Abstract
At Week 96 of the Single-Tablet Regimen (STaR) study, more treatment-naïve subjects that received rilpivirine/emtricitabine/tenofovir DF (RPV/FTC/TDF) developed resistance mutations compared to those treated with efavirenz (EFV)/FTC/TDF by population sequencing. Furthermore, more RPV/FTC/TDF-treated subjects with baseline HIV-1 RNA >100,000 copies/mL developed resistance compared to subjects with baseline HIV-1 RNA ≤100,000 copies/mL. Here, deep sequencing was utilized to assess the presence of pre-existing low-frequency variants in subjects with and without resistance development in the STaR study. Deep sequencing (Illumina MiSeq) was performed on baseline and virologic failure samples for all subjects analyzed for resistance by population sequencing during the clinical study (n = 33), as well as baseline samples from control subjects with virologic response (n = 118). Primary NRTI or NNRTI drug resistance mutations present at low frequency (≥2% to 20%) were detected in 6.6% of baseline samples by deep sequencing, all of which occurred in control subjects. Deep sequencing results were generally consistent with population sequencing but detected additional primary NNRTI and NRTI resistance mutations at virologic failure in seven samples. HIV-1 drug resistance mutations emerging while on RPV/FTC/TDF or EFV/FTC/TDF treatment were not present at low frequency at baseline in the STaR study.
Highlights
Drug resistance testing for HIV-infected patients is recommended by treatment guidelines as part of standard of care to inform the selection of initial, as well as next-line treatment strategies after virologic failure [1]
No drug resistance mutations were detected at low frequency in baseline samples from Resistance Analysis Population (RAP) subjects while primary nucleoside reverse transcriptase inhibitor (NRTI) or nucleoside reverse transcriptase inhibitors (NNRTIs) drug resistance mutations were detected at low frequency in 8.5% of samples from control subjects (6.6% of all baseline samples tested)
Baseline HIV-1 primary NNRTI- and NRTI-resistance associated mutations were detected as minority populations in 6.6% of subject isolates analyzed by deep sequencing in the Single-Tablet Regimen (STaR) study
Summary
Drug resistance testing for HIV-infected patients is recommended by treatment guidelines as part of standard of care to inform the selection of initial, as well as next-line treatment strategies after virologic failure [1]. The STaR study (GS-US-264-0110) was a randomized, open-label, 96-week study designed to directly compare the safety and efficacy of the two NNRTI-based single tablet regimens (STRs) rilpivirine (RPV)/emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) and efavirenz (EFV)/FTC/TDF in treatment-naïve HIV-1-infected adults [12,13]. Within the RPV/FTC/TDF arm, resistance development was more frequent in subjects with baseline HIV-1 RNA >100,000 copies/mL compared to baseline HIV-1 RNA ď100,000 copies/mL (9.0% vs 3.5%, respectively) [14] These results are consistent with the current indication for RPV/FTC/TDF in treatment-naïve patients, which is restricted to use in patients with HIV-1 RNA ď100,000 copies/mL due to an increased risk of virologic failure and resistance development in patients with high baseline viral load [15,16]
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