-line); alternatives: Dapsone (check G6PD!), Atovaquone, aerosolized Pentamidine | Stop when CD4 > 200 cells/μL for > 3 months on ART |
| CD4 < 100 cells/μL | Toxoplasma gondii, Cryptococcus neoformans, Candida (esophageal), Bartonella henselae | Multiple ring-enhancing brain lesions; subacute meningitis with high ICP; odynophagia | TMP-SMX DS daily (if Toxoplasma IgG seropositive; covers both Toxo & PJP!) | Stop when CD4 > 200 cells/μL for > 3 months on ART |
| CD4 < 50 cells/μL | Cytomegalovirus (CMV), Mycobacterium avium complex (MAC), JC Virus (PML), EBV (PCNSL) | Pizza-pie retinitis, linear esophageal ulcers; disseminated fever/night sweats/high ALP | No primary MAC prophylaxis if starting ART immediately (Azithromycin 1200 mg weekly only if ART delayed) | Prompt ART initiation + dilated funduscopic screening for CMV |
Structural Genes (gag, env) & Tropism Coreceptors (CCR5 R5 vs. CXCR4 X4)
The HIV genome contains three core structural genes required for board mastery: (1) env encodes the precursor glycoprotein gp160, which is cleaved by host furin proteases in the Golgi into gp120 (the outer surface attachment spike that binds the CD4 receptor on helper T cells, macrophages, microglia, and dendritic cells) and gp41 (the transmembrane hydrophobic fusion protein that mediates viral envelope fusion with the host plasma membrane—inhibited by enfuvirtide). (2) gag encodes the internal structural proteins, most notably the p24 conical capsid protein (used in 4th-generation antigen screening) and p17 matrix protein. (3) pol encodes Reverse Transcriptase, Integrase, and Protease (plus regulatory genes tat [transcriptional activator] and rev). To enter a host cell, gp120 must bind CD4 FIRST, which induces a conformational shift allowing gp120 to bind a mandatory chemokine coreceptor: during mucosal sexual transmission and early infection, macrophage-tropic (R5-tropic) HIV strains bind the CCR5 coreceptor (expressed on both macrophages and CD4+ T cells; inhibited by maraviroc). Later in chronic infection, viral evolution shifts tropism to T-cell-tropic (X4-tropic) strains that bind the CXCR4 coreceptor on CD4+ T cells, accelerating T-cell syncytia formation and rapid CD4 depletion. Crucially, individuals who inherit a homozygous 32-base-pair deletion in the CCR5 gene (CCR5-Δ32) completely lack surface CCR5 receptors and are genetically resistant to R5-tropic HIV-1 infection (heterozygotes experience a slower progression to AIDS)!
Acute Retroviral Syndrome, Clinical Latency & AIDS-Defining Thresholds
Approximately 2–4 weeks after HIV exposure, 50–80% of patients develop Acute Retroviral Syndrome (Primary HIV Infection), which closely mimics Infectious Mononucleosis (EBV): fever, generalized nontender lymphadenopathy, sore throat/pharyngitis, myalgias/arthralgias, mucocutaneous ulcerations, and a diffuse maculopapular rash (distinguished from EBV by mucocutaneous ulcers, rash, diarrhea, and a negative Heterophile Monospot test). During this acute window, HIV seeds the gut-associated lymphoid tissue (GALT) and lymph nodes, causing a transient dip in CD4+ T cells and a massive spike in plasma HIV RNA viral load (> 106 copies/mL) and p24 antigen before host anti-HIV IgG antibodies seroconvert at 3–4 weeks. Following seroconversion, the cytotoxic CD8+ T-cell response suppresses viremia to a viral set point, initiating an 8–10 year period of Clinical Latency during which the virus replicates relentlessly inside lymph node follicular dendritic networks while peripheral CD4+ counts fall by ~50–80 cells/μL per year. Acquired Immunodeficiency Syndrome (AIDS) is diagnosed when an HIV-positive patient develops EITHER an absolute CD4+ T-cell count < 200 cells/μL (or CD4 percentage < 14%) OR any AIDS-defining illness (such as PJP, esophageal candidiasis, Kaposi sarcoma, CNS toxoplasmosis, cryptococcal meningitis, disseminated MAC, CMV retinitis, invasive cervical cancer, or primary CNS lymphoma) regardless of CD4 count.
