Hiv
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I now have excellent source material from Harrison's 22E (2025), Rosen's Emergency Medicine, and other authoritative textbooks. Let me compile the comprehensive answer.
HIV (Human Immunodeficiency Virus) - Comprehensive Overview
1. What Is HIV?
HIV is a blood-borne retrovirus that attacks CD4+ T lymphocytes, the central coordinators of the immune system. Over time, untreated infection leads to AIDS (Acquired Immunodeficiency Syndrome), defined by a CD4 count <200 cells/µL or the presence of an AIDS-defining illness. Two species exist:
- HIV-1 - responsible for the global pandemic; multiple clades/subtypes
- HIV-2 - found mainly in West Africa; lower viral loads, slower progression; notably, NNRTIs (e.g., efavirenz), enfuvirtide, and fostemsavir are not active against HIV-2
As of 2024, an estimated 87% of people living with HIV know their status, 89% of those are on ART, and 94% of those on ART have a suppressed viral load (UNAIDS 2024).
2. Transmission
HIV is transmitted primarily through: - Harrison's Principles of Internal Medicine 22E (2025), p.1606
| Route | Risk per 10,000 exposures |
|---|---|
| Blood transfusion | 9,250 |
| Needle sharing (injection drug use) | 63 |
| Percutaneous needle stick | 23 |
| Receptive anal intercourse | 138 |
| Insertive anal intercourse | 11 |
| Receptive penile-vaginal intercourse | 8 |
| Insertive penile-vaginal intercourse | 4 |
| Receptive/insertive oral intercourse | Low |
| Biting, spitting, sharing sex toys | Negligible |
Key points:
- Only blood, semen, cervicovaginal secretions, and breast milk have been implicated - Red Book 2021
- Risk approaches zero when the infected partner is on effective ART (U=U: Undetectable = Untransmittable)
- Cofactors increasing risk: high viral load, concurrent STIs (especially ulcerative), genital inflammation
3. Pathophysiology
Viral Life Cycle
HIV is a lentivirus. It binds CD4+ cells via its gp120 envelope protein attaching to the CD4 receptor, then co-receptors CCR5 (early infection) or CXCR4 (later disease). After fusion, the reverse transcriptase enzyme converts viral RNA to DNA, which integrates into the host genome via integrase. New virions bud and mature via protease cleavage.
CD4+ T Cell Depletion - Mechanisms
Multiple mechanisms drive progressive immune failure:
- Direct viral cytopathicity - infected CD4+ cells die from viral budding
- Pyroptosis - inflammatory cell death via caspase-1, IL-1β, IL-18; depletes bystander (uninfected) CD4+ T cells
- Apoptosis - upregulation of death receptors (Fas/CD95, TNFR1, TRAIL); HIV proteins Env, Tat, Vpr enhance susceptibility
- Chronic immune activation - persistent antigen exposure drives T cell exhaustion and dysregulation of T-regulatory cells (T-regs)
- GALT destruction - the gut-associated lymphoid tissue (GALT) is the site of the earliest, most massive CD4+ depletion during acute infection
Lymphoid Tissue
Despite plasma viremia being the clinical measure of disease activity, most HIV replication occurs in lymphoid tissue. Virions are trapped on follicular dendritic cells (FDCs) in germinal centers, serving as a persistent reservoir that continuously activates CD4+ T cells and drives further replication. - Harrison's 22E
Chronic Complications of Immune Activation
Even with years of effective ART (viral load <50 copies/mL), persistent low-grade inflammation drives accelerated aging, including:
- Cardiovascular disease
- Bone fragility / osteoporosis
- Neurocognitive dysfunction
- Certain malignancies
- Kidney and liver disease
4. Clinical Stages
| Stage | CD4 Count | Features |
|---|---|---|
| Acute HIV (seroconversion) | Normal or falling | Flu-like illness (fever, rash, lymphadenopathy, pharyngitis) 2-4 weeks after exposure; very high viral load |
| Chronic/Clinical latency | 200-500+ cells/µL | Asymptomatic or persistent lymphadenopathy; can last years |
| AIDS | <200 cells/µL | Opportunistic infections, AIDS-defining malignancies |
AIDS-defining conditions include: Pneumocystis jirovecii pneumonia (PCP), cryptococcal meningitis, CMV retinitis, Toxoplasma encephalitis, esophageal candidiasis, disseminated MAC, Kaposi sarcoma, CNS lymphoma.
