Resistance to Tenofovir-Based Regimens during Treatment Failure of Subtype C HIV-1 in South Africa

Abstract

Background Tenofovir disoproxil fumarate (TDF) is increasingly available for patients infected with subtype C HIV-1. This subtype is reported to develop the principle TDF resistance mutation in the HIV reverse transcriptase, K65R, with greater propensity than other subtypes. We sought to describe K65R development during TDF use in a cohort of patients infected with subtype C HIV. Methods Using a prospectively followed cohort with 6 monthly HIV RNA assays, we identified virologic failure (defined as an HIV RNA >1000 c/mL) during treatment that included TDF. Residual serum, stored at the time of the HIV RNA assay, was used for consensus sequencing and allele-specific PCR. We assessed prevalence of resistance at failure during TDF-containing treatment and associated factors. Results Among 1,682 patients on a TDF-containing regimen, 270 developed failure of which 40 were assessed for resistance. By sequencing, the K65R was identified in 5 (12%), major NNRTI mutations in 24 (57%), and the M184V/I in 12 (28%) patients. The K65R was associated with lower HIV RNA at failure (HIV RNA log10 3.3 versus 4.2 c/mL) and prior stavudine exposure. An additional 5 patients had minority K65R populations identified by allele-specific PCR. Conclusions These data suggest that the K65R prevalence at virologic failure is moderately higher in our subtype C population than some non-subtype C HIV cohorts. However, we did not find that the K65R was highly selected in HIV-1 subtype C infected patients with up to 6 months of failure of a TDF-containing regimen.

Treatment failure and drug resistance in HIV‐positive patients on tenofovir‐based first‐line antiretroviral therapy in western Kenya

“…The high overall (89%) and dual-class (83%) resistance is consistent with other reports from AMPATH [23,26] and other RLS upon any (not solely TDF-based) first-line ART [37]. The few studies that evaluated resistance in TDF-based first-line regimens in RLS, mostly in subtypes C, G and CRF02_AG from Southern Africa and Nigeria, do not report overall resistance but estimate NRTI- (94 to 100%) and NNRTI-associated resistance (57 to 97%) to be high [9–11,13,16]. Though mutation frequencies in this study, other than K65R, were similar to prior reports [13], unique mutation patterns in 58% of the patients and specific mutation co-occurrence support the need for continued research on subtype-specific resistance, particularly with changing treatment guidelines [38].…”

“…K65R is a TDF signature mutation conferring resistance to all NRTIs but AZT, is rarely transmitted [27], is less common in subtype B-infected patients failing therapy [15], and is variable in RLS [9–11,13,16]. The high barrier to K65R development as reported in resource-rich settings may reflect high potency of K65R-selecting drugs, significant viral fitness constraints and unique RNA structural considerations [20].…”

Should we fear resistance from tenofovir/emtricitabine preexposure prophylaxis?

“…In patients on tenofovir-based regimens, almost 30% failed with K65R and half with M184V (36). In South African patients failing first line ART with TDF/FTC, K65R was detected in 5 of 40 (12%) and M184V/I in 12 of 40 (28%) (37). Another South African study looking at 80 patients failing on TDF-based ART with at least one resistance mutation found 10 (12.5%) had K70E, 43 (54%) had K65R and 72 (90%) had M184I/V (38*).…”

Prodrug strategies for improved efficacy of nucleoside antiviral inhibitors

“…This study concluded that TAF may be beneficial for individuals harboring certain resistant viruses [47]. The K65R mutation is a 'hallmark' resistance mutation of TFV and is associated with virologic failure in individuals administered TDF [48]. The utility of TFV prodrugs may be extnded if they are coadministered with an NAI with 'resistance repellant' properties versus K65R such as zidovudine (ZDV).…”