Antiviral (HIV, HCV, Herpes/CMV/Influenza), Systemic Antifungal & Antiparasitic Pharmacology

Every NRTI carries class-specific mitochondrial DNA polymerase-gamma toxicity (lactic acidosis and hepatic steatosis, historically severe with older dideoxynucleosides didanosine/stavudine) plus distinct drug-specific board signatures:

• Tenofovir Disoproxil Fumarate (TDF) vs. Tenofovir Alafenamide (TAF): TDF yields high plasma tenofovir concentrations that are actively concentrated into renal proximal convoluted tubule cells via basolateral OAT1/OAT3 transporters, causing proximal renal tubular dysfunction (acquired Fanconi syndrome: glycosuria with normoglycemia, phosphaturia, aminoaciduria, Type 2 proximal RTA) and decreased bone mineral density (osteopenia/osteoporosis). By contrast, TAF remains stable in plasma and is cleaved intracellularly within lymphoid cells by cathepsin A, achieving 90% lower plasma tenofovir levels and markedly reducing nephrotoxicity and bone loss! Importantly, Tenofovir (TDF/TAF), Emtricitabine (FTC), and Lamivudine (3TC) are highly active against BOTH HIV and Hepatitis B Virus (HBV)—stopping them abruptly in an HIV/HBV co-infected patient precipitates fulminant HBV reactivation hepatitis!

• Abacavir (ABC): Guanosine analog strictly contraindicated in patients who test positive for HLA-B*57:01 due to fatal Abacavir Hypersensitivity Reaction (fever, rash, GI symptoms, dyspnea).

• Zidovudine (AZT / ZDV): Thymidine analog used intrapartum for high-risk perinatal HIV prophylaxis (when maternal HIV RNA >1,000 copies/mL near delivery) and in neonates; causes megaloblastic macrocytic anemia, granulocytopenia/neutropenia, and mitochondrial myopathy.

• Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs: Efavirenz, Rilpivirine, Doravirine, Etravirine, Nevirapine): Do NOT require intracellular phosphorylation! NNRTIs bind an allosteric hydrophobic pocket on HIV-1 reverse transcriptase (adjacent to, but distinct from, the catalytic site), inducing a conformational change that halts polymerization (note: NNRTIs are intrinsically inactive against HIV-2!). Efavirenz causes vivid dreams, insomnia, depression/suicidality, dizziness, and false-positive cannabinoid (THC) urine drug screens; Rilpivirine requires gastric acid for absorption (contraindicated with proton pump inhibitors!) and must be taken with a meal.

HIV Protease Inhibitors (PIs—all end in -navir: Darunavir, Atazanavir, Lopinavir, Ritonavir): During late-stage virion assembly and budding, the HIV pol-encoded aspartyl protease cleaves nascent Gag and Gag-Pol polyproteins into mature structural proteins (p17, p24, p7) and enzymes. Protease inhibitors competitively block this proteolytic cleavage, resulting in the release of immature, non-infectious virions. Because all PIs are substrates and inhibitors of hepatic CYP3A4, therapeutic regimens co-administer low-dose Ritonavir or Cobicistat as a pharmacokinetic 'booster' to potently inhibit CYP3A4 and boost active PI plasma levels (creating severe CYP3A4 drug interactions with statins, midazolam, rifampin, and antiarrhythmics!). Signature PI toxicities include hyperglycemia / insulin resistance, hypertriglyceridemia, lipodystrophy (cushingoid buffalo hump), and crystal-induced nephrolithiasis (indinavir/atazanavir), while Atazanavir additionally inhibits hepatic UGT1A1, causing benign, asymptomatic unconjugated hyperbilirubinemia and scleral icterus (identical to Gilbert syndrome).

