A 38-year-old man with HIV-1 infection on efavirenz-based ART for 2 years presents with virological failure (VL 45,000 copies/mL). Genotyping shows K103N mutation. Which feature best distinguishes his options between switching to a PI-based regimen versus a dolutegravir-based regimen?

Explanation

## Treatment Options After NNRTI Resistance ### Clinical Scenario: K103N Mutation **Key Point:** K103N is a hallmark NNRTI resistance mutation that confers high-level resistance to all first-generation NNRTIs (efavirenz, rilpivirine). However, K103N does **not** confer resistance to integrase inhibitors or protease inhibitors — it is specific to reverse transcriptase binding. ### Comparison: PI-Based vs Dolutegravir-Based Regimens | Feature | PI-Based Regimen | Dolutegravir-Based Regimen | |---------|------------------|----------------------------| | **Activity vs K103N** | Retained (K103N is RT mutation, not protease) | Retained (targets integrase, not RT) | | **Genetic barrier** | High (multiple mutations needed for resistance) | Very high (rare resistance, even in treatment-experienced) | | **Pill burden** | Higher (PI + boosters + 2 NRTIs) | Lower (dolutegravir + 2 NRTIs) | | **Drug interactions** | Extensive (CYP3A4 inhibitor/inducer) | Minimal (UGT1A1 metabolism) | | **GI tolerability** | Moderate (nausea, diarrhea common) | Excellent | | **Resistance barrier in this setting** | Depends on concurrent protease mutations | Extremely high; K103N does not affect integrase | ### Why Dolutegravir Is Preferred Here **High-Yield:** Dolutegravir has become the preferred second-line integrase inhibitor in treatment-experienced patients because: 1. K103N (and all NNRTI mutations) do not affect its activity. 2. It has an exceptionally high genetic barrier to resistance — resistance requires accumulation of multiple integrase mutations (rare in clinical practice). 3. Simpler dosing, fewer drug interactions, and better tolerability than boosted PIs. 4. WHO and most national guidelines now recommend dolutegravir-based regimens as first-line salvage therapy after NNRTI failure. ### PI-Based Regimens: Still Valid But... **Clinical Pearl:** PIs retain full activity against K103N-containing virus. However, in a patient with 2 years of virological failure on efavirenz, there is a risk of **concurrent protease mutations** (especially if adherence was suboptimal). Genotyping should always be reviewed for protease mutations before committing to a PI-based regimen. Dolutegravir avoids this concern entirely. **Key Point:** K103N is **reverse transcriptase–specific**. It does not affect protease or integrase. Therefore: - PIs: Activity retained, but check for protease mutations. - Dolutegravir: Activity fully retained; K103N is irrelevant to integrase function. [cite:Harrison 21e Ch 197; WHO ART Guidelines 2023]