CDC 4th-Generation HIV Diagnostic Algorithm, Neonatal Testing & Opportunistic Prophylaxis Cutoffs
The CDC/USPSTF HIV Diagnostic Algorithm proceeds in three steps: (1) Step 1 (Screening): Combination 4th-Generation HIV-1/2 Antigen/Antibody Immunoassay, which simultaneously detects host HIV-1/2 IgM and IgG antibodies PLUS viral p24 capsid antigen (narrowing the diagnostic window period to ~14–18 days!). (2) Step 2 (Confirmation): HIV-1/HIV-2 Antibody Differentiation Immunoassay (note: the historical Western blot is obsolete because it misses acute infection and misclassifies HIV-2!). (3) Step 3 (Discordant Resolution): Qualitative/Quantitative HIV-1 Nucleic Acid Test (HIV RNA PCR)—if the 4th-gen screen is positive (due to p24 antigen) but the antibody differentiation assay is negative or indeterminate, a positive HIV RNA PCR confirms Acute HIV Infection! Two special testing rules are board favorites: First, in infants born to HIV-positive mothers (< 18 months old), maternal anti-HIV IgG antibodies cross the placenta and cause false-positive antibody tests in the baby; therefore, neonatal HIV diagnosis MUST be performed using HIV-1 DNA or RNA PCR (never ELISA/antibody tests!). Second, memorize the primary prophylaxis cutoffs in adults with HIV: start TMP-SMX at CD4 < 200 cells/μL (for Pneumocystis jirovecii; alternatively dapsone [check G6PD!], atovaquone, or inhaled pentamidine [which spares the upper lobes, allowing apical PJP cavities!]), and expand TMP-SMX to daily dosing at CD4 < 100 cells/μL if Toxoplasma IgG is positive (to prevent both PJP and cerebral toxoplasmosis; note that primary Azithromycin prophylaxis at CD4 < 50 for MAC is NO LONGER recommended if the patient immediately initiates effective ART!).
CNS Opportunistic Infections in AIDS Differential: Toxoplasmosis vs. Primary CNS Lymphoma vs. Cryptococcus vs. PML
When an HIV-positive patient with a CD4 count < 100–200 cells/μL presents with headache, confusion, seizures, or focal neurological deficits, Contrast-Enhanced Brain MRI and Lumbar Puncture immediately stratify the pathology into Ring-Enhancing Mass Lesions (Cerebral Toxoplasmosis vs. Primary CNS Lymphoma), Non-Enhancing White Matter Demyelination (JC Virus PML), or Diffuse Basilar Meningoencephalitis (Cryptococcus neoformans).
| CNS Opportunistic Infection | Etiologic Pathogen & CD4 Cutoff | Brain MRI Appearance | Definitive Diagnostic Test | First-Line Treatment Protocol |
|---|---|---|---|---|
| Cerebral Toxoplasmosis | Toxoplasma gondii (CD4 < 100; cat feces / undercooked meat) | MULTIPLE ring-enhancing lesions in basal ganglia with edema & mass effect | Positive serum Toxo IgG + response to 2-week empiric therapy | Pyrimethamine + Sulfadiazine + Leucovorin (folinic acid) |
| Primary CNS Lymphoma (PCNSL) | Epstein-Barr Virus (EBV) B-cell lymphoma (CD4 < 50–100) | SOLITARY periventricular / corpus callosum ring-enhancing lesion | Positive CSF EBV DNA PCR (or stereotactic biopsy if Toxo Rx fails) | High-dose IV Methotrexate + immediate ART (± rituximab) |
| Cryptococcal Meningitis | Cryptococcus neoformans (CD4 < 100; pigeon droppings) | Leptomeningeal enhancement, 'soap-bubble' Virchow-Robin space cysts | LP: High opening pressure + CSF CrAg, India ink halo, Mucicarmine red capsule | Amphotericin B + Flucytosine (2 wk) → Fluconazole + serial LPs (delay ART 4–6 wk!) |
| Progressive Multifocal Leukoencephalopathy (PML) | JC Polyomavirus infecting oligodendrocytes (CD4 < 200 or Natalizumab) | Asymmetric subcortical white matter T2 lesions with NO contrast enhancement & NO mass effect! | Positive CSF JC Virus DNA PCR | Immediate ART initiation to restore immune function (or stop Natalizumab) |
| HIV Encephalopathy (HAND) | HIV-1 in CNS microglia & macrophages (multinucleated giant cells) | Diffuse symmetric cortical atrophy + symmetric confluent white matter T2 changes (no enhancement) | Clinical diagnosis of exclusion (subcortical dementia + gait/motor slowing) | Antiretroviral Therapy (ART) |
Cerebral Toxoplasmosis vs. Primary CNS Lymphoma (EBV): Ring-Enhancing Lesion Algorithm
(1) Cerebral Toxoplasmosis (Toxoplasma gondii) is the most common cause of focal CNS mass lesions in AIDS, occurring via reactivation of latent tissue bradyzoite cysts (acquired from cat feces oocysts or undercooked meat) when CD4 falls < 100 cells/μL. Patients present subacutely with fever, headache, focal hemiparesis/aphasia, and seizures. Contrast Brain MRI characteristically shows MULTIPLE ring-enhancing lesions with surrounding vasogenic edema and mass effect, preferentially located in the BASAL GANGLIA and corticomedullary junction. In a patient with a positive serum Toxoplasma IgG and multiple ring-enhancing lesions, do NOT perform an immediate brain biopsy—instead, initiate an empiric 2-week trial of Pyrimethamine + Sulfadiazine + Leucovorin (folinic acid, to rescue host bone marrow from pyrimethamine-induced dihydrofolate reductase inhibition!). If the patient shows clinical and radiographic improvement at 10–14 days, the diagnosis of Toxoplasmosis is confirmed! (2) Primary CNS Lymphoma (PCNSL) is a high-grade diffuse large B-cell non-Hodgkin lymphoma occurring at CD4 < 50–100 cells/μL, universally driven by latent Epstein-Barr Virus (EBV) transformation of B lymphocytes. Unlike toxoplasmosis, PCNSL typically presents on MRI as a SOLITARY (or homogeneous), weakly ring-enhancing lesion in the PERIVENTRICULAR white matter or corpus callosum (with hypermetabolism on PET/SPECT scan). Diagnosis is confirmed without biopsy by detecting positive EBV DNA PCR in the CSF (or by stereotactic brain biopsy if empiric Toxoplasma therapy fails at 2 weeks); treat with high-dose IV Methotrexate + immediate ART.
