HIV prevention ring approved for women in South Africa, but next steps unclear
The South African Health Products Regulatory Authority recently approved the use of the monthly dapivirine vaginal ring for women 18 years and older to reduce the risk of HIV infection. Spotlight looks at the evidence for the ring’s efficacy and asks what plans there are for making it available to women in South Africa.
In a decision widely welcomed by civil society organisations, the South African Health Products Regulatory Authority (Sahpra) recently approved the use of the monthly dapivirine vaginal ring for women 18 years and older to reduce the risk of HIV infection.
South Africa is one of the first countries on the continent to approve the ring, which is already recommended as an additional HIV prevention option by the World Health Organization. Other proven HIV prevention methods include the use of male and female condoms, HIV prevention pills, voluntary medical male circumcision, and a monthly HIV prevention injection (called long-acting cabotegravir or CAB LA).
The dapivirine ring is only the second form of HIV pre-exposure prophylaxis (PrEP) to be approved in South Africa. PrEP involves taking antiretrovirals to prevent HIV infection. In 2015, Sahpra approved the combination of the antiretrovirals tenofovir and emtricitabine as oral PrEP. CAB LA is currently under consideration with Sahpra and will probably become the third PrEP product registered in South Africa later this year.
What is the dapivirine ring?
Dapivirine is an antiretroviral drug that belongs to a class of medicines known as non-nucleoside reverse transcriptase inhibitors or NNRTIs. NNRTIs work against HIV by blocking its ability to make copies of itself once inside a healthy cell.
The ring is made of flexible silicone loaded with 25mg of dapivirine. The ring provides sustained release of the drug inside the vagina over the course of a month with low exposure elsewhere in the body, which could help minimise side effects and reduce the risk of developing HIV resistance.
Professor Thesla Palanee-Phillips of Wits RHI says it’s advised that the ring is in place for at least 24 hours to allow sufficient drug release to happen. It is, however, essential to note that the ring should be kept in place and worn continuously for a month at a time to ensure that the highest level of risk reduction is achieved through the sustained release of the drug.
She says the ring should not be removed to be cleaned or washed, nor does it need to be removed during the menstrual cycle. “We recommend it is inserted and left in place for the month, whereafter it can be replaced with a new ring,” she says.
How effective is the ring?
Though the evidence is compelling that the dapivirine ring is effective, there is some uncertainty over just how effective it is. Two phase III trials first reported in 2016 found the ring to reduce HIV incidence by 27% (Aspire trial) and 30.7% (the ring trial) compared to placebo. In both studies, efficacy only just reached the threshold for statistical significance. Efficacy was found to be higher and lower in some sub-groups — an effect most likely driven by differing levels of adherence.
More recent evidence from two open-label trials (Dream and Hope) suggests efficacy in real-world use is better than in the two phase III trials, most likely due to better adherence. Even so, efficacy appears to be lower than that for oral PrEP.
“We can’t assume 100% efficacy. That’s tough for any prevention measure. But the data shows that the efficacy was better when the ring was used more than (in trials), so the dose-response curve is reassuring,” says Professor Linda-Gail Bekker of the Desmond Tutu HIV Foundation. According to Bekker, findings from randomised controlled trials of oral PrEP trials in women in Africa, such as Voice and Femprep, were even more disappointing.
“The best results in randomised controlled trials have been with CAB LA (the injection) since the adherence issues are reduced when a third party administers a prevention measure. With that said, the proof is in the real world effectiveness and we have seen oral PrEP do a lot better in reality compared with the randomised controlled trials. We hope the same will happen with the vaginal ring. The open-label study indicated it should,” she says.
An additional option
While the ring, according to Mitchel Warren of AVAC (a US-based HIV advocacy group), may not be as effective as oral PrEP, it can be a terrific option for someone who can’t take a pill every day or doesn’t want to take a pill every day to help them stay HIV negative.
Palanee-Phillips says the ring offers women a discreet way to reduce their HIV risk when they cannot or choose not to use higher efficacy methods like daily prevention pills.
“How effective an HIV prevention product is, is an important part of the equation but adherence or being able to comply with the use of it without feeling burdened for any reason is just as critical,” Palanee-Phillips says.
