Transmitted drug resistance mutations increase in HIV

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Transmitted drug-resistance mutations in HIV increased among ART–naive patients from 2000 to 2013, according to Gilead Sciences study findings.

“The research and discovery of chemical entities targeting HIV replication have provided the medical community with an arsenal of drugs to combat the advance of the Aids epidemic,” Healio reports that Nicolas A Margot, MA, of the department of biology at Gilead Sciences, and colleagues wrote. “However, concurrent to the use of ART with sub-optimal viral suppression and owing to the error-prone replication of HIV reverse transcriptase, drug-resistant strains of HIV have emerged.”

Researchers conducted resistance testing in 5,990 ART–naive patients who had participated in nine clinical studies performed by Gilead between 2000 and 2013. Across all nine studies, median age ranged from 34 to 38 years. The most common subtype was HIV-1 subtype B.

During the study period, the incidence of transmitted drug-resistance mutations increased from 5.2% to 11.4%, the researchers reported. This was driven mainly by non-nucleoside RT inhibitor resistance mutations, which increased incidence from 0.3% to 7.1%. K103N/S mutations in particular rose from 0.3% to 5.3%.

NRTI mutations occurred in 3.1% of patients, Margot and colleagues wrote. A small percentage of patients had at least one thymidine mutations: 0.07% had T215Y/F mutations and 2.7% had T215 revertant mutations. Those patients who had a combination of M41L+L210W+T215 revertant mutations showed full suppression when treated with a TDF or tenofovir alafenamide-containing regimen, the researchers reported.

“In summary, we have shown that the presence of common transmitted drug-resistance mutations, particularly the T215 revertant mutations, in ART–naive patients had no measurable impact on treatment response to TDF or tenofovir alafenamide-based regimens,” Margot and colleagues wrote. “This further suggests that the presence of T215 revertant mutations should not be a factor in the estimation of genotypic resistance to TDF or tenofovir alafenamide.”

Abstract
Background: The presence of transmitted drug-resistance mutations (TDRM) in antiretroviral (ARV) treatment-naïve patients can adversely affect the outcome of ARV therapy.
Methods: Resistance testing was conducted in 6704 ARV-naïve subjects predominantly from the U.S. and Europe in 9 Gilead clinical studies from 2000 to 2013.
Results: The presence of TDRM increased during this period (5.2% to 11.4%), primarily driven by non-nucleoside RT inhibitor resistance mutations (NNRTI; 0.3% to 7.1%), particularly K103N/S (0.3% to 5.3%). NRTI mutations were found in 3.1% of patients. Only 1 patient had K65R (0.01%) and 7 patients had M184V/I (0.1%) despite high use of tenofovir disoproxil fumarate (TDF), emtricitabine, and lamivudine and potential transmission of resistance to these drugs. One or more thymidine analog mutations (TAMs) were present in 2.7% of patients with 0.07% harboring T215Y/F and 2.7% harboring T215 revertant mutations (T215rev). Patients with the combination of M41L+L210W+T215rev showed full HIV RNA suppression while receiving a TDF- or tenofovir alafenamide (TAF)-containing regimen.
Conclusions: There was an overall increase of TDRMs among patients enrolling in clinical trials from 2000 through 2013 driven primarily by an increase in NNRTI-R. However, the presence of common TDRMs, including TAMs/T215rev, showed no impact on response to TDF- or TAF-containing regimens.

Authors
Nicolas A Margot, Pamela Wong, Rima Kulkarni, Kirsten White, Danielle Porter, Michael E Abram, Christian Callebaut, Michael D Miller

Healio report
Journal of Infectious Diseases abstract


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