HIV-1 Subtype Is an Independent Predictor of Reverse Transcriptase Mutation K65R in HIV-1 Patients Treated with Combination Antiretroviral Therapy Including Tenofovir

Abstract

Subtype-dependent selection of HIV-1 reverse transcriptase resistance mutation K65R was previously observed in cell culture and small clinical investigations. We compared K65R prevalence across subtypes A, B, C, F, G, and CRF02_AG separately in a cohort of 3,076 patients on combination therapy including tenofovir. K65R selection was significantly higher in HIV-1 subtype C. This could not be explained by clinical and demographic factors in multivariate analysis, suggesting subtype sequence-specific K65R pathways. Clinical relevance has been attributed to HIV-1 genomic diversity, classified in distinct groups and subtypes, since genetic variation can affect mutational pathways to drug resistance and possibly effectiveness of combination antiretroviral treatment (cART) (1, 2). The likelihood and rate of developing the lysine-toarginine resistance mutation at position 65 (K65R) of reverse transcriptase (RT) has been argued to vary depending on the viral subtype (3). In particular, studies have proposed lower and higher propensities to develop K65R mutation for subtypes A and C, respectively. However, studies reporting subtype dependency of K65R selection were based mainly on observations from cell culture experiments or from patient populations with limited sample size or subtype distribution (3-5). Other studies failed to detect similar associations (6, 7). While many clinical predictors of K65R selection have been identified to date (8, 9), a clear consensus on the role of genomic diversity is presently lacking. A large majority of K65R cases observed in recent years resulted from the administration of tenofovir (TDF) (10), which is currently the most widely used nucleoside RT inhibitor (NRTI) for first-line cART. Given the rising prevalence of non-B subtypes in Europe and treatment availability in other parts of the world, improved knowledge on subtype-specific K65R resistance pathways can be important in the planning of cART for HIV-1 non-B-infected patients.This study aimed specifically to evaluate the reported subtype-dependent selection of K65R rather than to identify novel predictors of its presence. We retrospectively investigated the emergence of K65R across different subtypes in a large TDFexperienced patient population, by integrating clinical and viral sequence data from eight countries (Belgium, Germany, Israel, Italy, Luxembourg, Portugal, Spain, and Sweden) in collaboration with the EuResist consortium. Viral isolates were obtained from genotypic resistance testing, recommended in case of therapy failure, while on treatment with a viral load high enough to allow successful sequencing. Together with information on demographics, treatment experience, and genotypic resistance profiles, we collected for each patient the most recent viral isolate while receiving TDF-based therapy, with a minimum of 30 days between the beginning of this therapy and the sampling date. When consecutive viral sequences were available, the first viral sequence containing K65R was selected. Patients were excluded if K65R was de...

Baseline Antiretroviral Resistance Mutations and Treatment-Emergent Resistance in HIV-1 RNA-Suppressed Patients Switching to EVG/COBI/FTC/TDF or Continuing on Their PI-, NNRTI-, or RAL-Based Regimen

“…All currently approved ARV agents are active against all subtypes of HIV-1; however, patterns of resistance emergence can vary among the 9 subtypes and 58 circulating recombinant forms. [46][47][48] In particular, there may be an increased propensity for development of the main TDF resistance mutation, K65R, among individuals infected with subtype C. [49][50][51][52][53] In the switch studies described here, there was no development of K65R, which included the 9 subjects with subtype C in the EVG/ COBI/FTC/TDF group. In general, overall treatment responses were similar across all subtypes in the EVG/COBI/FTC/TDF group, although only a small proportion of subjects studied were infected with non-B subtypes (12%).…”

Basis for Early and Preferential Selection of the E138K Mutation in HIV-1 Reverse Transcriptase

“…Likewise, 9% of drug-naive subtype C-infected patients harbor tiny K65R minority species, while this is true for only 2% of subtype B-infected patients (44). Consequently, a relatively high number of subtype C patients have failed first-line therapy with the K65R mutation (49,50). The fact that G¡A mutations were the most common minority species detected here, combined with the fact that G¡A mutations are the most common type of HIV-1 drug resistance mutation, further underlines the critical role that mutational bias plays in the evolution of clinically relevant HIV-1 drug resistance.…”

HIV-1 Resistance to Reverse Transcriptase Inhibitors

“…In contrast, all other HIV-1 subtypes harbor AAG (lysine), AAA (lysine), and AAA (lysine) at the same codons. There is recent clinical evidence demonstrating frequent and early emergence of K65R on TNF-based first-line ART regimens in South Africa (Sunpath et al 2012;Theys et al 2013). In this regard, Mark Wainberg's group has shown that the difference in selection of K65R between subtypes B and C is related to the template nucleotide sequence and preferential pausing of reverse transcription at the homopolymeric stretch of adenine bases at codons 64, 65, and 66 of RT (Coutsinos et al 2010;Invernizzi et al 2009).…”