Cryptococcal Meningoencephalitis: Opening Pressure, CrAg, India Ink & 3-Phase Antifungal Therapy
Cryptococcus neoformans is an encapsulated yeast (NOT dimorphic!) found worldwide in soil contaminated with pigeon/bird droppings. Acquired by inhalation into the lungs, it hematogenously disseminates to the meninges when CD4 drops < 100 cells/μL. Its major virulence factor is a thick polysaccharide capsule that inhibits phagocytosis and blocks arachnoid villi CSF outflow, causing severe communicating intracranial hypertension. Patients present over 1–2 weeks with progressively worsening frontal/temporal headache, fever, malaise, photophobia, cranial nerve VI palsies (diplopia), papilledema, and confusion (neck stiffness may be mild because severe immunosuppression blunts meningeal inflammation!). After ruling out mass effect with CT/MRI, Lumbar Puncture reveals a markedly elevated opening pressure (often > 250–350 mm H2O!), mild lymphocytic pleocytosis, elevated protein, and low glucose. Diagnostic confirmation is made by the CSF (and serum) Cryptococcal Antigen (CrAg) latex agglutination or lateral flow assay (> 99% sensitive and specific!), India Ink stain showing budding yeast surrounded by a wide clear unstained halo, and Mucicarmine stain coloring the polysaccharide capsule bright red (whilst cerebral cortex histology shows 'soap-bubble' lesions in the Virchow-Robin perivascular spaces). Treatment requires two simultaneous interventions: (1) Serial therapeutic Lumbar Punctures (daily if opening pressure is ≥ 250 mm H2O to drain CSF until pressure is < 200 mm H2O—the single most important intervention to prevent acute herniation and blindness!) and (2) 3-Phase Antifungal Regimen: Induction with IV Liposomal Amphotericin B + Oral Flucytosine for 2 weeks → Consolidation with high-dose Oral Fluconazole (400–800 mg/day) for 8 weeks → Maintenance with Oral Fluconazole (200 mg/day) until CD4 > 100 for > 3–6 months on ART. Remember: DELAY starting ART for 4–6 weeks in Cryptococcal meningitis to prevent fatal intracranial IRIS!
Progressive Multifocal Leukoencephalopathy (JC Virus) vs. HIV-Associated Dementia
(1) Progressive Multifocal Leukoencephalopathy (PML) is caused by reactivation of latent JC Polyomavirus (a non-enveloped dsDNA virus) in patients with AIDS (CD4 < 100–200 cells/μL), hematologic malignancies, or MS/Crohn patients treated with Natalizumab. JC virus productively infects and lyses myelin-producing oligodendrocytes, causing progressive subacute asymmetric hemiparesis, homonymous hemianopia / cortical blindness, cerebellar ataxia, and cognitive decline (without fever or headache). The unmistakable neuroimaging hallmark that separates PML from Toxoplasmosis and PCNSL is that PML lesions are ASYMMETRIC, MULTIFOCAL SUBCORTICAL WHITE MATTER (U-fiber) T2/FLAIR HYPERINTENSITIES THAT DO NOT ENHANCE WITH CONTRAST AND HAVE ZERO MASS EFFECT! Confirm with CSF JC virus DNA PCR; there is no specific antiviral cure—the only effective treatment is immediate initiation of ART (or stopping natalizumab) to restore cellular immunity. (2) HIV-Associated Neurocognitive Disorder (HAND / HIV Encephalopathy) results from direct HIV infection of CNS macrophages and microglia (forming pathognomonic multinucleated giant cells and microglial nodules in subcortical white and deep gray matter), presenting with subcortical dementia (bradykinesia, apathy, memory loss) and diffuse symmetric cerebral atrophy and confluent T2 white matter hyperintensity without contrast enhancement or mass effect; treat with CNS-penetrating ART.
