A flexible silicone ring that slowly releases antiretrovirals is one of just two long-acting HIV prevention products registered for use in South Africa. Results from a new study might pave the way for a longer-acting version of the vaginal ring that provides three months of protection at a time, as opposed to one month with the current ring. Elri Voigt reports on these findings and looks at how the one-month ring has influenced HIV prevention choices in South Africa.
A longer-acting version of an HIV prevention ring containing the antiretroviral drug dapivirine is being researched in South Africa.
Early results on the drug levels achieved in women and the safety of the newer three-monthly vaginal ring compared to the current one-month option were presented at the recent HIV Research for Prevention (HIVR4P) conference in Lima, Peru.
The Population Council, a global research organisation which owns and manufactures the monthly dapivirine ring, is developing the three-month ring. It is the same as the one-month ring, but it contains more dapivirine - 100mg instead of 25mg.
The current monthly ring is one of only two long-acting HIV prevention options approved for use in South Africa.
We are thrilled that @SAHPRA1 has approved the use of the dapivirine ring for women over 18! Find out more about the first long-acting HIV prevention device designed for women: https://t.co/3Pckei9908 #HIVprevention #dapivirinering pic.twitter.com/MMxS0hL3ZC
-- NACOSA (@NACOSANet) March 17, 2022
The other is long-acting cabotegravir (CAB-LA), an injection that provides two months of protection per shot. Both products are for now only available as part of implementation studies. There are more long-acting products to come, with the registration of a jab that provides six months of protection per shot expected within the next year or so.
Such use of antiretrovirals to prevent HIV infection is called pre-exposure prophylaxis (PrEP). The most widely used form of PrEP is a daily HIV prevention pill that contains the antiretrovirals tenofovir disoproxil fumarate and emtricitabine. This pill is widely available in the public sector and through private sector clinics. There is excitement about long-acting products like the HIV prevention ring and injections since they don't require taking a pill every day.
A ring every three months
A longer-acting ring means fewer insertions and clinic visits, which could lead to increased adherence and effectiveness as well as reduced annual costs, waste and environmental impact, said Jeremy Nuttall, senior director of preclinical sciences at the Population Council's Centre for Biomedical Research. Nuttall presented the findings of the phase one trial of the 3-monthly ring at HIVR4P.
The trial was conducted at FARMOVS, a clinical research organisation based at the University of the Free State in Bloemfontein. The researchers found that the drug concentrations in the blood of women receiving the three-monthly ring were at least as good as with the one-monthly ring (technically it met both non-inferiority and superiority thresholds).
As Professor Linda-Gail Bekker, chief executive officer of the Desmond Tutu Health Foundation, explained: "During the study, the three-month ring performed better than the one-month ring...these results showed that the levels of drug were better than seen for the monthly ring."
The 104 women enrolled received the three-month ring as well as three of the one-month rings during the study's two treatment phases. Half got the three-month ring and took a break for about a month and then received three consecutive one-month rings. The other half started with three consecutive one-month rings, had a month's break and then got the three-month ring.
The levels of dapivirine in the participant's blood and vaginal fluid were measured at set time points. The drug levels in the blood of participants when using the three-month ring were either greater or equivalent to levels in the one-month ring throughout the 90 days of use. The greatest difference in drug levels between the two rings was seen in the first month of use, where drug concentrations were somewhat higher in those using the three-month ring compared to the one-month ring.
Dapivirine levels in vaginal fluid were slightly higher in those using the three-month ring during the first month of use when compared to the one-month ring. After that drug levels for the three-month ring were similar to the one-month ring in the second and third month of use.
Based on the drug levels measured in the blood and the vaginal fluid it appears that the three-month ring delivers more drug over time compared to the three consecutive one-month rings.
"Both rings were well-tolerated with no notable differences in safety findings and no [HIV] infections," Nuttall told delegates at HIVR4P.
According to him, adverse events were similar between the two rings. There were no serious adverse events, with the most common adverse events being vaginal discharge, vaginal candidiasis and bacterial vaginosis, said Nuttall.
Although the study did not look at the efficacy of the three-month versus the one-month ring, Nuttall said based on the data collected, the efficacy of the long-acting ring should be at least equal to that of the one-month ring
Bekker told Spotlight that the best efficacy for the one-month ring was seen in women who did not remove the ring during a potential HIV exposure.
"So, the same adage will apply to the three-monthly ring - it will only do its work if it is in place at the time of HIV exposure (at the time of sex)," she said.
