What are the recommended first‑line and second‑line antiretroviral regimens for an HIV‑infected adult?

First-Line and Second-Line HIV Treatment

First-Line Antiretroviral Therapy

For treatment-naïve adults with HIV, the recommended first-line regimen consists of 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus an integrase strand transfer inhibitor (InSTI), or alternatively a 2-drug regimen of dolutegravir/lamivudine. 1

Preferred First-Line Regimens

Integrase Inhibitor-Based Triple Therapy:

• Tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF) + emtricitabine (FTC) or lamivudine (3TC) PLUS dolutegravir (DTG), bictegravir (BIC), or doravirine (DOR) 2
• Dolutegravir and bictegravir are the most favored InSTIs due to their high rates of viral suppression, minimal toxicity, low drug interaction risk, and high barrier to resistance 1
• Raltegravir is less preferred due to higher pill burden (≥3 pills daily) and lower resistance barrier 1
• Elvitegravir is the least favored InSTI because its required booster (cobicistat) causes significant drug interactions 1

Two-Drug Regimen:

• Dolutegravir/lamivudine is an appropriate first-line option providing comparable efficacy to 3-drug therapy 1, 2

Alternative Regimen:

• Abacavir/lamivudine + dolutegravir may be considered, though abacavir's role is now limited due to concerns about myocardial infarction risk and the requirement for HLA-B*5701 testing before use 1

NRTI Backbone Selection

• TAF-containing regimens have fewer tenofovir-associated adverse effects (proximal renal tubular toxicity, bone mineral density reduction) compared to TDF, particularly when combined with pharmacological boosters 1
• TDF lowers plasma lipid levels more than TAF, though the clinical significance remains unknown 1
• TAF is associated with greater weight gain than TDF 1
• TDF-containing regimens will become more cost-effective as generic formulations increase availability 1

Timing of ART Initiation

• ART should be started within 2 weeks after initiating treatment for most opportunistic infections 1
• For tuberculosis with CD4 <50 cells/μL (without TB meningitis): start ART within 2 weeks of TB treatment 1
• For tuberculosis with higher CD4 counts: start ART within 2-8 weeks of TB treatment 1
• For cryptococcal meningitis: start ART 4-6 weeks after beginning antifungal therapy 1
• For cancer diagnosis: immediate ART initiation with attention to drug-drug interactions 1

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Second-Line Antiretroviral Therapy

Second-line therapy selection depends on the drug class that failed in first-line treatment, guided by resistance testing performed while the patient remains on the failing regimen or within 4 weeks of stopping. 1

After NNRTI Failure

• Dolutegravir plus 2 NRTIs (with ≥1 active drug determined by genotypic testing) is the recommended second-line regimen 1

After InSTI Failure

• A boosted protease inhibitor (PI) plus 2 NRTIs (with ≥1 active NRTI) is recommended for initial treatment failure of an InSTI-containing regimen 1

After Raltegravir or Elvitegravir Resistance

• Dolutegravir (dosed twice daily) plus at least 1 fully active other agent is recommended when resistance to raltegravir or elvitegravir is documented 1

After PI Failure

• Virological failure due to resistance mutations is rare with PIs 1
• Focus on adherence support or switch to an alternative regimen that improves adherence and tolerability 1

Multiclass Resistance (3-Class Resistance)

• Construct the next regimen using drugs from new classes if available, such as fostemsavir or ibalizumab, with at least 1 additional active drug in an optimized ART regimen 1
• Lenacapavir (administered every 6 months) is recommended for patients with multiclass drug resistance 3

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Critical Principles for Switching Therapy

Before Any Switch

• Review the patient's complete ART history, regimen tolerability, co-medications, food requirements, cost, and all prior resistance test results 1
• Perform HIV viral load assessment 1 month after switching regimens 1

Switching During Viral Suppression

• Two-drug regimens are appropriate for managing toxicity, intolerance, adherence issues, or patient preference, provided both agents are fully active 1
• Recommended 2-drug options include: dolutegravir/rilpivirine, boosted PI with lamivudine, dolutegravir/lamivudine, or long-acting injectable cabotegravir/rilpivirine (every 4-8 weeks) 1
• Monotherapy with boosted PIs or dolutegravir is NOT recommended 1

Special Considerations for HBV Co-infection

• Patients with HIV/HBV co-infection switching therapy must continue tenofovir alafenamide or tenofovir disoproxil fumarate unless contraindicated 1
• Switching to a regimen with only lamivudine or emtricitabine (without tenofovir) will not maintain HBV suppression and risks severe hepatitis flare 1

Switching for Virological Failure

• Confirm virological failure (HIV RNA >200 copies/mL) and perform resistance testing while on the failing regimen 1
• Promptly switch to another active regimen using current and past resistance testing results 1
• Never add a single active agent to a failing regimen 1

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Monitoring Requirements

• Check HIV RNA viral load every 3 months during the first year, then every 3-6 months if stable 4
• Measure serum creatinine and calculate eGFR at baseline, 1 month, then every 3 months during the first year 5
• Perform HIV testing with combined antibody/antigen assay, STI screening, and hepatitis screening at baseline and regularly during treatment 5