What is a standard HIV triple therapy regimen?

Standard HIV Triple Therapy

The current standard HIV triple therapy consists of two nucleoside reverse transcriptase inhibitors (NRTIs) plus an integrase strand transfer inhibitor (INSTI), with the preferred first-line regimen being bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) or dolutegravir plus tenofovir alafenamide/emtricitabine (DTG + TAF/FTC). 1, 2

Core Components of Triple Therapy

The triple therapy framework has three essential elements:

• Two NRTIs (the "backbone"): Tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF) combined with either emtricitabine (FTC) or lamivudine (3TC) 1, 2
• Third agent (the "anchor"): An INSTI (dolutegravir, bictegravir, or raltegravir), boosted protease inhibitor (PI/r), or non-nucleoside reverse transcriptase inhibitor (NNRTI) 3
• The INSTI-based regimens have supplanted NNRTI and PI-based regimens as preferred first-line therapy due to superior efficacy, tolerability, and resistance profiles 3, 1

Preferred First-Line Regimens

INSTI-Based Combinations (Highest Priority)

• Bictegravir/TAF/FTC: Single-tablet regimen with high efficacy, favorable side effect profile, and high barrier to resistance 2
• Dolutegravir + TAF/FTC: Highly effective with strong resistance profile 2
• Dolutegravir/abacavir/lamivudine (DTG/ABC/3TC): Effective alternative but requires mandatory HLA-B*5701 testing before use to prevent potentially life-threatening hypersensitivity reactions 3, 2

Alternative Regimens

• Boosted protease inhibitor-based: Darunavir/ritonavir (DRV/r) or darunavir/cobicistat (DRV/c) plus TAF/FTC, recommended when INSTI resistance is suspected 3, 2
• NNRTI-based regimens: Efavirenz, rilpivirine, or nevirapine with two NRTIs are now considered less preferred due to lower genetic barrier to resistance and more side effects 3, 1

Evolution of Standard Therapy

The concept of triple therapy emerged in the late 1990s and has evolved significantly:

• Historical context: By 2002-2003, the standard regimens included NNRTI + 2 NRTIs, PI + 2 NRTIs, and ritonavir-boosted PI + 2 NRTIs 3
• Triple-NRTI regimens (such as zidovudine/lamivudine/abacavir) are no longer recommended due to higher rates of virologic failure compared to other regimens 3, 4
• Current guidelines prioritize INSTI-based regimens, with the IAS-USA naming tenofovir with emtricitabine as the preferred backbone 3

NRTI Backbone Selection

Tenofovir Formulations

• TAF vs TDF: TAF has fewer tenofovir-associated adverse effects (proximal renal tubular toxicity and bone mineral density reductions) compared to TDF, particularly when used with pharmacological boosters 3, 2
• TDF considerations: Results in lower plasma lipid levels than TAF, though clinical significance is unknown; generic formulations are increasingly available and cost-effective 3
• Renal impairment: For patients with creatinine clearance <60 mL/min, replace TDF with TAF 1, 5

Companion NRTI

• Emtricitabine or lamivudine: Both are equally effective when combined with tenofovir 3, 5
• Abacavir: Limited role in initial therapy given the efficacy of two-drug dolutegravir/lamivudine regimens and concerns about potential cardiovascular risk 3

Special Population Considerations

Hepatitis B Co-infection

• Mandatory dual HBV activity: Patients with HIV/HBV co-infection must receive regimens containing tenofovir (TDF or TAF) plus either emtricitabine or lamivudine 1, 2
• Avoid two-drug regimens: Dolutegravir/lamivudine should not be used in HBV co-infection 3, 2

High Viral Load or Low CD4 Count

• Patients with HIV RNA >100,000 copies/mL or CD4 <200 cells/μL: INSTI-based triple therapy is particularly important for optimal virologic suppression 3
• Two-drug regimens: Dolutegravir/lamivudine demonstrated lower rates of viral suppression in patients with CD4 <200 cells/μL (79% vs 93% with triple therapy) 3

