What to do with an HIV (Human Immunodeficiency Virus) positive patient on TLD (Tenofovir/Lamivudine/Dolutegravir) regimen who tests ELISA (Enzyme-Linked Immunosorbent Assay) negative on multiple occasions?

HIV Patient on TLD Testing ELISA Negative: Diagnostic Approach and Management

Immediate Assessment Required

This scenario represents a false-negative ELISA result in a virologically suppressed HIV patient on effective antiretroviral therapy, and you must confirm true HIV status using HIV RNA viral load testing and review the complete treatment history before making any treatment decisions. 1

Understanding the Phenomenon

• Seroreversion (loss of detectable HIV antibodies) can occur in patients on highly effective antiretroviral therapy, particularly with integrase inhibitor-based regimens like TLD (tenofovir/lamivudine/dolutegravir), though this remains extremely rare 1, 2

• The TLD regimen achieves virologic suppression rates of 92-99% in clinical trials, with viral loads suppressed to undetectable levels (<50 copies/mL) in the vast majority of adherent patients 2, 3, 4

• Fourth-generation combination antigen/antibody assays can occasionally produce false-negative results in patients with profound viral suppression, particularly if antibody titers decline over time with sustained viral control 1

Diagnostic Algorithm

Step 1: Confirm HIV Status with Viral Load Testing

• Order HIV RNA viral load testing immediately - this is the definitive test to confirm ongoing HIV infection regardless of antibody status 1

• If viral load is undetectable (<50 copies/mL), this confirms the patient remains HIV-positive with excellent virologic suppression on TLD 1, 3

• If viral load is detectable, proceed to resistance testing while the patient continues current therapy 1, 5

Step 2: Review Complete Treatment History

• Document all prior antiretroviral regimens, duration of use, and any history of treatment interruptions or virologic failure 2, 1

• Review all historical resistance testing results (genotypic and phenotypic) to assess for archived resistance mutations 2, 1

• Confirm duration on current TLD regimen and adherence patterns over the past several years 3, 4

Step 3: Verify Laboratory Testing Quality

• Repeat HIV ELISA testing using a different fourth-generation combination antigen/antibody assay to rule out laboratory error 1

• Consider HIV Western blot or HIV-1/HIV-2 differentiation assay if ELISA remains negative but viral load confirms infection 1

• Ensure specimens were properly collected, stored, and processed according to manufacturer specifications 1

Management Based on Viral Load Results

If Viral Load is Undetectable (<50 copies/mL)

• Continue TLD regimen without modification - the patient has excellent virologic suppression and changing therapy is not indicated 1, 2

• Monitor HIV RNA every 6 months as the patient has maintained suppression for over 1 year 1, 6

• Document this as a case of serological non-reactivity in the setting of virologic suppression, which does not change HIV diagnosis or treatment 1

• Counsel the patient that they remain HIV-positive despite negative antibody tests, and must continue lifelong antiretroviral therapy 1, 6

If Viral Load is Detectable (≥50 copies/mL)

• Assess for virologic failure (defined as HIV RNA ≥200 copies/mL) versus low-level viremia or blips 1

• For confirmed virologic failure, obtain genotypic resistance testing while patient continues TLD to prevent accumulation of additional resistance mutations 1, 5

• Evaluate adherence barriers, drug-drug interactions, and malabsorption issues that could compromise TLD efficacy 1, 2

• If extensive multiclass resistance is documented including integrase resistance, consider novel agents (ibalizumab, fostemsavir, or lenacapavir) in combination to achieve two fully active drugs 1

Critical Pitfalls to Avoid

• Never discontinue antiretroviral therapy based solely on negative ELISA results - this would lead to viral rebound and potential resistance development 1, 6

• Do not switch regimens without confirming virologic status and reviewing complete resistance history, as this may compromise future treatment options 2, 1

• Avoid using ELISA testing alone for monitoring treatment response in patients on long-term suppressive therapy - viral load is the appropriate monitoring test 1, 6

• Do not assume the patient is HIV-negative or "cured" - sustained virologic suppression does not equal eradication of HIV infection 1, 6

Ongoing Monitoring Protocol

• Continue HIV RNA monitoring every 6 months if virologically suppressed for >1 year with good adherence 1, 6

• Monitor CD4+ cell counts every 6 months until >250 cells/μL for at least 1 year with viral suppression 6

• Assess renal function (serum creatinine and eGFR) at least every 6 months given tenofovir component of TLD 2, 1

• Screen for drug toxicities and tolerability at each visit, as TLD is generally well-tolerated with <1% requiring permanent discontinuation 3