Distinct Pattern of Thymidine Analogue Mutations with K65R in Patients Failing Tenofovir-Based Antiretroviral Therapy

Abstract

Historically, in HIV patients, the K65R mutation and thymidine analogue mutations (TAMs) have been reported to rarely coexist. We retrospectively reviewed genotype data from paired samples in a cohort of HIV-1-infected Nigerian patients failing first-line antiretroviral therapies containing zidovudine (AZT) or tenofovir (TDF). Samples for each patient were taken at initial confirmed virological failure ≥1000 copies/ml (S1) and then at the latest available sample with viral load ≥1000 copies/ml before switch to second line (S2). Among 103 patients failing AZT, 19 (18.4%) had TAM-1s, 29 (28.2%) TAM-2s, and 21 (20.4%) mixed TAMs by S2. In contrast, in the 87 patients failing TDF, drug resistance mutations at S2 included K65R in 56 (64.4%), TAM-1s in 1 (1.1%), and TAM-2s in 25 patients (28.7%). Interestingly, 30.4% of patients with K65R in our study developed TAMs. These were exclusively K219E ± D67N and were not predicted to confer a resistance cost to future AZT-containing regimens.

Keywords: HIV; HIV drug resistance; Nigeria; tenofovir; thymidine analogue mutations; zidovudine.

FIG. 1.

Frequency of NRTI DRMs in patients on AZT-based 1L regimen or TDF-based 1L regimen. Solid colors show the percentage accumulation of each mutation by the S1 sampling, and dotted colors show the continued accumulation between S1 and S2. Mutations that occur at significantly different frequencies between the two groups at S2, after correcting for multiple comparisons, are indicated with an asterisks. DRMs, drug resistance mutations.

FIG. 2.

TAM distribution by NRTI backbone and associated DRMs. (A) TDF or (B) AZT. The cumulative frequencies of individual TAMs are shown in the bar charts to the right: i. Frequency of individual TAMs coexisting with K65R at S2, in patients on 1L TDF. ii. Frequency of individual TAMs in samples with no K65R at S2, in patients on 1L TDF. iii. Frequency of individual TAMs at S2, in patients on 1L AZT. TAM, thymidine analogue mutation.

FIG. 3.

Predicted response to AZT or TDF component of 2L regimen, as evaluated by the Stanford University HIVdb program. Resistance is graded on a 5-level scale: high-level resistance, intermediate resistance, low-level resistance, potential low-level resistance, or susceptible. (A) TDF-based 1L regimen: predicted response to AZT. (B) AZT-based 1L regimen: predicted response to TDF. All predicted resistance to AZT in TDF patients comes from samples in which K65R is not present. In the samples for which K65R is present, (shown with diagonal marks), patients are all susceptible to AZT.