No Evidence That HIV-1 Subtype C Infection Compromises the Efficacy of Tenofovir-Containing Regimens: Cohort Study in the United Kingdom

Abstract

Concern has been expressed that tenofovir-containing regimens may have reduced effectiveness in the treatment of human immunodeficiency virus type 1 (HIV-1) subtype C infections because of a propensity for these viruses to develop a key tenofovir-associated resistance mutation. We evaluated whether subtype influenced rates of virological failure in a cohort of 8746 patients from the United Kingdom who received a standard tenofovir-containing first-line regimen and were followed for a median of 3.3 years. 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 (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.50–2.31; P < .001). However, the increased risk was greatly attenuated in analyses adjusting for demographic and clinical factors (adjusted HR, 1.14; 95% CI, .83–1.58; P = .41). There were no differences between subtypes C and subtypes non-B and non-C in either univariate or multivariate analysis. These observations imply there is no intrinsic effect of viral subtype on the efficacy of tenofovir-containing regimens.

Nucleoside reverse-transcriptase inhibitor cross-resistance and outcomes from second-line antiretroviral therapy in the public health approach: an observational analysis within the randomised, open-label, EARNEST trial

“…Mutations conferring NRTI drug resistance differ little between subtypes, however, and do not seem to affect outcomes. 25 , 26 A cohort study 17 in a subtype-B population drew similar conclusions with respect to predicted NRTI activity and outcomes. For our binary classification of NRTI drugs as active or inactive we used a cutoff (NRTI considered active if no more than low-level resistance) that corresponds to the way many clinicians interpret resistance tests.…”

Human Immunodeficiency Virus Drug Resistance: 2018 Recommendations of the International Antiviral Society–USA Panel

“…Virtually all amino acid differences between subtypes are polymorphisms: variants that occur commonly in the absence of therapy and have little, if any, phenotypic or clinical effect on antiretroviral drugs (ARVs). Thus, most studies suggest that individual ARVs and standard ART regimens are similarly active, regardless of subtype [56–63]. Increased risk of virologic failure has been associated with particular subtypes, but most studies are confounded by geographic location, treatment facilities, and clinical, social, and economic statuses that could affect outcome differences among individuals infected with different subtypes [64–67].…”

HIV-1 drug resistance and resistance testing

“…Second, K65R emerges more rapidly during in vitro passage of subtype C viruses than during passage of subtype B viruses in the presence of tenofovir (Brenner et al, 2006). Third, three retrospective studies have suggested that in patients who develop VF on a TDF-containing regimen are at a somewhat higher risk of developing K65R if they are infected with a subtype C virus (TenoRes Study, 2016; Theys et al, 2013; White et al, 2016). Despite the reported tendency to acquire the K65R DRM, a recent study showed that when demographic and clinical factors are controlled for among patients receiving at TDF-containing regimen, infection with a subtype C virus does not increase the risk of developing VF (White et al, 2016).…”