HIV & AIDS

1. Clinical Overview

Definition

Human Immunodeficiency Virus (HIV) is a lentivirus belonging to the Retroviridae family that selectively infects and depletes CD4+ T-helper lymphocytes, leading to progressive immunodeficiency. [1] Acquired Immunodeficiency Syndrome (AIDS) represents the advanced stage of HIV infection, defined by either a CD4+ T-cell count below 200 cells/μL or the occurrence of specific AIDS-defining opportunistic infections or malignancies, regardless of CD4 count. [2]

HIV infection has transformed from a universally fatal diagnosis in the 1980s to a chronic, manageable condition with the advent of combination antiretroviral therapy (ART). When diagnosed early and treated appropriately, individuals living with HIV can expect near-normal life expectancy and quality of life. [3,4] The principle of U=U (Undetectable = Untransmittable) has revolutionized HIV prevention: individuals with sustained viral suppression on ART do not sexually transmit the virus to their partners. [5,6]

Despite remarkable therapeutic advances, late diagnosis remains a critical challenge globally. Approximately 30-40% of HIV diagnoses in the UK occur at a late stage (CD4 less than 350 cells/μL), associated with significantly worse clinical outcomes and increased onward transmission. [7] Universal testing in appropriate settings and awareness of indicator conditions are essential to earlier diagnosis.

Clinical Significance

HIV remains one of the world's most significant public health challenges. Globally, an estimated 39 million people were living with HIV in 2022, with 1.3 million new infections and 630,000 AIDS-related deaths annually. [8] While mortality has declined by 68% since the peak in 2004, HIV continues to disproportionately affect sub-Saharan Africa, men who have sex with men (MSM), people who inject drugs, and sex workers.

In the UK, approximately 105,000 people are living with HIV, with around 4,000 new diagnoses annually (declining trend). [9] The shift toward test-and-treat strategies and expanding pre-exposure prophylaxis (PrEP) access has led to significant reductions in new infections, particularly among MSM populations in urban centers.

Clinical Pearls

Seroconversion Illness - "The Great Mimic": Acute HIV infection presents 2-6 weeks after exposure in 40-90% of cases with a mononucleosis-like syndrome featuring fever (80%), pharyngitis (50-70%), rash (40-80%), lymphadenopathy (40-70%), myalgia/arthralgia (50-70%), and less commonly meningoencephalitis or oral ulceration. [10] Critical Pearl: Always test for HIV in young adults presenting with "glandular fever" who have negative heterophile antibody testing (Monospot). The viral load during acute infection can exceed 10⁶ copies/mL, making this the period of highest transmission risk.

Indicator Conditions for HIV Testing: Be alert to clinical presentations that warrant routine HIV testing regardless of perceived risk:

• Dermatological: Seborrhoeic dermatitis (severe/sudden onset), oral hairy leukoplakia (white corrugated lesions on lateral tongue borders - pathognomonic for immunodeficiency), recurrent or multidermatomal herpes zoster in adults less than 50 years
• Haematological: Unexplained thrombocytopenia, leucopenia, or lymphopenia
• Neurological: Aseptic meningitis, peripheral neuropathy, dementia in young adults
• Constitutional: Persistent generalized lymphadenopathy (> 1cm nodes in ≥2 non-contiguous sites for > 3 months), unexplained weight loss > 10%, persistent pyrexia > 38°C for > 3 weeks

IRIS (Immune Reconstitution Inflammatory Syndrome): A paradoxical clinical deterioration occurring in 10-25% of patients within weeks to months of initiating ART, caused by restoration of pathogen-specific immune responses. [11] Most commonly seen with TB, cryptococcal meningitis, CMV, and hepatitis B. Critical Management Pearl: In TB-HIV co-infection with CD4 less than 50, delay ART initiation for 2-8 weeks after starting TB treatment to reduce IRIS risk, EXCEPT in TB meningitis where earlier ART (after 2 weeks) may improve survival despite IRIS risk. [12]

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2. Epidemiology

Global Burden

UK Epidemiology

Prevalence: Estimated 105,200 people living with HIV (2021), with 94% diagnosed and 98% of those diagnosed on treatment. [9] The proportion achieving viral suppression is 97%, meeting UNAIDS 95-95-95 targets.

New Diagnoses: Declined from peak of 7,800 (2005) to approximately 4,000 annually (2021), representing a 48% reduction. [9] Most dramatic decline among MSM in London (-71% since 2014), attributed to combination prevention strategies including widespread PrEP uptake.

Transmission Categories (UK):

• MSM: 45% of new diagnoses
• Heterosexual contact: 49% (majority acquired abroad, particularly sub-Saharan Africa)
• People who inject drugs (PWID): less than 2%
• Mother-to-child transmission: less than 0.5% (due to universal antenatal screening and effective interventions)
• Blood products: Negligible since universal donor screening (1985)

Late Diagnosis: Remains problematic at 42% of new diagnoses (CD4 less than 350 cells/μL at diagnosis), higher among heterosexual men (54%) and older adults (> 50 years: 60%). [7] Late diagnosis accounts for the majority of HIV-related morbidity and mortality in the UK.

Risk Factors

Behavioral Risk Factors:

• Condomless anal intercourse (highest per-act risk: receptive 1.38%, insertive 0.11%) [13]
• Condomless vaginal intercourse (receptive female 0.08%, insertive male 0.04%) [13]
• Multiple concurrent sexual partners
• Sex work involvement
• Injection drug use with shared equipment (0.63% per sharing episode) [14]
• Presence of sexually transmitted infections (2-5 fold increased transmission risk) [15]
• Ulcerative genital lesions (herpes simplex, syphilis) increase transmission 10-50 fold

Host Biological Factors:

• CCR5-Δ32 homozygosity: Natural resistance to HIV-1 infection (1% European ancestry)
• CCR5-Δ32 heterozygosity: Slower disease progression if infected
• HLA-B27, HLA-B57 alleles: Associated with slower progression (elite controllers)
• HLA-B*35 alleles: Associated with rapid progression

Healthcare-Associated Transmission (now extremely rare in developed countries):

• Needlestick injury: 0.3% average risk, higher with hollow-bore needles, deep injury, visible blood, source with high viral load [14]
• Mucous membrane exposure: 0.09% risk
• Blood transfusion: Risk less than 1 in 1.5 million in UK due to nucleic acid testing of donations

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3. Aetiology & Pathophysiology

Viral Classification

HIV is a member of the Lentivirus genus within the Retroviridae family. Two distinct species exist:

• HIV-1: Responsible for > 95% of global infections; pandemic form with multiple subtypes (clades A-D, F-H, J, K) and circulating recombinant forms. Subtype B predominates in Europe/North America, subtype C in southern Africa (50% global).
• HIV-2: Endemic to West Africa; generally less virulent with slower progression, lower viral loads, and reduced transmission efficiency. Naturally resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Viral Structure

HIV is an enveloped, spherical virus approximately 120nm in diameter containing:

• Envelope: Lipid bilayer derived from host cell membrane with embedded viral glycoproteins (gp120 surface protein, gp41 transmembrane protein)
• Matrix: p17 protein layer beneath envelope
• Core (Capsid): p24 protein shell containing two copies of single-stranded RNA genome (9.7kb) plus essential enzymes:
  • "Reverse transcriptase (RT): RNA-dependent DNA polymerase"
  • "Integrase: Facilitates proviral DNA integration into host genome"
  • "Protease: Cleaves viral polyproteins during virion maturation"

Pathophysiology of HIV Infection

Stage 1: Viral Entry and Initial Infection

Cellular Tropism: HIV primarily targets cells expressing CD4 surface receptor:

