What are the typical first-line, second-line, and third-line antiretroviral therapy (ART) regimens for patients living with Human Immunodeficiency Virus (HIV), and how are treatment failure and monitoring assessed?

First-Line, Second-Line, and Third-Line ART Regimens with Treatment Failure and Monitoring

For initial HIV treatment, use dolutegravir (DTG) plus tenofovir (TDF or TAF) and lamivudine (3TC) or emtricitabine (FTC) as the preferred first-line regimen, with viral load monitoring at 6 weeks, then every 3 months until suppressed, followed by every 6 months thereafter. 1

First-Line ART Regimens

Preferred First-Line Regimen

• DTG-based regimens are now the standard of care for treatment-naïve patients, consisting of:
  • Dolutegravir (integrase inhibitor) + 2 NRTIs (tenofovir alafenamide or tenofovir disoproxil fumarate + lamivudine or emtricitabine) 1
  • This regimen achieves 89-93% virologic suppression (HIV-1 RNA <50 copies/mL) at 48 weeks with no treatment-emergent resistance in clinical trials 2
  • DTG has a high genetic barrier to resistance and superior efficacy compared to NNRTI-based regimens 1

Alternative First-Line Options

• NNRTI-based regimens (now considered alternative, not preferred):

  • Efavirenz + 2 NRTIs (TDF/3TC or FTC) 3
  • Nevirapine + 2 NRTIs 3
  • These regimens were historically dominant but have lower genetic barriers to resistance 4, 5

• Boosted protease inhibitor (PI/r) regimens:

  • Ritonavir-boosted atazanavir, darunavir, or lopinavir + 2 NRTIs 3
  • More drug interactions and side effects than integrase inhibitors 3

NRTI Backbone Selection

• Tenofovir alafenamide (TAF) is preferred over tenofovir disoproxil fumarate (TDF) for most patients due to reduced renal and bone toxicity 2
• Use TAF/FTC/DTG for patients with eGFR <60 mL/min/1.73 m² or bone disease risk 2
• TDF should be avoided or dose-adjusted if creatinine clearance is below 60 mL/min 1

Second-Line ART Regimens

After NNRTI-Based First-Line Failure

• Dolutegravir + 2 NRTIs (with at least 1 active by genotype) is superior to boosted PI regimens for NNRTI failure 3, 1
• This recommendation has the highest evidence rating (AIa) 3
• Typical regimen: DTG + TDF/3TC (or TAF/FTC) if no NRTI resistance detected 1

After Integrase Inhibitor First-Line Failure

• Boosted protease inhibitor + 2 NRTIs (with at least 1 active NRTI) is recommended 3
• Common regimens include darunavir/ritonavir or lopinavir/ritonavir + active NRTIs 3, 1
• Evidence rating: AIII 3

Resource-Limited Settings

• Second-line therapy typically consists of tenofovir + lamivudine + lopinavir/ritonavir 3
• Limited access to newer agents like darunavir, etravirine, maraviroc, and integrase inhibitors in resource-poor settings 3

Third-Line ART Regimens (Salvage Therapy)

For Multiclass Resistance

• Construct regimens using drugs from new classes if available, with at least 2 fully active agents from different classes 3
• Options include:
  • Dolutegravir (50 mg twice daily) + at least 1 other active drug for raltegravir/elvitegravir resistance 3
  • Maraviroc (if CCR5-tropic virus confirmed) 3
  • Ibalizumab (anti-CD4 monoclonal antibody) for multidrug-resistant virus, achieving ~50% undetectable viral load at 24 weeks 3

Critical Principle

• Never add a single active agent to a failing regimen (evidence rating AIa) 3

Types of Treatment Failure

Virologic Failure

• Defined as inability to achieve or maintain HIV-1 RNA suppression 3
• Confirm with repeat testing before switching regimens 1
• Perform resistance testing while taking the failing regimen or within 4 weeks of stopping 3

Immunologic Failure

• CD4 count is insensitive and nonspecific as a measure of virologic failure 3
• Relying on CD4 alone can result in:
  • Unnecessary switches in virologically suppressed patients 3
  • Continued failing therapy despite virologic failure 3

Clinical Failure

• Progression to AIDS-defining illness (ADI) or death 3
• 30% of trials failed to report mortality and 51% failed to report ADI progression 3

Monitoring Protocols

Initial Monitoring (First 6 Weeks)

• HIV-1 RNA testing within 6 weeks of starting ART to assess early virologic response 3, 1
• Assess adherence and tolerability 3
• Baseline resistance testing (HIV RT-pro genotype) before initiating therapy 1

Ongoing Monitoring for Virologically Suppressed Patients

• HIV-1 RNA every 3 months until <50 copies/mL for 1 year, then every 6 months 3, 1
• CD4 count monitoring (though viral load is the primary efficacy measure) 3
• Renal function monitoring (serum creatinine and eGFR), particularly for TDF-containing regimens 1, 2
• Liver enzyme tests every 6 months for long-acting injectable regimens 6
• Bone density assessment if risk factors present and using TDF 2

Monitoring for Specific Toxicities

• Neuropsychiatric symptoms for efavirenz-based regimens 1
• Hepatotoxicity monitoring for nevirapine (especially in women with CD4 >250 cells/μL and men with CD4 >400 cells/μL) 3
• Lipid profiles and glucose for PI-based regimens 3

Post-Switch Monitoring

• HIV-1 RNA at 1 month after switching regimens to confirm maintained or achieved viral suppression 3, 2
• Continue every 3 months for first year, then every 6 months if stable 2

Critical Pitfalls to Avoid

Resistance Testing Errors

• Switching without reviewing complete resistance testing history compromises efficacy 2
• Perform genotypic resistance testing while on failing regimen, not after discontinuation 3
• In resource-limited settings, lack of resistance testing leads to empiric second-line choices that may include drugs with existing resistance 3

HBV Co-infection Management

• Never discontinue tenofovir in HBV co-infected patients without alternative HBV suppressive therapy - risk of hepatitis flare 2
• HBV co-infected patients require 2 drugs active against HBV (usually TAF or TDF plus lamivudine or emtricitabine) 3
• Do not switch to 2-drug ART regimens in HBV co-infection 3

Drug Interaction Errors

• Dolutegravir requires twice-daily dosing (50 mg) when used with rifampin for tuberculosis co-infection 2
• Standard once-daily dosing is insufficient due to drug interaction 2
• For tuberculosis co-infection in resource-limited settings, efavirenz-based regimens may be preferred due to fewer interactions 1

Renal Dosing Errors

• Do not use standard dosing if eGFR <30 mL/min/1.73 m² without dose adjustment 2
• Switch from TDF to TAF proactively for patients at high risk of renal or bone toxicity 3

Pregnancy Considerations

• Efavirenz has teratogenicity concerns in first trimester 3
• Nevirapine has hepatotoxicity risk in women with CD4 >250 cells/μL 3
• Dolutegravir with TAF/FTC is now the recommended regimen in pregnancy with high efficacy and low adverse birth outcomes 2

Monotherapy Error

• Monotherapy with boosted PIs or dolutegravir is not recommended due to higher rates of virologic rebound with resistant virus 3