Entry, Fusion, Attachment & Capsid Inhibitors: HIV-1 entry requires viral gp120 to bind host CD4, inducing a conformational shift that exposes the V3 loop to bind a chemokine co-receptor—either CCR5 (on macrophages and mucosal T cells, R5-tropic strains) or CXCR4 (on T cells, X4-tropic strains)—followed by gp41-mediated membrane fusion. Maraviroc is a small-molecule allosteric antagonist of the host CCR5 receptor; before prescribing maraviroc, a viral tropism assay MUST confirm pure CCR5-tropic (R5) HIV-1 (maraviroc is useless against CXCR4-tropic or dual/mixed-tropic virus; note also that individuals homozygous for the natural 32-base-pair deletion CCR5-Δ32 are genetically resistant to R5-tropic HIV infection!). Enfuvirtide (T-20) is a subcutaneous 36-amino-acid peptide that binds viral gp41, preventing the heptad-repeat hairpin conformational change required for viral-host membrane fusion (causes painful injection-site nodules). Ibalizumab is an IV anti-CD4 monoclonal antibody blocking post-attachment entry, Fostemsavir binds viral gp120, and Lenacapavir is a long-acting (every 6 months subcutaneous) HIV-1 p24 capsid inhibitor that disrupts both capsid nuclear import/disassembly and late virion capsid assembly.

Mastering the three-suffix nomenclature of HCV Direct-Acting Antivirals makes every board pharmacology question instant:

• -buvir = NS5B RNA-Dependent RNA Polymerase Inhibitor (Sofosbuvir): Sofosbuvir is a nucleotide prodrug phosphorylated intracellularly into a uridine triphosphate analog that incorporates into the growing HCV RNA strand and causes immediate chain termination by NS5B polymerase. Because sofosbuvir is cleared via the kidneys and has a high barrier to resistance, it is safe in decompensated cirrhosis (Child-Pugh B/C, when paired with velpatasvir/ledipasvir + ribavirin), though Amiodarone co-administration is strictly contraindicated due to life-threatening bradycardia.

• -asvir = NS5A Phosphoprotein Inhibitor (Ledipasvir, Velpatasvir, Pibrentasvir, Elbasvir): NS5A is a non-enzymatic membrane-associated phosphoprotein essential for both the membranous web HCV RNA replication complex and virion assembly/secretion. Note that Ledipasvir and Velpatasvir require gastric acid for dissolution—co-administration with high-dose proton pump inhibitors (omeprazole >20 mg) significantly reduces their absorption and can cause virologic relapse!

• -previr = NS3/4A Serine Protease Inhibitor (Glecaprevir, Grazoprevir, Voxilaprevir): Inhibits the viral NS3/4A protease from cleaving the translated HCV polyprotein into functional nonstructural enzymes. Crucial hepatic board pearl: All NS3/4A protease inhibitors (-previrs) undergo hepatic metabolism and are STRICTLY CONTRAINDICATED in decompensated cirrhosis (Child-Pugh Class B or C) because they accumulate to cause fatal hepatotoxicity and liver decompensation!

Unlike HCV (which is an RNA virus cured in 8–12 weeks), Hepatitis B Virus (HBV) is a partially double-stranded DNA hepadnavirus that establishes a stable, episomal covalently closed circular DNA (cccDNA) minichromosome inside hepatocyte nuclei and replicates via an RNA intermediate using viral reverse transcriptase. Because nucleos(t)ide analogs do not eradicate intranuclear cccDNA, chronic HBV therapy generally requires long-term or indefinite suppression rather than short-course cure. First-line oral monotherapies with a high genetic barrier to resistance are Entecavir (a guanosine nucleoside analog that inhibits all three steps of HBV polymerase: base priming, reverse transcription of the negative strand, and DNA-dependent synthesis of the positive strand), Tenofovir Alafenamide (TAF), and Tenofovir Disoproxil Fumarate (TDF) (older agents like lamivudine, adefovir, and telbivudine have high resistance rates and are no longer first-line). Crucial board trap: Never use Entecavir as monotherapy in an HIV/HBV co-infected patient who is not receiving suppressive HIV ART, because entecavir has weak activity against HIV reverse transcriptase and rapidly selects for the M184V HIV resistance mutation (which cross-resists lamivudine and emtricitabine!).

