What is the recommended initial antiretroviral therapy regimen for a patient with Impaired renal function, high HIV RNA viral load, and specific genotype mutations?

Recommended Antiretroviral Therapy for Treatment-Naive Patient with Renal Impairment and Drug Resistance

For this 51-year-old treatment-naive patient with eGFR 51 mL/min and significant NRTI and NNRTI resistance mutations, I recommend darunavir/ritonavir (or darunavir/cobicistat) plus tenofovir alafenamide (TAF)/emtricitabine as the optimal initial regimen.

Rationale for Regimen Selection

Why Integrase Inhibitor-Based Regimens Are Not Optimal Here

• Bictegravir/TAF/emtricitabine, while generally the preferred first-line regimen for most patients 1, contains two NRTIs that may have reduced activity given the patient's NRTI mutations (K65K/R, T69T/I, L74L/V, Y115Y/F) 2
• Dolutegravir-based regimens similarly rely on fully active NRTI backbones for optimal efficacy 2
• The presence of multiple NRTI resistance mutations (particularly K65R and L74V when fully expressed) can compromise the activity of tenofovir and emtricitabine 2

Why Boosted Protease Inhibitor is the Preferred Choice

• Darunavir has a high genetic barrier to resistance and maintains activity even when NRTI resistance is present 2, 3
• Boosted darunavir plus TAF/emtricitabine is specifically recommended when InSTI resistance is suspected or when NRTI mutations are present 1
• The protease inhibitor genotype shows only D60D/E, which is not a major darunavir resistance-associated mutation 3
• Darunavir retains potency against multidrug-resistant HIV-1 strains and requires at least three darunavir resistance-associated mutations (V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, L89V) to confer resistance 3

Why TAF Over TDF

• With eGFR 51 mL/min, this patient has moderate renal impairment 2
• TDF is not recommended for individuals with or at risk for kidney disease 2
• TAF has fewer renal and bone toxicities compared to TDF, especially when used with pharmacological boosters like cobicistat or ritonavir 1, 4
• TAF-containing regimens are effective in maintaining viral suppression even in patients with baseline renal concerns 2, 4

Specific Regimen Recommendations

Primary Recommendation

• Darunavir 800 mg/cobicistat 150 mg plus TAF 10 mg/emtricitabine 200 mg once daily (available as fixed-dose combination D/C/F/TAF) 4
• This regimen demonstrated noninferior efficacy to component regimens with favorable bone and renal outcomes at 48 weeks 4

Alternative if Cobicistat Not Available

• Darunavir 800 mg/ritonavir 100 mg once daily plus TAF/emtricitabine 2
• Both boosting agents (ritonavir and cobicistat) are effective, though cobicistat-boosted regimens have more drug interactions 1

Why NNRTI-Based Regimens Are Contraindicated

• The patient has multiple NNRTI resistance mutations (K103N, V106V/L, V179V/E, Y181Y/C) 2
• K103N is a major NNRTI resistance mutation that confers high-level resistance to efavirenz and nevirapine 2
• NNRTIs should not be used for rapid ART start in any case 2
• Rilpivirine is not appropriate as it requires HIV RNA <100,000 copies/mL (this patient has 358,069 copies/mL) 2

Evidence Supporting Boosted Darunavir in Resistant Virus

• In treatment-experienced patients with background resistance, darunavir/ritonavir plus tenofovir/emtricitabine achieved viral suppression in >75% of patients even with M184V/I mutations present 5
• Darunavir/cobicistat/emtricitabine/TAF maintained virologic suppression even in patients with previous virologic failure, provided there was no history of darunavir failure or darunavir-resistance mutations 2
• The high viral load (358,069 copies/mL) and CD4 count of 428 cells/μL indicate the need for a regimen with high potency and genetic barrier to resistance 2

Critical Monitoring Parameters

Baseline Testing Required

• Confirm resistance testing results and review for any additional mutations 2
• Assess for hepatitis B co-infection as this would require maintaining TAF or TDF in the regimen 1
• Baseline renal function, bone density assessment given moderate renal impairment 4

Follow-Up Monitoring

• Measure HIV RNA at 4-6 weeks to assess initial virologic response 1
• Monitor renal function closely given baseline eGFR of 51 mL/min 4
• Continue viral load monitoring every 3 months until suppression achieved 1
• Assess for drug-specific toxicities including gastrointestinal symptoms and lipid abnormalities 3

Common Pitfalls to Avoid

• Do not use a standard integrase inhibitor-based regimen without considering the NRTI resistance mutations present 2
• Do not use TDF-containing regimens in this patient with eGFR 51 mL/min 2
• Do not attempt two-drug regimens (such as dolutegravir/lamivudine) in treatment-naive patients with high viral loads and resistance mutations 2, 1
• Do not delay ART initiation while awaiting additional testing; start treatment as soon as possible 2
• Do not add a single active agent if virologic failure occurs; always switch to a fully suppressive regimen 2

Expected Outcomes

• Darunavir-based regimens achieve viral suppression in >80% of treatment-naive patients at 48 weeks 6
• The high genetic barrier of darunavir minimizes risk of resistance development even with partially active NRTI backbone 3
• TAF provides renal-sparing benefits critical for this patient with baseline renal impairment 4