Pulmonary, GI, Retinal & Cutaneous Opportunistic Infections (PJP, MAC, CMV, Esophagitis, Kaposi vs. Bartonella)
Beyond the central nervous system, board vignettes test the organ-specific diagnostic algorithms and histopathological signatures of pulmonary, gastrointestinal, ocular, and cutaneous opportunistic infections across the CD4 decline spectrum.
| Opportunistic Entity | Pathogen & CD4 Threshold | Classic Clinical & Endoscopic / Exam Clues | Pathognomonic Histopathology / Stain | First-Line Therapy |
|---|---|---|---|---|
| Pneumocystis Pneumonia (PJP) | Pneumocystis jirovecii (CD4 < 200) | Subacute dyspnea, dry cough, diffuse bilateral ground-glass infiltrates, ↑ LDH, ↑ β-D-glucan | BAL GMS silver stain: disc/cup-shaped cysts in foamy alveolar exudate | TMP-SMX (21d) + Prednisone if PaO2 < 70 or A-a ≥ 35 |
| Candida vs. HSV vs. CMV Esophagitis | Candida (< 100), HSV-1 (< 100), CMV (< 50) | Odynophagia; Candida: white plaques; HSV: small punched-out ulcers; CMV: deep linear ulcers | Candida: pseudohyphae; HSV: Cowdry A; CMV: basophilic 'Owl's-Eye' inclusions | Candida: Oral Fluconazole; HSV: Acyclovir; CMV: Ganciclovir / Valganciclovir |
| Disseminated MAC | Mycobacterium avium complex (CD4 < 50) | Fever, drenching night sweats, weight loss, diarrhea, pancytopenia, ↑↑ ALP | Positive mycobacterial blood culture; macrophages packed with acid-fast bacilli | Clarithromycin (or Azithromycin) + Ethambutol (± Rifabutin) |
| Kaposi Sarcoma | HHV-8 (CD4 < 200–500; MSM) | Violaceous plaques/nodules on skin, hard palate, GI tract, lungs | Spindle cells, slit-like vascular spaces + LYMPHOCYTIC infiltrate | Antiretroviral Therapy (ART) + liposomal doxorubicin if visceral |
| Bacillary Angiomatosis | Bartonella henselae (CD4 < 100; cat scratch/fleas) | Friable violaceous vascular papules/nodules mimicking Kaposi sarcoma + fever | Lobular capillaries + NEUTROPHILIC (PMN) infiltrate + Warthin-Starry silver stain bacilli | Doxycycline or Azithromycin / Erythromycin |
Pneumocystis jirovecii Pneumonia (PJP): Silver Stain, LDH/Beta-D-Glucan & The PaO2 < 70 Steroid Rule
Pneumocystis jirovecii (formerly P. carinii) is an atypical ubiquitous fungus (whose cell membrane contains cholesterol rather than ergosterol, explaining why it is resistant to azoles and amphotericin B!) that causes life-threatening Pneumocystis Pneumonia (PJP) when CD4 drops < 200 cells/μL. Unlike bacterial pneumonia (which presents acutely over 2 days with lobar consolidation and productive purulent sputum), PJP presents subacutely over 2–4 weeks with progressive exertional dyspnea, fever, non-productive dry cough, and severe hypoxia/tachypnea that worsens dramatically with walking (and may be complicated by spontaneous pneumothorax from ruptured subpleural pneumatoceles!). Chest radiograph and CT demonstrate diffuse bilateral symmetric perihilar interstitial and alveolar 'ground-glass' infiltrates ('bat-wing' appearance). Laboratory hallmarks include a markedly elevated serum Lactate Dehydrogenase (LDH) and elevated serum 1,3-β-D-glucan (fungal cell wall polysaccharide). Definitive diagnosis is established by Bronchoalveolar Lavage (BAL) (or induced sputum) showing foamy eosinophilic intra-alveolar exudates and disc-shaped ('crushed ping-pong ball' or 'cup-shaped') cysts on Gomori Methenamine Silver (GMS) stain or fluorescent antibody staining. First-line treatment is high-dose IV or oral Trimethoprim-Sulfamethoxazole (TMP-SMX) for 21 days (alternatives for sulfa allergy: Clindamycin + Primaquine, IV Pentamidine, or Atovaquone/TMP-Dapsone for mild cases). MANDATORY STEROID RULE: Because dying Pneumocystis organisms trigger a violent alveolar inflammatory response that worsens oxygenation, ALWAYS co-administer systemic corticosteroids (Prednisone) whenever the room-air arterial PaO2 is < 70 mmHg OR the alveolar-arterial (A-a) O2 gradient is ≥ 35 mmHg (roughly corresponding to room-air pulse oximetry SpO2 < 92%)!