• CD4+ T-helper lymphocytes (primary target)
• Monocytes/macrophages (viral reservoir)
• Dendritic cells (facilitate transmission and dissemination)
• Microglial cells in CNS

Entry Mechanism (multi-step process):

1. Attachment: Viral envelope gp120 binds with high affinity to CD4 receptor on target cell
2. Co-receptor binding: Conformational change in gp120 exposes binding site for chemokine co-receptors:
   • CCR5 (β-chemokine receptor): Used by R5-tropic (macrophage-tropic) strains predominant in early infection and transmission
   • CXCR4 (α-chemokine receptor): Used by X4-tropic (T-cell-tropic) strains, emergence associated with disease progression
3. Fusion: gp41 undergoes conformational change forming fusion peptide that inserts into cell membrane, bringing viral and cellular membranes into contact
4. Viral core release: Capsid and contents released into cytoplasm

Stage 2: Reverse Transcription and Integration

5. Reverse Transcription: Viral RNA genome converted to double-stranded DNA by reverse transcriptase in cytoplasm

   • Error-prone enzyme (lacks 3' to 5' exonuclease proofreading): ~1 error per genome per replication cycle
   • Generates viral genetic diversity: ~10¹⁰ virions produced daily with substantial sequence variation
   • Foundation for rapid drug resistance emergence

6. Nuclear Import: Viral DNA (pre-integration complex) transported into nucleus via nuclear pores

7. Integration: Integrase enzyme catalyzes insertion of viral DNA (provirus) into host chromosomal DNA at semi-random sites

   • Once integrated, provirus persists for the life of the cell
   • Latently infected resting CD4+ T cells form long-lived viral reservoir (major barrier to cure)

Stage 3: Viral Replication and Dissemination

8. Transcription: Host cellular machinery transcribes proviral DNA to viral mRNA
9. Translation: Viral proteins synthesized as polyproteins requiring protease cleavage
10. Assembly: New virions assembled at cell membrane
11. Budding: Immature virions bud from cell surface, acquiring envelope
12. Maturation: Protease cleaves polyproteins producing mature infectious virion

Acute Infection Dynamics:

• Explosive viral replication in first weeks: plasma viremia can exceed 10⁶-10⁷ copies/mL
• Systemic dissemination via blood and lymphatics
• Massive CD4+ T-cell depletion in gut-associated lymphoid tissue (GALT) - irreversible damage occurring within days to weeks [16]
• Viral set-point established after 3-6 months (balance between viral replication and immune control)
• Higher viral set-point predicts more rapid progression to AIDS

Stage 4: Chronic Infection and Immunodeficiency

Mechanisms of CD4+ T-cell Depletion:

• Direct cytopathic effect: Viral replication kills infected cells
• Syncytium formation: Fusion of infected cells with uninfected CD4+ cells via gp120/CD4 interaction
• Apoptosis: Increased programmed cell death in infected and uninfected bystander cells
• Immune-mediated destruction: Cytotoxic T-lymphocyte killing of infected cells
• Impaired thymic regeneration: Reduced production of new CD4+ T cells

Progressive Immune Dysfunction:

• CD4+ T-helper cell depletion: Loss of orchestration of both cellular and humoral immunity
• Immune activation and inflammation: Chronic immune activation ("inflammaging") drives disease progression and non-AIDS comorbidities [17]
• Loss of immune surveillance: Increased susceptibility to opportunistic pathogens and malignancies
• Mucosal barrier dysfunction: Microbial translocation from damaged gut mucosa perpetuates immune activation

Natural History Without Treatment:

• CD4+ count declines approximately 50-100 cells/μL/year (highly variable between individuals)
• Median time from infection to AIDS: 8-10 years (range 2-15 years)
• Median survival after AIDS diagnosis (pre-ART era): 2-3 years
• Rapid progressors (5-10%): Progress to AIDS within 2-3 years
• Typical progressors (80-90%): Progress over 8-12 years
• Long-term non-progressors (5%): Stable CD4 counts for > 10 years without treatment
• Elite controllers (less than 1%): Maintain undetectable viral load without treatment (unique HLA types, effective CTL responses)

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4. Clinical Presentation

Classification of HIV Infection Stages

Stage 1: Acute HIV Infection (Seroconversion)

Timeline: 2-6 weeks post-exposure (range 1-8 weeks)

Presentation: Symptomatic in 40-90% of cases, often non-specific and frequently unrecognized. [10]

Common Features:

• Fever (80%): Typically 38-40°C, persistent for 1-2 weeks
• Pharyngitis (50-70%): Non-exudative, resembles viral pharyngitis
• Rash (40-80%): Maculopapular, erythematous, affecting trunk and face; may involve palms/soles
• Lymphadenopathy (40-70%): Generalized, symmetrical, non-tender
• Myalgia/Arthralgia (50-70%)
• Headache (30-60%): May indicate aseptic meningitis

Less Common but Important Features:

• Mucocutaneous ulceration (10-20%): Oral, genital, or esophageal ulcers
• Neurological (10-15%): Aseptic meningitis, encephalitis, peripheral neuropathy, Guillain-Barré syndrome
• Gastrointestinal (20-40%): Nausea, vomiting, diarrhea

Laboratory Features:

• Very high plasma viral load: Often > 100,000 copies/mL (> 1 million not uncommon)
• p24 antigen: Positive before antibody seroconversion
• HIV antibody: Initially negative, becomes positive after 2-8 weeks (seroconversion)
• CD4+ count: Transient profound drop (may fall to less than 200), then partial recovery
• Transient lymphopenia: Followed by lymphocytosis with atypical lymphocytes

Clinical Importance:

• Period of highest infectivity due to extremely high viral load
• Early diagnosis enables immediate ART initiation with maximal benefit
• Most cases missed due to non-specific presentation

Stage 2: Chronic Asymptomatic HIV Infection (Clinical Latency)

Duration: Highly variable, 2-15 years (median 8-10 years without treatment)

Characteristics:

• Generally asymptomatic with normal daily functioning
• Persistent generalized lymphadenopathy (PGL) may be present: nodes > 1cm at ≥2 non-contiguous sites for > 3 months
• Progressive CD4+ count decline (average 50-100 cells/μL/year)
• Ongoing viral replication despite clinical quiescence

Clinical Significance:

• "Silent" disease progression occurring
• Many individuals unaware of infection status
• Period when most transmission occurs (undiagnosed individuals)

Stage 3: Symptomatic HIV Infection (CD4 less than 500 cells/μL)

Early Symptomatic Features (CD4 350-500):

• Oral hairy leukoplakia: White, corrugated, painless lesions on lateral tongue borders (EBV-driven, pathognomonic for immunodeficiency)
• Recurrent vaginal candidiasis: > 2 episodes/year
• Herpes zoster (shingles): Single dermatomal distribution; recurrent episodes suspicious
• Seborrhoeic dermatitis: Severe or sudden onset
• Oral candidiasis (thrush): Recurrent, may extend to esophagus

Moderate Symptomatic Features (CD4 200-350):

• Oral/oesophageal candidiasis: More persistent, symptomatic
• Multidermatomal herpes zoster
• Bacterial infections: Increased frequency of sinusitis, bronchitis, pneumonia
• Cervical dysplasia: Higher grade CIN lesions (HPV-related)
• Constitutional symptoms: Low-grade fever, night sweats, unintentional weight loss (less than 10%)

Stage 4: AIDS (CD4 less than 200 cells/μL or AIDS-Defining Illness)

Definition (CDC 1993 Revised Classification):

• CD4+ count less than 200 cells/μL, OR
• CD4+ percentage less than 14%, OR
• Occurrence of an AIDS-defining opportunistic infection or malignancy (regardless of CD4 count)