Bekker added the hope is that the three-month ring will be approved in South Africa, noting that women would need just four rings in a year "for discreet protection". This is seen to be particularly important in the context of South Africa where women face high rates of gender-based violence, which erodes their autonomy over their bodies and sexual and reproductive health.
If the ring does come to market, Bekker said it is a prevention option that activists and health providers should be advocating to add to the existing basket of PrEP options. "[T]here is a definite group of women who will prefer this option or may prefer this option at a particular time in their sexual lives," she said. "It is an option that should be on the menu."
Another thing Bekker is hoping for, is that the recent data on safety in pregnant and breastfeeding women as well as in adolescents using the one-month ring will be submitted for regulatory approval along with the three-month ring so these populations can also benefit from the ring. Several countries, including South Africa, have not approved the one-month ring for use when pregnant or breastfeeding because of the initial lack of safety data in these population groups.
In response to this, Nuttall gave an overview of the recent data collected in pregnant and breastfeeding women using the one-month ring. (You can read it here). The South African study on the three-month ring did not have any pregnant or breastfeeding women in it and only enrolled women older than 18. However, he said, because the products are similar, the assumption is that regulators will consider the safety data from the one-month ring as relevant to the three-month ring.
Next steps
No further clinical trials are planned for the three-month ring. The Population Council will submit the data from the study to regulators to support approval as a line-extension. A line-extension is when a manufacturer produces variations of their products already on the market - in this case the one-month ring.
This is possible, according to Nuttall, because the study was designed and conducted after the Population Council consulted with the European Medicines Agency (EMA) to find out what kind of data would be needed on the longer-acting ring in order to "bridge" the existing safety and efficacy data for the one-month ring. Essentially, this means that a long and expensive phase three trial won't be necessary to establish safety and efficacy, since the products are identical except for how much dapivirine they contain.
"The [EMA's] Medicines-For-All procedure will facilitate registration of the three-month ring in African countries, like it did for the one-month ring," Nuttall said.
The Population Council's chief scientific officer, Dr Bríd Devlin, told Spotlight that the current timeline for filing for regulatory approval with the EMA is early next year as chemical tests on the ring must still be done in the laboratory. The hope is that the ring could be brought to market by the end of 2026, but this will depend on how long the EMA takes to review the study data.
The price of manufacturing the three month-ring is still being finalised, but the aim is to cap it at $16 per ring, excluding distribution costs. The one-month ring costs about $12.8 per ring.
"[I]f you divide it [the price] by three, it is a much cheaper and affordable product on a monthly basis. So, it's still a very large cost savings, which is why we embarked on this line extension in the first place to improve the product," said Devlin.
Manufacturing the three-month ring could lead to about a 60% reduction in cost per year compared to the one-month ring, Nuttall said, with 67% fewer rings that will need to be produced each year.
The Population Council has a Memorandum of Understanding with South African pharmaceutical company Kiara Health, which is headquartered in Johannesburg, to eventually manufacture and distribute the three-month ring, Devlin said.
"Negotiations for that license are still underway and once the license is in place, the strategy would shift leadership of the dapivirine vaginal ring to sub-Saharan Africa where the HIV products are needed most by women," she said.
The Population Council's selection of an African-based manufacturing partner is notable as holders of intellectual property protections on HIV health technologies have typically sought out companies in Asia, and India in particular, as manufacturing partners, Spotlight reported previously.
Earlier this year, the Children's Investment Fund Foundation announced that it was partnering with the Global Fund in an initiative to invest up to $2 million to buy about 150 000 dapivirine rings to distribute in countries, including South Africa, which implement Global Fund grants to fight HIV.
Role of long-acting PrEP in South Africa
While it will likely be a few years before the three-month ring comes to market, early implementation science research has started to show what role the two current long-acting options for HIV prevention are playing in South Africa.
Some of this data was presented at HIVR4P. Hasina Subedar, a senior technical advisor at the National Department of Health, gave an overview of the implementation of the PrEP options currently offered in the country. Unlike the prevention pill, the two long-acting PrEP options - the monthly dapivirine ring, and CAB-LA - are not available in South Africa's public sector outside of study and pilot sites.
Subedar said there are currently 87 sites providing one, or two or all three of these products as part of the pilot studies. Across these 87 sites, so far 23 997 people started using a prevention option. 81% started daily prevention pills, 13% started on CAB-LA, and 6% started on the one-month vaginal ring. She cautioned that it's too early to draw any concrete conclusions from this data.
