What is the best next step in managing a patient with HIV and persistent low-level viremia on bictegravir (Biktarvy)/emtricitabine (Emtriva)/tenofovir alafenamide (Vemlidy) with an HIV RNA <200 copies/mL?

Management of Persistent Low-Level Viremia in HIV

Stop ashwagandha and check HIV RNA in one month (Answer C). The most critical and immediately actionable step is to eliminate potential drug-drug interactions from supplements before pursuing more aggressive interventions like resistance testing or regimen changes.

Rationale for Supplement Discontinuation

The patient's use of ashwagandha represents a potential drug-drug interaction that could be compromising bictegravir efficacy. The 2016 IAS-USA guidelines explicitly state that clinicians should "review the complete medication list, including nonprescribed supplements, to ensure that drug-drug interactions are not compromising therapeutic efficacy" when evaluating persistent low-level viremia 1. This recommendation is reinforced in the 2025 guidelines, which specifically mention that supplements containing multivalent cations (calcium, magnesium, iron, zinc) can impair InSTI absorption 1. While ashwagandha's specific interaction profile with bictegravir isn't fully characterized, many herbal supplements contain minerals or affect drug metabolism, making this a high-yield intervention.

Why Not Resistance Testing Now?

Resistance testing is not indicated at this viral load level. The patient's HIV RNA is <200 copies/mL, which does not meet the definition of virologic failure (confirmed HIV RNA >200 copies/mL) 1. The 2025 IAS-USA guidelines are clear that patients with persistent low-level viremia between 50-200 copies/mL and confirmed adherence "are unlikely to benefit from ART intensification" and that changing regimens "is not recommended" provided the patient is on a high-barrier regimen like bictegravir 1.

Technical Limitations of Early Testing

• Genotypic resistance testing has poor amplification success at HIV RNA levels below 500-1000 copies/mL 1
• The patient reports 100% adherence, making non-adherence less likely as the primary cause
• Bictegravir has a high genetic barrier to resistance, making resistance development less probable 1

Why Not Add Darunavir/Cobicistat?

ART intensification is explicitly not recommended in this scenario. The 2025 guidelines provide Level AIa evidence that "patients with low-level viremia and confirmed adherence are unlikely to benefit from ART intensification" and that "such changes are not recommended" for patients on high-barrier regimens like bictegravir 1. Studies show no reduction in low-level viremia from intensifying therapy in adherent patients 1.

Additional Concerns with Intensification

• Adding darunavir/cobicistat increases pill burden and potential drug-drug interactions 1
• The patient has multiple comorbidities (CAD, diabetes, CKD stage 3) that increase risk of drug interactions and side effects
• Cobicistat can affect renal function parameters, which is particularly concerning given his existing CKD 1

Clinical Context Supporting Supplement Removal

This patient has multiple risk factors for drug-drug interactions:

• He takes atorvastatin, which can interact with some supplements 1
• His CKD stage 3 may affect drug metabolism and clearance
• The timing of persistent low-level viremia (developing after 2 years of suppression) suggests an acquired factor rather than baseline resistance 1

Appropriate Follow-Up Algorithm

After stopping ashwagandha, the management pathway should be:

1. Recheck HIV RNA in 4 weeks to assess response to supplement discontinuation 1
2. If viremia persists <200 copies/mL: Continue current ART with close monitoring every 3 months 1
3. If HIV RNA rises to >200 copies/mL on two consecutive measurements: Order resistance testing (both reverse transcriptase and integrase) 1
4. If resistance is detected: Modify regimen based on resistance profile 1

Common Pitfalls to Avoid

• Don't order resistance testing prematurely - it's unlikely to amplify successfully and doesn't meet criteria for virologic failure 1
• Don't intensify therapy without clear indication - this increases toxicity risk without proven benefit in adherent patients on high-barrier regimens 1
• Don't ignore supplements - they are frequently overlooked causes of treatment compromise 1
• Don't assume resistance in long-term suppressed patients - acquired resistance is uncommon with bictegravir when adherence is good 1

Evidence Quality Considerations

The 2025 IAS-USA guidelines 1 represent the most current evidence and explicitly address persistent low-level viremia in the modern ART era with high-barrier InSTIs like bictegravir. These supersede older 2016 recommendations 1 that were developed before widespread bictegravir use. The newer guidelines provide Level AIa evidence against intensification, making supplement removal the most appropriate first step before considering more aggressive interventions.