15th International HIV Drug Resistance Workshop 13-17 June 2006, Sitges, Spain

SEQUENTIAL EMERGENCE AND CLINICAL IMPLICATIONS OF K70E AND K65R VIRAL MUTANTS DURING PROLONGED TENOFOVIR MONOTHERAPY IN RHESUS MACAQUES WITH CHRONIC RT-SHIV INFECTION

Antivir Ther. 2006, 11:S41 (abstract no. 33)

KKA Van Rompay¹, JA Johnson², EJ Blackwood¹, J Lipscomb², N Bischofberger³, W Heneine² and TW North^4,5
1California National Primate Research Center, School of Veterinary Medicine, University of California, Davis, CA; ²National Center for HIV and AIDS Prevention, CDC, Atlanta, GA; ³Gilead Sciences, Foster City, CA; ⁴Center for Comparative Medicine; ⁵Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA

BACKGROUND: We previously reported on the emergence and clinical implications of SIV mutants with the K65R mutation in reverse transcriptase (RT) and the role of CD8+ cell-mediated immune responses in suppressing SIV viraemia during tenofovir therapy. The sequence differences between SIV and HIV-1 RT make it unclear whether these findings with SIV can be extrapolated to HIV-1.

METHODS: To model HIV-1 RT responses, twelve macaques were inoculated with RT-SHIV, a chimeric SIV containing HIV-1 RT, then started on tenofovir (10 mg/kg subcutaneously once daily) 5 months later. Sensitive real-time PCR assays were used to monitor for the RT K65R and K70E resistance-associated mutations.

RESULTS: Prior to tenofovir therapy, animals had viral RNA setpoints of 6-7 log RNA copies/ml plasma and no detectable K65R or K70E by sensitive testing. The early virological response to tenofovir correlated with baseline viral RNA levels and expression of the major histocompatibility (MHC) class I allele Mamu-A*01. For all animals, tenofovir treatment led to transient emergence of K70E mutants within four weeks of treatment which were then replaced by K65R mutants; the occurrence of these mutants preceded a partial rebound of viraemia (which stabilized at ~1 log below baseline levels for most animals). Population genotyping was unable to detect K70E in two animals. The median times to K70E and K65R emergence were 2 and 4 weeks of treatment, respectively. One tenofovir-treated animal eventually suppressed K65R viraemia to undetectable levels for more than 4 years. CD8+ cell depletion during continued tenofovir treatment in this animal resulted in a transient one-million-fold rebound of K65R viraemia (22 million copies/ml). Following the return of CD8+ cells and viral suppression, tenofovir interruption led to a slow rebound in viraemia. Thus, both CD8+ cells and tenofovir were required to suppress K65R viraemia.

CONCLUSIONS: These observations suggest that K70E and K65R emerge sequentially, often prior to their detection by conventional sequencing. Immune-mediated and residual drug-dependent antiviral activities both play a role in diminishing viraemia in some animals despite the emergence of K65R mutants. This implies that for persons infected with K65R-mutant HIV-1, continued tenofovir treatment may offer some benefit.

2006-06-13
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