AIDS-Defining Opportunistic Infections

CD4 less than 200 cells/μL

Pneumocystis jirovecii Pneumonia (PCP) - Most common AIDS-defining illness in UK

• Presentation: Subacute (weeks) progressive exertional dyspnea, dry cough, fever
• Key examination finding: Desaturation on exertion ("walk test"
• oxygen saturation drops ≥4% with exercise)
• Chest X-ray: Bilateral perihilar interstitial infiltrates ("bat-wing"); may be normal in early disease (10-20%)
• High-resolution CT: Ground-glass opacification
• Laboratory: Markedly elevated LDH (> 500 U/L highly suggestive), hypoxemia, respiratory alkalosis
• Diagnosis: Bronchoalveolar lavage with immunofluorescence or PCR
• Treatment: High-dose co-trimoxazole 120mg/kg/day IV in 4 divided doses for 21 days; prednisolone if PaO₂ less than 9.3kPa

Toxoplasma gondii Encephalitis

• Presentation: Subacute headache, confusion, focal neurological deficits, seizures
• Risk factor: Toxoplasma IgG positive (latent infection reactivation)
• Imaging: Multiple ring-enhancing lesions with surrounding edema, predilection for basal ganglia
• Treatment: Empirical treatment initiated if typical presentation (response expected in 7-14 days)
  • Sulfadiazine + pyrimethamine + folinic acid for 6 weeks
  • If no response, brain biopsy to exclude primary CNS lymphoma

CD4 less than 100 cells/μL

Cryptococcus neoformans Meningitis

• Presentation: Subacute/chronic headache (often for weeks), fever, altered mental status, minimal meningism
• Key feature: Elevated opening pressure (> 25 cm H₂O in 70%) - may cause visual loss if untreated
• CSF: Lymphocytic pleocytosis (may be minimal if profound immunosuppression), elevated protein, low glucose
• Diagnosis: India ink stain (positive in 70%), cryptococcal antigen (CrAg) - sensitivity > 95% in CSF and serum
• Treatment: Induction (amphotericin B + flucytosine 2 weeks) → consolidation (fluconazole 8 weeks) → maintenance
• Critical management: Serial lumbar punctures if elevated opening pressure (prevent blindness)

Cytomegalovirus (CMV) Disease

• CMV Retinitis: Most common manifestation
  • Painless progressive visual loss (floaters, scotomas, visual field defects)
  • Fundoscopy: "Pizza pie" or "cottage cheese and ketchup" appearance - areas of retinal necrosis with hemorrhage
  • Ophthalmology emergency (risk of retinal detachment)
  • "Treatment: Ganciclovir or foscarnet (IV induction then maintenance)"
• CMV Colitis: Bloody diarrhea, abdominal pain
• CMV Esophagitis: Odynophagia, dysphagia
• CMV Encephalitis: Ventriculoencephalitis with rapid cognitive decline

Mycobacterium avium Complex (MAC)

• Presentation: Chronic wasting illness - fever, night sweats, profound weight loss, chronic diarrhea, hepatosplenomegaly
• Laboratory: Anemia, elevated alkaline phosphatase
• Diagnosis: Blood cultures (mycobacterial isolator), bone marrow biopsy
• Treatment: Combination therapy (clarithromycin/azithromycin + ethambutol + rifabutin)

CD4 less than 50 cells/μL

Progressive Multifocal Leukoencephalopathy (PML)

• Cause: JC virus (polyomavirus) reactivation causing oligodendrocyte destruction
• Presentation: Progressive focal neurological deficits (hemiparesis, visual field defects, ataxia, cognitive decline) over weeks to months
• MRI: Multiple asymmetric white matter lesions without mass effect or enhancement
• Diagnosis: JC virus PCR in CSF (sensitivity 70-90%)
• Treatment: No specific antiviral therapy; ART initiation with immune restoration is mainstay (though may cause IRIS)

AIDS-Defining Malignancies

Kaposi Sarcoma (HHV-8/KSHV-related)

• Violaceous/purple cutaneous nodules or plaques, often on lower extremities, face, oral mucosa
• May involve visceral organs (lungs, GI tract)
• Responds to ART with immune restoration; chemotherapy if extensive/symptomatic disease

Non-Hodgkin Lymphoma

• EBV-associated in most cases
• High-grade B-cell lymphomas (Burkitt, diffuse large B-cell, primary CNS lymphoma)
• Extranodal sites common (CNS, GI tract, bone marrow)

Cervical Cancer (Invasive)

• HPV-driven; increased incidence and more aggressive course in HIV
• Screening essential for women living with HIV

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5. Differential Diagnosis

Acute HIV (Seroconversion Syndrome)

Critical Point: HIV testing should be performed in any patient presenting with mononucleosis-like syndrome and negative heterophile antibody (Monospot negative), particularly if risk factors present or atypical features.

Chronic HIV (Established Infection)

When Considering Diagnosis in Previously Undiagnosed Individuals:

Presentations warranting HIV testing (BHIVA/NICE Indicator Conditions):

1. Respiratory: PCP, bacterial pneumonia (recurrent), TB (pulmonary or extrapulmonary)
2. Neurological: Aseptic meningitis, cerebral toxoplasmosis, PML, cryptococcal meningitis, primary CNS lymphoma
3. Dermatological: Severe/recurrent seborrhoeic dermatitis, Kaposi sarcoma, oral hairy leukoplakia
4. Gastrointestinal: Oral candidiasis, chronic diarrhea (cryptosporidiosis, microsporidiosis), unexplained weight loss
5. Haematological: Any unexplained blood dyscrasia (thrombocytopenia, leucopenia, lymphopenia)
6. Malignancy: Non-Hodgkin lymphoma, Kaposi sarcoma, cervical/anal cancer
7. Constitutional: Pyrexia of unknown origin, lymphadenopathy (persistent generalized)

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6. Investigations

Initial Diagnostic Testing

Screening Tests

Fourth-Generation HIV Antibody/Antigen Test (Standard in UK/developed countries)

• Components:
  • HIV-1 and HIV-2 antibodies (IgG and IgM)
  • HIV-1 p24 antigen
• Window Period: 45 days for conclusive result
  • Detects > 95% of infections at 4 weeks post-exposure

  • 99% sensitivity at 6 weeks post-exposure

  • Definitive at 12 weeks (current UK testing guidelines)
• Advantages: Reduces window period by 1-2 weeks compared to antibody-only tests by detecting p24 antigen before seroconversion
• Laboratory method: Enzyme immunoassay (EIA) or chemiluminescent immunoassay (CLIA)

Point-of-Care Rapid Tests

• Technology: Lateral flow immunoassay detecting HIV antibodies (usually antibody-only, some 4th generation)
• Sample: Fingerstick blood, oral fluid
• Turnaround: 15-30 minutes
• Sensitivity/Specificity: > 99% when used correctly
• Window Period: Longer than laboratory 4th generation tests (90 days recommended)
• Use: Emergency departments, sexual health clinics, community testing
• Limitations: Requires confirmatory laboratory testing if positive

Confirmatory Testing

If Screening Test Positive:

1. Confirmatory Test: HIV-1/HIV-2 antibody differentiation immunoassay
2. Supplementary Test: HIV-1 Western blot or line immunoassay (if differentiation unclear)
3. HIV RNA PCR (viral load): Confirms active infection, quantifies viral burden

Special Scenarios:

Acute HIV (Suspected Seroconversion):