“Open-label studies among African women, including women here in South Africa, have shown high acceptability of the ring as well as high adherence (and hence higher estimated levels of effectiveness). Encouraging findings from a study called Reach, among younger girls and women aged 16-21 years, also show that a monthly ring is a feasible option for younger women in Africa who cannot or choose not to use daily oral PrEP,” she says.
Professor Saiqa Mullick of Wits RHI similarly stresses to Spotlight that both the ring and prevention pills are effective. “Highly effective methods that are partially used are not able to work as well as with perfect use. That’s why getting the epidemic under control will require multiple types of prevention methods, so a woman can choose the most effective product that best meets her needs and life circumstances,” she says.
Yvette Raphael, Executive Director of Advocacy for Prevention of HIV and Aids (Apha), says she is worried about the population with higher rates of incidents not using PrEP. “Young girls are not accessing PrEP in high numbers because they don’t like swallowing pills. So let us open the basket, let young people get more choice,” she says.
“We are giving the government one and a half years to make sure every girl who needs to use PrEP has it,” says Raphael.
The National Department of Health says that it will review the clinical indication and the implementation requirements approved by Sahpra. In addition, the department will assess the dapivirine ring regarding its effectiveness, cost of procurement and delivery, and potential impact on HIV incidence.
“Implementation policy and guidelines are required for public healthcare facilities. They will have to be drafted and presented to the National Health Council,” Foster Mohale, the department’s spokesperson, tells Spotlight.
“Procurement of the commodity will require projected quantity, budgets, supply chain in accordance with public procurement requirements. “While the Department of Health embarks on those processes, the support of the product developer and the donor community will be enlisted to make the product available for implementing at selected health facilities,” says Mohale.
Mohale says that the existing HIV prevention and Oral Pre-Exposure Prophylaxis guidelines will require updating with additional information pertaining to the delivery of the dapivirine ring.
“This is a new commodity that is not part of the existing ARV tender. Therefore, if approved for implementation, a new tender will be required,” he says. He did not, however, provide a timeline for either the guideline or tender processes.
When asked if the Department will roll the ring out only through public sector clinics or through other channels, Mohale tells Spotlight that there are no immediate details and plans for implementation at this stage. However, these will be considered once there is approval and resources for implementation are available.
Cost and access
Leonard Solai, who is responsible for Product Access and External Affairs at the International Partnership for Microbicides (IPM), says that as a non-profit, the goal is for the ring to be publicly funded and provided to women at low or no cost. IPM began developing dapivirine as a microbicide in 2004 when it received a royalty-free licence from Janssen Pharmaceuticals, part of Johnson & Johnson.
“The ring’s ultimate cost will vary by country and IPM is working with donors, governments, civil society, and other partners to keep costs to women low. IPM is also developing a three-month dapivirine ring that would further lower costs in the future as fewer rings per year would be needed,” he says.
He says that the cost to produce the ring and prepare it for procurement is around $12 to $13 per ring for donors and multilateral agencies and other partners. “Further costs might be incurred for country shipping and logistics.
Getting ready for roll-out
While the National Department of Health will lead the roll-out plan for the ring, including the development of guidelines for the ring in its current HIV prevention strategy, Palanee-Phillips says it is important that the supply chain and procurement processes are put in place before the ring is introduced to ensure adequate supply and this can only happen after approval of guidelines.
According to Mullick, there has been a great deal of work done to engage communities around the ring, particularly in communities where ring clinical trials and other research, such as qualitative studies and market research to inform demand creation strategies, took place.
“Moving ahead, we anticipate that the Department of Health’s HIV prevention strategy, which all partners will implement, will include awareness of the comprehensive range of options available, including condoms, daily oral PrEP, and the ring. Wits RHI will support such plans,” says Mullick.
Warren says he hopes that the South African government will roll out the ring soon, pointing out that South Africa has been at the forefront of rolling out other prevention methods such as voluntary medical male circumcision.
“South Africa hosted some of the earliest oral PrEP studies and has been at the forefront of introducing oral PrEP to a range of populations and now in a number of facilities around the country. So I hope that the government will work rapidly with programmes and implementers and, most importantly, with civil society and communities to make the ring available in national guidelines and provincial Aids programmes,” Warren adds. DM
This article was published by Spotlight — health journalism in the public interest.