What You Just Learned - Structure

PART I: Mycobacterial Diseases

• Organism (M. tuberculosis complex, acid-fastness, cell wall)
• Epidemiology (global burden, mortality)
• Full pathogenesis sequence (inhalation → macrophage invasion → phagosome subversion → granuloma)
• Clinical manifestations (primary, LTBI, pulmonary, every extrapulmonary site)
• Diagnosis (smear, culture, GeneXpert, TST vs IGRA)
• Treatment (2HRZE/4HR, all drug mechanisms and toxicities, MDR-TB regimens, LTBI treatment)
• Special situations (TB/HIV, IRIS, pediatric, pregnancy)
• Prevention (BCG, infection control)

• Organism (M. leprae, cannot be cultured, temperature preference)
• Ridley-Jopling spectrum (TT to LL) with immune basis
• WHO classification (PB vs MB)
• Clinical features (skin, nerve involvement, specific nerves and deficits)
• Leprosy reactions (Type 1 reversal vs Type 2 ENL - emergency management)
• Treatment (MDT regimens, drug toxicities including clofazimine pigmentation)

• Key species and their syndromes
• Disseminated MAC in AIDS
• Lady Windermere syndrome
• ATS diagnostic criteria
• Treatment principles

PART II: HIV/AIDS

• Virus structure, genome, all regulatory genes
• 2023 global epidemiology
• Transmission routes and risks
• Full replication cycle (step by step)
• Viral dynamics (set point, virion half-life, daily production)
• Immunopathogenesis (CD4 destruction, chronic immune activation, B/NK/monocyte dysfunction)
• Clinical stages (acute → latency → AIDS)
• AIDS-defining OIs by CD4 threshold with treatments
• Diagnosis (4th-gen testing, viral load, CD4)
• All ART drug classes with mechanisms and toxicities
• Preferred first-line regimens
• IRIS
• Prevention (PrEP, PEP, PMTCT, U=U)
• Neurological complications
• Other organ involvement (cardiovascular, renal HIVAN)
• Host genetic factors (CCR5Δ32, HLA, restriction factors)

