Resistance implications from PrEP and microbicide studies in macaques
3 August 2006. Related: Conference reports, Drug resistance, Intl Drug Resistance Workshop 15 Sitges 2006.
Simon Collins, HIV i-Base
Several studies looking at pre-exposure prophylaxis (PrEP) were included in the meeting.
Garcia-Lerme and colleagues presented data from a study that exposed 12 macaques rectally to SHIV each week for 14 weeks, with 6 animals each receiving either tenofovir/FTC of FTC alone, and a comparitor group of 15 animals who received no ARV treatment. [1]
14/15 of the control animals became infected after a median of two challenges (range 1-10), with 4/6 animals in the FTC group becoming infected after a median of 11 exposures, at 5, 6, 12 and 13 weeks. All six macaques receiving tenofovir/FTC were protected from infection.
A second abstract from the same study, reported that peak viremia was 2.2-fold lower in the animals receiving FTC vs the control group (4.5 +/- 0.4 log versus 6.7 +/- 0.3 log), and remained lower over the 14 week follow-up period. Resistance to FTC occurred in only 2/4 animals at weeks 6 and 7, which was longer than has been seen previously in monotherapy studies. This study was first presented at the Retrovirus conference in February 2006, and was reported in the May issue of HTB. [3]
Previous studies have shown the potentially high risk of resistance to tenofovir occurring in monotherapy after 1-6 weeks. [4] Koen Van Rompay from California National Primate Research Centre, presented results from a study in which 12 SHIV-infected rhesus macaques were treated with tenofovir monotherapy at week 20, and had the development of resistance monitored by PCR 5 months later. All animals had an approximate 1.0 log drop in viral load, that remained stable for 20 weeks. All animals developed K70E at median 2 weeks, which tended to be replaced by K65R after a median of 4 weeks (K65R was present in 80% animals after 12 weeks). Each of these mutations developed on different genomes.
Dawn Moore, from Case Western Reserve University, presented results from another rhesus monkey study, looking at whether resistance developed following a single dose of the microbicide PSC-RANTES (PSC). [6] While high concentrations of PSC (1mM) have been shown to inhibit SHIV infection, at lower concentrations this protection is lost, and this has been difficult to explain given a low IC50 of <1-10nM.
In this study, although stable sequences were seen post-exposure in nearly all animals, discreet mutations developed in the V3 crown and in gp41 of env in a number of PSC-treated animals. These included K311R (V3) and N631D (HR2 gp41), and this conferred 18-fold resistance to PSC compared to wild-type SHIV virus.
References:
Unless stated otherwise, all references to abstracts relate to the Programme and Abstracts from the XV International Drug Resistance Workshop, 13-17 June 2006, Sitges, Spain. The abstract book is published as a supplement to Antiviral Therapy 2006, Volume 11.
- García-Lerma J, Qari S, Otten R et al. Prevention of SHIV transmission in macaques by tenofovir/FTC combination. Abstract 94.
- García-Lerma J, Qari S, Otten R et al. Blunted viraemia and slow drug resistance emergence in rhesus macaques failing chemoprophaxis with emtracitabine. Abstract 44.
- Heneine W, Garcia-Lerma J, Qari S et al. Prevention of Rectal SHIV Transmission in Macaques by Tenofovir/FTC Combination. 13th CROI. Abstract 32LB. See HIV Treatment Bulletin, May 2006.
https://www.i-base.info/htb/2320 - 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.
https://www.i-base.info/htb/2320 - Van Rompay KKA, Johnson JA, Blackwood EJ et al. Sequential emergence and clinical implications of K70E and K65R viral mutants during prolonged tenofovir monotherapy in rhesus macaques with chronic RT-SHIV infection. Abstract 33.
- Moore DM, McGhee JL, Veazey RS et al. Selection of drug resistance mutations in SHIV following a single dose treatment of the microbicide PSC-RANTES in a rhesus macaque model. Abstract 131.