Potent combination therapy for HIV-positive people (commonly called ART or HAART) is highly effective. However, a drawback of ART is that sometimes multiple pills have to be taken once or twice daily. The ability to take pills exactly as directed for many years does not come to everyone easily.
In an attempt to make HIV drug regimens simpler and easier to take, researchers are investigating new drugs and new formulations of drugs.
One research team is a collaboration between two companies—Shionogi & Co. Ltd. based in Japan and GlaxoSmithKline in the U.S. This collaboration has focussed on producing novel integrase inhibitors with the following features:
- they can be taken orally or injected
- only relatively small doses are needed
- they have the potential to treat HIV that is resistant to other integrase inhibitors (such as raltegravir and elvitegravir)
- they fit into a single tablet when co-formulated with other drugs
So far the collaboration has yielded two HIV integrase inhibitors, as follows:
- dolutegravir – in the final phase of clinical trials prior to licensure
- S/GSK 1265744 (also known as ’744) – this has been made into a long-acting oral formulation and also a nanosuspension that can be injected
Using different doses (between 100 and 800 mg), researchers have found that ’744 can be injected into muscle or just under the skin, leading to high concentrations in the blood.
In the lab
Laboratory experiments with cells and ’744 have found that this drug has significant antiviral activity against HIV, generally greater than any other integrase inhibitor tested so far.
’744 is also active against a range of strains, or subtypes, of HIV-1, including subtypes A, B, C, D, E, F, G; group O and group M. It is also effective in lab experiments against HIV-2.
’744 shows substantial activity against strains of HIV that are resistant to the other three integrase inhibitors (dolutegravir, elvitegravir, raltegravir).
Experiments with people
In experiments with 42 healthy HIV-negative volunteers, researchers found that ’744 was generally well tolerated. Importantly, the concentration of this drug in the blood of participants remained there for prolonged periods, depending on the dose used. In theory, this could mean that ’744 could be injected once monthly or once every three months (again, depending on the dose used).
In a placebo-controlled clinical trial with 20 HIV-positive participants who had no previous exposure to integrase inhibitors, ’744 was tested at doses of 5 mg or 30 mg taken orally once daily for 10 days. No other anti-HIV drugs were used during this period.
After 10 days of monotherapy with ’744, viral load fell between 2 and 2.5 logs. In contrast, viral load did not decrease significantly among participants given placebo. At day 11, participants received standard ART (without ’744). Fourteen days after having first taken ’744, and three days after switching to standard ART, viral load was less than 50 copies/ml in seven out of eight participants who received the 30 mg/day dose of ’744. Results with the 5 mg dose were not as dramatic.
No resistance to ’744 was detected in the blood after 10 days of monotherapy.
These results underscore the power and promise of ’744.
The unique dosing schedules (one monthly or once every three months) have the potential to substantially reduce pill burden. Now other potent drugs need to be created or old ones reformulated so that monthly or quarterly dosing becomes possible with an entire regimen.
—Sean R. Hosein
- Yoshinaga T, Kobayashi M, Seki T, et al. Antiviral characteristics of S/GSK 1265744, an HIV integrase inhibitor dosed by oral or long-acting parenteral injection. In: Program and abstracts of the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy, 9-12 September 2012. San Francisco, California. Abstract H-550.
- ViiV Health Care. Shionogi and ViiV Healthcare announce new agreement to commercialise and develop integrase inhibitor portfolio. Press release. 28 October, 2012. Available at: http://www.viivhealthcare.com/media-room/press-releases/2012-10-28.aspx?...