What pre-treatment reverse transcriptase genotype results indicate a low risk of treatment failure with cabotegravir (Integrase Strand Transfer Inhibitor)/rilpivirine (Non-Nucleoside Reverse Transcriptase Inhibitor) in a patient with Human Immunodeficiency Virus (HIV)?

Pre-Treatment Genotype Indicating Low Risk of Treatment Failure with Cabotegravir/Rilpivirine

The correct answer is C) K103N only, as this mutation indicates low risk of treatment failure with cabotegravir/rilpivirine. K103N is a first-generation NNRTI resistance mutation that does not significantly affect rilpivirine susceptibility, making it the safest option among the choices provided.

Critical Contraindications for Cabotegravir/Rilpivirine

Long-acting cabotegravir plus rilpivirine is not recommended in individuals with documented or suspected resistance to either agent to minimize the risk of treatment failure 1. This is particularly important because:

• An important limitation of injectable cabotegravir and rilpivirine is a 1-2% incidence of virologic failure with emergence of 2-class resistance even with adherence to scheduled injections 1
• Risk factors for virologic failure include rilpivirine-associated resistance at baseline as detected by proviral DNA genotyping, viral subtype A6, and BMI >30 1
• This patient has a BMI of 32 kg/m², which already places her at increased risk 1

Analysis of Each Genotype Option

Option A: E138K Only - CONTRAINDICATED

• E138K is a rilpivirine-associated resistance mutation that emerged in clinical trials of cabotegravir/rilpivirine 2
• In FLAIR and ATLAS trials, 88% of confirmed virologic failures had treatment-emergent NNRTI resistance-associated substitutions including E138K 2
• Cell culture studies showed that E138K+Q148K combinations conferred 53- to 260-fold reductions in cabotegravir susceptibility 2
• Patients with documented rilpivirine resistance should not receive cabotegravir/rilpivirine due to increased risk of treatment failure 3

Option B: Y181C Only - CONTRAINDICATED

• Y181C is a major NNRTI resistance mutation that confers high-level resistance to rilpivirine 2
• This mutation would compromise one of the two active components of the regimen 3
• Using cabotegravir/rilpivirine in patients with rilpivirine resistance would significantly increase the risk of virologic failure 3

Option C: K103N Only - ACCEPTABLE (Correct Answer)

• K103N is a first-generation NNRTI mutation (associated with efavirenz/nevirapine resistance) that has minimal impact on rilpivirine susceptibility 2
• This mutation does not appear in the list of rilpivirine-associated resistance mutations that emerged during cabotegravir/rilpivirine clinical trials 2
• K103N alone does not significantly reduce the efficacy of second-generation NNRTIs like rilpivirine 2

Option D: L74I and M230L - CONTRAINDICATED

• L74I is an integrase polymorphism strongly associated with virologic failure on cabotegravir/rilpivirine 2
• Eight of 18 (44%) confirmed virologic failures in FLAIR, ATLAS, and ATLAS-2M had HIV-1 subtype A1, with 7 of 8 having the L74I polymorphism detected at baseline 2
• In ATLAS-2M, the L74I polymorphism was detected at baseline in 5 of the virologic failure participants 2
• M230L is a rilpivirine-associated resistance mutation that emerged in clinical trials 2
• The combination of both mutations represents dual-class vulnerability and is strongly contraindicated 2

Additional Risk Considerations for This Patient

BMI >30 as a Risk Factor

• This patient's BMI of 32 kg/m² is an independent risk factor for virologic failure with cabotegravir/rilpivirine 1
• The combination of elevated BMI with any baseline resistance mutations would further increase failure risk 1

Importance of Comprehensive Baseline Testing

• Clinicians should perform proviral DNA genotyping to detect archived NNRTI resistance-associated substitutions before switching to cabotegravir/rilpivirine 2
• Standard plasma RNA genotyping may miss archived resistance mutations that can emerge during treatment 2

Common Pitfalls to Avoid

• Do not assume all NNRTI mutations equally affect rilpivirine: First-generation NNRTI mutations like K103N have minimal impact on rilpivirine, while mutations like E138K, Y181C, and M230L are specifically associated with rilpivirine resistance 2
• Do not overlook integrase polymorphisms: The L74I polymorphism, even without phenotypic resistance at baseline, is strongly associated with treatment failure 2
• Do not ignore BMI as a risk factor: Patients with BMI >30 require careful counseling about the increased risk of virologic failure 1
• Do not proceed without discussing treatment failure risks: Clinicians must discuss the possibility of treatment failure, potential for viral transmission if virologic rebound occurs, and future limitations of treatment options 1