Recommended Regimen for Multiclass-Resistant HIV with Dual-Tropic Virus
The most appropriate regimen is Option D: Dolutegravir twice daily plus fostemsavir twice daily plus ibalizumab once every 2 weeks. This patient requires a salvage regimen incorporating novel mechanism agents to overcome extensive multiclass resistance.
Resistance Profile Analysis
This patient demonstrates extensive resistance across all traditional antiretroviral classes:
Reverse transcriptase mutations include M184V (high-level resistance to emtricitabine/lamivudine), multiple thymidine analog mutations (M41L, L210W, T215Y conferring NRTI cross-resistance), and NNRTI mutations (K103N, V106M, E138A causing resistance to efavirenz, nevirapine, and likely doravirine) 1
Protease mutations (I54V, L76V, V82F, I84V, N88D) confer high-level resistance to multiple protease inhibitors including lopinavir, atazanavir, and likely darunavir 1
Integrase mutation E92Q reduces susceptibility to first-generation integrase inhibitors (raltegravir, elvitegravir) but maintains activity against dolutegravir when used at twice-daily dosing 1
Dual-tropic virus (both CCR5 and CXCR4-tropic) precludes maraviroc use, as maraviroc only blocks CCR5-tropic virus 1
Why Each Option Fails or Succeeds
Option A: Doravirine + Bictegravir/Emtricitabine/Tenofovir Alafenamide
This regimen is contraindicated. The patient has documented NNRTI resistance mutations (K103N, V106M, E138A) that confer cross-resistance to doravirine 1. The M184V mutation eliminates emtricitabine activity 1. While bictegravir may retain some activity against E92Q, this would constitute functional monotherapy, which rapidly selects for additional resistance 1, 2.
Option B: Doravirine + Fostemsavir + Ibalizumab
This regimen fails due to doravirine resistance. As noted above, the patient's NNRTI mutations render doravirine ineffective 1. This leaves only two active agents (fostemsavir and ibalizumab), which is insufficient for durable viral suppression in heavily treatment-experienced patients 1.
Option C: Dolutegravir Twice Daily + Lenacapavir + Maraviroc Twice Daily
This regimen is contraindicated due to dual-tropic virus. Maraviroc exclusively inhibits CCR5-tropic virus and has no activity against CXCR4-tropic virus 1. Using maraviroc in a patient with dual/mixed-tropic virus constitutes functional monotherapy with the remaining active agents, risking rapid resistance development 1.
Option D: Dolutegravir Twice Daily + Fostemsavir Twice Daily + Ibalizumab (CORRECT)
This regimen provides three fully active agents with novel mechanisms:
Dolutegravir 50 mg twice daily retains activity against E92Q mutation, which causes minimal resistance to second-generation integrase inhibitors 1, 3. The twice-daily dosing overcomes low-level resistance 1.
Fostemsavir is a gp120-directed attachment inhibitor with a novel mechanism unaffected by reverse transcriptase, protease, or integrase resistance 1, 2. It remains fully active against viruses resistant to traditional antiretroviral classes 2.
Ibalizumab is an anti-CD4 monoclonal antibody that inhibits HIV entry and is active against both CCR5- and CXCR4-tropic virus 1. It demonstrated approximately 50% virologic suppression at 24 weeks in heavily treatment-experienced patients when combined with at least one other active drug 1.
Critical Guideline Support
The 2025 International Antiviral Society-USA guidelines explicitly recommend that "in individuals with virologic failure with extensive multiclass resistance (including to InSTIs), agents with novel mechanisms of action such as ibalizumab, fostemsavir, or lenacapavir are recommended, ideally in combination to allow for 2 fully active drugs" 1. This patient requires at least two, preferably three, fully active agents from different classes 1.
Important Clinical Considerations
Resistance testing and adherence optimization are mandatory. Given the risk of developing resistance with functional monotherapy, careful consideration must be given to having active drugs in addition to each component 2. The patient should receive intensive adherence counseling, as suboptimal adherence to any component could lead to resistance development across the remaining active agents 2.
Avoid lenacapavir in this scenario despite its novel mechanism. While lenacapavir is an excellent capsid inhibitor, the FDA label warns that "given the risk of developing resistance in situations of functional monotherapy, careful consideration should be given to having active drugs in addition to SUNLENCA in the treatment regimen" 2. In Option C, combining lenacapavir with ineffective maraviroc creates exactly this high-risk scenario.
Monitor closely for virologic response. Viral load should be checked at 4 weeks, then monthly for the first 3 months, then every 3 months thereafter 1, 3. Any confirmed viremia >200 copies/mL should trigger immediate resistance testing 1, 3.