• 4th generation Ag/Ab test may be negative in very early infection
• HIV RNA PCR (viral load): Detectable from ~10 days post-infection
• High viral load (> 100,000 copies/mL) with negative/weakly positive antibody test indicates acute infection
• Repeat antibody test 2-4 weeks later to confirm seroconversion

HIV-2 Testing: Consider in individuals from West Africa; HIV-2 infection may cross-react on HIV-1 tests but has distinct treatment implications (natural NNRTI resistance)

Baseline Investigations After HIV Diagnosis

Mandatory Baseline Tests (BHIVA Guidelines):

Additional Baseline Screening:

• Tuberculosis screening: Symptom screen, chest X-ray, consider QuantiFERON/T-SPOT (especially if from endemic areas or CD4 less than 350)
• Sexually transmitted infection screen: Comprehensive STI testing (gonorrhea, chlamydia, mycoplasma genitalium)
• Varicella zoster virus (VZV) serology: If no history of chickenpox (vaccination if seronegative)
• Measles/mumps/rubella serology: Assess immunity (vaccination if seronegative and CD4 > 200)
• Cardiovascular risk assessment: Framingham or QRISK score
• Mental health and substance use screening: Depression, anxiety, alcohol, recreational drug use

Monitoring Investigations on ART

Routine Monitoring:

Virological Failure:

• Defined as: Confirmed viral load > 200 copies/mL after initial suppression, OR failure to suppress less than 50 copies/mL after 24 weeks on ART
• Requires: Intensive adherence assessment, genotypic resistance testing (if viral load > 500 copies/mL), consideration of pharmacokinetic drug levels

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7. Classification and Staging

CDC Classification System (1993 Revised)

Combines clinical categories (A, B, C) with CD4+ T-cell counts:

Category A: Asymptomatic HIV, persistent generalized lymphadenopathy (PGL), acute HIV infection with symptoms

Category B (Examples): Oral/vulvovaginal candidiasis, cervical dysplasia/carcinoma in situ, constitutional symptoms, oral hairy leukoplakia, herpes zoster (multidermatomal), peripheral neuropathy

Category C: AIDS-defining conditions (see Clinical Presentation section)

Note: Once a person has reached Category C (AIDS diagnosis), they remain classified as having AIDS regardless of subsequent CD4+ recovery.

WHO Clinical Staging (2007)

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8. Management

Fundamental Principles

Modern HIV Management Paradigm:

1. Test and Treat: ART recommended for ALL individuals living with HIV, regardless of CD4 count [18]
2. Treat as Prevention: Effective ART prevents sexual transmission (U=U concept) [5,6]
3. Early Initiation: ART should be offered as soon as possible after diagnosis, ideally within days to weeks [19]
4. Single-Tablet Regimens: Preferred for convenience and adherence
5. Lifelong Treatment: ART must be continued indefinitely (no cure currently available)
6. Multidisciplinary Care: Integration of infectious diseases, pharmacy, mental health, social support

Antiretroviral Therapy (ART)

Standard First-Line ART Regimens (BHIVA/EACS 2023)

Preferred Regimens (evidence-based, high barrier to resistance, favorable tolerability):

Integrase Strand Transfer Inhibitor (INSTI)-Based Regimens - Current standard of care

Components of ART:

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) - "Backbone"

• Tenofovir: TAF (tenofovir alafenamide - preferred, less renal/bone toxicity) or TDF (tenofovir disoproxil fumarate - generic available)
• Emtricitabine (FTC) or Lamivudine (3TC): Typically combined with tenofovir
• Abacavir (ABC): Alternative to tenofovir; requires HLA-B*5701 screening (hypersensitivity risk)

Integrase Strand Transfer Inhibitors (INSTIs) - "Anchor" (current preferred class)

• Bictegravir: High barrier to resistance, once daily, well-tolerated, minimal drug interactions
• Dolutegravir: High barrier to resistance, once daily, extensive real-world data, generic available
• Raltegravir: Twice daily dosing (less convenient); still used in special situations (e.g., pregnancy)

Alternative Anchor Agents:

• Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Efavirenz, rilpivirine, doravirine (less commonly used first-line due to lower barrier to resistance and more drug interactions)
• Protease Inhibitors (PIs): Darunavir/ritonavir, atazanavir/ritonavir (reserved for specific situations; higher pill burden, more drug interactions, metabolic side effects)

ART Initiation Timing

Standard Patients: Within 2 weeks of diagnosis [19]

• Allows time for education, psychosocial assessment, baseline investigations
• Exceptions: May start same-day if patient motivated and clinically appropriate

Specific Scenarios:

Special Considerations by Opportunistic Infection:

• Tuberculosis:

  • "CD4 > 50: Start TB treatment, then ART after 2-8 weeks"
  • "CD4 less than 50: Start TB treatment, then ART within 2 weeks [12]"
  • "TB meningitis: More complex; consider delaying ART 4-6 weeks to reduce severe IRIS risk (though some evidence for earlier initiation)"

• Cryptococcal meningitis: Complete induction antifungal therapy (2 weeks), defer ART for 4-6 weeks due to high IRIS risk and mortality [21]

• Other OIs: Generally start ART within 2 weeks once OI treatment initiated and patient stable

Monitoring ART Response

Virological Response:

• Expected trajectory:
  • 1 log₁₀ (90%) reduction in viral load by 4 weeks
  • Viral load less than 50 copies/mL by 12-24 weeks (85-90% of patients)
  • "If not suppressed by 24 weeks: Virological failure - assess adherence and resistance"

Immunological Response:

• CD4+ count typically increases 50-100 cells/μL in first year, then 50-100 cells/μL annually
• Greater increases if starting CD4 count is lower
• Discordant responses (virological suppression but poor CD4 recovery) occur in ~10-20%; management controversial

Treatment Failure:

• Virological failure: Confirmed viral load > 200 copies/mL
• Immunological failure: Persistent CD4 less than 100 or fall to pre-treatment baseline despite virological suppression
• Clinical failure: New/recurrent WHO stage 4 events despite ART

Management of Virological Failure:

1. Confirm adherence (primary cause of failure)
2. Genotypic resistance testing (if viral load > 500 copies/mL)
3. Consider therapeutic drug monitoring
4. Switch to fully suppressive regimen based on resistance profile

Opportunistic Infection Prophylaxis

Primary Prophylaxis (prevent first occurrence):

Alternative agents:

• PCP: Dapsone 100mg daily, atovaquone 1500mg daily, inhaled pentamidine 300mg monthly (if co-trimoxazole intolerant)
• Toxoplasmosis: Dapsone + pyrimethamine + folinic acid
• MAC: Clarithromycin 500mg twice daily, rifabutin 300mg daily

Secondary Prophylaxis (prevent recurrence after treatment):

• Required for all AIDS-defining OIs after successful treatment
• Can discontinue when CD4 > 200 cells/μL for > 3 months on suppressive ART (varies by OI)
• Exception: Cryptococcal meningitis requires longer duration (CD4 > 100-200, minimum 12 months treatment)

Prevention Strategies

Pre-Exposure Prophylaxis (PrEP)

Indications (BHIVA/BASHH Guidelines):

• HIV-negative individuals at substantial ongoing HIV risk:
  • MSM with condomless anal intercourse
  • Serodiscordant couples (HIV-positive partner not virally suppressed)
  • People who inject drugs sharing equipment
  • Sex workers
  • Anyone with recent bacterial STI or repeated use of PEP

Regimens:

• Daily PrEP: Tenofovir DF/emtricitabine 300/200mg once daily (most common in UK)
  • "Protective levels: 7 days for rectal exposure, 21 days for vaginal exposure"
• Event-driven PrEP (ED-PrEP): For MSM with infrequent exposure
  • 2 tablets 2-24 hours before sex, 1 tablet 24h after first dose, 1 tablet 48h after first dose ("2-1-1")
• Cabotegravir long-acting injectable: 600mg IM every 2 months (superior efficacy to TDF/FTC, approved but limited UK availability)

