Monthly injectable drug offers 100% protection against HIV in monkeys – could be dosed every three months

Chasity Andrews, of the Aaron Diamond AIDS Research Center, presenting at CROI 2013.
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Injectable integrase inhibitor protects monkeys against rectal exposure

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 six months, and above four times this level for four months.

This means that if it proves safe and effective in humans, it could be given as an injection as little as four times a year, though individual variations seen in this study mean that monthly dosing may be safer.

None of the monkeys given GSK744 became infected or have shown any sign of virus in their blood.

GSK744 is similar to dolutegravir, which is already nearing approval as an anti-HIV drug in Europe and the US. It is effective against HIV, though, at lower concentrations in the body, which means manufacturers GlaxoSmithKline have 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 eight male macaques and then a week later started 'challenging' them by introducing SHIV, a monkey adapted version of HIV as weekly doses (eight in total) in the rectum, to simulate anal sex. At the same time they challenged eight control monkeys without giving them GSK744 first. The monkeys on GSK744 were given a second dose four weeks after the first.

Glossary

rectum

The last part of the large intestine just above the anus.

IC90

The concentration of a drug needed to inhibit viral replication by 90%. IC stands for 'inhibitory concentration'.

integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase, which is an HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected. Blocking integrase prevents HIV from replicating.

microbicide

A product (such as a gel or cream) that is being tested in HIV prevention research. It could be applied topically to genital surfaces to prevent or reduce the transmission of HIV during sexual intercourse. Microbicides might also take other forms, including films, suppositories, and slow-releasing sponges or vaginal rings.

phase I

The first stage of human testing of a new drug or intervention, typically involving a small number (10-100) of participants who do not have the condition the drug is intended to treat. Phase I clinical trials evaluate safety, side-effects, dosage and how a drug is metabolised and excreted in the body.

All the monkeys not given GSK744 became infected, on average after two challenges, though one took seven challenges. In contrast, none of the monkeys given GSK744 became infected or have shown any sign of virus in their blood up to three 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 eight weeks of viral challenge in six monkeys. In the other two monkeys, it fell below the four-times IC90 level at week seven, 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 – see this report and this one on 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 vaginal exposure

In a separate monkey study, researchers from the US Centers for Disease Control 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 four weeks over a 16-week period.

Six monkeys exposed to SHIV were protected against infection, whereas eleven out of twelve 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 III studies of an intravaginal ring impregnated with the NNRTI drug dapivirine well underway and rings containing the CCR5 inhibitor maraviroc  in phase I trials too.

In this case the researchers, for the first time, used the tenofovir prodrug that is actually used in the oral tenofovir pill – 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 drug tenofovir to completely protect monkeys, and is the first time a ring has been demonstrated to protect monkeys who are repeatedly vaginally challenged with virus. It will help to advance development of this option in humans .

References

Andrews C et al. Long-acting parenteral formulation of GSK1265744 protects macaques against repeated intrarectal challenges with SHIV. 20th Conference on Retroviruses and Opportunistic Infections (CROI), Atlanta, abstract 24LB, 2013.

View abstract 24LB on the conference website.

Smith J 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 (CROI), Atlanta, abstract 25LB, 2013.

View abstract 25LB on the conference website.

A webcast of the session in which this research was presented, HIV prevention: ARV, counseling, contraception, and condoms, is available on the conference website.