The first trial in humans of an injectable, once-a-month formulation of an HIV drug has found that drug levels were maintained at a level that should in theory be high enough to protect recipients against infection, and that the drug has so far produced very few side effects. The research was presented at the 19th Conference on Opportunistic Infections (CROI), in Seattle.
The small trial at the St Stephen’s AIDS Trust (SSAT) at London’s Chelsea and Westminster Hospital gave 27 women and six men a single injection of the long-acting formulation of the drug rilpivirine, which was licensed as an oral HIV treatment last year as Edurant and is also in the tenofovir/FTC/rilpivirine pill Complera. Rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) drug and is especially suitable to be turned into a long-lasting injectable form because the daily dose of it required to suppress HIV is very small.
No other HIV drugs are currently in a usable long-lasting injectable form, which will limit the use of long-acting rilpivirine (RPV-LA) in combination therapy, but it could conceivably make an ideal candidate as a prevention drug, as people would not need to remember to take it every day. Other preventative drugs already formulated as monthly injections include the injectable contraceptive Depo Provera and some anti-psychotic drugs.
SSAT recruited 27 HIV-negative women aged 18 to 50, more than 50% of them black African or Caribbean, for the trial and gave them one of three doses of RPV-LA as an intramuscular injection: 300, 600 or 1200mg (the oral dose of RPV is 25 mg/day). Drug levels were then measured over the course of the next twelve weeks in blood, vaginal fluid and in vaginal tissue samples. A substudy gave six men the 600mg dose and measured RPV-LA levels in blood, rectal fluid and rectal tissue samples.
Thirty days after injection, blood and vaginal fluid levels of rilpivirine were about 60 nanograms per millilitre (ng/ml) in both blood and vaginal fluid in women given the 600mg dose, and about 80 and 120ng/ml respectively in women given the 1200mg dose. Blood levels in men given the 600mg dose were about 70ng/ml at 30 days. For comparison, the trough levels of rilpivirine in people taking daily oral doses is about 140ng/ml; but the EC50 (the amount needed to reduce viral replication by 50%) in newly-infected T-cells is 27ng/ml. It is thought these levels should be adequate to prevent HIV infection.
Over the time period, levels of drug seen were about 80% higher in vaginal fluid than in blood in women taking the 300mg dose and about 20% higher in the other two doses: conversely, drug levels in vaginal tissue were about 25% lower than in blood, and 50% lower up to day 14 in the 300mg dose group.
Drug levels in rectal fluid were low but it is thought this was due to sample contamination: concentrations in rectal tissue were about the same as concentrations in blood.
The trial participants complained of very few side-effects apart from tenderness and some swelling at the injection site. There were no allergic reactions, psychological symptoms or effects on heart rate. Safety is of course a major consideration in a drug that remains in the body for up to twelve weeks.
Researcher Akil Jackson said, "There is an obvious need in HIV prevention and treatment for formulations that reduce the need for the user to depend on daily administration,” but added that these were very preliminary results and did not establish what dose would actually be protective. Further safety and drug-level studies in HIV-negative volunteers are to be conducted at the University of Pittsburgh, home of the Microbicide Trials Network, before the drug is given to volunteers with HIV.
Jackson A et al. Rilpivirine-LA formulation: pharmacokinetics in plasma, genital tract in HIV- females and rectum in males. 19th Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 35, 2012. The abstract is available on the official conference website.