Clinically relevant thresholds for ultrasensitive HIV drug resistance testing: a multi-country nested case-control...

Area of Science:

• Virology
• Infectious Diseases
• Genetics

Background:

• Clinical implementation of ultrasensitive HIV drug resistance tests is hindered by the uncertain clinical relevance of drug-resistant minority variants.
• Assessing pretreatment drug resistance is crucial for predicting virological failure in HIV patients.

Purpose of the Study:

• To evaluate different detection thresholds for pretreatment drug resistance in predicting virological failure risk.
• To compare ultrasensitive next-generation sequencing with conventional Sanger sequencing for HIV drug resistance detection.

Main Methods:

• A case-control study nested within a prospective multicountry cohort of HIV patients in Africa.
• Pretreatment drug resistance assessed using Illumina MiSeq next-generation sequencing at 1%, 5%, 10%, and 20% detection thresholds.
• Virological failure defined as viral load ≥400 copies/mL or switch to second-line ART; viral suppression defined as <400 copies/mL.

Main Results:

• Lowering the detection threshold from 20% improved sensitivity for identifying virological failure risk but reduced specificity.
• At a 1% threshold, sensitivity increased to 17% and specificity reduced to 92%, with an adjusted odds ratio for virological failure of 4.5.
• Similar results were observed using Stanford HIV Drug Resistance Database genotypic sensitivity scores.

Conclusions:

• Ultrasensitive resistance testing enhances the identification of individuals at risk of virological failure.
• Further modeling is necessary to determine optimal thresholds, balancing improved case detection with the risk of unnecessary treatment changes.