HIV Esophagitis (Candida vs. HSV vs. CMV) & Chronic Diarrhea (Cryptosporidium, MAC)
Two GI symptom complexes in AIDS require precise endoscopic and microbiologic differentiation: (1) Infectious Esophagitis (CD4 < 100 cells/μL): First, distinguish oropharyngeal thrush (painless white plaques with NO dysphagia/odynophagia; treat with topical nystatin swish-and-swallow or clotrimazole troches) from Esophageal Candidiasis (presenting with severe odynophagia and retrosternal dysphagia; treat empirically with systemic oral Fluconazole for 14–21 days!). If odynophagia fails to improve within 72 hours of empiric fluconazole, perform upper endoscopy (EGD) with biopsy to differentiate the three viral/fungal causes: Candida albicans shows adherent white cottage-cheese plaques with pseudohyphae; Herpes Simplex Virus-1 (HSV-1) shows multiple small, shallow, 'punched-out' volcano-like vesicles and round ulcers with multinucleated giant cells and eosinophilic Cowdry type A intranuclear inclusions at the ulcer margin (treat with IV Acyclovir); and Cytomegalovirus (CMV, CD4 < 50) shows ONE or a few LARGE, deep, linear serpiginous ulcers in the distal esophagus with enlarged stromal/endothelial cells containing basophilic 'OWL'S-EYE' intranuclear and intracytoplasmic inclusions at the ulcer base (treat with IV Ganciclovir or oral Valganciclovir—foscarnet if ganciclovir-resistant UL97 mutation or severe neutropenia!).Note that CMV at CD4 < 50 also causes CMV Retinitis (painless vision loss/floaters with fluffy yellow-white retinal necrosis and intraretinal hemorrhages along vascular arcades ['pizza-pie' or 'ketchup-and-cottage-cheese' retinopathy]). (2) AIDS Enteropathy & Disseminated MAC: At CD4 < 180–200, profuse watery secretory diarrhea (> 10 L/day) is classically caused by Cryptosporidium parvum (diagnosed by acid-fast staining of stool showing bright red 4–6 μm oocysts; treat with ART immune reconstitution + nitazoxanide; similar larger acid-fast oocysts include Cystoisospora belli [TMP-SMX] and Cyclospora cayetanensis). At CD4 < 50 cells/μL, Disseminated Mycobacterium avium complex (MAC) presents with high spiking fevers, drenching night sweats, profound weight loss, chronic diarrhea, hepatosplenomegaly, pancytopenia (anemia/neutropenia from bone marrow infiltration), and markedly elevated Alkaline Phosphatase; diagnose via mycobacterial blood cultures (or bone marrow biopsy showing macrophages stuffed with acid-fast bacilli) and treat with Clarithromycin (or Azithromycin) + Ethambutol (± Rifabutin).
Kaposi Sarcoma (HHV-8) vs. Bacillary Angiomatosis (Bartonella henselae) & Molluscum Contagiosum
A classic board pathology trap in an HIV-positive patient with CD4 < 200 cells/μL is differentiating Kaposi Sarcoma from Bacillary Angiomatosis, because both present with violaceous, erythematous, vascular-appearing cutaneous papules, plaques, and nodules that bleed easily: (1) Kaposi Sarcoma (KS) is an endothelial vascular neoplasm driven by Human Herpesvirus-8 (HHV-8 / KSHV) (transmitted sexually, especially among men who have sex with men), which upregulates VEGF. Lesions evolve from flat violaceous macules into plaques and nodules on the skin (face, nose tip, lower extremities), hard palate (oral mucosa), gastrointestinal tract, and lungs. Skin biopsy is diagnostic, demonstrating whorls of proliferating spindle-shaped endothelial cells forming slit-like vascular spaces containing extravasated erythrocytes and hemosiderin, accompanied by a MONONUCLEAR LYMPHOCYTIC and plasma cell infiltrate; treatment is immediate ART (plus liposomal doxorubicin for visceral disease). (2) Bacillary Angiomatosis (BA) is a benign bacterial vascular proliferation caused by Bartonella henselae (acquired from a cat scratch or kitten flea bite!) or Bartonella quintana (body lice in unhoused patients), which also secretes factors stimulating endothelial proliferation (and causes hepatic peliosis). Unlike Kaposi sarcoma, skin biopsy of Bacillary Angiomatosis reveals lobular capillary proliferation accompanied by a dense NEUTROPHILIC (PMN) infiltrate with nuclear dust and clusters of black pleomorphic bacilli visible on Warthin-Starry silver stain! Bacillary angiomatosis is rapidly cured with oral Doxycycline or Erythromycin/Azithromycin. (Also remember that Molluscum contagiosum—a poxvirus causing flesh-colored dome-shaped papules with central umbilication and eosinophilic cytoplasmic Henderson-Paterson molluscum bodies—presents in AIDS with giant, confluent facial lesions).
