On 24 July, fittingly just days before the start of Women’s Month in South Africa, the European Medicines Agency (EMA) delivered a positive opinion on a vaginal ring to prevent HIV.
The ring, intended to be inserted once-monthly, contains the antiretroviral (ARV) dapivirine, and was developed by the non-profit organisation International Partnership for Microbicides (IPM). IMP’s Dr Zeda Rosenberg described the product as the very first long-acting HIV prevention tool “designed to help women manage their HIV risk on their own terms”.
The EMA’s announcement paves the way for the dapivirine ring to be prequalified by the World Health Organisation (WHO), followed by the anticipated adoption of the ring by countries after national regulatory approvals.
IPM, and others in the field, have lauded the EMA announcement as a “milestone for women’s HIV prevention”.
First in prevention specifically designed for women
Despite the significantly higher risk for HIV infection faced by women, particularly in sub-Saharan Africa, the world has not seen an HIV prevention option specifically designed for women since the female condom was approved nearly three decades ago. Earlier hopes for a vaginal gel (microbicide) containing the ARV tenofovir were dashed when the gel failed to prevent sufficient HIV infections in pivotal studies.
At around 25%, HIV prevalence in women aged 15 to 49 in South Africa is roughly double that of men in the same age group, according to estimates from the Thembisa mathematical model.
Currently, South Africa’s HIV prevention strategy hinges mainly on three tools – condoms, oral PrEP (pre-exposure prophylaxis) and expanding access to ARV treatment (ART). But activists and experts pointed out that there are issues with all three methods – especially for women who are most at risk of acquiring HIV due to a combination of biological and societal factors.
For example, some research has shown women in a largely patriarchal society often struggle to negotiate condom use with male partners who hold the power in decision-making.
Women face a similar dilemma when it comes to oral PrEP. PrEP comes in the form of a daily pill containing the ARV Truvada, which HIV-negative individuals, at high risk of HIV infection, can take as a means of prevention. PrEP is effective at preventing HIV – close to 100% – if taken as prescribed. However, it is not very discreet and women have reported that they struggle to hide the pills from partners who do not know they are taking them.
Hits and misses with PrEP
Moreover, access to PrEP in South Africa is “dismal” at best, according to long-standing HIV activist and director of Advocacy for Prevention of HIV and Aids, Yvette Raphael.
This is despite the national department of health’s (NDoH) ambitious plans to roll out PrEP across the country, as announced in early February this year.
These targets included making PrEP available in every community health centre and clinic in the country by the end of September this year. By the end of March, the department’s target was to have the HIV prevention pill available in at least one health facility in each sub-district.
Admittedly, the department set its bold PrEP targets before Covid-19 hit South Africa.
However, the department has been criticised for how it has handled the Covid-19 response – particularly with the continued running of critical and life-saving health programmes and services, especially those related to HIV and tuberculosis (TB). This limited access to care sparked warnings from clinicians, including Prof Francois Venter, that “far more people are going to die because of the inadequate response to Covid-19 than the virus itself”.
“And make no mistake, a lot of people are going to die of Covid. Covid-19 has interrupted everything. We shouldn’t have allowed this. Our gains when it comes to HIV and TB will sadly be reversed because of the Covid disaster and how government has responded,” said Venter, who is the deputy executive director for the University of the Witwatersrand’s Reproductive Health and HIV Institute (WRHI).
As anticipated, the national department confirmed that the PrEP rollout has not happened as planned.
“The scale-up of PrEP in public health facilities did not proceed at the pace it was scheduled due to the disruptions resulting from the Covid-19 pandemic and lockdown regulations,” department spokesperson, Popo Maja, told Spotlight.
“Currently there are over 160 facilities offering PrEP. Although the aim was to scale-up PrEP in at least one facility per district, there are some districts in the Northern Cape, Limpopo and Western Cape where this is not the case. [In] Mpumalanga, North West, Eastern Cape, Free State, Gauteng and KZN, most, if not all districts, have at least one public clinic offering PrEP.”
However, Maja said that the number of people taking PrEP has increased over this period. In February, the department reported that 50,000 people had been started on PrEP over the last four years. Maja told Spotlight that this figure has increased to 70,000.
“Covid-19 did affect PrEP during the months of April and May when we experienced a dip in the uptake of PrEP. By June we saw the demand for PrEP increase to 128% of the average month’s uptake. Various strategies were also put in place to ensure that those on PrEP could remain on PrEP through decentralised pick-up points, multi-month prescriptions, social media, web-based and online support tools,” said Maja.
“All those who are at substantial risk should continue to access PrEP for prevention of HIV acquisition,” he said.
Gender, HIV, and choice
When it comes to treatment as a prevention strategy, heterosexual women are also disadvantaged, as data shows HIV-positive men are significantly less likely to be on ART than HIV-positive women.
According to Venter, women make up just under 70% of South Africa’s ART programme – one of the highest gender disparities in the world.
“We almost have two different countries in terms of gender and HIV success in SA. The UNAIDS 90-90-90 targets were probably achieved a few years ago for women. Men are woefully left behind and nowhere near any of the targets,” explained Venter.
The UNAIDS targets are that, by 2020, 90% of people living with HIV know their status; 90% of people diagnosed with HIV are taking ART; and 90% of people on ART have achieved viral suppression (meaning there is not enough virus in the blood to transmit HIV to others).
Moreover, during the Covid-19 pandemic there have been multiple reports of people not being able to access ARVs.