Efficacy: > 99% reduction in HIV acquisition when adherent [22]

Monitoring:

• HIV test, STI screening, renal function: baseline, 1 month, then every 3 months
• HBV serology at baseline (caution stopping if HBV positive - flare risk)

Post-Exposure Prophylaxis (PEP)

Indications: Significant HIV exposure within previous 72 hours (the sooner the better)

• Receptive/insertive anal intercourse with known HIV-positive source not on ART or unknown status
• Receptive vaginal intercourse with known positive source
• Needlestick injury with HIV-positive source
• Sharing injecting equipment
• Human bites with blood exposure

Regimen (BASHH 2021):

• Preferred: Tenofovir DF/emtricitabine + raltegravir for 28 days
• Alternative: Tenofovir DF/emtricitabine + dolutegravir
• Ideally start within 1 hour (certainly within 72 hours; negligible benefit after)

Monitoring:

• Baseline HIV test, HBV/HCV serology, STI screen
• Follow-up HIV testing at 8-12 weeks

Efficacy: Approximately 80% reduction in HIV transmission if initiated promptly and completed [23]

Prevention of Mother-to-Child Transmission (PMTCT)

Without Intervention: 25-40% transmission risk (in utero 5-10%, intrapartum 10-20%, breastfeeding 10-20%)

With Comprehensive Intervention: less than 0.5% transmission risk in UK [24]

Key Components:

1. Universal antenatal HIV screening (offered to all pregnant women)
2. Immediate ART for pregnant women living with HIV (regardless of CD4 count)
3. Goal: Viral load less than 50 copies/mL by delivery
4. Mode of delivery:
   • Vaginal delivery safe if viral load less than 50 copies/mL at 36 weeks
   • Elective caesarean section at 38 weeks if viral load > 50 copies/mL or > 400 copies/mL
5. Intrapartum: Continue ART throughout labour; IV zidovudine if viral load > 10,000 copies/mL
6. Neonatal PEP: Zidovudine for 4 weeks if maternal viral load undetectable; combination ART if higher/unknown
7. Infant feeding: Formula feeding recommended in UK (breastfeeding carries residual transmission risk even if mother suppressed)
8. Infant testing: HIV antibody testing at 18 months (maternal antibodies clear by this time); HIV RNA PCR at 1 and 3 months of age

Management of Complications

Immune Reconstitution Inflammatory Syndrome (IRIS)

• Pathophysiology: Excessive inflammatory response to antigens (pathogenic or self) as immune function recovers on ART
• Risk factors: Very low baseline CD4 (less than 50), high baseline viral load, rapid CD4 recovery, early ART initiation relative to OI diagnosis
• Common presentations: TB IRIS (lymph node enlargement, new infiltrates), cryptococcal IRIS, CMV IRIS
• Management: Continue ART in most cases; NSAIDs/corticosteroids for severe inflammation; treat/optimize OI therapy; rarely need to interrupt ART temporarily

Drug-Induced Hypersensitivity

• Abacavir hypersensitivity: 5-8% in HLA-B*5701 positive individuals
  • "Presents within 6 weeks: fever, rash, GI symptoms, malaise"
  • Never rechallenge (can be fatal)
  • Prevented by universal HLA-B*5701 screening before use

Lipodystrophy and Metabolic Complications

• Lipoatrophy (peripheral fat loss): Primarily older NRTIs (stavudine, zidovudine - rarely used now)
• Lipohypertrophy (central fat accumulation): Associated with some PIs and INSTIs
• Dyslipidemia: Elevated cholesterol/triglycerides (some PIs, older NNRTIs)
• Insulin resistance: More common in PLWH even on modern ART
• Management: Switch ART regimen if implicated; statins for dyslipidemia; lifestyle modification; emerging treatments (tesamorelin for visceral adiposity)

Cardiovascular Disease

• Increased risk in PLWH (1.5-2 fold) due to chronic inflammation, traditional risk factors, some ART agents
• Aggressive cardiovascular risk factor modification essential
• Statin therapy (check interactions with ART - avoid simvastatin with PIs)

Renal Disease

• HIV-associated nephropathy (HIVAN): Collapsing focal segmental glomerulosclerosis; more common in African ancestry; treated with ART
• TDF-associated renal toxicity: Proximal tubular dysfunction, Fanconi syndrome; monitor renal function; switch to TAF if eGFR declining
• Chronic kidney disease: More common; multifactorial

Bone Disease

• Osteopenia/osteoporosis: 3-fold increased prevalence
• Fracture risk increased
• Screen with DEXA if > 50 years or risk factors
• Optimize vitamin D, calcium; bisphosphonates if indicated; switch from TDF to TAF reduces bone loss

Neurological Complications

• HIV-associated neurocognitive disorder (HAND): Spectrum from asymptomatic impairment to dementia (rare with modern ART)
• Peripheral neuropathy: Multifactorial (HIV, older ART, vitamin deficiencies)
• CNS opportunistic infections: See earlier sections

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9. Prognosis and Outcomes

Life Expectancy

Modern Era (Effective ART):

• Individual diagnosed at age 20 with prompt ART initiation and viral suppression: Life expectancy approaches general population (near-normal) [3,4]
• CD4 > 350 at ART initiation: Expected additional 46-51 years of life (comparable to HIV-negative)
• Late diagnosis (CD4 less than 200): Reduced but still substantial life expectancy (approximately 80% of HIV-negative comparator)

Key Determinants of Outcomes:

1. CD4 count at ART initiation: Single most important prognostic factor
   • Starting ART at CD4 > 500: Best outcomes [18]
   • Starting ART at CD4 less than 200: 10-fold increased 1-year mortality vs. early starters
2. Viral suppression: Achieving and maintaining undetectable viral load
3. Adherence: > 95% adherence associated with optimal outcomes
4. Comorbidities: Management of cardiovascular disease, diabetes, liver disease, malignancies
5. Late diagnosis: Remains major challenge (40% of UK diagnoses); accounts for majority of HIV-related mortality

Causes of Mortality in ART Era

Early After Diagnosis (first year, especially if late diagnosis):

• AIDS-defining opportunistic infections (40-50%)
• Non-AIDS-defining infections (bacterial pneumonia, sepsis)
• Malignancies

Long-term (Established on ART):

• Non-AIDS-defining conditions now predominate (> 70% of deaths):
  • Cardiovascular disease (myocardial infarction, stroke)
  • Non-AIDS malignancies (lung, liver, anal, Hodgkin lymphoma)
  • Liver disease (especially HBV/HCV co-infection, alcohol, NASH)
  • Renal disease
  • Chronic obstructive pulmonary disease
• AIDS-defining illnesses: less than 25% of deaths (primarily in poorly adherent/undiagnosed individuals)

Viral Suppression and Transmission

U=U (Undetectable = Untransmittable): Landmark concept established by PARTNER studies [5,6]

• Individuals with sustained viral suppression on ART (less than 200 copies/mL) do not sexually transmit HIV to partners
• PARTNER 1 and 2 studies: Zero transmissions among serodiscordant couples over 76,000 condomless sex acts
• Applies to vaginal and anal intercourse
• Requires: Sustained viral suppression (> 6 months), adherence to ART, regular monitoring

Public Health Impact: Revolutionized HIV prevention

• "Treatment as Prevention" (TasP): ART as potent prevention tool
• HPTN 052 trial: 96% reduction in transmission when HIV-positive partner on ART [25]
• Underpins global "95-95-95" targets (95% diagnosed, 95% on ART, 95% virally suppressed)

