- Category: HIV Prevention
- Published on Wednesday, 06 March 2013 00:00
- Written by Gus Cairns
A long-acting injectable integrase inhibitor (GSK1265744) protected male macaque monkeys from rectal infection with an HIV-like virus, while a vaginal ring containing tenofovir prevented infection of female monkeys, researchers reported at the this week at the 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013) in Atlanta.
Injectable Integrase Inhibitor
An injectable, long-lasting integrase inhibitor drug, when given to rhesus macaques exposed to a monkey-adapted version of HIV, completely protected them against the virus.
This drug, an injectable version of GSK1265744 (GSK744), has already been given as a single dose to HIV negative human volunteers, and has a half-life of 21 to 50 days. Levels stayed above the IC90 (the level necessary to suppress 90% of HIV replication) for 6 months, and above 4 times this level for 4 months.
This means that if it proves safe and effective in humans, it could be given as an injection as little as 4 times a year, though individual variations seen in this study mean that monthly dosing may be safer.
GSK744 is similar to dolutegravir, which is already nearing approval as an anti-HIV drug in Europe and the U.S. It is effective against HIV, though at lower concentrations in the body, which means manufacturer GlaxoSmithKline has been able to formulate it as a nanoparticle suspension -- tiny "packets" of the drug floating in fluid, which provide a long-lasting supply of the drug when injected.
Scientists at the Aaron Diamond AIDS Research Institute injected GSK744 into 8 male macaques and then a week later started "challenging'" them by introducing SHIV, a monkey adapted version of HIV, via weekly doses (8 in total) in the rectum, to simulate anal sex. At the same time they challenged 8 control monkeys without giving them GSK744 first. The monkeys on GSK744 were given a second dose 4 weeks after the first.
All the monkeys not given GSK744 became infected, on average after 2 challenges, though 1 took 7 challenges. In contrast, none of the monkeys given GSK744 became infected or have shown any sign of virus in their blood up to 3 weeks after the last challenge.
Levels of GSK744 seen in these monkeys’ rectal tissues were equivalent to a level that would be expected to be protective in humans, and stayed above the four-times-IC90 level for the full 8 weeks of viral challenge in 6 monkeys. In the other 2 animals, it fell below the 4-times IC90 level at week 7, in other words, just before the last viral challenge.
Given that adherence is turning out to be a major barrier to the effectiveness of pre-exposure prophylaxis -- as demonstrated in the VOICE trial -- HIV drugs that can be given by injection at quarterly sexual health check-ups could, in the long term, be a more feasible way of offering biomedical protection against HIV. The researchers are studying the protected monkeys to see if there is any sign of virus in their systems and to determine the minimum effective dose.
Tenofovir Vaginal Ring Protects Monkeys against Exposure
In a separate monkey study, researchers from the U.S. Centers for Disease Control and prevention (CDC) protected female monkeys using another long-lasting PrEP method -- a ring impregnated with tenofovir that could be inserted into the vagina. In this case, they used a polyurethane ring that was replaced every 4 weeks over a 16-week period.
They found that 6 monkeys exposed to SHIV were protected against infection, whereas 11 out of 12 not given the ring became infected. Unlike the injectable formulation, human research into vaginal rings is already well advanced, with the International Partnerships for Microbicides’ RING and ASPIRE Phase 3 studies of an intravaginal ring impregnated with the NNRTI drug dapivirine well underway, and rings containing the CCR5 inhibitor maraviroc in Phase 1 trials too.
In this case the researchers, for the first time, used the tenofovir pro-drug that is actually used in the oral tenofovir pills (Viread, Truvada, and other coformulations) -- tenofovir disoproxil fumarate or TDF. In previous microbicides, they have used the biologically active tenofovir molecule, but this is not as well absorbed and does not produce such high concentrations in tissues as TDF. However, TDF is not as stable, and the team had to develop a new polyurethane ring rather than the silicone ring used in other vaginal ring studies.
This is the first time it has been shown that a ring can deliver enough of the widely used NRTI tenofovir to completely protect monkeys, and is also the first time a ring has been demonstrated to protect monkeys who are repeatedly vaginally challenged with virus. This research will help to advance development of this option for humans .
C Andrews, A Gettie, K Russell-Lodrigue, et al. Long-acting Parenteral Formulation of GSK1265744 Protects Macaques against Repeated Intrarectal Challenges with SHIV. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, March 3-6, 2013. Abstract 24LB.
J Smith, R Rastogi, R Teller,et al. A Tenofovir Disoproxil Fumarate Intravaginal Ring Completely Protects against Repeated SHIV Vaginal Challenge in Nonhuman Primates. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, March 3-6, 2013. Abstract 25LB.