In patients with chronic HBV or HCV who receive potent immunosuppression—especially anti-CD20 monoclonal antibodies (rituximab, ofatumumab, ocrelizumab), anthracyclines, high-dose corticosteroids, or hematopoietic stem cell transplantation—prophylactic antiviral therapy with entecavir or tenofovir must be initiated before starting rituximab and continued for at least 12 to 18 months after completing anti-CD20 therapy to prevent fatal HBV reactivation! Finally, remember that Ribavirin (a guanosine nucleoside analog that competitively inhibits inosine monophosphate dehydrogenase [IMPDH] and induces lethal viral RNA mutagenesis) is rarely needed in modern HCV regimens except in decompensated cirrhosis; its two absolute board signatures are dose-limiting extravascular hemolytic anemia and severe teratogenicity (FDA Category X—contraception required during and for 6–9 months after treatment in both female AND male patients!).

When an immunocompromised patient (AIDS with CD4 <50 cells/mm³ or transplant recipient) develops ganciclovir-resistant CMV (most commonly via a mutation in the UL97 kinase gene) or acyclovir-resistant mucocutaneous HSV/VZV (most commonly via a deficiency or mutation in viral Thymidine Kinase [TK]), any nucleoside analog requiring viral kinase activation will fail. The board-tested drug of choice is Foscarnet (phosphonoformic acid). Foscarnet is an inorganic pyrophosphate analog that directly binds the pyrophosphate-binding site of viral DNA polymerase (and HIV reverse transcriptase) in a noncompetitive manner WITHOUT requiring any intracellular phosphorylation by viral Thymidine Kinase or CMV UL97 kinase!

High-yield Foscarnet toxicities: (1) Severe nephrotoxicity (acute tubular necrosis and crystalline glomerulopathy); and (2) Because foscarnet is a negatively charged pyrophosphate chelator, it avidly chelates divalent cations in plasma—causing severe hypocalcemia (perioral paresthesias, Chvostek/Trousseau signs, tetany, seizures), hypomagnesemia, and hypokalemia (along with painful penile/vulvar genital ulcerations from urinary excretion of unchanged drug).

Alternative second-line agents for CMV include: (1) Cidofovir, a cytosine nucleotide (monophosphate) analog that already contains one phosphate group and is phosphorylated solely by host cellular kinases (bypassing viral TK and UL97!). Cidofovir causes severe proximal tubular nephrotoxicity and MUST always be co-administered with IV normal saline hydration plus oral Probenecid (probenecid competitively blocks basolateral organic anion transporters OAT1/OAT3 in the proximal tubule, preventing cidofovir uptake into renal tubular epithelial cells!). (2) Letermovir, which inhibits the CMV viral terminase complex (UL56) required to cleave concatemeric viral DNA and package it into capsids; used for CMV prophylaxis in allogeneic hematopoietic stem cell transplant recipients without causing myelosuppression or nephrotoxicity. (3) Maribavir, an oral direct UL97 kinase inhibitor approved for refractory/resistant post-transplant CMV infection (causes dysgeusia / metallic taste).

