20.5 HIV Infection & Opportunistic Diseases

Human Immunodeficiency Virus (HIV) medicine is a heavily examined component of the MRCP(UK) curriculum. Candidates must demonstrate deep understanding of contemporary diagnostic algorithms, viral kinetics, lifelong antiretroviral therapy (ART) regimens, pharmacogenomic safety markers, class-specific toxicities, and the clinical recognition and emergency management of opportunistic infections stratified by CD4 T-cell thresholds.

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1. Virology, Diagnostic Testing & Clinical Course

HIV is an enveloped single-stranded RNA lentivirus belonging to the Retroviridae family. Viral surface glycoprotein gp120 binds to the host CD4 receptor on T-helper lymphocytes, monocytes, and macrophages. Consequential conformational changes allow gp120 to interact with chemokine co-receptors (CCR5 in macrophage-tropic strains; CXCR4 in T-cell-tropic strains). Viral glycoprotein gp41 then mediates fusion of the viral envelope with the host cell membrane.

Modern Laboratory Diagnostics & The Diagnostic Window

• 4th Generation Laboratory Assay (The Gold Standard): Combined enzyme immunoassay (EIA) detecting both HIV-1 and HIV-2 antibodies (IgM and IgG) AND circulating free HIV-1 p24 antigen. The addition of p24 viral capsid protein shortens the diagnostic window period to approximately 4 weeks (28 days) post-exposure (compared to 6–12 weeks for antibody-only tests).
• Confirmatory Algorithm: A reactive 4th generation screen mandates automated confirmatory testing using a secondary HIV-1/HIV-2 antibody differentiation immunoassay, followed by quantitative plasma HIV-1 RNA PCR.
• Point-of-Care (POCT) Rapid Tests: Third-generation fingerprick capillary blood or oral fluid tests detect antibodies only; they have a prolonged window period of up to 12 weeks. Negative rapid tests following recent high-risk exposure require formal laboratory 4th generation testing at 4 weeks.

Primary HIV Seroconversion Illness

Occurs in $70\text{–}80%$ of newly infected individuals, typically 2 to 6 weeks following viral inoculation. It coincides with massive exponential viral replication, transient immune depletion, and high infectivity.

• Clinical Syndrome: Resembles infectious mononucleosis (glandular fever-like): high fever, pharyngitis, non-tender generalized lymphadenopathy, myalgias, arthralgias, and a faint, non-pruritic erythematous maculopapular rash over the trunk and face. Mucocutaneous ulcerations (oral aphthous-like or genital ulcers) and aseptic meningoencephalitis are highly characteristic clues.
• Diagnostic Caveat: In the earliest days of seroconversion, anti-HIV antibodies may still be undetectable (negative 3rd generation test), but p24 antigen and plasma HIV RNA PCR are astronomically elevated ($> 1,000,000\text{ copies/mL}$).

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2. Antiretroviral Therapy (ART) Principles & Classes

Modern Treatment Mandates: Universal Immediate Initiation

• Universal ART Initiation: British HIV Association (BHIVA) and WHO guidelines mandate initiation of ART in all individuals diagnosed with HIV, regardless of baseline CD4+ cell count or clinical stage.
• Therapeutic Goals: Suppress viral replication to an undetectable plasma viral load ($< 50\text{ copies/mL}$), restore functional CD4+ T-cell counts, halt disease progression, and eliminate horizontal transmission (Undetectable = Untransmittable [U=U]).
• Standard First-Line Regimen (Triple Therapy Backbone):
  • Dual Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs): e.g., Tenofovir (TDF or TAF) + Emtricitabine (FTC), OR Abacavir (ABC) + Lamivudine (3TC).
  • PLUS a High-Barrier Third Agent: Preferably an Integrase Strand Transfer Inhibitor (INSTI): Dolutegravir or Bictegravir.