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10. Evidence and Guidelines

Key Guidelines

Landmark Evidence

1. START Trial (Strategic Timing of Antiretroviral Treatment) [18]

• Design: Randomized controlled trial, 4685 participants
• Question: Immediate ART (CD4 > 500) vs. deferred (CD4 less than 350 or AIDS)
• Results: Immediate ART reduced AIDS events by 72% and serious non-AIDS events by 39%
• Impact: Paradigm shift to "test and treat"
• ART recommended for all HIV-positive individuals regardless of CD4 count

2. PARTNER Studies (PARTNER 1 and 2) [5,6]

• Design: Prospective observational studies of serodiscordant couples (one partner HIV-positive on ART with viral suppression)
• Results: Zero phylogenetically-linked transmissions over 76,000 condomless sex acts in couples with sustained viral suppression
• Impact: Established U=U concept; profound effect on stigma reduction and prevention strategies

3. HPTN 052 (Treatment as Prevention) [25]

• Design: RCT in serodiscordant couples, early vs. delayed ART
• Results: 96% reduction in HIV transmission to seronegative partner with early ART
• Impact: Demonstrated ART as powerful prevention tool; underpins "treatment as prevention" approach

4. TEMPRANO Trial [19]

• Design: RCT in Côte d'Ivoire, immediate ART vs. WHO criteria-based initiation
• Results: Early ART reduced severe illness or death by 44%
• Impact: Supported early ART initiation in resource-limited, high-TB-burden settings

5. iPrEx Study (PrEP Efficacy) [22]

• Design: RCT of daily TDF/FTC vs. placebo in MSM and transgender women
• Results: 44% reduction in HIV acquisition (intent-to-treat); 92% reduction among those with detectable drug levels
• Impact: First proof of concept for PrEP; led to widespread implementation

6. DISCOVER Trial [26]

• Design: Non-inferiority RCT comparing TAF/FTC vs. TDF/FTC for PrEP in MSM and transgender women
• Results: TAF/FTC non-inferior for HIV prevention with improved bone and renal safety markers
• Impact: Expanded PrEP options with potentially safer long-term profile

7. PROMISE Trial (PMTCT) [24]

• Design: Series of RCTs evaluating ART regimens for PMTCT
• Results: Demonstrated safety and efficacy of maternal ART throughout pregnancy; transmission rates less than 1% achievable
• Impact: Refined PMTCT strategies; supported current policies for universal ART in pregnancy

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11. Special Populations

Pregnancy and HIV

Management Principles:

• ART should be started or continued throughout pregnancy
• Goal: Viral load less than 50 copies/mL by delivery
• Preferred regimens: Regimens with most data in pregnancy (raltegravir-based, atazanavir/ritonavir-based, or dolutegravir-based - data increasingly support dolutegravir safety)
• Avoid efavirenz in first trimester (historical neural tube defect concerns, though recent data reassuring)
• Transmission risk with viral load less than 50 copies/mL: less than 0.1%

Older Adults (> 50 years)

• Increasing proportion of PLWH (> 50% in developed countries)
• Age-related comorbidities occur earlier and with higher frequency
• Polypharmacy concerns - drug-drug interactions
• Importance of cardiovascular risk management, cancer screening, cognitive assessment
• Frailty assessment and falls prevention

Co-infections

HIV/HBV Co-infection (5-10% prevalence):

• Select ART regimen with anti-HBV activity: Tenofovir + emtricitabine or lamivudine
• Monitor HBV DNA and liver function
• Risk of HBV flare if anti-HBV agents stopped

HIV/HCV Co-infection (30-50% in PWID):

• Accelerated HCV-related liver disease progression
• Direct-acting antivirals (DAAs) highly effective; check drug interactions with ART
• HCV cure achievable in > 95%

HIV/TB Co-infection:

• TB is leading cause of death in PLWH globally
• Complex drug interactions (rifampicin induces metabolism of PIs and some INSTIs)
• Preferred regimens: Dolutegravir (dose increase may be needed with rifampicin), efavirenz, raltegravir (dose increase)
• Avoid rifampicin with most PIs (rifabutin alternative)
• IRIS risk high (see Management section)

Adolescents and Young Adults

• Transition from pediatric to adult services challenging
• Adherence concerns (neurodevelopmental, psychosocial factors)
• Perinatally-infected individuals: May harbor drug resistance from maternal/infant regimens
• Sexual health counseling, pregnancy prevention, disclosure support essential

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12. Patient and Layperson Explanation

What is HIV?

HIV stands for Human Immunodeficiency Virus. It is a virus that attacks your body's immune system, specifically cells called CD4 cells (also called T-helper cells). These cells coordinate your immune system's response to infections and diseases. Over time, if untreated, HIV destroys so many CD4 cells that your body becomes unable to fight off infections and certain cancers. This advanced stage of HIV infection is called AIDS (Acquired Immunodeficiency Syndrome).

How is HIV Transmitted?

HIV is passed from person to person through specific body fluids:

• Blood
• Semen and vaginal fluids
• Breast milk

Common ways HIV is transmitted:

• Unprotected sexual intercourse (anal or vaginal) with someone who has HIV
• Sharing needles or syringes with someone who has HIV
• From mother to baby during pregnancy, childbirth, or breastfeeding (if mother is not on treatment)

HIV is NOT transmitted by:

• Kissing, hugging, or casual contact
• Sharing food, drinks, or utensils
• Toilet seats, swimming pools
• Mosquitoes or other insects

The Good News: HIV is Treatable

Although we cannot yet fully "cure" HIV (remove it completely from the body), we have excellent medications called antiretroviral therapy (ART) that control the virus very effectively. With treatment:

You can live a normal lifespan: People diagnosed with HIV today who take their medication as prescribed can expect to live as long as people without HIV.

The virus becomes "undetectable": After taking ART for 3-6 months, the amount of virus in your blood typically becomes so low that standard tests cannot detect it. This is called having an "undetectable viral load."

Undetectable = Untransmittable (U=U): When your viral load is undetectable and stays that way, you cannot pass HIV to sexual partners. This has been proven through large scientific studies with thousands of couples where one partner had HIV and the other didn't - there were zero transmissions when the HIV-positive partner had an undetectable viral load.

What Does Treatment Involve?

• Daily medication: Usually one or two tablets taken once daily
• Regular check-ups: Blood tests every 3-6 months to ensure the medication is working
• Near-normal life: You can work, exercise, have relationships, and have healthy children (who will not have HIV if you are on treatment)

Can HIV Be Prevented?

Yes, several highly effective prevention methods exist:

PrEP (Pre-Exposure Prophylaxis): A daily pill for people who don't have HIV but are at risk. It reduces the risk of getting HIV from sex by more than 99% when taken as prescribed.

Condoms: Highly effective at preventing HIV and other sexually transmitted infections when used correctly.

Not sharing needles: If you inject drugs, never share needles or other equipment.

Treatment during pregnancy: With proper treatment, mothers living with HIV can have healthy babies without HIV (transmission risk less than 0.5% with treatment).

What Happens Without Treatment?

Without treatment, HIV gradually weakens the immune system over many years (average 8-10 years). Eventually, the immune system becomes so damaged that the body cannot fight off infections that healthy immune systems would normally control (called "opportunistic infections"). This stage is called AIDS. With modern treatment started early, progression to AIDS is preventable.