Pregnancy

• Dolutegravir plus TAF/FTC is the recommended regimen; bictegravir/TAF/FTC is an alternative 2
• Efavirenz: Can be continued in pregnant women presenting in the first trimester if already virologically suppressed 3

Tuberculosis Co-infection

• Drug interactions: Rifampin cannot be used with many regimens including BIC/TAF/FTC, DTG/3TC, elvitegravir/cobicistat, and rilpivirine 2
• Efavirenz-based regimens: May still be considered due to fewer drug interactions with TB medications 5

Two-Drug Regimens: A Departure from Standard Triple Therapy

While triple therapy remains standard, certain two-drug regimens are now guideline-recommended:

Dolutegravir/Lamivudine (DTG/3TC)

• Indications: Only if HIV RNA <500,000 copies/mL, no lamivudine resistance, and no HBV co-infection 3, 2
• Efficacy: Demonstrated non-inferiority to three-drug regimens in the GEMINI studies, with no virological resistance in either group 3
• Limitations: Cannot be started on the same day as HIV diagnosis (requires resistance testing results); numerically lower suppression rates in patients with CD4 <200 cells/μL 3

Other Two-Drug Options

• Dolutegravir/rilpivirine: For switching in the setting of viral suppression 3
• Boosted PI with lamivudine: For switching in virologically suppressed patients 3
• Real-world data: INSTI-based triple therapy shows significantly higher time to discontinuation and lower probability of virologic failure compared to two-drug combinations 6

Monitoring After Initiation

Virologic Monitoring

• Initial assessment: HIV RNA testing within 4-6 weeks of starting therapy 1, 2
• Until suppression: Every 3 months until HIV RNA <50 copies/mL for at least 1 year 1, 2
• After suppression: Can extend to every 6 months once viral suppression is maintained 1, 2

Immunologic Monitoring

• CD4+ cell counts: Every 6 months until >250 cells/μL for at least 1 year with viral suppression 1
• Expected response: Mean CD4 increase of approximately 190-260 cells/mm³ at 48 weeks with effective therapy 7, 8

Resistance Testing

• Baseline: HIV genotype testing before initiating therapy 5
• Virologic failure: Resistance testing while taking the failing regimen or within 4 weeks of stopping 3

Critical Pitfalls to Avoid

Pre-Treatment Errors

• Not testing for HLA-B*5701 before prescribing abacavir-containing regimens can lead to potentially life-threatening hypersensitivity reactions 3, 2
• Starting DTG/3TC without confirming HIV RNA level, resistance status, and HBV status 2
• Overlooking drug interactions, particularly with cobicistat-boosted regimens or in patients taking rifampin 2

Regimen Selection Errors

• Using triple-NRTI regimens: These are virologically inferior to NNRTI or PI-containing regimens and should not be used 3, 4
• Unboosted protease inhibitors: No longer recommended due to inferior efficacy compared to ritonavir-boosted PIs 3
• Single-drug switches or additions: Not recommended except in the setting of optimal viral suppression 3

Monitoring Errors

• Delaying ART initiation: Treatment should be started as soon as possible after diagnosis to prevent disease progression 2
• Inadequate virologic monitoring: Failure to confirm viral suppression can lead to accumulation of resistance mutations 3

Virologic Failure Management

When triple therapy fails:

• Confirm virologic failure with repeat testing and reinforce adherence counseling before switching 3, 5
• Resistance testing is essential to guide selection of the new regimen 3
• After NNRTI failure: Dolutegravir plus 2 NRTIs (with at least 1 active by genotype) 3
• After INSTI failure: Boosted PI plus 2 NRTIs (with at least 1 active NRTI) 3
• Dolutegravir resistance: May still be effective if dosed twice daily with at least 1 fully active other agent 3
• Never add a single active agent to a failing regimen 3