A 28-year-old woman with HIV-1 infection (CD4 count 180 cells/μL) who is currently on dolutegravir + tenofovir + lamivudine for 6 months presents with virological failure (viral load 45,000 copies/mL). Genotypic testing shows M184V mutation (lamivudine resistance) and no integrase inhibitor resistance mutations. What is the preferred next-line regimen?

Explanation

## Second-Line Regimen for M184V Resistance with Intact Integrase Susceptibility **Key Point:** In a patient with M184V mutation (lamivudine/emtricitabine resistance) but no integrase inhibitor resistance, the preferred second-line regimen is **dolutegravir + tenofovir alafenamide (TAF) + emtricitabine (FTC)**. ### Rationale for DTG-Based Second-Line **High-Yield:** Dolutegravir retains full activity in this scenario because: - No integrase mutations are present (genotype confirms susceptibility) - DTG has the highest genetic barrier to resistance (requires ≥2 mutations) - DTG maintains efficacy even in advanced immunosuppression (CD4 = 180) - Switching to a different drug class (PI) is unnecessary when DTG remains active **Clinical Pearl:** The principle of **"keep what works"** applies here — if the integrase inhibitor remains susceptible, continue it and optimize the nucleoside backbone. ### Nucleoside Backbone Optimization: TAF + FTC | Feature | TAF + FTC | TDF + 3TC (Previous) | |---------|-----------|---------------------| | **M184V Activity** | FTC retains activity; M184V causes low-level resistance | 3TC has complete resistance with M184V | | **Renal Safety** | TAF: minimal renal toxicity; better bone safety | TDF: requires monitoring; mild bone loss | | **Barrier to Resistance** | FTC: single mutation (M184V) but DTG compensates | 3TC: complete loss with M184V | | **Dosing** | Once-daily; no food requirement | Once-daily; no food requirement | **Warning:** Although FTC also has M184V resistance, the combination of **DTG (high barrier) + TAF (excellent safety) + FTC** is superior to adding a protease inhibitor, which increases pill burden and drug interactions without additional benefit when DTG is still active. ### Why Other Options Are Not Preferred **Ritonavir-boosted Darunavir (Option 1):** Protease inhibitor-based regimen is appropriate for integrase inhibitor resistance, but DTG is still fully active here; adding a PI increases toxicity and drug interactions unnecessarily. **Raltegravir (Option 2):** Lower barrier to resistance than DTG; switching from DTG to raltegravir is a step backward; abacavir is contraindicated in HLA-B*5701-positive patients (unknown status here) and offers no advantage. **Efavirenz (Option 3):** NNRTI-based regimens are outdated for second-line therapy; EFV has lower barrier to resistance, more CNS toxicity, and is no longer recommended by WHO or Indian guidelines for treatment-experienced patients. **Mnemonic:** **"TAF-FTC-DTG = Two Anchors, One Fortress"** — TAF (anchor 1: renal safety), FTC (anchor 2: nucleoside), DTG (fortress: high barrier to resistance). **High-Yield:** Current WHO and Indian guidelines recommend **maintaining DTG in second-line** if no integrase resistance is detected, optimizing the nucleoside backbone to TAF + FTC. Protease inhibitor-based regimens are reserved for confirmed integrase inhibitor resistance.