HIV and AIDS — CD4 staging, antiretroviral therapy, opportunistic infections and PrEP

Definition / Overview

• HIV is a retrovirus that progressively depletes CD4⁺ T-lymphocytes, resulting in acquired immunodeficiency and susceptibility to opportunistic infections (OIs) and malignancies
• AIDS (Stage 3) is defined by either a CD4⁺ count $< 200\,\text{cells/μL}$ or the diagnosis of an AIDS-defining illness, regardless of CD4⁺ count
• Global burden remains substantial; in Australia and New Zealand, men who have sex with men (MSM) represent the largest transmission group
• Effective antiretroviral therapy (ART) has transformed HIV into a chronic, manageable condition, a 20-year-old diagnosed today and treated appropriately can expect near-normal life expectancy

Pathophysiology

• HIV-1 encodes gp120, which binds CD4 receptors and co-receptors (CCR5 or CXCR4) on T-helper lymphocytes, macrophages, and dendritic cells
• Following cell entry, reverse transcriptase (an error-prone RNA-dependent DNA polymerase) produces a DNA copy; this integrates into the host genome via integrase
• The high mutation rate during reverse transcription drives viral diversity and underpins resistance emergence
• Progressive CD4⁺ depletion occurs through direct cytopathic effect, immune activation, and bystander apoptosis
• Once CD4⁺ count falls below $200\,\text{cells/μL}$, immune surveillance fails and OIs emerge; counts $< 50\,\text{cells/μL}$ confer the highest morbidity and mortality

CD4 Staging and Clinical Correlation

CDC/WHO Staging Framework

Clinically Important CD4 Thresholds

Clinical Features and Diagnosis

Acute HIV Seroconversion (Acute Retroviral Syndrome)

• Occurs 2-4 weeks post-exposure; affects up to 75% of newly infected individuals
• Presentation mimics infectious mononucleosis: fever, lymphadenopathy, pharyngitis, rash, myalgia, oral ulcers, aseptic meningitis
• Key diagnostic pitfall: standard HIV antibody tests may be negative at this stage, order HIV RNA (viral load) or 4th-generation HIV Ag/Ab combination assay
• Peak viraemia correlates with CD4 nadir; immune partial recovery follows spontaneously

Established HIV and AIDS-Defining Conditions

Common AIDS-defining illnesses by system:

• Pulmonary: Pneumocystis jirovecii pneumonia (PCP), pulmonary TB, recurrent bacterial pneumonia
• CNS: Toxoplasma encephalitis (ring-enhancing lesions, focal deficits, seizures), cryptococcal meningitis, PML (JC virus), HIV-associated dementia
• GI: CMV oesophagitis/colitis, cryptosporidiosis, oesophageal candidiasis
• Oncologic: Kaposi sarcoma (HHV-8), primary CNS lymphoma, invasive cervical carcinoma, high-grade B-cell lymphoma
• Disseminated: Mycobacterium avium complex (MAC), CMV retinitis, disseminated histoplasmosis/coccidioidomycosis (region-dependent)

Investigation and Monitoring

Baseline Assessment at HIV Diagnosis

1. Confirm HIV with 4th-generation Ag/Ab assay; reactive results require confirmatory differentiation assay and HIV RNA
2. CD4⁺ T-cell count and percentage, absolute count guides prophylaxis thresholds
3. HIV RNA (viral load), baseline and monitors treatment response; target is undetectable ($< 20-50\,\text{copies/mL}$)
4. HIV genotypic resistance testing, guides first-line ART selection
5. HLA-B*5701 testing, contraindication to abacavir if positive (risk of hypersensitivity syndrome)
6. Tropism assay, if CCR5 antagonist (maraviroc) considered
7. Hepatitis B and C serology, important for ART selection (tenofovir active against HBV; consider dual coverage)
8. STI screen, syphilis, gonorrhoea, chlamydia, LGV
9. TB screening, symptom screen, IGRA or TST; CXR
10. Lipid profile, renal function, urinalysis, ART nephrotoxicity monitoring
11. Cervical cytology (females); anal Pap smear in high-risk MSM
12. Vaccination review, pneumococcal (PCV followed by 23vPPV), hepatitis A/B, influenza, HPV