Some private sector pharmacies form part of this network, with nine offering only the daily prevention pill and three offering the pill and CAB-LA.
In the public sector, 61 sites are offering the daily pill along with the injection and 14 are offering all three prevention options. "Those [14] facilities that are offering all three products had the highest uptake [of prevention] compared to those that were offering the oral prep and ring only," she said.
It is important to take into account when reading these statistics that not all sites are offering all three prevention options, and the ring can only be offered to women. Another factor that could influence prevention uptake is the limited availability of CAB-LA in the country.
Early data on uptake of the one-month ring
Early data about which prevention options women in South Africa are choosing in pilot studies showed a moderate uptake of the monthly ring across all age categories. However, notably women aged 25 and older were more likely to choose the ring compared to adolescent girls and young women - who preferred the prevention pill. Those who were PrEP naïve were also less likely to choose the ring than those who had used oral PrEP before.
The study, called DREAMS PrEP Choice, funded by USAID and conducted by Wits RHI was also presented at HIVR4P. Researchers provided the ring and pill PrEP options through a community-based delivery model. This approach targets people in settings like youth and skills centres, higher learning institutions and other community-based sites.
The researchers enrolled 657 women aged 18 years and upwards and offered them HIV prevention services through either a mobile van or pop-up gazebo across 36 sites in Johannesburg. Most of these women were between the ages of 18 and 24. Of the 657, 451 (69%) of women chose prevention pills, while 175 (27%) chose the ring, 20 women (3%) chose not to initiate either of the prevention options, and 11 women (around 2%) did not receive choice counselling as they left before seeing a nurse. This means around 626 women (96%) chose to take up one of the prevention options.
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Spotlight spoke to the Principal Investigator for the DREAMS study. (You can read her full response here). Nicolette Naidoo, who is the Programme Head for Implementation Science at Wits RHI, said they were particularly interested in adolescent girls and young women. This group, she said, is not familiar with the ring and is instead more familiar with injectable products like contraception injections. "This could be a product characteristic that influences choice," Naidoo said.
In a poster presentation at HIVR4P, the DREAMS PrEP Choice study team also shared that the main reason women chose not to use the ring was fear of inserting or removing it and concern about placing something foreign in their body.
Women aged 25 to 34 were more likely to choose the ring than those aged 18 to 24. Their reasons included wanting to avoid daily pill taking, fear of side effects, and the ring's more discreet HIV prevention compared to pills.
As Naidoo explained: "[T]he PrEP ring may still have a role to play in meeting the prevention needs of older women and those having used oral PrEP before and looking for another method that meets their needs."
She added that participants who reported transactional sex were more likely to choose the ring than other women in the study, possibly indicating that a higher perception of risk may also be a key factor for determining who to prioritise for roll out, if cost and supply are concerns.
"The PrEP ring is an important method in the HIV prevention toolbox," Naidoo said. "It allows women, who are looking for a longer-acting and more discreet method, who do not want to undergo blood tests to initiate a PrEP method and take a daily pill, to choose a method that align with their preferences, values and changing lifestyle context ."
In some cases, blood tests are recommended before one starts taking HIV prevention pills. The Southern Africa HIV Clinician Society recommends that if a person is older than 40, has co-morbidities or are on concomitant medication, their kidney function should be tested before they are given the pill. A blood test is not required before initiating the ring.
Data from the DREAMS PrEP Choice study aligns with early findings from the CATALYST study presented at HIVR4P by Dr Elizabeth Irungu, the regional technical advisor for implementation science and PrEP service delivery at Jhpiego (a Johns Hopkins University affiliate) in Kenya. The study, which examines the choices of 3 967 women offered either the pill or the ring, spans across Kenya, Lesotho, Zimbabwe, Uganda, and South Africa. (Naidoo is the country principal investigator for CATALYST in South Africa.)
Around 3 483 (91%) of the women enrolled had a choice between the pill and the ring (some of the women were pregnant and breastfeeding and the ring is not approved for this population in all the countries). Of these, 2 301 (66%) chose the pill, and 1 182 (34%) chose the ring. Women aged 25 and over, those with prior PrEP experience, women with multiple partners, and those using contraceptives were more likely to choose the ring. While younger women aged 18 to 24, those new to PrEP, and pregnant or breastfeeding women preferred the daily pill.
