Recommended Antiretroviral Regimen
For this heavily treatment-experienced patient with stage 3 CKD (eGFR 51 mL/min) and extensive NRTI/NNRTI resistance but no integrase resistance, the most appropriate regimen is Option B: Dolutegravir and darunavir/cobicistat.
Rationale for Selection
Why Dolutegravir Plus Darunavir/Cobicistat is Optimal
This dual therapy regimen combines two high genetic barrier agents that are both fully active based on the resistance profile 1. The patient has no integrase mutations, making dolutegravir fully active, and only minor protease inhibitor mutations (D60D/E), which do not confer darunavir resistance 1.
Darunavir/cobicistat is specifically recommended for patients with known or suspected pretherapy multidrug resistance 1, which directly applies to this heavily treatment-experienced patient with extensive NRTI (K65K/R, T69T/I, L74L/V, Y115Y/F) and NNRTI (K103N, V106V/I, V179V/E, Y181%/C) mutations.
Recent high-quality evidence demonstrates excellent efficacy and safety of dolutegravir plus boosted-darunavir dual therapy in heavily treatment-experienced patients 2, 3, 4. A 2019 study showed 90% efficacy at week 48 in patients with mean PI mutations of 3.5 2, and a 2024 study confirmed sustained effectiveness through 144 weeks 4.
Why Other Options Are Inappropriate
Option A (Dolutegravir/lamivudine): This two-drug regimen is contraindicated because:
- The patient has documented NRTI resistance mutations (K65K/R, L74L/V) that compromise lamivudine activity 1
- This regimen should only be used when HIV RNA is <100,000 copies/mL and CD4 >200 cells/mm³ 1, but this patient has HIV RNA of 358,069 copies/mL
Option C (Bictegravir/emtricitabine/tenofovir alafenamide): This is inappropriate because:
- The patient has NRTI resistance mutations that would compromise both emtricitabine and tenofovir activity 1
- The fixed-dose combination cannot be dose-adjusted for renal impairment 1
Option D (Darunavir and elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate): This is contraindicated because:
- Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (Stribild) must be discontinued when creatinine clearance falls below 50 mL/min 1, and this patient has an eGFR of 51 mL/min
- The NRTI backbone would be compromised by existing resistance mutations 1
Renal Safety Considerations
Dolutegravir in Stage 3 CKD
Dolutegravir requires no dose adjustment for patients with mild, moderate, or severe renal impairment 1, 5. The usual dose of 50 mg once daily is appropriate for this INSTI-naive patient 1.
Dolutegravir causes a benign increase in serum creatinine (approximately 0.15 mg/dL) through inhibition of tubular creatinine secretion without affecting actual glomerular filtration 5. This is not true nephrotoxicity.
Darunavir/Cobicistat in Stage 3 CKD
Darunavir requires no dose adjustment for CKD or ESRD 1. The standard dose of 800 mg once daily with cobicistat 150 mg is appropriate 1.
Cobicistat, like dolutegravir, causes a benign increase in serum creatinine through inhibition of tubular secretion without affecting true GFR 1. This effect is reversible and does not represent actual kidney damage.
A 2019 study of dolutegravir plus boosted-darunavir showed mean eGFR decreased by 8.8 mL/min/1.73 m², but kidney tubular parameters actually improved 2, suggesting the creatinine increase is pharmacologic rather than pathologic.
Clinical Monitoring
Essential Follow-Up Parameters
Monitor HIV RNA at 4 weeks, 12 weeks, 24 weeks, and 48 weeks 2, 3. Evidence shows viral suppression rates of 45% at 4 weeks, 50% at 12-24 weeks, and 66.7% at 48 weeks in treatment-failure patients 3.
Monitor CD4 counts every 3-6 months 2, 3. Expected mean increase is approximately 162 cells/mm³ by week 48 5.
Monitor serum creatinine and eGFR at baseline, 2-4 weeks after initiation, then every 3-6 months 1. Expect a 0.15-0.3 mg/dL increase in creatinine from both dolutegravir and cobicistat, which stabilizes after 2-4 weeks 5.
Common Pitfalls to Avoid
Do not discontinue therapy due to the expected pharmacologic creatinine increase 5. This is not true nephrotoxicity and does not require dose adjustment or discontinuation.
Do not add NRTIs to this dual therapy regimen 2, 3, 4. The extensive NRTI resistance makes them ineffective, and avoiding NRTIs eliminates their associated toxicities while maintaining high efficacy.
Monitor for neuropsychiatric adverse events from dolutegravir 2. In the 2019 study, 3 of 51 patients (6%) discontinued due to neuropsychiatric symptoms, though overall tolerability was excellent at 96.8% 2.
Expected Outcomes
Virologic suppression to <50 copies/mL is achievable in 66-90% of heavily treatment-experienced patients by week 48 2, 3, 4, with sustained efficacy through 144 weeks 4.
This regimen provides high genetic barrier protection against resistance development 1, 2 due to the combination of two drugs with minimal cross-resistance to the patient's existing mutations.
Improved lipid profiles and renal tubular parameters are expected benefits 2 compared to regimens containing tenofovir or ritonavir-boosted protease inhibitors.