Living Well with HIV

• Take medication every day: This is the most important thing. Missing doses can allow the virus to multiply and develop resistance.
• Attend regular appointments: Monitoring ensures treatment is working and catches any problems early.
• Look after your overall health: Healthy diet, regular exercise, don't smoke, moderate alcohol.
• Mental health matters: Living with HIV can be challenging emotionally. Support services, counseling, and peer support groups are available.
• You are not alone: Approximately 105,000 people in the UK are living with HIV, the vast majority healthy and well on treatment.

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13. Examination Focus

Common MRCP/Postgraduate Exam Questions

1. Diagnosis and Testing

• "What is the window period for a 4th generation HIV test?"

  • "Answer: Detects > 95% of infections at 4 weeks, > 99% at 6 weeks, definitive at 12 weeks (45-day window period is standard quoted timeframe). The 4th generation test detects both HIV antibody and p24 antigen, reducing the window period compared to antibody-only tests."

• "A patient presents with fever, pharyngitis, and rash 3 weeks after high-risk exposure. Rapid HIV antibody test is negative. What should you do?"

  • "Answer: Clinical picture suggests acute HIV seroconversion illness. The antibody test may be negative in very early infection. Perform HIV RNA PCR (viral load) which will detect infection from ~10 days post-exposure. Expect very high viral load (> 100,000 copies/mL) in acute infection. Repeat antibody test in 2-4 weeks to confirm seroconversion."

2. CD4-Specific Prophylaxis

• "At what CD4 count do you start PCP prophylaxis, and what is the agent?"

  • "Answer: CD4 less than 200 cells/μL. Agent: Co-trimoxazole 960mg once daily or three times weekly (also provides toxoplasmosis prophylaxis if toxoplasma IgG positive). Can discontinue when CD4 > 200 for > 3 months on suppressive ART."

• "A patient has CD4 count of 40 cells/μL. What prophylaxis is indicated?"

  • "Answer: "
    • Co-trimoxazole 960mg daily (PCP and toxoplasmosis if seropositive)
    • Azithromycin 1200mg once weekly for MAC (Mycobacterium avium complex) prophylaxis
    • Screen for and treat latent TB if present

3. Opportunistic Infections

• "What is the most likely cause of multiple ring-enhancing brain lesions in HIV with CD4 less than 100?"

  • "Answer: Cerebral toxoplasmosis (reactivation of latent Toxoplasma gondii). Typically see multiple lesions with predilection for basal ganglia. Differential: primary CNS lymphoma (usually single lesion, more common if EBV positive). Management: Empirical anti-toxoplasma treatment (sulfadiazine + pyrimethamine + folinic acid); if no response in 2 weeks, brain biopsy to exclude lymphoma."

• "Describe the presentation of PCP"

  • "Answer: Subacute onset (over weeks) of progressive exertional dyspnea, dry non-productive cough, fever. Key examination: Oxygen saturation drops with exertion ("exercise desaturation test"). CXR: Bilateral perihilar interstitial infiltrates ("bat-wing"), but may be normal in 10-20%. LDH markedly elevated (> 500 U/L highly suggestive). Diagnosis: BAL with immunofluorescence. Treatment: High-dose co-trimoxazole ± steroids (if PaO₂ less than 9.3 kPa)."

4. Drug Safety

• "Which HIV drug requires HLA-B*5701 testing before use, and why?"
  • "Answer: Abacavir. HLA-B*5701 allele present in ~5-8% of population predicts abacavir hypersensitivity reaction (fever, rash, GI symptoms, can be fatal on rechallenge). Universal screening before prescribing abacavir is mandatory. If positive, abacavir is permanently contraindicated."

5. IRIS

• "What is IRIS and when does it occur?"

  • "Answer: Immune Reconstitution Inflammatory Syndrome - paradoxical worsening of opportunistic infection or inflammatory condition within weeks to months of starting ART, caused by restoration of pathogen-specific immune responses. Most common with TB, cryptococcal meningitis, CMV. Risk factors: Very low baseline CD4 (less than 50), high baseline viral load, early ART initiation relative to OI diagnosis."

• "In TB-HIV co-infection with CD4 less than 50, when should you start ART?"

  • "Answer: Start TB treatment first, then initiate ART within 2 weeks (reduces mortality despite IRIS risk). Exception: TB meningitis is more complex - some advocate delaying ART for 4-6 weeks to reduce severe CNS IRIS, though recent evidence suggests earlier may be beneficial. Balance individual risk-benefit."

6. Antiretroviral Therapy

• "What are the current preferred first-line ART regimens?"

  • "Answer: INSTI (integrase inhibitor)-based regimens:"
    • Bictegravir/TAF/FTC (Biktarvy) - single tablet once daily
    • Dolutegravir + tenofovir/emtricitabine - generic option
    • Dolutegravir/lamivudine (Dovato) - 2-drug regimen if VL less than 500,000 and no HBV
  • All offer high efficacy, high barrier to resistance, favorable tolerability, and minimal drug interactions

• "What is the target for viral suppression on ART?"

  • Answer: Viral load less than 50 copies/mL ("undetectable") by 24 weeks. Confirmed viral load less than 50 copies/mL means treatment is working optimally and the person cannot sexually transmit HIV (U=U concept).

7. Prevention

• "How effective is PrEP?"

  • "Answer: Daily tenofovir/emtricitabine (TDF/FTC) reduces HIV acquisition risk by > 99% when taken as prescribed. Protective drug levels achieved after 7 days for rectal exposure, 21 days for vaginal exposure. Requires HIV testing and STI screening every 3 months."

• "What is the transmission risk from mother to baby with and without treatment?"

  • "Answer: Without intervention: 25-40%. With comprehensive PMTCT (maternal ART throughout pregnancy, viral suppression less than 50 copies/mL, appropriate delivery mode, neonatal prophylaxis, formula feeding): less than 0.5% in high-resource settings."

Viva Voce Points

Opening Statement for HIV Topic: "HIV is a lentivirus that selectively depletes CD4+ T-helper lymphocytes, leading to progressive immunodeficiency. AIDS is defined by CD4 count less than 200 cells/microlitre or the occurrence of AIDS-defining opportunistic infections. With modern antiretroviral therapy, HIV is a chronic manageable condition with near-normal life expectancy when diagnosed early and treated appropriately. The principle of Undetectable equals Untransmittable has transformed both individual prognosis and public health prevention strategies."

Key Facts to Confidently State:

• Approximately 105,000 people living with HIV in UK; 4,000 new diagnoses annually (declining)
• 4th generation HIV test detects antibody and p24 antigen; window period 45 days (definitive at 12 weeks)
• Current treatment: INSTI-based triple therapy (e.g., bictegravir/TAF/FTC); target viral load less than 50 copies/mL
• START trial proved benefit of immediate ART regardless of CD4 count (test and treat approach)
• PARTNER studies established U=U: zero transmissions with sustained viral suppression
• PCP prophylaxis (co-trimoxazole) indicated when CD4 less than 200; MAC prophylaxis (azithromycin) when CD4 less than 50
• Late diagnosis (CD4 less than 350) occurs in 40% of UK diagnoses; accounts for majority of HIV mortality
• IRIS risk highest with TB and cryptococcal infections in patients with very low CD4 counts

Common Viva Scenarios:

Scenario 1: "A 35-year-old man who has sex with men presents with 2 weeks of progressive breathlessness and dry cough. Oxygen saturations 94% at rest, 88% on exertion. How would you approach this?"