Influenza A & B Antivirals: (1) Neuraminidase Inhibitors (Oseltamivir [oral], Zanamivir [inhaled], Peramivir [IV]): During the final stage of influenza replication, progeny virions budding from the respiratory epithelium remain tethered to host cell surface sialic acid (N-acetylneuraminic acid) residues via viral hemagglutinin. Viral neuraminidase cleaves these sialic acid linkages to release progeny virions so they can infect adjacent cells. Oseltamivir and zanamivir are sialic acid transition-state analogs that competitively inhibit Influenza A and B neuraminidase, trapping budding virions on the host cell surface. To shorten illness duration by 24–48 hours in healthy outpatients, therapy must be initiated within 48 hours of symptom onset; however, in hospitalized, severely ill, or pregnant/immunocompromised patients, start oseltamivir IMMEDIATELY even if >48 hours have elapsed! (Note: inhaled zanamivir can precipitate bronchospasm and is contraindicated in asthma/COPD; older adamantanes amantadine/rimantadine targeted the Influenza A M2 proton channel for viral uncoating, but >99% of circulating Influenza A strains now carry the S31N M2 resistance mutation). (2) Baloxavir marboxil: A single-dose oral inhibitor of the influenza polymerase acidic (PA) cap-dependent endonuclease, blocking 'cap-snatching' of host mRNA primers required for viral transcription.

RSV & SARS-CoV-2 Pharmacology: For Respiratory Syncytial Virus (RSV) immunoprophylaxis in infants (especially premature infants <29 weeks or those with bronchopulmonary dysplasia / hemodynamically significant congenital heart disease), monoclonal antibodies targeting the RSV Fusion (F) glycoprotein prevent viral-host membrane fusion and syncytia formation: Nirsevimab (a long-acting single-dose IM monoclonal antibody targeting the pre-fusion F conformation for all infants entering their first RSV season) and Palivizumab (monthly IM injection during RSV season). For SARS-CoV-2 (COVID-19), high-risk outpatients within 5 days of symptom onset receive oral Nirmatrelvir-Ritonavir (Paxlovid)—where nirmatrelvir inhibits the SARS-CoV-2 main protease (Mpro / 3CLpro) and ritonavir inhibits host CYP3A4 (creating major drug interactions with statins, tacrolimus, amiodarone, and rivaroxaban!)—while hospitalized patients requiring supplemental oxygen receive IV Remdesivir (an adenosine nucleotide prodrug inhibiting viral RNA-dependent RNA polymerase).

Azole Antifungals (imidazoles: ketoconazole, clotrimazole, miconazole; triazoles: fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole) inhibit the fungal cytochrome P450 enzyme lanosterol 14-alpha-demethylase, blocking the conversion of lanosterol into ergosterol and accumulating toxic 14-alpha-methylated sterols that disrupt fungal membrane integrity. All azoles inhibit human hepatic CYP450 enzymes (especially CYP3A4, CYP2C9, and CYP2C19), cause hepatotoxicity, and—with the sole exception of isavuconazole (which uniquely SHORTENS the QT interval!)—prolong the cardiac QTc interval. Each systemic triazole has a distinct board indication and signature pearl:

• Fluconazole: Hydrophilic, minimal plasma protein binding, and achieves excellent CSF and urinary tract penetration; drug of choice for candidemia (except intrinsically resistant Candida krusei and dose-dependent/resistant Candida glabrata!), esophageal/vulvovaginal candidiasis, coccidioidal meningitis maintenance, and cryptococcal meningitis consolidation. Fluconazole has ZERO activity against Aspergillus or Mucorales!

• Itraconazole: Lipophilic drug of choice for mild-to-moderate non-meningeal blastomycosis, histoplasmosis, and sporotrichosis. Capsule formulations require gastric acid for absorption (avoid PPIs/H2 blockers!), and itraconazole carries an FDA boxed warning for negative inotropy / acute decompensated heart failure.

• Voriconazole: The #1 first-line drug of choice for Invasive Aspergillosis (as well as Fusarium and Scedosporium). High-yield Voriconazole toxicities: (1) Transient visual disturbances (~30% of patients: blurred vision, altered color perception, photopsia/flashing lights, photophobia) within 30 minutes of dosing due to reversible retinal bipolar cell dysfunction; (2) Photosensitivity dermatitis and cutaneous squamous cell carcinoma with chronic use; (3) Central nervous system visual/auditory hallucinations; and (4) Fluorosis and painful periostitis (elevated alkaline phosphatase and bony exostoses) due to its three fluorine atoms!

