Nucleoside reverse transcriptase inhibitor resistance mutations associated with first-line stavudine-containing antiretroviral therapy: programmatic implications for countries phasing out stavudine

Abstract

Background: The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure.

Methods: We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance.

Results: Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥ two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M.

Conclusions: Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy.

Keywords: AZT; HIV-1; NRTI; TDF; d4T; drug resistance; mutations; nucleoside reverse transcriptase inhibitor; stavudine; subtypes; tenofovir; zidovudine.

Figures

Figure 1.

Proportion of viruses with 3 categories of nucleoside reverse-transcriptase inhibitor mutations according to subtype, concomitant nonnucleoside reverse-transcriptase inhibitor (NNRTI), and years of antiretroviral therapy. The K65R category includes viruses with K65R but not Q151M. It also includes a small number of viruses with K65N or K70EGQ. Thymidine analog mutations include M41L, D67NG, K70R, L210W, T215YF, and K219QE. The numbers of viruses with each covariable pattern (subtype, NNRTI, and year) are shown at the base of each plot. Sequences were available from 31 subtype A, 7 CRF02_AG, and 2 subtype G viruses from individuals who received stavudine/lamivudine + efavirenz. Plots of data from these 40 individuals are not shown. Abbreviations: NVP, individuals receiving stavudine/lamivudine/nevirapine; EFV, individuals receiving stavudine/lamivudine/efavirenz.

Figure 2.

Summary of the zidovudine (AZT) and tenofovir (TDF) drug resistance estimates reported by the Stanford HIV Drug Resistance Database (HIVDB) drug resistance interpretation system (http://hivdb.stanford.edu; accessed 10 December 2012). Each of the 4 subplots indicates the numbers of individuals having viruses with 16 different resistance profiles according to a 4-tiered susceptibility estimate: susceptible, low-level resistance (low-level), intermediate resistance (intermediate), and high-level resistance. The HIVDB drug resistance interpretation system also contains a fifth tier, potential low-level resistance, but for this analysis these viruses were reclassified as susceptible. The number of viruses estimated to be susceptible to both AZT and TDF is not shown but can be calculated from the total number of viruses in each category minus the sum of the remaining 15 categories. Abbreviations: AZT, zidovudine; TDF, tenofovir.