Pharmacogenomic Safety & Antiretroviral Drug Classes

[HIV Entry / Fusion]
       │ (CCR5 Antagonists: Maraviroc; Fusion Inhibitor: Enfuvirtide)
       ▼
[Reverse Transcription: Viral RNA → cDNA]
       │ (NRTIs: Tenofovir, Abacavir, Emtricitabine, Lamivudine)
       │ (NNRTIs: Efavirenz, Rilpivirine, Nevirapine)
       ▼
[Proviral Integration into Host DNA]
       │ (INSTIs: Dolutegravir, Bictegravir, Raltegravir)
       ▼
[Viral Protein Cleavage & Virion Assembly]
       │ (Protease Inhibitors: Darunavir, Atazanavir [+ Ritonavir / Cobicistat])
       ▼
[Mature Infectious Virion]

1. Nucleoside / Nucleotide Reverse Transcriptase Inhibitors (NRTIs):
   • Mechanism: Competitive inhibitors of HIV reverse transcriptase; lack a 3'-hydroxyl group, acting as obligate DNA chain terminators.
   • Class Toxicity: Inhibit host mitochondrial DNA polymerase-gamma, predisposing to lactic acidosis, hepatic steatosis, and peripheral lipoatrophy (most pronounced with historical agents: stavudine, didanosine, zidovudine).
   • Abacavir (ABC) & HLA-B*5701: Prescribing abacavir to patients carrying the major histocompatibility complex allele HLA-B*5701 triggers an acute, life-threatening multisystem hypersensitivity reaction (fever, rash, nausea, vomiting, dyspnoea). Mandatory genetic screening for HLA-B*5701 is legally required prior to prescribing abacavir; if positive, abacavir is permanently contraindicated.
   • Tenofovir Disoproxil Fumarate (TDF) vs. Tenofovir Alafenamide (TAF): TDF delivers high systemic plasma tenofovir levels, which accumulate within renal proximal tubular cells, causing proximal renal tubular dysfunction (acquired Fanconi syndrome: hypophosphataemia, normoglycaemic glycosuria, proteinuria) and bone mineral density loss. TAF is a novel prodrug with targeted intracellular uptake into lymphocytes, yielding $> 90%$ lower plasma concentrations and negligible renal/bone toxicity.
2. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs):
   • Mechanism: Non-competitive allosteric inhibitors binding an adjacent hydrophobic pocket of reverse transcriptase (e.g., Efavirenz, Rilpivirine, Nevirapine).
   • Toxicities: Efavirenz causes severe central nervous system neuropsychiatric adverse effects in $> 50%$ (vivid nightmares, insomnia, depression, dizziness, daytime somnolence, depersonalization) and skin rash. Nevirapine causes severe fulminant hepatotoxicity and Stevens-Johnson syndrome.
3. Integrase Strand Transfer Inhibitors (INSTIs):
   • Mechanism: Bind catalytic divalent magnesium ions within the integrase active site, preventing strand transfer and incorporation of proviral cDNA into the host genome (e.g., Dolutegravir, Bictegravir, Raltegravir).
   • Profile: Exceptional viral suppression efficacy, high genetic barrier to resistance, minimal drug-drug interactions. Adverse effects include modest weight gain and rare insomnia.
4. Protease Inhibitors (PIs):
   • Mechanism: Inhibit HIV aspartyl protease, preventing the cleavage of Gag-Pol polyprotein precursors and rendering budding virions immature and non-infectious (e.g., Darunavir, Atazanavir).
   • Pharmacokinetic Boosting: Co-administered with low-dose ritonavir or cobicistat to inhibit cytochrome P450 CYP3A4, dramatically increasing PI plasma half-life.
   • Toxicities: Metabolic complications including dyslipidaemia, central visceral adiposity ('buffalo hump'), insulin resistance, and accelerated cardiovascular disease.

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3. Opportunistic Infections Stratified by CD4 Thresholds

In untreated HIV infection, progressive depletion of CD4+ helper T-lymphocytes exposes the patient to opportunistic pathogens along predictable immunological thresholds.

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4. In-Depth Management of Major Opportunistic Conditions

Pneumocystis jirovecii Pneumonia (PCP)