• Posaconazole & Isavuconazole: Broad-spectrum triazoles that uniquely cover Mucorales (mucormycosis: Mucor, Rhizopus) as well as Aspergillus and Candida. Meanwhile, Flucytosine (5-FC) is a fluorinated pyrimidine prodrug taken up via fungal cytosine permease and converted specifically by fungal cytosine deaminase (absent in human cells!) into 5-Fluorouracil (5-FU), which inhibits thymidylate synthase (5-FdUMP) and fungal RNA synthesis; it is ALWAYS combined with amphotericin B for cryptococcal meningitis (never monotherapy due to rapid resistance) and causes severe bone marrow suppression (leukopenia/thrombocytopenia).

Echinocandins (all end in -fungin: Caspofungin, Micafungin, Anidulafungin): Large cyclic lipopeptides administered intravenously once daily that noncompetitively inhibit the fungal cell wall enzyme beta-1,3-D-glucan synthase, disrupting cell wall integrity and causing osmotic lysis. Echinocandins are the #1 empiric first-line therapy for invasive candidemia in critically ill or neutropenic patients (including azole-resistant Candida glabrata and Candida krusei!) and serve as salvage therapy for invasive aspergillosis. Crucial spectrum gap on boards: Echinocandins are completely INEFFECTIVE against Cryptococcus neoformans (because its thick polysaccharide capsule and cell wall architecture resist beta-1,3-glucan inhibition) and Mucorales, and they do NOT penetrate the CSF or urine! Adverse effects include histamine-mediated flushing, GI upset, and mild transaminitis.

Dermatophyte & Onychomycosis Agents (Terbinafine vs. Griseofulvin): (1) Terbinafine (an oral and topical allylamine) inhibits fungal squalene epoxidase—the step immediately upstream of lanosterol synthesis—causing toxic intracellular accumulation of squalene that kills dermatophytes. Oral terbinafine concentrates in keratin and nail plates, making it the #1 first-line oral drug of choice for dermatophyte onychomycosis (tinea unguium) and a top choice for tinea capitis (alongside griseofulvin). Its signature board toxicities are hepatotoxicity (always check baseline LFTs!) and reversible dysgeusia (loss or alteration of taste). (2) Griseofulvin binds fungal alpha/beta-tubulin to disrupt mitotic spindle microtubule polymerization and arrest fungal mitosis in metaphase. It deposits in newly synthesized keratin precursor cells and is a classic oral treatment for pediatric tinea capitis (taken with a high-fat meal to enhance absorption); signature board pearls include CYP450 enzyme induction (warfarin failure, OCP failure), teratogenicity, disulfiram-like ethanol reaction, and severe photosensitivity.

• Metronidazole & Tinidazole: Nitroimidazoles whose nitro group is chemically reduced by anaerobic/microaerophilic ferredoxin electron transport proteins into reactive cytotoxic free radicals that cause helical DNA strand breaks. Metronidazole is the drug of choice for Giardia lamblia, Trichomonas vaginalis (treat patient AND sexual partner simultaneously!), and invasive Entamoeba histolytica colitis or amebic liver abscess. High-yield board rule for Entamoeba histolytica: after treating invasive tissue trophozoites with metronidazole, you MUST administer a non-absorbable luminal cysticidal agent—Paromomycin or Iodoquinol—to eradicate surviving intraluminal cysts and prevent relapse! (Recall that metronidazole inhibits acetaldehyde dehydrogenase to cause a severe disulfiram-like flushing/vomiting reaction with ethanol and causes peripheral neuropathy/metallic taste).

• Nitazoxanide: Inhibits the anaerobic energy enzyme pyruvate:ferredoxin oxidoreductase (PFOR); it is the FDA-approved drug of choice for Cryptosporidium parvum/hominis watery diarrhea (though in AIDS patients with CD4 <100, immune reconstitution with ART is the definitive cure!).