MCQ ONE-LINERS: MYCOBACTERIAL DISEASES & HIV/AIDS

🦠 TUBERCULOSIS

1. M. tuberculosis is acid-fast due to high mycolic acid content in cell wall
2. M. tuberculosis is neutral on Gram stain (neither Gram+ nor Gram-)
3. M. tuberculosis size: 0.5 × 3 μm
4. M. bovis is characteristically resistant to pyrazinamide
5. M. tuberculosis emerged ~70,000 years ago in Africa
6. Untreated TB is fatal in >70% of cases
7. TB returned as #1 infectious killer after COVID-19 displaced it in 2020-22
8. First cells affected after inhalation: myeloid dendritic cells (before alveolar macrophages)
9. M. tuberculosis survives in macrophage by blocking phagosome-lysosome fusion
10. Phagosome-lysosome fusion is blocked via Ca²+/calmodulin pathway inhibition by LAM (lipoarabinomannan)
11. ESX-1 secretion system (encoded in RD1 locus) mediates macrophage rupture
12. RD1 locus is absent in BCG - this is the key attenuating mutation
13. katG gene encodes catalase/peroxidase - required for INH activation; loss = INH resistance
14. ESAT-6 and CFP-10 are the two key antigens encoded by RD1 (used in IGRA)
15. Surfactant protein D prevents phagocytosis of M. tuberculosis
16. Only <10% of inhaled bacilli reach the alveoli
17. Lifetime risk of reactivation from LTBI: ~10% overall
18. HIV increases TB reactivation risk to 5-10% per year
19. BCG is highly effective against miliary TB and TB meningitis in children (~80%)
20. BCG has variable efficacy (0-80%) against pulmonary TB
21. Upper lobe predominance in post-primary TB: posterior segments of upper lobes + superior segments of lower lobes
22. Most common extrapulmonary TB site: lymph nodes (scrofula)
23. Spinal TB (Pott's disease): lower thoracic > lumbar spine most affected
24. Ileocecal TB can mimic Crohn's disease
25. Genitourinary TB: classic "sterile pyuria" (pyuria with negative routine cultures)
26. Miliary TB: "millet seed" pattern on CXR; choroid tubercles on fundoscopy
27. ADA (adenosine deaminase) is elevated in tuberculous pleural effusion
28. Xpert MTB/RIF gives results in 2 hours and simultaneously detects rifampicin resistance
29. IGRA is preferred over TST in BCG-vaccinated individuals
30. TST is preferred over IGRA in children <5 years
31. TST false positive causes: BCG vaccination, NTM infection
32. Standard TB regimen: 2HRZE / 4HR (2 months intensive + 4 months continuation)
33. Pyrazinamide is the drug responsible for shortening treatment from 9 to 6 months
34. Pyrazinamide kills semi-dormant bacilli in acidic macrophage environment
35. Isoniazid mechanism: inhibits mycolic acid synthesis (InhA enzyme, enoyl-ACP reductase)
36. Isoniazid toxicity: peripheral neuropathy (prevent with pyridoxine/B6), hepatotoxicity
37. Rifampicin mechanism: inhibits bacterial RNA polymerase (rpoB)
38. Rifampicin is a CYP450 inducer - major drug interactions (reduces levels of ARVs, warfarin, OCP)
39. Rifampicin causes orange discoloration of urine, tears, sweat
40. Ethambutol mechanism: inhibits arabinosyl transferase (arabinogalactan synthesis)
41. Ethambutol toxicity: optic neuritis (dose-dependent; check visual acuity monthly)
42. Pyrazinamide toxicity: hepatotoxicity, hyperuricemia/gout
43. Streptomycin is contraindicated in pregnancy (fetal ototoxicity)
44. MDR-TB = resistance to INH + Rifampicin
45. XDR-TB = MDR + fluoroquinolone + one injectable resistance
46. Bedaquiline = first new TB drug in 40 years; mechanism: ATP synthase inhibitor
47. WHO MDR-TB regimen: BPaL(M) = Bedaquiline + Pretomanid + Linezolid ± Moxifloxacin for 6 months
48. LTBI shortest regimen: 1HP (1 month INH + Rifapentine daily)
49. LTBI best-adherence regimen: 3HP (3 months weekly INH + Rifapentine)
50. In TB/HIV: start ART within 2 weeks if CD4 <50; 8 weeks if CD4 >50
51. In TB/HIV: prefer rifabutin over rifampicin to avoid ART drug interactions
52. IRIS = paradoxical worsening 2-8 weeks after starting ART in TB/HIV; treat with NSAIDs/corticosteroids

🟤 LEPROSY (HANSEN'S DISEASE)