“Since the lockdown, what’s happened is people who have gone to facilities are likely not receiving the services they need, which has impacted heavily on access to ARVs. I know of at least 34 people in Gauteng who have not been able to access their medication for weeks,” said Tshepo Maboe, acting manager for the Treatment Action Campaign in Gauteng.
Dr Thesla Palanee, who heads up network trials at WRHI, says compared to existing methods, the dapivirine ring offers a potential solution to women as it is more discreet and can be hidden from male partners who are opposed to using existing prevention methods.
“We all know women like choices. Like in the contraceptive field, there are a range of options to prevent pregnancy – from condoms, to the oral pill, to injectables to long-acting intrauterine devices. With a range of options, women can choose one or the other over the course of their lifespan. Similarly, we need a range of options for women when it comes to protecting themselves from HIV,” she said.
Palanee was also the South African-based protocol chair for the ASPIRE trial, which measured the safety and efficacy of the dapivirine ring.
“Currently we see that the oral PrEP option is not for everyone and there is a high challenge with adherence,” she said.
According to Venter, “the benefit of the ring is you don’t have to remember to swallow a tablet every day”.
Questions on efficacy
Some have asked what the ring’s role in HIV prevention should be, considering it only showed around a 30% efficacy rate in trials.
Venter explained that there are inherent difficulties measuring actual efficacy rates in phase three randomised control trials, because researchers cannot ensure study participants use the medicines or tools exactly as directed.
According to Venter, because of this, the initial studies done on oral PrEP showed an efficacy rate of about 50%. It was only in later trials among select high-risk populations that it was found that oral PrEP was over 90% effective.
“My instinct is that the efficacy of the ring is much higher [than 30%] but not as high as oral PrEP, however it is not insignificant. With PrEP, as I anticipate will also be the case for the ring, we get better adherence in the real world versus in clinical trials. We’ve seen that people’s self-perceived risk for HIV is very real and has an impact on adherence,” he said.
He noted that adherence rates for oral PrEP are much higher in the highest risk groups such as sex workers, intravenous drug users and gay men.
Rosenberg told Spotlight that the ring can’t possibly be as effective as oral PrEP, even if used correctly, because it only protects against transmission through vaginal sex – and not for transmission via anal sex or intravenous drug use.
“We want women to choose oral PrEP, but if they can’t or won’t use it, then the ring is an excellent alternative option,” she said.
The dapivirine ring has been 16 years in the making. IPM received the licence to use the drug in 2004, and the first prototype was developed in 2005. The current ring is the fourth rendition of the product and was developed primarily for low and middle-income countries with high HIV infection rates.
“After a number of rounds refining the design, we’ve finally got a product that is easy to use, relatively inexpensive to manufacture and one that has a long shelf life, lasting up to five years,” said Rosenberg.
How much will it cost?
Currently, one ring, which lasts one month, costs $8 (about R137).
“We fully anticipate the number to go down as efficiencies in manufacturing and volumes go up. The goal over the next several years is to get the cost down to under $5 a ring,” she said.
IPM is also working on a ring that will last for three months instead of one.
“This should bring the cost down even further, because one would need four rings per year rather than 12,” said Rosenberg.
But when will those who need it most be able to actually use it?
According to Rosenberg, the IPM anticipates receiving WHO prequalification and the inclusion of the ring in global HIV prevention guidelines by the end of this year or the first quarter of 2021.
“The South African government has been briefed all along this pathway and they were waiting as eagerly as we were for the EMA opinion. Of course, their regulatory agency will do an independent review. We don’t want to preordain anything,” said Rosenberg.
According to Maja, having “an additional HIV prevention option for women can make a meaningful contribution to achieving the goal of ending new HIV infections”.
The way forward
“Once WHO prequalification is available, the NDoH will welcome the rapid registration of the dapivirine ring by SAHPRA [the South African Health Products Regulatory Authority] so that it can be offered as an additional prevention option to women at risk of HIV infections. The SAHPRA approval is not necessarily dependent on WHO prequalification so the application can be submitted; however, the department will wait for WHO prequalification before implementation,” he said.
The EMA positive opinion on the ring follows another massive announcement for the HIV prevention field. On 7July new results for long-acting injectable PrEP were announced at the 23rd International Aids Conference.
The results showed that injectable PrEP, which uses the ARV cabotegravir and is delivered every two months, is not only as effective as oral PrEP, but in fact superior in preventing HIV in gay and bisexual men and transgender women. A study (called HPTN084) testing the same injection in women is ongoing with results expected in 2021.
“Women need options and there needs to be additional options [such as] injectable PrEP and even more than that – just like how women have multiple choices when it comes to contraception. The more choice women have, the more likely they can find an option that fits their stage of life, circumstances and personal preferences,” said Rosenberg.
“The aim is to empower women so they can choose a method that works best for them.”
Note: The Treatment Action Campaign is mentioned in this article. Spotlight is published by SECTION27 and the TAC, but is editorially independent, an independence that the editors guard jealously. Spotlight is a member of the South African Press Council.
What do women want?
Safety and efficacy are important when it comes to new HIV prevention products, but without the buy-in of users themselves, these tools could be rendered useless. A number of qualitative studies have asked women about their views about the dapivirine vaginal ring. The reviews are mixed – some love it and some are apprehensive. Here’s what women had to say:
"Five exclamation marks - the sure sign of an insane mind." ~ Terry Pratchett