High Prevalence of the K65R Mutation in HIV-1 Subtype C Infected Patients Failing Tenofovir-Based First-Line Regimens in South Africa

Abstract

BackgroundTenofovir (TDF) has replaced stavudine (d4T) as the preferred nucleoside reverse transcriptase inhibitor (NRTI) in first-line regimens in South Africa, but limited information is available on the resistance patterns that develop after the introduction of TDF. This study investigated the antiretroviral drug resistance patterns in South African HIV-1 subtype C-infected patients failing stavudine- (d4T) and tenofovir- (TDF) based first-line regimens and assess the suitability of TDF as the preferred first-line nucleotide reverse transcriptase inhibitor (NRTI).MethodsResistance patterns of HIV-1 from 160 adult patients virologically failing TDF- (n = 80) and d4T- (n = 80) based first-line regimens were retrospectively analyzed. The pol gene was sequenced using an in-house protocol and mutations were analysed using the IAS-USA 2014 Drug Resistance Mutation list.ResultsCompared to d4T-exposed patients (n = 7), patients failing on a TDF-containing regimen (n = 43) were almost 5 times more likely to present with a K65R mutation (aRR 4.86 95% CI 2.29 – 10.34). Y115F was absent in the d4T group, and detected in 13.8% (n = 11) of TDF-exposed patients, p = 0.0007. Virus from 9 of the 11 patients (82.0%) who developed the Y115F mutation also developed K65R. Intermediate or high-level resistance to most NRTIs was common in the TDF-treatment group, but these patients twice more likely to remain susceptible to AZT as compared to those exposed to d4T (aRR 2.09 95% CI 1.13 – 3.90).ConclusionThe frequency of the TDF induced K65R mutation was higher in our setting compared to non-subtype C dominated countries. However, despite the higher frequency of cross-resistance to NRTIs, most patients remained susceptible to AZT, which is reflected in the South African treatment guidelines that recommend AZT as an essential component of second-line regimens.

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

“…These data augment prior contradicting reports from Europe, one reporting low K65R rates in subtype A compared to other subtypes [12] and another reporting no inter-subtype difference [8]. Although very small in numbers, these data also support high K65R occurrence in subtype C (100%, 4/4) [9,13] and introduce its high occurrence in subtype D (50%, 2/4). According to our analysis of subtypes A and D from Stanford and AMPATH, these high K65R rates are not explained by the adjacent poly-A template, as proposed for subtype C [20].…”

“…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].…”

Strengthening HIV therapy and care in rural Tanzania affects rates of viral suppression

“…32,33 Interestingly, we did not detect the K65R mutation, which reduces the susceptibility to tenofovir disoproxil fumarate, despite the fact that one-third of patients with detectable HIV-DRM had been on a tenofovir-based regimen for a minimum of 6 months. K65R is the most important discriminatory mutation, causing intermediate resistance to tenofovir, while increasing the susceptibility to zidovudine, and is mostly selected in patients with HIV subtype C. 34 Our observation provides relevant preliminary information on the mutational patterns among patients under the current WHO guideline recommendations for tenofovir-based regimens. However, this observation warrants further in-depth studies on the emergence of HIV-DRM among patients on tenofovir-based regimens in these settings.…”

Low-Frequency Drug Resistance in HIV-Infected Ugandans on Antiretroviral Treatment Is Associated with Regimen Failure

“…For example, the frequencies of treatment failure and drug resistance were significantly greater in patients infected with the more pathogenic subtype D than in patients infected with subtype A HIV-1 strains (9). Similarly, the TDF resistance K65R mutation and the NNRTI resistance V106M mutation are more common in patients infected with subtype C HIV-1 strains than in individuals infected with other subtypes (45,46). Despite extensive studies on HIV-1 drug resistance in sub-Saharan Africa, few studies have screened for minority drug-resistant variants in treatment-naive or -experienced patients.…”