1. Leprosy caused by M. leprae - an obligate intracellular AFB
2. M. leprae cannot be cultured on artificial media (only in armadillo footpads/mouse footpads)
3. M. leprae doubling time: 12-14 days (one of the slowest-growing bacteria)
4. M. leprae optimal temperature: 27-30°C - explains predilection for skin, peripheral nerves, testes, upper airways
5. M. leprae predominantly infects macrophages and Schwann cells
6. Global leprosy cases in 2022: 174,087 from 182 countries
7. Tuberculoid leprosy: strong CMI, few bacilli (1-3 well-defined skin lesions)
8. Lepromatous leprosy: absent CMI, many bacilli (BI 5-6+), numerous symmetric lesions
9. Lepromin test: positive in tuberculoid, negative in lepromatous
10. WHO Paucibacillary = 1-5 skin patches (TT, BT)
11. WHO Multibacillary = >5 skin patches (BB, BL, LL)
12. Hallmark of leprosy diagnosis: anaesthetic skin patch (loss of sensation within lesion)
13. Leonine facies = diffuse lepromatous infiltration of face
14. Madarosis = loss of lateral eyebrows in lepromatous leprosy
15. Lagophthalmos (inability to close eye) = facial nerve involvement → corneal damage → blindness
16. Ulnar nerve at elbow → claw hand (4th, 5th fingers)
17. Common peroneal nerve at fibular head → foot drop
18. Posterior tibial nerve → plantar anesthesia → neuropathic ulcers
19. Type 1 (Reversal) Reaction: occurs in borderline leprosy, sudden increase in CMI, existing lesions inflame, nerve function loss is the emergency
20. Type 1 reaction treatment: Prednisolone 40-60 mg/day for 6 months
21. Type 2 (ENL) Reaction: immune complex-mediated (Type III hypersensitivity), only in BL/LL, systemic features
22. ENL treatment: Thalidomide (most effective; teratogenic) or prednisolone
23. Clofazimine has anti-inflammatory effect in ENL
24. PB leprosy treatment: Rifampicin + Dapsone × 6 months
25. MB leprosy treatment: Rifampicin + Clofazimine + Dapsone × 12 months
26. Dapsone toxicity: hemolytic anemia (especially in G6PD deficiency), methemoglobinemia
27. Clofazimine toxicity: gray-brown skin pigmentation (major cause of non-adherence) + ichthyosis
28. Bacteriologic Index (BI): 0 to 6+, logarithmic scale, falls 1 log unit/year with MDT
29. Morphologic Index (MI): % of viable (solid, uniformly stained) bacilli

🌿 NONTUBERCULOUS MYCOBACTERIA (NTM)

1. NTM = >199 identified species; ubiquitous in soil and water
2. NTM: no human-to-human transmission except in cystic fibrosis
3. Disseminated NTM = significant immune dysfunction (CD4 <50 in HIV)
4. Pulmonary NTM = associated with pulmonary structural disease (bronchiectasis), NOT systemic immunodeficiency
5. M. avium complex (MAC): most common NTM in disseminated AIDS disease and pulmonary NTM
6. M. marinum = "fish tank granuloma" - ascending nodular lymphangitis; aquarium/pool exposure
7. M. ulcerans = Buruli ulcer - painless necrotizing ulcer; West Africa
8. M. fortuitum = wound infections; pedicure-associated furunculosis
9. M. kansasii = pulmonary disease resembling TB; COPD/HIV patients
10. Lady Windermere syndrome = pulmonary MAC in post-menopausal, tall/slender women; middle lobe/lingula bronchiectasis
11. Disseminated MAC treatment: Clarithromycin + Ethambutol ± Rifabutin
12. MAC prophylaxis: Azithromycin 1200 mg/week when CD4 <50; stop when CD4 >100 on ART