• Pathogen: Atypical, unicellular fungus with cholesterol rather than ergosterol in its plasma membrane (explaining intrinsic resistance to amphotericin B and azoles).
• Clinical Presentation: Classically subacute (over 2–4 weeks): progressive exertional breathlessness, persistent non-productive cough, and fever. Auscultation is frequently unremarkable despite profound dyspnoea. Auscultation while walking demonstrates catastrophic, rapid exercise-induced arterial oxygen desaturation.
• Biochemical & Radiographic Findings: Marked elevation of serum lactate dehydrogenase (LDH $> 500\text{ IU/L}$) reflects diffuse alveolar injury. Chest radiograph demonstrates symmetrical bilateral perihilar bat-wing interstitial and alveolar infiltrates. HRCT reveals patchy or diffuse ground-glass attenuation with subpleural sparing.
• Therapy & Systemic Corticosteroid Criteria:
  • First-line: High-dose oral or intravenous co-trimoxazole (trimethoprim $15\text{–}20\text{ mg/kg/day}$ plus sulfamethoxazole $75\text{–}100\text{ mg/kg/day}$ in 3–4 divided doses) for 21 days.
  • Adjunctive Corticosteroid Therapy: Dying fungal organisms release intense inflammatory antigens that trigger acute alveolar capillary injury, precipitating respiratory arrest 48–72 hours after commencing antibiotics. Systemic corticosteroids (oral prednisolone or IV methylprednisolone) are strictly indicated if:
    1. Room air arterial $\text{PaO}_2 < 9.3\text{ kPa}$ ($< 70\text{ mmHg}$), OR
    2. Alveolar-arterial oxygen gradient ($A\text{-}a\ \text{gradient}$) $\ge 35\text{ mmHg}$.
  • Steroids must be administered prior to or concurrently with the first dose of co-trimoxazole (prednisolone $40\text{ mg}$ BD for 5 days, $40\text{ mg}$ OD for 5 days, then $20\text{ mg}$ OD for 11 days).

Cerebral Toxoplasmosis vs. Primary CNS Lymphoma

A classic MRCP diagnostic dilemma in patients with CD4 $< 100\text{ cells/}\mu\text{L}$:

• Toxoplasma Encephalitis: Reactivation of encysted Toxoplasma gondii. MRI demonstrates multiple ring-enhancing lesions, classically located in the basal ganglia, thalamus, and corticomedullary junction, accompanied by prominent vasogenic oedema. Serum Toxoplasma IgG is positive in $> 95%$ (negative IgG strongly points away from toxoplasmosis). First-line treatment: pyrimethamine, sulfadiazine, and folinic acid (leucovorin, added to prevent pyrimethamine-induced bone marrow suppression). Clinical and radiological improvement should be documented within 10 to 14 days.
• Primary CNS Lymphoma (PCNSL): High-grade B-cell non-Hodgkin lymphoma driven by latent Epstein-Barr Virus (EBV) infection. MRI shows solitary (or fewer, larger) lesions, typically in a periventricular or subependymal distribution, demonstrating intense nodular or ring-like enhancement with mass effect. Lumbar puncture demonstrates positive EBV DNA by PCR in the CSF ($> 90%$ sensitivity and specificity), confirming the diagnosis and precluding brain biopsy.

Cryptococcal Meningitis (Cryptococcus neoformans)

• Clinical Presentation: Encapsulated yeast acquired by inhalation of pigeon droppings. Disseminates to the central nervous system in profoundly immunosuppressed hosts (CD4 $< 100$). Presents indolently with persistent headache, malaise, low-grade fever, and vomiting, frequently with absent signs of meningism.
• Severely Elevated Intracranial Pressure: Fungal capsular polysaccharide (glucuronoxylomannan) clogs arachnoid villi, producing severe non-communicating/communicating hydrocephalus with opening pressures $> 30\text{–}40\text{ cmH}_2\text{O}$. Uncontrolled intracranial pressure is the principal cause of death and blindness.
• Induction Therapy & ICP Management:
  • Induction: IV Liposomal Amphotericin B ($3\text{–}4\text{ mg/kg/day}$) plus oral Flucytosine ($100\text{ mg/kg/day}$) for 14 days (or high-dose single-dose liposomal amphotericin B $10\text{ mg/kg}$ stat with flucytosine/fluconazole as per the AMBITION-cm trial).
  • Daily Therapeutic Lumbar Punctures: Mandatory if opening pressure is $> 25\text{ cmH}_2\text{O}$; remove large volumes of CSF until pressure falls below $20\text{ cmH}_2\text{O}$ or by $50%$.
  • Timing of ART: ART initiation must be delayed for 2 to 4 weeks after starting antifungal therapy. Immediate ART triggers massive intracranial Immune Reconstitution Inflammatory Syndrome (IRIS), with fatal cerebral herniation.

Prophylaxis Guidelines

• Primary Prophylaxis against PCP: Recommended for all patients with a CD4 count $< 200\text{ cells/}\mu\text{L}$ (or CD4 percentage $< 14%$). First-line agent: oral co-trimoxazole ($960\text{ mg}$ three times weekly or $480\text{ mg}$ once daily). Also confers cross-prophylaxis against Toxoplasma gondii. Discontinued once CD4 count remains $> 200\text{ cells/}\mu\text{L}$ for $\ge 3$ consecutive months on suppressive ART.