Antiretroviral Pharmacology, Toxicities, IRIS & PrEP / PEP / Peripartum MTCT Protocols
Antiretroviral Therapy (ART) is indicated immediately for ALL individuals diagnosed with HIV regardless of CD4 count to achieve undetectable viral load (< 20–50 copies/mL, rendering the patient sexually non-infectious: U=U, Undetectable = Untransmittable). Standard first-line initial ART consists of an Integrase Strand Transfer Inhibitor (INSTI: Bictegravir or Dolutegravir) PLUS two Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (2 NRTIs: Tenofovir [TAF or TDF] + Emtricitabine [FTC] or Lamivudine [3TC]).
| Antiretroviral Drug / Protocol | Pharmacologic Class & Target | Signature Adverse Effect / Toxicity | High-Yield Clinical & Board Rule |
|---|---|---|---|
| Bictegravir / Dolutegravir / Cabotegravir | Integrase Strand Transfer Inhibitors (INSTIs) | Mild weight gain; benign +0.15 mg/dL creatinine rise (blocks OCT2 secretion, normal GFR) | 1st-line anchor for initial ART and PEP; separate from Ca2+/Mg2+/Fe2+ antacids |
| Abacavir (ABC) | NRTI (guanosine analog chain terminator) | Fatal Type IV Hypersensitivity Syndrome (fever, rash, dyspnea, GI distress) | MANDATORY HLA-B*5701 screening prior to use; strictly contraindicated if positive! |
| Tenofovir (TDF vs. TAF) + Emtricitabine (FTC) | NRTIs (adenosine/cytidine analogs) | TDF causes Fanconi proximal renal tubular acidosis (glucosuria, phosphaturia) & bone loss | Backbone of ART & PrEP; co-treats Hepatitis B (HBV)—stopping abruptly causes HBV flare! |
| Zidovudine (AZT / ZDV) | NRTI (thymidine analog) | Megaloblastic anemia, neutropenia (bone marrow suppression), myopathy | Given IV intrapartum + scheduled C-section at 38 wk if maternal VL > 1,000; given orally to newborn |
| Efavirenz | NNRTI (allosteric RT binder; no phosphorylation) | CNS toxicity (vivid nightmares, insomnia, depression/suicidality), rash, hepatotoxicity | Ineffective against HIV-2; avoid in patients with severe psychiatric history |
| Darunavir / Atazanavir (+ Ritonavir) | Protease Inhibitors (PIs) (block gag-pol cleavage) | Hyperglycemia, hyperlipidemia, lipodystrophy; Atazanavir: indirect hyperbilirubinemia | Ritonavir/Cobicistat potently inhibit CYP3A4 (contraindicated with simvastatin/lovastatin!) |
Antiretroviral Classes, Mechanisms & Signature Board Toxicities
Every antiretroviral class carries signature board-tested mechanisms and adverse effects: (1) NRTIs (Nucleoside/Nucleotide Reverse Transcriptase Inhibitors — Abacavir, Tenofovir [TDF/TAF], Emtricitabine, Lamivudine, Zidovudine [AZT]): Competitive nucleoside analogs lacking a 3'-OH group that terminate nascent proviral DNA chains (all require intracellular phosphorylation by host kinases; Tenofovir is a nucleotide that already possesses one phosphate!). Class-wide toxicity is mitochondrial DNA polymerase-γ inhibition (lactic acidosis and hepatic steatosis). Drug-specific pearls: Abacavir (ABC) is strictly contraindicated in patients positive for the HLA-B*5701 allele due to a potentially fatal Type IV hypersensitivity syndrome (fever, rash, GI/respiratory symptoms; ALWAYS screen for HLA-B*5701 before prescribing Abacavir, and NEVER rechallenge!); Tenofovir Disoproxil Fumarate (TDF) causes proximal renal tubular dysfunction (Fanconi syndrome: glucosuria with normal serum glucose, phosphaturia, aminoaciduria, Type 2 RTA) and osteopenia/decreased bone mineral density (Tenofovir Alafenamide [TAF] has markedly lower renal/bone toxicity; both TDF/TAF and Emtricitabine/Lamivudine also have potent activity against Hepatitis B Virus [HBV]!); Zidovudine (AZT) causes megaloblastic anemia and neutropenia (bone marrow suppression); and older 'd-drugs' (Didanosine) cause acute pancreatitis and peripheral neuropathy. (2) INSTIs (Integrase Inhibitors — Bictegravir, Dolutegravir, Raltegravir, Cabotegravir): Block HIV integrase from inserting viral DNA into host chromosomes; well-tolerated, may cause mild weight gain and reversibly inhibit renal tubular creatinine secretion (Dolutegravir/Bictegravir cause a benign 0.1–0.2 mg/dL rise in serum creatinine WITHOUT reducing true GFR!; also avoid coadministering divalent cations [Ca2+, Mg2+, iron antacids] simultaneously, which chelate INSTIs in the gut). (3) NNRTIs (Non-Nucleoside RTIs — Efavirenz, Rilpivirine, Doravirine): Bind an allosteric hydrophobic pocket on HIV-1 reverse transcriptase (do NOT require phosphorylation; intrinsically inactive against HIV-2!); Efavirenz causes vivid dreams, insomnia, depression/suicidality, dizziness, and hepatotoxicity/rash. (4) Protease Inhibitors (PIs — Darunavir, Atazanavir, Lopinavir; all end in '-navir'): Prevent cleavage of gag-pol polyproteins; boosted with Ritonavir or Cobicistat (potent CYP3A4 inhibitors!); cause hyperglycemia/insulin resistance, hyperlipidemia, lipodystrophy (Cushingoid buffalo hump), and GI intolerance (Atazanavir inhibits UGT1A1 causing benign unconjugated hyperbilirubinemia, while Indinavir causes radiolucent nephrolithiasis).
