HIV
Description
- Retroviral infection causing progressive CD4+ T cell depletion -> opportunistic infection and malignancy
- With treatment it is a chronic manageable condition with near-normal life expectancy; the modern problems are late diagnosis, comorbidity and stigma
Stages
- Acute (seroconversion) illness - 2-4 weeks after exposure, in ~50-90%
- Fever, pharyngitis, generalised lymphadenopathy, maculopapular rash, myalgia, mouth/genital ulcers, headache; a "glandular fever-like illness with a rash and mucosal ulcers"
- Very high viral load and high transmissibility; CD4 dips transiently
- *Antibody tests may still be negative - this is the moment HIV is most often missed*
- Clinical latency - median ~8-10 yr untreated; persistent generalised lymphadenopathy
- Symptomatic / AIDS - CD4 <200 or an AIDS-defining illness
AIDS-defining illnesses
- **Pneumocystis jirovecii pneumonia, oesophageal candidiasis, cerebral toxoplasmosis, cryptococcal meningitis, CMV retinitis/colitis, disseminated MAC, TB, cryptosporidiosis, PML**
- Kaposi sarcoma, non-Hodgkin lymphoma (incl. primary CNS lymphoma), invasive cervical cancer
- HIV-associated dementia (AIDS dementia complex), HIV wasting syndrome
Opportunistic infection by CD4 count - the examinable table
| CD4 (cells/microL) | At risk of |
|---|---|
| Any count | TB, Kaposi sarcoma, bacterial pneumonia, shingles, candidiasis (oral) |
| <200 | **Pneumocystis pneumonia**, oesophageal candidiasis |
| <100 | Cerebral toxoplasmosis, cryptococcal meningitis, cryptosporidiosis |
| <50 | CMV retinitis, disseminated MAC, primary CNS lymphoma, PML |
Epidemiology
- ~29,000 people living with HIV in Australia; ~700-800 new diagnoses per year, and falling
- Predominant transmission in Australia: men who have sex with men; rising proportion of heterosexual transmission, particularly in people born overseas
- ~1 in 3-4 Australian diagnoses are "late" (CD4 <350 at diagnosis) - the main cause of preventable HIV morbidity here
- Aboriginal and Torres Strait Islander notification rates now exceed those of the non-Indigenous population
- Mother-to-child transmission without intervention: ~25-33%
- Maternal viral load is the major determinant; risk inc with low CD4, prolonged rupture of membranes, chorioamnionitis, vaginal delivery and breastfeeding
- <1% with suppressive ART, appropriate delivery planning and formula feeding
Aetiopathogenesis
- HIV-1 (worldwide) and HIV-2 (West Africa; slower progression, intrinsically resistant to NNRTIs) - enveloped RNA retroviruses
- Entry: gp120 binds CD4 + a co-receptor
- CCR5 (macrophage-tropic, transmitted strains) or CXCR4 (T-cell-tropic, later disease)
- *Homozygous CCR5-delta32 deletion -> near-complete resistance to CCR5-tropic HIV*; heterozygotes progress more slowly
- The basis of maraviroc and of the "Berlin/London patient" cures by CCR5-delta32 stem cell transplant
- Reverse transcriptase -> proviral DNA -> integrase -> integration into host genome -> latent reservoir in resting memory CD4 cells
- *The reservoir is why treatment is lifelong and why HIV is not cured by suppressing replication*
- RT has no proofreading -> high mutation rate -> resistance if adherence is imperfect
- CD4 depletion: direct cytopathic effect, pyroptosis, immune activation, CTL killing
- Chronic immune activation and microbial translocation persist even on ART -> accelerated cardiovascular, renal, bone and neurocognitive disease
Diagnosis
A. Test widely - the barrier is thinking of it
- Offer testing in: any STI presentation, TB, unexplained fever/weight loss/lymphadenopathy, shingles in a young adult, unexplained thrombocytopenia or cytopenias, seborrhoeic dermatitis, oral candidiasis, hepatitis B or C, pregnancy, needlestick, and any AIDS-defining illness
- Australian HIV testing is by consent with pre- and post-test discussion, but no longer requires formal counselling for a routine test
B. The tests
- 4th-generation combination assay (HIV antibody + p24 antigen) is the standard screening test
- Window period ~2-4 weeks; repeat at 6 and 12 weeks if the exposure was recent
- HIV RNA (viral load) PCR - positive earliest (~7-10 days); use for suspected acute seroconversion, neonates and indeterminate serology
- Confirmation with a second assay/Western blot-equivalent on a separate specimen