🔴 HIV / AIDS

1. HIV is a retrovirus (family Retroviridae, genus Lentivirus)
2. HIV genome: 2 identical copies of (+)ssRNA, ~9.7 kb
3. HIV surface proteins: gp120 (binds CD4) + gp41 (membrane fusion)
4. HIV requires CD4 + CCR5 or CXCR4 co-receptor for entry
5. R5-tropic (CCR5) = macrophage-tropic; X4-tropic (CXCR4) = T-cell tropic
6. Nef = downregulates CD4 and MHC-I; increases infectivity
7. Tat = transcriptional transactivator (essential for viral replication)
8. Vif = counteracts host restriction factor APOBEC3G
9. Vpu = counteracts tetherin; degrades CD4
10. High HIV mutation rate: RT lacks 3'→5' proofreading exonuclease
11. HIV virions produced daily: 10¹⁰ - 10¹¹
12. Half-life of circulating HIV virion: ~30-60 minutes
13. Half-life of productively infected cell: ~1 day
14. Minimum HIV replication cycle in vivo: ~2 days
15. Main site of HIV replication: lymphoid tissue (lymph nodes + GALT)
16. GALT (gut-associated lymphoid tissue): massive CD4 depletion within days to weeks of infection
17. Viral set point established at 6-12 months post-infection - key prognostic marker
18. Elite controllers: <50 HIV RNA copies/mL without ART (<1% of infected individuals)
19. Global HIV prevalence 2023: 39.9 million
20. New HIV infections 2023: 1.3 million (down 60% from peak of 3.3 million in 1995)
21. HIV peak incidence year: 1995
22. Most affected region: WHO Eastern and Southern Africa (>1 in 20 adults = 5.7%)
23. HIV highest risk sexual exposure: receptive anal intercourse (~1.4% per act)
24. Needlestick injury HIV risk: ~0.3% per exposure
25. Without PMTCT, mother-to-child transmission: 25-40%; with PMTCT: <1-2%
26. Acute HIV syndrome occurs 2-4 weeks after infection
27. Acute HIV: viral load >10⁶ copies/mL + sharp CD4 drop → then partial recovery
28. Acute HIV resembles infectious mononucleosis (fever, pharyngitis, lymphadenopathy, rash)
29. PGL (Persistent Generalized Lymphadenopathy): ≥2 extralinguinal sites >3 months; during clinical latency
30. Clinical latency average duration without ART: ~10 years
31. CD4 decline rate without ART: ~50-100 cells/μL/year
32. AIDS definition (CDC): CD4 <200 cells/μL OR presence of AIDS-defining condition
33. HIV B cell defect: polyclonal hypergammaglobulinemia + poor response to vaccination
34. Microbial translocation from gut: LPS enters circulation → chronic immune activation (even on ART)
35. sCD14 remains elevated even with suppressive ART = marker of residual monocyte activation
36. Tissue macrophages serve as persistent HIV reservoir - obstacle to eradication
37. 4th-generation HIV Ag/Ab combo test: detects HIV-1/2 Ab + HIV-1 p24 antigen; window period ~18-45 days
38. U=U: Undetectable = Untransmittable (virologically suppressed cannot sexually transmit HIV)

💊 OIs BY CD4 THRESHOLD

1. CD4 <500: TB, Kaposi's sarcoma, recurrent herpes zoster, oral hairy leukoplakia
2. CD4 <200: PCP (start TMP-SMX prophylaxis), Toxoplasma, Cryptococcus, Histoplasma, Coccidioides, PML, Cryptosporidium
3. CD4 <100: Cryptococcus, Toxoplasma, Bartonella
4. CD4 <50: Disseminated MAC, CMV retinitis, CNS lymphoma, Aspergillosis

🫁 OI TREATMENT ONE-LINERS

1. PCP treatment: TMP-SMX × 21 days; add prednisone if PaO₂ <70 mmHg or A-a gradient >35
2. PCP prophylaxis: TMP-SMX when CD4 <200; stop when CD4 >200 on ART for >3 months
3. PCP diagnosis: BAL with GMS (Gomori methenamine silver) or direct fluorescent antibody
4. PCP CXR: bilateral perihilar ground-glass infiltrates
5. Cryptococcal meningitis CSF: India ink positive; CrAg positive; low glucose, mild lymphocytosis
6. Cryptococcal meningitis induction: Amphotericin B liposomal + Flucytosine × 2 weeks
7. Cryptococcal meningitis consolidation: Fluconazole 400 mg/day × 8 weeks
8. Cryptococcal meningitis maintenance: Fluconazole 200 mg/day until CD4 >200
9. In cryptococcal meningitis - delay ART 4-6 weeks to avoid IRIS
10. Toxoplasma encephalitis: multiple ring-enhancing lesions at basal ganglia on MRI
11. Toxoplasma treatment: Pyrimethamine + Sulfadiazine + Folinic acid
12. Toxoplasma prophylaxis: TMP-SMX DS when CD4 <100 + Toxo IgG positive
13. CMV retinitis: "pizza pie" or "brush fire" appearance; most common cause of blindness in AIDS
14. CMV retinitis treatment: Ganciclovir / Valganciclovir
15. PML (progressive multifocal leukoencephalopathy): JC virus; no mass effect/enhancement on MRI; treat with ART only
16. HIV Wasting Syndrome: >10% involuntary weight loss + chronic diarrhea OR fever >30 days
17. Kaposi's sarcoma: caused by HHV-8; violaceous lesions; most common AIDS cancer in MSM

