The burden of the HIV epidemic is disproportionately concentrated in sub-Saharan Africa, where 71% of people living with the disease reside – despite being home to only around 13% of the global population.
Globally, more than half of all people currently living with HIV are cisgender women, and in sub-Saharan Africa women account for nearly 60% of new infections among adults and adolescents aged 15 and older. Unprotected vaginal sex is the primary driver of the epidemic in the region.
Positive results from a Phase I clinical trial were reported earlier this month at the Conference on Retroviruses and Opportunistic Infections (CROI) regarding two 90-day versions of the ring. These devices are developing on IPM’s monthly dapivirine ring, which is already under regulatory review.
How does the dapivirine ring work?
The study evaluated two 90-day formulations of the ring, one containing 100mg of dapivirine and the other containing 200mg. Both formulations were well-tolerated by the study participants, with results suggesting that the devices have the potential to provide long-acting, sustainable protection against HIV.
The study enrolled 49 HIV-negative women, who were randomly assigned the 100mg ring, the 200mg ring or a monthly version of the ring which contains 25mg of the drug. All three rings reported no safety concerns.
The two 90-day rings achieved higher dapivirine concentrations in blood plasma and vaginal fluid, with levels that were 1.3 to 1.9 times higher in plasma and 1.5 to 2.9 times higher in vaginal fluid. Similarly, cervical tissue concentrations were higher in the two three-month rings compared to the monthly ring.
“We don’t know exactly how it works, but if the virus comes into the cell the dapivirine prevents the virus from replicating in the cell,” says IPM executive vice president of product development Bríd Devlin. “We know that there’s a very large amount of dapivirine in the vaginal fluid, there’s some in the tissue, there’s a very small amount in the plasma, but the theory is that it’s mostly working in a local action setting.”
These results, together with those of a bioavailability study IPM is planning, will be considered in its decision about which of the two formulations to move forward for further development.
One-month ring already recommended by health agencies
The one-month ring received a positive opinion from the European Medicines Agency (EMA) for its use among cisgender women aged 18 and older in developing countries last year. In January of this year, the World Health Organisation (WHO) recommended the ring as an additional HIV prevention choice for women at substantial risk of HIV.
The nature of the ring means that while it protects against HIV transmitted through vaginal sex, and wouldn’t be effective against the spread of disease through transmission pathways such as shared needles.
Devlin says: “We wanted to develop something that would be a female-specific, discrete option as an additional tool in the toolbox of HIV prevention. Some people can’t tolerate PrEP or prefer not to have the burden of daily pill use and would instead like to have a set-it-and-forget-it type option.”
Research thus far suggests the rings can have an efficacy of up to 60%, but this varies depending on factors like patient adherence – however, IPM is looking into increasing the dosage in the device, hoping not to have to repeat its efficacy studies in the process.
“It’s incredibly costly and time-consuming and we’re a non-profit,” says Devlin, referring to the cost burden of clinical research. “If you’re adding a follow-on product, typically if you can mimic your initial drug levels then you don’t have to repeat the same study and you can add on.”
IPM’s contraceptive hybrid device: the next step in HIV prevention?
As well as the HIV-prevention ring, IPM is working on developing a device that combines the antiretroviral properties of dapivirine with a traditional contraceptive ring.
“It’s dapivirine plus the contraceptive, and we’ve chosen levonorgestrel,” says Devlin. “It’s a very common progesterone and it’s available in multiple areas which means it’s a more affordable contraceptive to use.”
The multi-prevention technology (MPT) ring would contain levonorgestrel in the centre of the device, while the sheath around it would contain dapivirine. The device would mimic the release of dapivirine from IPM’s original invention, while adding a contraceptive benefit.
In two Phase I studies conducted by the Microbicide Trials Network, a dual-purpose ring containing 200mg dapivirine and 350mg of the contraceptive hormone levonorgestrel was found to be well tolerated.
When it comes to official approval, Devlin says the MPT is several years away from distribution. However, for the dapivirine-only ring, regulatory approval could be just around the corner.
Devlin says: “We’ve submitted all of our applications to our target African countries for the dapivirine ring and we’re hoping to start distributing by the end of this year.”