• Approach: High suspicion for PCP given demographics and exercise desaturation
• Immediate investigations: CXR (may show bilateral interstitial infiltrates or be normal), LDH (expect elevation), arterial blood gas (hypoxemia, ↑A-a gradient)
• Urgent HIV test (4th generation Ag/Ab + viral load if high suspicion)
• If PCP suspected: Induced sputum or bronchoscopy with BAL for Pneumocystis immunofluorescence/PCR
• Empirical treatment: High-dose co-trimoxazole (120mg/kg/day IV divided); add prednisolone if PaO₂ less than 9.3kPa
• Assess for other OIs and start ART once stable on PCP treatment

Scenario 2: "A patient newly diagnosed with HIV has CD4 count 450 cells/μL and viral load 12,000 copies/mL. When and with what would you start treatment?"

• Answer: Start ART within 2 weeks of diagnosis (test and treat approach supported by START trial)
• Preferred regimen: INSTI-based triple therapy (e.g., bictegravir/TAF/FTC single tablet once daily)
• Must check: HLA-B*5701 before abacavir, baseline resistance testing, HBV/HCV serology, renal function, cardiovascular risk factors
• No prophylaxis needed at this CD4 count
• Education on adherence (> 95% required), U=U concept, follow-up schedule
• Target: Viral load less than 50 copies/mL by 24 weeks

Common Mistakes to Avoid

❌ Assuming negative antibody test rules out HIV in acute infection: Antibody tests may be negative for 2-8 weeks after infection; use HIV RNA PCR if clinical suspicion of acute HIV

❌ Starting ART before screening for HLA-B*5701 if using abacavir: This is mandatory before abacavir prescription (hypersensitivity risk)

❌ Delaying ART in pregnancy: Start immediately regardless of CD4 count to prevent mother-to-child transmission

❌ Starting ART immediately in cryptococcal meningitis: Defer ART for 4-6 weeks after starting antifungal therapy to reduce IRIS mortality risk (exception to early ART rule)

❌ Forgetting to discontinue PCP prophylaxis: Can stop co-trimoxazole when CD4 > 200 for > 3 months on suppressive ART (saves unnecessary medication)

❌ Missing indicator conditions: Failing to offer HIV test in presentations like severe seborrhoeic dermatitis, oral hairy leukoplakia, multidermatomal zoster in young adults

❌ Confusing U=U with cure: Undetectable viral load means cannot transmit sexually, but HIV persists in latent reservoirs; ART must be continued lifelong

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14. References

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2. Centers for Disease Control and Prevention. Revised Classification System for HIV Infection and Expanded Surveillance Case Definition for AIDS Among Adolescents and Adults. MMWR. 1992;41(RR-17):1-19.

3. Antiretroviral Therapy Cohort Collaboration. Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies. Lancet HIV. 2017;4(8):e349-e356. doi:10.1016/S2352-3018(17)30066-8

4. Marcus JL, et al. Narrowing the Gap in Life Expectancy Between HIV-Infected and HIV-Uninfected Individuals With Access to Care. J Acquir Immune Defic Syndr. 2016;73(1):39-46. doi:10.1097/QAI.0000000000001014

5. Rodger AJ, et al. Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study. Lancet. 2019;393(10189):2428-2438. doi:10.1016/S0140-6736(19)30418-0

6. Rodger AJ, et al. Sexual Activity Without Condoms and Risk of HIV Transmission in Serodifferent Couples When the HIV-Positive Partner Is Using Suppressive Antiretroviral Therapy. JAMA. 2016;316(1):171-181. doi:10.1001/jama.2016.5148

7. Croxford S, et al. Mortality and causes of death in people diagnosed with HIV in the era of highly active antiretroviral therapy compared with the general population: an analysis of a national observational cohort. Lancet Public Health. 2017;2(1):e35-e46. doi:10.1016/S2468-2667(16)30020-2

8. UNAIDS. Global HIV & AIDS Statistics — Fact Sheet 2023. Available at: https://www.unaids.org/en/resources/fact-sheet

9. UK Health Security Agency. HIV Testing, PrEP and Care Data Report 2022. London: UKHSA; 2022.

10. Braun DL, et al. Acute HIV Infection: Diagnosis, Treatment, and Prevention. Curr HIV/AIDS Rep. 2021;18(3):221-228. doi:10.1007/s11904-021-00556-3

11. Haddow LJ, et al. A systematic review of the screening accuracy of the HIV dementia scale and international HIV dementia scale. PLoS One. 2013;8(4):e61826. doi:10.1371/journal.pone.0061826

12. Abdool Karim SS, et al. Timing of Initiation of Antiretroviral Drugs during Tuberculosis Therapy. N Engl J Med. 2010;362(8):697-706. doi:10.1056/NEJMoa0905848

13. Patel P, et al. Estimating per-act HIV transmission risk: a systematic review. AIDS. 2014;28(10):1509-1519. doi:10.1097/QAD.0000000000000298

14. Kuhar DT, et al. Updated US Public Health Service Guidelines for the Management of Occupational Exposures to Human Immunodeficiency Virus and Recommendations for Postexposure Prophylaxis. Infect Control Hosp Epidemiol. 2013;34(9):875-892. doi:10.1086/672271

15. Fleming DT, Wasserheit JN. From epidemiological synergy to public health policy and practice: the contribution of other sexually transmitted diseases to sexual transmission of HIV infection. Sex Transm Infect. 1999;75(1):3-17. doi:10.1136/sti.75.1.3

16. Brenchley JM, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12(12):1365-1371. doi:10.1038/nm1511

17. Deeks SG, et al. Systemic effects of inflammation on health during chronic HIV infection. Immunity. 2013;39(4):633-645. doi:10.1016/j.immuni.2013.10.001

18. INSIGHT START Study Group. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med. 2015;373(9):795-807. doi:10.1056/NEJMoa1506816

19. Danel C, et al. A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa (TEMPRANO). N Engl J Med. 2015;373(9):808-822. doi:10.1056/NEJMoa1507198

20. Grijsen ML, et al. No Treatment versus 24 or 60 Weeks of Antiretroviral Treatment during Primary HIV Infection: The Randomized Primo-SHM Trial. PLoS Med. 2012;9(3):e1001196. doi:10.1371/journal.pmed.1001196

21. Boulware DR, et al. Timing of Antiretroviral Therapy after Diagnosis of Cryptococcal Meningitis. N Engl J Med. 2014;370(26):2487-2498. doi:10.1056/NEJMoa1312884

22. Grant RM, et al. Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men. N Engl J Med. 2010;363(27):2587-2599. doi:10.1056/NEJMoa1011205

23. Irvine C, et al. Effectiveness of HIV post-exposure prophylaxis: a systematic review of systematic reviews. BMJ Open. 2015;5(11):e008061. doi:10.1136/bmjopen-2015-008061

24. Flynn PM, et al. Prevention of HIV-1 Transmission Through Breastfeeding: Efficacy and Safety of Maternal Antiretroviral Therapy Versus Infant Nevirapine Prophylaxis for Duration of Breastfeeding in HIV-1-Infected Women with High CD4 Cell Count (IMPAACT PROMISE). J Acquir Immune Defic Syndr. 2018;77(4):383-392. doi:10.1097/QAI.0000000000001612

25. Cohen MS, et al. Antiretroviral Therapy for the Prevention of HIV-1 Transmission. N Engl J Med. 2016;375(9):830-839. doi:10.1056/NEJMoa1600693

26. Mayer KH, et al. Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. Lancet. 2020;396(10246):239-254. doi:10.1016/S0140-6736(20)31065-5

27. British HIV Association. British HIV Association Guidelines for the Treatment of HIV-1-Positive Adults with Antiretroviral Therapy 2023. Available at: www.bhiva.org

28. World Health Organization. Consolidated Guidelines on HIV Prevention, Testing, Treatment, Service Delivery and Monitoring: Recommendations for a Public Health Approach. Geneva: WHO; 2021.

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