💉 ART ONE-LINERS

1. ALL people with HIV should start ART regardless of CD4 count
2. Goal of ART: HIV RNA <50 copies/mL within 24 weeks
3. NRTIs mechanism: incorporated into viral DNA → chain termination
4. TDF (tenofovir) toxicity: nephrotoxicity, bone demineralization
5. AZT (zidovudine) toxicity: anemia, myopathy, macrocytosis
6. Abacavir hypersensitivity: screen for HLA-B*5701 before prescribing
7. NNRTIs mechanism: bind allosteric site on reverse transcriptase
8. Efavirenz toxicity: CNS effects (vivid dreams, dizziness), teratogenicity (neural tube defects)
9. Nevirapine toxicity: hepatotoxicity, Stevens-Johnson syndrome
10. Rilpivirine: requires food + acidic pH for adequate absorption
11. Protease inhibitors require boosting with ritonavir or cobicistat (pharmacokinetic enhancers)
12. PIs cause: dyslipidemia, lipodystrophy, insulin resistance
13. INSTIs (Dolutegravir, Bictegravir) mechanism: block integration of proviral DNA
14. Dolutegravir concern in early pregnancy: neural tube defects (now considered low risk but counsel)
15. Dolutegravir is WHO preferred first-line ART drug globally
16. Maraviroc (CCR5 antagonist): requires tropism testing before use (must confirm R5-tropic virus)
17. Enfuvirtide (T-20): first fusion inhibitor; gp41; injectable; expensive
18. Cabotegravir + Rilpivirine LA: long-acting injectable every 1-2 months (best adherence option)
19. PrEP: TDF/FTC daily reduces HIV acquisition by >99% when adherent
20. PEP: must start within 72 hours; 28-day course; reduces transmission ~80-85%
21. IRIS occurs weeks to months after starting ART; continue ART; treat severe cases with corticosteroids
22. In TB/HIV IRIS: NSAIDs first; corticosteroids if severe

🧬 GENETIC FACTORS

1. CCR5 Δ32 homozygous = complete resistance to R5-tropic HIV
2. HLA-B*57 and B*27 = associated with elite controllers and slow progression
3. APOBEC3G = host restriction factor that mutates HIV DNA (C→U); counteracted by Vif
4. TRIM5α = binds HIV capsid; blocks infection (especially in non-human primates)
5. Tetherin (BST-2) = tethers budding virions; counteracted by Vpu
6. SAMHD1 = depletes dNTPs; blocks reverse transcription in non-dividing cells; counteracted by Vpx (HIV-2/SIV)
7. Berlin/London patient: CCR5 Δ32 homozygous bone marrow transplant → apparent HIV cure (proof of concept)

🧠 NEURO-HIV

1. HAND (HIV-Associated Neurocognitive Disorder): subcortical pattern - attention, processing speed, motor
2. HIV encephalopathy = subcortical dementia (AIDS Dementia Complex); MRI: white matter changes + atrophy
3. Vacuolar myelopathy: thoracic cord; progressive spastic paraparesis
4. CNS lymphoma in AIDS: EBV-associated; ring-enhancing lesion; CD4 <50; treat with ART + radiation

🫀 HIV AND OTHER ORGANS

1. HIVAN (HIV-Associated Nephropathy): collapsing FSGS; almost exclusively in Black patients; ART is primary treatment
2. HIV increases risk of myocardial infarction × 2 (chronic inflammation → accelerated atherosclerosis)
3. LIP (Lymphocytic Interstitial Pneumonitis): especially in HIV-positive children

All one-liners sourced from Harrison's Principles of Internal Medicine, 22nd Edition (2025) - Chapters 183, 184, 185, 208.