Screening HIV-1 patients for the presence of low-frequency HIV-1 drug resistance mutations can help identify which patients are more likely to fail first-line antiretroviral treatment with NNRTIs, according to scientists at Brigham and Women’s Hospital and Harvard Medical School. The researchers evaluated the relationship between baseline low-frequency HIV-1 drug resistance mutations and the risk of virologic failure with NNRTI-based treatment regmens.
They found that patients who carried these types of mutations had a 2.3-times increased risk of virologic failure compared with patents who didn't have the mutations even after controlling for other factors. The presence of NNRTI-resistant minority variants in particular was associated with a 2.6-fold increased risk of virologic failure. The results are reported in the latest issue of JAMA in a paper titled "Low-Frequency HIV-1 Drug Resistance Mutations and Risk of NNRTI-Based Antiretroviral Treatment Failure."
Results from traditional testing approaches suggest the prevalence of transmitted drug resistance mutations is about 8–16% in HIV-1 patients in North America and Europe, report Brigham and Harvard’s Jonathan Z. Li, M.D., and colleagues. However, these tests can’t detect the presence of low-frequency, or minority drug-resistance mutations, and the clinical significance of these variants in terms of response to antiretroviral therapy “continues to be the subject of considerable debate and uncertainty,” the team writes.
The researchers detected identified low-frequency drug resistance mutations in 187 participants including 117 of 808 patients in the cohort studies. They found that 35% of patients with detectable minority variants experienced virologic failure compared with a failure rate of just 15% among patients who didnt carry minority variants.
This increased risk of virologic failure was significant even at very low minority variant frequences of less than 0.5% and 10–99 copies per mL. “A dose-dependent increased risk of virologic failure was found in participants with a higher proportion or quantity of drug-resistance variants,” the authors add.
Adherence to retroviral therapy was in addition a major predictor of viral suppression and disease progression. "In this analysis, we found that the risk of virologic failure associated with the presence of drug-resistant minority variants was similar to that conferred by suboptimal medication adherence," the authors write. Patients who managed only suboptimal adherence and also carried minority variants had a 10-fold increased risk of virologic failure compared with those with wild-type virus and excellent adherence.
Interestingly, race/ethnicity appeared to be a significant predictor of virologic failure even after controlling for adherence to medication. "White participants had a lower risk of virologic failure compared with black and Hispanic participants," the authors state. "This risk difference was not attributable to differing rates of minority variant detection."
The researchers suggest that by using the most sensitive tests for NNRTI resistance mechanisms, only 11 patients would need to be screened prior to starting an NNRTI-based treatment regimen to avoid one case of virologic failure.
“These data provide a rationale for developing standardized clinical assays for the detection of NNRTI-resistant minority variants,” they conclude. “Because NNRTI-based regimens are the most commonly prescribed first-line antiretroviral therapy, the clinical use of ultrasensitive screening for drug-resistant HIV could help identify individuals at greatest risk of virologic failure and allow ART to be tailored appropriately.”