## Resistance Mechanisms: PIs vs NNRTIs ### Key Differences in Mutation Patterns **Key Point:** NNRTIs have a low genetic barrier to resistance — a single nucleotide change in the reverse transcriptase gene (e.g., K103N, Y181C) can confer high-level resistance to the entire NNRTI class. In contrast, PIs have a high genetic barrier, requiring accumulation of multiple mutations (often 10+ amino acid changes) before clinically significant resistance emerges. ### Cross-Resistance Patterns | Feature | NNRTIs | PIs | |---------|--------|-----| | **Genetic barrier** | Low (1–2 mutations) | High (multiple mutations needed) | | **Cross-resistance** | High within class (single mutation affects all) | Partial/variable (depends on mutation profile) | | **Resistance development** | Rapid, often early in therapy | Slower, requires prolonged suboptimal adherence | | **Reversion** | Slow (mutations persist) | Faster (mutations revert if drug stopped) | ### Clinical Pearl **High-Yield:** This distinction explains why: - NNRTIs are contraindicated in treatment-experienced patients with prior NNRTI exposure (cross-resistance is near-universal). - PIs remain active in some treatment-experienced patients because resistance is mutation-specific; switching to a different PI may restore activity. - Boosted PI regimens (with ritonavir) are preferred in resource-limited settings because the high barrier to resistance provides a safety margin even with imperfect adherence. ### Mechanism Basis **Key Point:** NNRTIs bind to a non-catalytic pocket on reverse transcriptase; single amino acid changes dramatically alter the binding pocket geometry. PIs bind to the catalytic protease active site; the enzyme can tolerate multiple amino acid substitutions while retaining partial catalytic function, hence the requirement for multiple mutations. [cite:Harrison 21e Ch 197]
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