5. Diagnosis
- 4th-generation HIV-1/2 antigen/antibody combination immunoassay - preferred initial test; detects both p24 antigen (acute) and antibody
- Positive screen confirmed by HIV-1/HIV-2 antibody differentiation assay
- HIV-1 RNA (viral load) - confirms acute infection when antibody tests may still be negative; also used for monitoring
- CD4+ T cell count - used for staging and to guide prophylaxis decisions
Drug resistance testing (genotypic or phenotypic) is recommended:
- At initial diagnosis
- Before starting ART if not started immediately
- At virologic failure (while still on the failing regimen) - Harrison's 22E
6. Treatment - Antiretroviral Therapy (ART)
When to Start
ART should be initiated as soon as possible after diagnosis, ideally same-day ("same-day initiation"), regardless of CD4 count. - DHHS 2025 guidelines
Drug Classes
| Class | Mechanism | Examples |
|---|---|---|
| NRTIs (nucleoside/nucleotide RT inhibitors) | Block reverse transcription | Tenofovir (TDF/TAF), emtricitabine (FTC), abacavir (ABC), lamivudine (3TC) |
| NNRTIs | Non-competitive RT inhibition | Efavirenz, rilpivirine, doravirine |
| PIs (protease inhibitors) | Block viral protease; given with ritonavir/cobicistat booster | Darunavir |
| INSTIs (integrase strand transfer inhibitors) | Block viral DNA integration | Dolutegravir (DTG), bictegravir (BIC), raltegravir |
| Entry inhibitors | Block fusion, CCR5, or CD4 receptor | Maraviroc (CCR5 antagonist), enfuvirtide, fostemsavir (CD4 antagonist) |
| Capsid inhibitor | Disrupts viral capsid | Lenacapavir |
Preferred First-Line Regimens (2025 DHHS)
- Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) - single pill, once daily
- Dolutegravir + TAF/FTC - once daily
- Dolutegravir + lamivudine (DTG/3TC) - 2-drug option if HIV RNA <500,000 copies/mL, CD4 >200, no HBV, resistance test available
Special Considerations
- HBV coinfection: use TDF or TAF (both active against HBV); discontinuing can cause HBV flare
- Cardiovascular risk: avoid abacavir if possible
- HLA-B*5701 positive: avoid abacavir (risk of hypersensitivity reaction)
- CKD: avoid TDF if CrCl <60 mL/min; avoid TAF if CrCl <30 mL/min
- Prior long-acting cabotegravir PrEP: consider darunavir-based regimen pending INSTI resistance results
7. Prevention
Pre-Exposure Prophylaxis (PrEP)
- Oral PrEP: Emtricitabine/TDF or emtricitabine/TAF once daily - highly effective in high-risk individuals
- Long-acting injectable PrEP: Cabotegravir LA (every 2 months) - superior to oral TDF/FTC in clinical trials
Post-Exposure Prophylaxis (PEP)
- Indicated within 72 hours of exposure to HIV-infected blood or body fluids
- Regimen: Tenofovir/emtricitabine + dolutegravir (or raltegravir) for 28 days
- Follow up with HIV testing at 6 weeks - Washington Manual of Medical Therapeutics
Other Prevention
- Condom use
- Needle exchange programs
- Treating STIs (reduce mucosal barrier disruption)
- Voluntary male circumcision (reduces female-to-male transmission)
- Universal testing (know your status)
8. Monitoring
- HIV RNA (viral load): Measured at baseline, 2-8 weeks after starting ART, then every 3-6 months. Goal: <50 copies/mL (undetectable)
- CD4 count: Baseline, then every 3-6 months until stable; guides prophylaxis
- Virologic failure: Defined as HIV RNA persistently >200 copies/mL despite ART - requires resistance testing
Recent Evidence (2024-2026)
- Low-level viraemia (LLV) during ART (detectable but <1000 copies/mL) is associated with increased risk of virologic failure - a 2025 meta-analysis (PMID 39727007) confirmed this association across populations
- Perinatal transmission: A 2025 Lancet meta-analysis (PMID 40652949) quantified the dose-response relationship between maternal viral load and mother-to-child HIV transmission, reinforcing the importance of viral suppression during pregnancy
- With effective ART throughout pregnancy, mother-to-child transmission rates have fallen from ~25% (1994) to <1% today - Creasy & Resnik's Maternal-Fetal Medicine
Sources: Harrison's Principles of Internal Medicine 22E (2025); Rosen's Emergency Medicine; Washington Manual of Medical Therapeutics; Red Book 2021; Goodman & Gilman's Pharmacological Basis of Therapeutics; Goldman-Cecil Medicine; DHHS 2025 ART Guidelines; UNAIDS 2024
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