• Pyrimethamine + Sulfadiazine + Leucovorin (Folinic Acid): Synergistically blocks two sequential enzymes in protozoal folate synthesis (dihydropteroate synthase and dihydrofolate reductase); it is the gold-standard treatment for CNS Toxoplasmosis (Toxoplasma gondii multiple ring-enhancing brain lesions) and congenital toxoplasmosis, with Leucovorin co-administered to rescue host human bone marrow progenitor cells from folate-deficiency megaloblastic pancytopenia! For Babesia microti (intraerythrocytic 'Maltese cross' tetrad rings transmitted by the Ixodes scapularis tick in the Northeast/Upper Midwest), first-line therapy is Atovaquone + Azithromycin (or Clindamycin + Quinine in severe life-threatening babesiosis).

Vector-borne flagellated kinetoplastids require targeted antiparasitic regimens tested on step examinations:

• Trypanosoma cruzi (Chagas Disease—transmitted by the Reduviid 'kissing' bug painless bite/feces, causing unilateral periorbital Romana sign, dilated cardiomyopathy with apical aneurysm, megaesophagus, and megacolon): Treated during the acute or early indeterminate phase with Benznidazole or Nifurtimox (which generate nitro-anion free radicals toxic to T. cruzi).

• Trypanosoma brucei gambiense / rhodesiense (African Sleeping Sickness—transmitted by the painful bite of the Tsetse fly, causing posterior cervical Winterbottom lymphadenopathy, recurring antigenic-variation fevers, and somnolent encephalitis): Treatment is stratified by subspecies and CNS penetration: early hemolymphatic stage uses Suramin (for East African T. b. rhodesiense) or Pentamidine (for West African T. b. gambiense), whereas late CNS meningoencephalitic stage uses oral Fexinidazole, Eflornithine + Nifurtimox (for T. b. gambiense), or the trivalent arsenical Melarsoprol (for CNS T. b. rhodesiense, which causes fatal reactive arsenical encephalopathy in 5–10% of patients unless co-administered with prednisolone!).

• Leishmania donovani / infantum (Visceral Leishmaniasis / Kala-Azar: fever, massive hepatosplenomegaly, pancytopenia, hyperpigmented skin, amastigotes inside macrophages transmitted by the Phlebotomus/Lutzomyia sandfly) & Cutaneous Leishmaniasis: First-line therapy for visceral leishmaniasis in the United States is Liposomal Amphotericin B (because Leishmania membranes contain ergosterol!) or oral Miltefosine, while pentavalent antimonial compounds—Sodium Stibogluconate or meglumine antimoniate—are classic board associations for cutaneous and mucocutaneous leishmaniasis.

Ivermectin: A macrocyclic lactone that selectively binds and opens glutamate-gated chloride (Cl-) channels (and potentiates GABA-A Cl- channels) unique to invertebrate nematode and arthropod nerve and muscle cells. The resulting chloride influx causes neuronal and muscular hyperpolarization and tonic flaccid paralysis of the parasite (because mammalian CNS GABA neurons are protected behind the blood-brain barrier by P-glycoprotein efflux pumps, ivermectin spares the human host). Ivermectin is the #1 drug of choice for two major nematode infections: (1) Strongyloides stercoralis (threadworm) and (2) Onchocerca volvulus (River Blindness, transmitted by the female Simulium blackfly), as well as oral treatment for crusted Norwegian scabies (Sarcoptes scabiei) and pediculosis. High-yield board traps with Ivermectin: First, before giving ivermectin for onchocerciasis in Central/West Africa, always screen for heavy co-infection with Loa loa (African eye worm), because rapid killing of high-density Loa loa microfilariae precipitates fatal encephalopathy! Second, in Onchocerca volvulus, rapid microfilarial death releases endosymbiotic Wolbachia bacteria, triggering the Mazzotti reaction (fever, pruritus, hypotension, lymphadenitis, arthralgias; Doxycycline can be given to kill endosymbiotic Wolbachia and sterilize adult female worms!).