- Rapid point-of-care and self-tests: screening only; all reactive results need laboratory confirmation
C. Baseline workup after diagnosis
- CD4 count and percentage; HIV viral load
- Genotypic resistance testing before starting therapy
- *HLA-B57:01* (only if abacavir is contemplated - hypersensitivity*)
- Co-infections: hepatitis A, B and C serology, syphilis, gonorrhoea/chlamydia NAAT (throat, rectal, urine), TB (IGRA), toxoplasma IgG, CMV serology, measles/varicella immunity
- FBE, UEC, LFT, lipids, glucose, urinalysis with protein:creatinine ratio
- Cervical screening; anal cytology where indicated; pregnancy test
- Vaccination status; mental health and social assessment; partner notification
D. Examination - what to look for
- Nutritional state and wasting
- Skin: seborrhoeic dermatitis, Kaposi sarcoma (violaceous plaques), molluscum, shingles, prurigo
- Mouth: candidiasis, oral hairy leukoplakia (EBV, lateral tongue, does not scrape off), periodontal disease, aphthous ulcers, KS of the palate
- Generalised lymphadenopathy, hepatosplenomegaly, perianal disease (HSV, warts, fissure)
- Fundoscopy for CMV retinitis if CD4 <50 ("pizza pie" haemorrhages and exudates)
- Neurological: cognitive screen, focal signs, peripheral neuropathy
Management
A. Antiretroviral therapy - start at diagnosis, in everyone, regardless of CD4
- Rapid or same-day initiation is now standard; do not wait for baseline results unless a confounder demands it
- Goals: undetectable viral load by ~12-24 weeks, CD4 recovery, and U=U (undetectable = untransmittable)
First-line regimens - an INSTI backbone
- Bictegravir/emtricitabine/tenofovir alafenamide (single tablet), or
- Dolutegravir + tenofovir (TAF or TDF)/emtricitabine or lamivudine, or dolutegravir/lamivudine (2-drug, in selected patients)
- Second-generation integrase inhibitors have a high barrier to resistance, few interactions and excellent tolerability - they have displaced PI- and NNRTI-based first-line therapy
- Long-acting injectable cabotegravir + rilpivirine (2-monthly) for virologically suppressed patients with adherence difficulties
Class hazards to know
- INSTI: weight gain, insomnia, dolutegravir raises creatinine by inhibiting tubular secretion without changing GFR; separate from polyvalent cations (antacids, calcium, iron, magnesium)
- Tenofovir: TDF -> renal tubulopathy and dec bone density; TAF -> less renal/bone toxicity but more weight gain and dyslipidaemia
- Abacavir: **HLA-B57:01 hypersensitivity - never rechallenge***
- Efavirenz (NNRTI): vivid dreams, neuropsychiatric effects
- Protease inhibitors and NNRTIs are CYP3A4 substrates/inhibitors/inducers
- Ritonavir and cobicistat are potent CYP3A4 inhibitors used deliberately as "boosters"
- *Interactions that kill or harm: sildenafil (prolonged hypotension), midazolam (prolonged sedation), atorvastatin/simvastatin (rhabdomyolysis - use pravastatin or low-dose rosuvastatin), inhaled/intranasal fluticasone* (iatrogenic Cushing syndrome), ergot alkaloids, amiodarone, warfarin, OCP
- Rifampicin induces PI and INSTI metabolism - use rifabutin, or double the dolutegravir dose
- Class effect: hepatotoxicity (hepatocellular and cholestatic) - monitor LFTs
- Older agents: lipodystrophy, lactic acidosis and mitochondrial toxicity (stavudine, didanosine - historical, but examined)
B. Special situations
- HIV/hepatitis B co-infection: the regimen MUST include tenofovir + emtricitabine or lamivudine
- Dual-active against both viruses; a non-tenofovir regimen risks HBV breakthrough, and stopping these drugs can precipitate a severe HBV flare
- HIV/TB co-infection: treat TB first, start ART within 2 weeks if CD4 <50, otherwise by 8 weeks; watch for IRIS and rifampicin interactions
- Pregnancy: ART for all; aim for undetectable viral load by delivery
- Vaginal delivery is appropriate if the viral load is suppressed; elective caesarean if VL >1000 copies/mL or unknown
- Neonatal post-exposure prophylaxis; formula feeding is recommended in Australia
- Renal or bone disease -> TAF over TDF; monitor phosphate and urinary protein
C. Opportunistic infection prophylaxis - by CD4 count
| Start when | Against | Agent |
|---|---|---|
| CD4 <200 (or oral candidiasis/AIDS illness) | *Pneumocystis jirovecii* | Trimethoprim-sulfamethoxazole (also covers toxoplasma) |
