Concern has been expressed that tenofovir-containing regimens may have reduced effectiveness in the treatment HIV-1 subtype C infections because of a propensity for these viruses to develop a key TDF-associated resistance mutation.
Methods : We evaluated whether subtype influenced rates of virological failure in a cohort of patients from the United Kingdom who received a standard TDF-containing first-line regimen. A total of 8746 patients were included, of whom 6149 (70.3%) had a determined subtype: 4123 subtype B, 823 subtype C, and 1203 non-B/C subtypes. The most common non-B/C subtypes were A (n = 272), CRF02_AG (n = 267), G (n = 118), CRF01_AE (n = 114), other CRFs (n = 90), and D (n = 80). Patients infected with subtype B viruses were mainly white (82.7%) and MSM (85.0%), whereas the subtype C group was mainly black (70.2%) and heterosexual (79.2%). Overall, 74.4% of first-line regimens included a NNRTI (mostly EFV), while 25.6% included a PI/r. First-line regimens were broadly comparable across the different viral subtype groups, although there was proportionately greater use of EFV for subtype B and proportionately greater use of LPV/r for subtype C. Patients were followed up for a median of 3.3 years (IQR 2.0–4.9 years). Virological failure was defined as the first of 2 consecutive viral loads (<6 months apart) of >200 copies/mL after 6 months of ART. Follow-up was censored at the earlier of the last viral load measurement or the discontinuation of tenofovir, ignoring changes in the prescription of other ARV.
Results : On average, 309 (5.7%) of subtype B–infected patients, 142 (9.8%) of subtype C–infected patients, and 173 (9.5%) of non-B/C subtype–infected patients experienced virological failure. In unadjusted analyses, the rate of failure was approximately 2-fold higher among patients infected with subtype C virus as compared to those with subtype B virus (HR 1.86; 95% CI 1.50–2.31; p < 0.001). The increased risk was greatly attenuated in analyses adjusting for demographic and clinical factors (aHR, 1.14; 95% CI 0.83–1.58; p = 0.41). Adjusted Kaplan–Meier curves of the time to virological failure confirmed the lack of association with viral subtype, after accounting for potential confounders. The most influential factors explaining changes in the estimated effect of subtype between unadjusted and adjusted analyses were exposure group (lower rate of virological failure among MSM) and ethnicity (lower rate of virological failure among white and Asian patients). There were no differences between subtypes C and subtypes non-B and non-C in either univariate or multivariate analysis. Genotypic resistance tests were available for 260 of 624 patients (41.7%) who experienced virological failure. TDF-associated resistance mutations, predominantly K65R, were observed significantly more frequently in subtype C viruses (22.7%) than in subtype B virus (6.1%) or non-B/C viruses (8.1%; p = .003).
Conclusion : There is no intrinsic effect of viral subtype on the efficacy of TDF containing regimens. However, if patients infected with subtype C do not respond to treatment, the likelihood is higher to select for the K65R mutation. An explanation for this phenomenon could be that, in an optimal treatment setting, treatment response is not affected by the single point mutation. However, if adherence is suboptimal or detection of viral failure is delayed or done at higher viral load, then the mutation occurs much faster in subtype C than in subtype B.
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