Pyrantel Pamoate & Diethylcarbamazine (DEC): Pyrantel pamoate acts as a nicotinic acetylcholine receptor agonist and cholinesterase inhibitor at the nematode neuromuscular junction, causing persistent depolarizing neuromuscular blockade and spastic (rigid) paralysis so the worm loses its grip on the intestinal mucosa and is expelled alive by peristalsis. Because it is poorly absorbed from the GI tract, pyrantel pamoate is a safe, over-the-counter alternative to albendazole for Enterobius vermicularis (pinworm—diagnosed by the Scotch tape test; treat the entire household!), Ascaris lumbricoides, and hookworms (Ancylostoma duodenale, Necator americanus), especially in pregnant women or young children. Diethylcarbamazine (DEC) immobilizes microfilariae and alters their surface membranes to enhance host eosinophil/macrophage phagocytosis; it is the drug of choice for Wuchereria bancrofti / Brugia malayi (lymphatic filariasis / elephantiasis) and Loa loa.

Praziquantel is the definitive broad-spectrum drug of choice for all Trematodes (Flukes: Schistosoma mansoni, S. haematobium, S. japonicum, Clonorchis sinensis, Paragonimus westermani; note that only Fasciola hepatica sheep liver fluke is resistant to praziquantel and requires Triclabendazole!) and adult intestinal Cestodes (Tapeworms: Taenia saginata, Taenia solium intestinal tapeworm, Diphyllobothrium latum, Hymenolepis nana). Praziquantel binds beta-subunits of voltage-gated calcium channels on the helminthic tegument, increasing membrane permeability to divalent calcium ions (Ca2+). The massive intracellular Ca2+ influx triggers rapid tetanic (spastic) muscular contraction and paralysis alongside vacuolization and sloughing of the parasite's protective tegument, exposing hidden parasite antigens to host antibody-dependent eosinophil destruction.

Two critical surgical and neurological board rules govern larval cestode tissue infections:

1. Neurocysticercosis (Taenia solium larval cysts in the brain parenchyma from ingesting eggs in human fecal-contaminated food—presenting with adult-onset seizures and calcified/cystic 'Swiss-cheese' brain lesions): Treated with Albendazole (plus Praziquantel in multiple viable cysts), which MUST be preceded and accompanied by systemic Corticosteroids (Dexamethasone or Prednisone) plus antiepileptic therapy (levetiracetam/phenytoin)! Why? Because killing intracerebral cysticerci releases degenerating parasite antigens that trigger intense perilesional vasogenic cerebral edema, intracranial hypertension, status epilepticus, and fatal brain herniation unless blunted by corticosteroids! (And always perform a dilated funduscopic eye exam BEFORE starting albendazole/praziquantel to rule out ocular cysticercosis, where killing an intraocular larva causes irreversible blindness!)

2. Cystic Echinococcosis / Hydatid Liver Cysts (Echinococcus granulosus eggs from dog feces causing unilocular 'eggshell-calcified' liver cysts with daughter cysts): Treated medically with Albendazole and, if large/complex, percutaneous PAIR (Puncture, Aspiration, Injection of scolicidal hypertonic saline/ethanol, Re-aspiration) or surgical resection under albendazole cover—never perform an unprotected diagnostic needle biopsy, as spilling hydatid fluid causes fatal anaphylactic shock and peritoneal seeding!