| CD4 <100 AND toxoplasma IgG positive | Toxoplasmosis | Trimethoprim-sulfamethoxazole (higher dose) |
| CD4 <50 | Disseminated MAC | Azithromycin weekly (often omitted now if ART starts promptly) |
| Positive IGRA/TST | Latent TB | Isoniazid + pyridoxine, or rifamycin-based short course |
- Stop prophylaxis once CD4 is above the threshold for >3-6 months on suppressive ART
D. Treating established opportunistic infection
- **Pneumocystis pneumonia: trimethoprim-sulfamethoxazole, plus adjunctive corticosteroid if PaO2 <70 mmHg or A-a gradient >35**
- CMV disease: valganciclovir (foscarnet if resistant or intolerant)
- Disseminated MAC: azithromycin or clarithromycin + ethambutol (+/- rifabutin)
- Cerebral toxoplasmosis: pyrimethamine + sulfadiazine + folinic acid
- Cryptococcal meningitis: liposomal amphotericin B + flucytosine, then fluconazole; repeated therapeutic lumbar punctures for raised ICP
- Kaposi sarcoma: ART alone may suffice; chemotherapy for visceral/extensive disease
E. Immune reconstitution inflammatory syndrome (IRIS)
- Paradoxical clinical worsening 2-12 weeks after starting ART as immunity returns
- Highest risk: low starting CD4, high viral load, and an untreated opportunistic infection (especially TB and cryptococcus)
- Treat the underlying infection, continue ART, add corticosteroid if severe
F. Long-term care - the chronic disease
- Viral load and CD4 every 3-6 months, then annually once stable
- Cardiovascular risk - calculate and treat aggressively (risk is underestimated by standard equations); smoking cessation is the highest-yield intervention
- Bone density, renal function and urinary protein, lipids, glucose
- Cancer screening: cervical (annual), anal, and standard population screening
- Vaccination: influenza, COVID, pneumococcal, hepatitis A and B, HPV, Shingrix; avoid live vaccines if CD4 <200
- Mental health, depression, substance use, HIV-associated neurocognitive disorder
- Partner notification, disclosure support, stigma, U=U counselling
G. Prevention
- PrEP: daily tenofovir disoproxil/emtricitabine (or event-driven "2-1-1" dosing in men); long-acting injectable options are emerging - lenacapavir 6-monthly is approved in the US and under review in Australia
- PEP within 72 h, for 28 days
- Treatment as prevention: U=U - an undetectable viral load means no sexual transmission
- Condoms, needle and syringe programmes, STI screening, doxycycline PEP for bacterial STI prevention in selected populations
Associations
- Tuberculosis - the leading cause of death in people with HIV globally
- Hepatitis B and C co-infection; syphilis and other STIs
- Malignancy: Kaposi sarcoma (HHV-8), non-Hodgkin and primary CNS lymphoma (EBV), cervical and anal cancer (HPV), Hodgkin lymphoma, lung cancer
- Accelerated cardiovascular disease, CKD (HIVAN - collapsing FSGS, commoner in African ancestry), osteoporosis, frailty
- HIV-associated neurocognitive disorder; distal sensory polyneuropathy
- Cytopenias - thrombocytopenia, anaemia of chronic disease
- Seborrhoeic dermatitis, psoriasis, prurigo nodularis
- Depression, anxiety, substance use; stigma, disclosure and partner notification issues
Natural history & complications
- Untreated: median ~8-10 yr from infection to AIDS, then ~1-2 yr survival
- Rapid progressors (~10%): <5 yr; long-term non-progressors/elite controllers (<1%): maintain CD4 and undetectable VL untreated
- On effective ART: near-normal life expectancy, particularly if treatment starts with CD4 >500
- CD4 predicts short-term risk of opportunistic infection; viral load predicts rate of decline and transmissibility
- Late diagnosis (CD4 <200) is the strongest determinant of poor outcome - CD4 recovery may be incomplete even with viral suppression
- Causes of death have shifted from opportunistic infection to cardiovascular disease, non-AIDS malignancy, liver disease and the complications of ageing
- Resistance emerges with incomplete adherence, not with no treatment at all - adherence support is a clinical intervention
Monitor
- Viral load and CD4; adherence at every visit
- Renal function, urine protein, lipids, glucose, bone density, LFTs
- STI screening, cervical/anal screening, mental health, cardiovascular risk
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