K65R frequently emerges within 1-6 weeks of tenofovir monotherapy in macaques

Jeffrey Johnson and colleagues from CDC Atlanta and the University of California performed longitudinal resistance tests on plasma sample from eleven SIV-infected macaques, receiving 30mg/kg tenofovir daily using a test sensitive to 0.2% mutant virus.

K65R was detected after one week in 4 animals, and by week 6 in another 4 animals. All animals had a one-week treatment interruption at week 6. The remaining 3 macaques developed K65 by week 9.

Mutations were originally at frequencies too low to be detected by population sequencing (~ 1-10%) in 5 or 11 animals, but increased to sequence-detectable levels 2 to 4 weeks after their initial identification by the real-time PCR assay.

The researchers concluded that despite the high fitness cost conferred by the K65R mutation, resistance can emerge rapidly, and that this may have implications for people who become infected with HIV while using tenofovir pre-exposure prophylaxis.

Comment

The emergence of K65R over such short periods in most of these animals, is too rapid to be detected by any real world monitoring within human trials.

This increases the importance of treatment programmes to be established in trials of tenofovir pre-exposure prophylaxis (PrEP), especially as the human trials are proposed in high-risk populations.

It would be very important to know whether the addition of FTC provided any level of protective benefit, as anecdotally, Truvada is being used instead of tenofovir therapy, when used off-label as chemoprophylaxis.

Johnson J, Van Rompay K, Delwart E et al. Rapid emergence of drug-resistant SIV in tenofovir-treated macaques: implications for tenofovir chemoprophylaxis against HIV. 13th CROI, Denver, 2006. Abstract 609.
http://www.retroconference.org/2006/Abstracts/27822.HTM