Memorize the exact CD4+ prophylaxis and treatment ladder tested on USMLE and COMLEX:

• CD4 <200 cells/mm³ — Pneumocystis jirovecii Pneumonia (PJP—diffuse bilateral ground-glass interstitial infiltrates, severe hypoxemia, elevated serum LDH and 1,3-β-D-glucan, disc-shaped yeasts on methenamine silver stain): #1 Prophylaxis and #1 Treatment is TMP-SMX (plus adjunctive systemic Corticosteroids [Prednisone 40 mg BID tapered over 21 days] whenever room-air PaO2 <70 mmHg or A-a gradient ≥35 mmHg to prevent fungal-lysis alveolar inflammation!). In patients with G6PD deficiency or sulfa allergy, alternative PJP prophylaxis drugs are Dapsone (screen G6PD first!), Atovaquone (oral suspension taken with fatty food), or Inhaled Pentamidine; for moderate-to-severe PJP treatment in sulfa-allergic patients, use IV Pentamidine or Primaquine + Clindamycin.

• CD4 <150 cells/mm³ (in endemic Ohio/Mississippi River Valley areas) — Histoplasma capsulatum: Prophylaxis with oral Itraconazole.

• CD4 <100 cells/mm³ AND Positive Toxoplasma IgG Serology — Toxoplasma gondii Encephalitis: #1 Prophylaxis is Double-Strength daily TMP-SMX (which simultaneously covers both PJP and Toxoplasma!), or Dapsone + Pyrimethamine + Leucovorin (or Atovaquone) in sulfa allergy. Active CNS Toxoplasmosis (multiple ring-enhancing brain lesions) is treated for ≥6 weeks with Pyrimethamine + Sulfadiazine + Leucovorin.

• CD4 <50 cells/mm³ — Disseminated Mycobacterium avium Complex (MAC: high fevers, drenching night sweats, weight loss, watery diarrhea, hepatosplenomegaly, anemia, elevated alkaline phosphatase): Active disseminated MAC treatment requires at least two drugs: a Macrolide (Clarithromycin or Azithromycin—Azithromycin is preferred due to fewer CYP3A4 interactions!) PLUS Ethambutol (± Rifabutin). Note: Primary MAC prophylaxis with weekly Azithromycin is now ONLY indicated if the patient is NOT immediately initiating suppressive HIV ART! At CD4 <50 cells/mm³, patients are also at high risk for CMV Retinitis/Colitis (screen with dilated funduscopy and treat with Valganciclovir / IV Ganciclovir; routine primary oral ganciclovir prophylaxis is NOT recommended due to severe neutropenia).

When an antiretroviral-naive AIDS patient with a very low CD4+ count (<50–100 cells/mm³) and a high burden of an occult or newly treated opportunistic infection starts potent ART, rapid recovery of pathogen-specific CD4+ Th1 lymphocytes and drop in HIV viral load triggers a paradoxical, exuberant inflammatory surge within 2 to 8 weeks—termed Immune Reconstitution Inflammatory Syndrome (IRIS) (presenting as paradoxical fever, worsening lymphadenopathy, expanding pulmonary infiltrates, or intracranial hypertension despite sterile/improving microbial cultures).

Crucial board management rule for ART Timing in Active Opportunistic Infections: For almost all opportunistic infections (including PJP, MAC, CMV, and non-CNS tuberculosis with CD4 <50), initiate HIV ART early (within 2 weeks of starting OI antimicrobial therapy), and if mild-to-moderate IRIS occurs later, CONTINUE BOTH HIV ART and OI antimicrobials while adding NSAIDs or systemic Corticosteroids! However, there is ONE absolute lethal exception tested on boards: Cryptococcal Meningitis (and Tuberculous Meningitis)! In Cryptococcal Meningitis (treated with 2 weeks of induction Liposomal Amphotericin B + Flucytosine, followed by 8 weeks of consolidation Fluconazole, plus serial therapeutic lumbar punctures to keep CSF opening pressure <20 cm H2O), you MUST DELAY starting HIV ART for 4 to 6 weeks after starting antifungal therapy! Starting ART too early in cryptococcal or tuberculous meningitis precipitates closed-space intracranial IRIS, cerebral edema, cerebellar tonsillar herniation, and death!