Ongoing Monitoring on ART

Antiretroviral Therapy

Principles

• Universal treatment, ART is recommended for all people living with HIV regardless of CD4⁺ count; the START trial demonstrated a 57% reduction in AIDS, serious non-AIDS events, or death with immediate versus deferred ART
• Viral suppression to undetectable eliminates sexual transmission risk (U=U: Undetectable = Untransmittable)
• ART is lifelong; adherence counselling is critical from day one
• Goal: plasma viral load undetectable within 24 weeks of initiation

Drug Classes and Mechanisms

Preferred First-Line Regimens (Australian/NZ practice)

• Preferred backbone: two NRTIs (typically tenofovir AF [TAF] + emtricitabine, or abacavir + lamivudine if HLA-B*5701 negative)
• Preferred third agent: INSTI, bictegravir or dolutegravir (high barrier to resistance, well tolerated)
• Common single-tablet regimen: bictegravir/TAF/emtricitabine (Biktarvy), once daily, no food requirement, minimal drug interactions
• Dolutegravir-based regimens preferred in those with TB co-infection (rifampicin interaction requires dose adjustment); avoid rilpivirine if pre-treatment VL $> 100{,}000\,\text{copies/mL}$ or CD4 $< 200$

Key Drug Toxicities and Monitoring Points

Immune Reconstitution Inflammatory Syndrome (IRIS)

• Paradoxical worsening of a known or subclinical OI within weeks of ART initiation due to restored immune response
• High-risk scenarios: TB (most common), cryptococcal meningitis, CMV, MAC, especially when ART started with CD4 $< 50\,\text{cells/μL}$
• Management strategy: For OI diagnosed simultaneously with HIV and CD4 $> 50\,\text{cells/μL}$, delay ART by 2-4 weeks to reduce antigenic burden; for TB or CNS cryptococcosis, delay ART 4-8 weeks
• For advanced HIV (CD4 $< 50\,\text{cells/μL}$), do not delay ART beyond management of the acute OI
• Treatment of IRIS: continue ART and treat underlying OI; corticosteroids for severe paradoxical IRIS (especially TB-IRIS)

Opportunistic Infection Prophylaxis

Primary Prophylaxis by CD4 Threshold

Discontinuation of Prophylaxis

• PCP and toxoplasma prophylaxis can be safely discontinued once CD4 $> 200\,\text{cells/μL}$ for at least 3 months on suppressive ART
• MAC prophylaxis can be discontinued when CD4 $> 100\,\text{cells/μL}$ sustained for $\geq 3$ months
• Secondary prophylaxis (maintenance therapy post-OI) follows similar thresholds but requires longer sustained immune reconstitution

Secondary Prophylaxis Examples

Pre-Exposure Prophylaxis (PrEP)

Indications

PrEP is recommended for HIV-negative individuals at substantial ongoing risk, including:

• MSM with multiple partners or inconsistent condom use
• HIV-discordant couples with detectable viral load in the partner with HIV
• Heterosexual individuals with multiple partners or inconsistent condom use
• People who inject drugs sharing needles
• Sex workers

Regimens

• Oral PrEP: Tenofovir disoproxil fumarate + emtricitabine (TDF/FTC) 245/200 mg once daily, approved and subsidised in Australia/New Zealand
• Event-driven (2-1-1) PrEP: 2 tablets 2-24 hours before sex, 1 tablet 24 hours later, 1 tablet 48 hours later, validated in MSM; not recommended for anal receptive intercourse in cisgender women or for PWID
• Long-acting injectable cabotegravir 600 mg IM every 8 weeks, may offer superior adherence and efficacy; emerging option in Australian practice