Immune Reconstitution Inflammatory Syndrome (IRIS): Pathophysiology & Cryptococcal / TB Timing
Immune Reconstitution Inflammatory Syndrome (IRIS) occurs 2–8 weeks after initiating effective ART in a severely immunocompromised patient (typically baseline CD4 < 50–100 cells/μL and high viral load). As ART rapidly suppresses HIV replication and restores pathogen-specific CD4+ Th1 lymphocytes, the recovering immune system mounts an exuberant, dysregulated inflammatory cytokine storm against either a previously diagnosed, partially treated opportunistic infection ('paradoxical IRIS') or a previously subclinical occult opportunistic infection ('unmasked IRIS'). The patient presents with new high fevers, worsening pulmonary infiltrates, enlarging painful lymphadenitis (classic with MAC or TB), or worsening meningeal/brain edema—at a time when the HIV RNA viral load has PLUMMETED and the CD4 count is RISING (confirming that this is IRIS, NOT ART treatment failure!). Management of IRIS: (1) CONTINUE Antiretroviral Therapy (do NOT stop ART unless life-threatening CNS herniation is imminent); (2) Continue antimicrobial therapy directed against the opportunistic pathogen; and (3) Add NSAIDs for mild IRIS or systemic Corticosteroids (Prednisone) for severe life-threatening IRIS. Crucially, while ART is started within 2 weeks of most opportunistic infections (including PJP and bacterial pneumonia), in Cryptococcal Meningitis, you MUST DELAY starting ART for 4–6 weeks after initiating Amphotericin B/Flucytosine (and delay ART for 2–8 weeks in tuberculous meningitis), because early CNS IRIS inside the rigid cranium causes fatal cerebral edema and herniation!
PrEP, PEP (28-Day Rule) & Prevention of Peripartum Mother-to-Child Transmission (MTCT)
Three HIV prevention protocols are tested across Internal Medicine, Emergency Medicine, OB/GYN, and Pediatrics shelves: (1) Pre-Exposure Prophylaxis (PrEP): Indicated for HIV-negative individuals at ongoing sexual or injection-drug risk; before starting PrEP, mandatory baseline tests are a negative 4th-generation HIV Ag/Ab screen (plus HIV RNA if recent exposure), serum creatinine/eGFR, Hepatitis B surface antigen (HBsAg), and STI screening. First-line PrEP regimens are daily oral Emtricitabine + Tenofovir (TDF or TAF; note TAF/FTC is not approved for receptive vaginal sex) OR long-acting intramuscular Cabotegravir every 2 months (monitor HIV testing every 3 months). (2) Post-Exposure Prophylaxis (PEP): Following a high-risk percutaneous needlestick injury or sexual assault from an HIV-positive or high-risk source, initiate 3-drug ART—Tenofovir (TDF or TAF) + Emtricitabine PLUS Dolutegravir or Raltegravir (or boosted Darunavir)—as soon as possible (ideally within 1–2 hours, and no later than 72 hours post-exposure) and continue for a FULL 28 DAYS! (3) Peripartum Prevention of Mother-to-Child Transmission (MTCT): Every pregnant patient must be screened for HIV. All HIV-positive pregnant women receive combination 3-drug ART throughout pregnancy. Delivery mode and intrapartum management are governed by the maternal HIV RNA viral load near delivery (36 weeks gestation): If maternal HIV viral load is ≤ 1,000 copies/mL on ART, the patient may safely undergo normal vaginal delivery (and intrapartum IV Zidovudine is not required if VL is < 50 copies/mL). Conversely, if maternal HIV viral load is > 1,000 copies/mL (or unknown) near delivery, she requires scheduled Cesarean delivery at 38 weeks gestation (prior to labor onset and rupture of membranes) PLUS intravenous Zidovudine (AZT) started 3 hours prior to surgery! After birth, the newborn infant receives oral Zidovudine (AZT) prophylaxis for 4–6 weeks (expanded to 3-drug empiric neonatal ART if maternal viral load was > 1,000 copies/mL).
