HIV Antiretroviral Therapy: Modern Treatment Guide

HIV Treatment: A 40-Year Revolution

In 1987, zidovudine (AZT) became the first antiretroviral medicine approved for HIV — offering modest benefit at significant toxicity. By the mid-1990s, AIDS was the leading cause of death in Americans ages 25-44. Today, a person diagnosed with HIV at age 20 and started on effective treatment can expect to live into their 70s — a near-normal lifespan.

This transformation is the result of one of the most remarkable pharmacological achievements in history: the development of combination antiretroviral therapy (ART) that can suppress HIV replication to undetectable levels.

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How HIV Replicates (and How Medicines Stop It)

HIV must complete a replication cycle to spread through the body:

1. Attachment/Entry — HIV binds CD4 receptor and CCR5/CXCR4 co-receptors on T cells
2. Fusion — viral envelope fuses with cell membrane
3. Reverse transcription — viral RNA converted to DNA by reverse transcriptase
4. Integration — viral DNA integrated into host genome by integrase
5. Transcription/translation — viral proteins produced
6. Assembly/Budding — new viral particles assembled
7. Maturation — protease cleaves polyproteins; infectious virions released

Each step is a potential medicine target.

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Antiretroviral Medicine Classes

NRTIs (Nucleoside/Nucleotide Reverse Transcriptase Inhibitors)

• Mechanism: Incorporated into viral DNA, causing chain termination during reverse transcription
• Medicines: Tenofovir (TDF, TAF), emtricitabine (FTC), lamivudine (3TC), abacavir (ABC), zidovudine (AZT)
• Backbone of most regimens: TDF/FTC (Truvada) or TAF/FTC (Descovy) is the most common NRTI backbone
• Key toxicities: Tenofovir TDF — renal toxicity, bone density loss; TAF safer for kidney/bone; abacavir — HLA-B*5701 hypersensitivity reaction (genetic test required)

NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors)

• Mechanism: Bind allosteric site on reverse transcriptase — distinct from NRTIs
• Medicines: Efavirenz (EFV), rilpivirine (RPV), doravirine (DOR), etravirine (ETR)
• Key toxicities: Efavirenz — CNS effects (vivid dreams, dizziness), rash; rilpivirine — requires food and low stomach acid (proton pump inhibitors are a problem)
• Single K103N mutation confers efavirenz/rilpivirine resistance — genetic barrier is lower than integrase inhibitors

Integrase Strand Transfer Inhibitors (INSTIs)

• Mechanism: Block integration of viral DNA into host genome
• Medicines: Dolutegravir (DTG), bictegravir (BIC), cabotegravir (CAB), raltegravir (RAL), elvitegravir (EVG)
• Preferred regimen basis — superior efficacy, tolerability, and high genetic barrier to resistance
• Key toxicities: Dolutegravir — insomnia, neuropsychiatric effects (rare); weight gain (class effect); neural tube defects concern in early pregnancy (updated to low risk based on data)

Protease Inhibitors (PIs)

• Mechanism: Block viral protease from cleaving polyproteins — produce immature, non-infectious virions
• Medicines: Darunavir (DRV), atazanavir (ATV), lopinavir (LPV) — all boosted with ritonavir or cobicistat
• High genetic barrier to resistance — useful in complex patients
• Key toxicities: GI effects, hyperlipidemia, insulin resistance, cardiovascular risk, medicine interactions (potent CYP3A4 inhibitors)

Entry/Fusion Inhibitors

• Maraviroc (Selzentry) — CCR5 antagonist; requires tropism testing (CCR5 vs CXCR4 virus)
• Enfuvirtide (Fuzeon) — subcutaneous injection; rarely used due to injection burden
• Fostemsavir (Rukobia) — CD4 attachment inhibitor for multidrug-resistant HIV
• Lenacapavir (Sunlenca) — capsid inhibitor; biannual subcutaneous injection; for multidrug-resistant HIV

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Preferred First-Line Regimens (2024)

DHHS guidelines recommend these preferred regimens:

• Bictegravir/TAF/FTC (Biktarvy) — single tablet once daily; no food requirement; preferred for most new patients
• Dolutegravir + TAF/FTC (Triumeq/separate) — high barrier, excellent tolerability
• Dolutegravir/lamivudine (Dovato) — 2-medicine regimen; alternative where resistance testing confirms no resistance

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Undetectable = Untransmittable (U=U)

Perhaps the most important public health advance in HIV: people with HIV who achieve and maintain an undetectable viral load (< 200 copies/mL) cannot sexually transmit HIV to their partners. This was definitively proven by the PARTNER and PARTNER 2 studies — over 100,000 condomless sex acts with zero transmissions.

U=U has profound implications for the stigma of HIV and for adherence motivation.

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Pre-Exposure Prophylaxis (PrEP)

PrEP allows HIV-negative individuals at high risk to prevent infection:

• Truvada (TDF/FTC) — daily oral; 99% effective when taken consistently
• Descovy (TAF/FTC) — approved for men and transgender women (not cisgender women — not studied)
• Apretude (cabotegravir injection) — bimonthly intramuscular injection; non-inferior to daily pills; preferred for those with adherence challenges

PrEP requires HIV testing before starting, every 3 months while on PrEP, and kidney function monitoring with TDF.