Pre-PrEP Workup

1. Confirm HIV-negative status (4th-generation assay), must document no signs of acute HIV infection
2. Renal function, TDF/FTC contraindicated if eGFR $< 60\,\text{mL/min/1.73m}^2$
3. Hepatitis B serology, screen and vaccinate if non-immune; HBsAg positive patients risk HBV flare if TDF/FTC discontinued
4. Hepatitis C serology
5. STI screen at baseline

Monitoring on PrEP

• Every 3 months: HIV test (4th-generation), STI screen (including pharyngeal, rectal, urethral), risk reduction counselling, medication adherence
• Every 6 months: Renal function, eGFR

Post-Exposure Prophylaxis (PEP)

• Initiated within 72 hours of high-risk exposure (occupational or non-occupational); the sooner the better, ideally within 2-4 hours
• Regimen: Tenofovir/emtricitabine + dolutegravir for 28 days
• Follow-up HIV testing at 6 weeks and 3 months post-completion
• If exposure ongoing, transition to PrEP

Complications and Special Considerations

Pregnancy

• ART should be continued or commenced in all pregnant women with HIV
• Dolutegravir carries a small but documented risk of neural tube defects if taken at conception; advise appropriate contraception in women of childbearing potential and discuss risk/benefit at time of conception planning
• Efavirenz is also teratogenic, avoid in first trimester
• Goal: undetectable viral load by delivery to prevent mother-to-child transmission; caesarean section if VL remains detectable
• Neonatal prophylaxis (zidovudine ± other agents) based on maternal viral suppression

Cardiovascular Risk

• People living with HIV have elevated baseline cardiovascular risk from chronic immune activation, dyslipidaemia (especially with PI-based regimens), and lifestyle factors
• Integrate cardiovascular risk assessment into routine HIV care; calculate absolute cardiovascular risk using validated tools and manage modifiable risk factors aggressively

Non-AIDS Malignancies

• Anal, oropharyngeal, liver, and lung cancers are elevated in HIV-positive populations
• Maintain age-appropriate cancer screening; consider annual anal Pap smear in high-risk groups
• Kaposi sarcoma staging uses the ACTG TIS system (Tumour, Immune status, Systemic illness); ART optimisation is core therapy for limited disease

Drug Interactions

• Rifampicin (TB treatment) is a potent CYP3A4 inducer, significantly reduces levels of PIs and cobicistat-boosted regimens; switch to dolutegravir (double dose to 50 mg twice daily) or efavirenz-based regimen
• Review all medications at every visit using a validated interaction checker (e.g. HIV Drug Interactions database), statins, anticoagulants, antiepileptics, and hormonal contraceptives are commonly affected
• Methadone levels may be significantly reduced by NNRTIs

Long-Term Care and Consultant Approach

• Treat-to-target: viral suppression is the primary goal; switch regimen if VL detectable on two consecutive tests while adherent
• Elite controllers ($< 1\%$ of people with HIV): maintain undetectable viraemia without ART; still benefit from ART due to ongoing immune activation
• Multidisciplinary care: infectious diseases physician, GP, sexual health, mental health, social support, and pharmacy, essential for adherence optimisation
• Mental health: depression, anxiety, and substance use are prevalent co-morbidities; screen routinely
• Bone health: dual-energy X-ray absorptiometry (DEXA) scanning in patients with additional osteoporosis risk factors, prolonged TDF use, or post-menopausal women
• Vaccination: annual influenza; pneumococcal (PCV13 followed by 23vPPV after 8 weeks); hepatitis A and B if non-immune; avoid live vaccines when CD4 $< 200\,\text{cells/μL}$
• Disclosure, stigma, and cultural safety: in the long case, demonstrate awareness of the psychological and social dimensions of HIV diagnosis; in Aboriginal and Torres Strait Islander populations, culturally safe care, community-based testing programs, and addressing systemic barriers to access are essential components of equitable HIV management

Sources

• Therapeutic Guidelines (eTG)
• NHMRC clinical practice guidelines