COMLEX / OMM Integration
NBOME High-Yield Correlate
Lymphatic Pump Immunology, Pulmonary PJP & Esophageal Autonomics, Chapman Points & Contraindications
- Thoracic Inlet & Lymphatic Pump Techniques in Immunocompromised States: The thoracic duct (draining 75% of the body's lymph into the left junction of the internal jugular and subclavian veins) and right lymphatic duct traverse Sibson fascia at the thoracic inlet (T1–T4, first ribs, manubrium, clavicles). In patients with HIV and opportunistic pneumonia (e.g., Pneumocystis jirovecii once antimicrobial therapy has been initiated), myofascial release of the thoracic inlet (always Step #1!), doming the thoracoabdominal diaphragm, rib raising, and thoracic/pedal lymphatic pump techniques enhance lymph circulation, mobilize antigen-presenting cells and lymphocytes through lymph nodes, and improve mucociliary clearance. (Note: Vigorous lymphatic pump techniques are contraindicated in untreated acute bacterial sepsis with hemodynamic instability, osteolytic bone metastases, or active Primary CNS Lymphoma / visceral Kaposi sarcoma where mechanical pumping could theoretically promote tumor dissemination or fluid overload.)
- Pulmonary & Esophageal Viscerosomatic Reflexes: In PJP pneumonia or pulmonary tuberculosis, afferent visceral fibers trigger T2–T7 sympathetic paraspinal tissue texture changes and anterior Chapman points in the 3rd and 4th intercostal spaces near the sternum (upper/lower lung; posterior: T3–T4), plus C3–C5 (phrenic) and OA/AA (vagal) somatic dysfunctions. In Candida, HSV, or CMV esophagitis, sympathetic viscerosomatic reflexes localize to T3–T6 and parasympathetic reflexes localize to the vagus nerve (CN X) at the occipitoatlantal (OA) junction.
- AIDS Enteropathy & Cryptococcal Meningitis Cranial Considerations: In chronic secretory diarrhea (Cryptosporidium or MAC), T9–L2 paraspinal inhibition reduces sympathetic-mediated gut stasis, while in Cryptococcal meningitis with severely elevated intracranial pressure (> 250 mm H2O), forceful cranial compression techniques (such as CV4) and cervical HVLA are contraindicated during the acute hypertensive phase; gentle venous sinus drainage may be utilized as an adjunct only after therapeutic lumbar puncture has normalized ICP.
Board Traps & Common Distractors
- PJP Pneumonia Corticosteroid Rule (PaO2 < 70 mmHg or A-a Gradient ≥ 35 mmHg): Whenever an HIV-positive patient with Pneumocystis jirovecii pneumonia (PJP) presents with a room-air arterial PaO2 < 70 mmHg or an A-a oxygen gradient ≥ 35 mmHg (SpO2 < 92%), you MUST co-administer systemic corticosteroids (Prednisone) alongside TMP-SMX to prevent lethal antibiotic-induced alveolar inflammation and respiratory failure.
- Cryptococcal Meningitis ART Delay & Serial LP Rule: In an AIDS patient newly diagnosed with Cryptococcal meningitis, perform serial therapeutic lumbar punctures if opening pressure is ≥ 250 mm H2O, start Liposomal Amphotericin B + Flucytosine, and DELAY initiating Antiretroviral Therapy (ART) for 4–6 weeks! Starting ART immediately in cryptococcal meningitis precipitates fatal intracranial Immune Reconstitution Inflammatory Syndrome (IRIS) and brain herniation.
- Abacavir & HLA-B*5701 Screening Requirement: Never prescribe Abacavir (an NRTI) without first testing the patient for the HLA-B*5701 allele; HLA-B*5701-positive patients develop a life-threatening Type IV hypersensitivity reaction, and re-challenging a patient after a suspected Abacavir reaction can cause rapid anaphylactic shock and death.
- Kaposi Sarcoma (HHV-8) vs. Bacillary Angiomatosis (Bartonella henselae): Do not assume every violaceous vascular skin lesion in an AIDS patient is Kaposi sarcoma! If the patient has cat exposure and biopsy shows a dense NEUTROPHILIC infiltrate with Warthin-Starry silver-staining bacilli (rather than spindle cells and lymphocytes), the diagnosis is Bacillary Angiomatosis—cure with Doxycycline or Erythromycin.
- Oral Thrush vs. Esophageal Candidiasis Treatment Trap: While painless oral thrush is treated with topical nystatin swish-and-swallow or clotrimazole troches, the presence of odynophagia or dysphagia indicates Esophageal Candidiasis (an AIDS-defining illness at CD4 < 100), which requires systemic oral Fluconazole (topical nystatin is ineffective!). If odynophagia fails to improve after 72 hours of fluconazole, perform EGD with biopsy to rule out CMV or HSV esophagitis.
- Peripartum HIV Viral Load > 1,000 Copies/mL Delivery Rule: If an HIV-positive pregnant woman has a plasma HIV RNA viral load > 1,000 copies/mL (or unknown viral load) near 36–38 weeks gestation, schedule a Cesarean delivery at 38 weeks (before labor or rupture of membranes) and administer intravenous Zidovudine (AZT) starting 3 hours before delivery, followed by neonatal oral AZT prophylaxis.
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Volume 2: Organ System Clinical Pathology • Chapter 36 of 60