HIV prevention injections have been registered for use in South Africa, but their high price and limited supply means that for the next few years, while awaiting more affordable generics, very few people will be able to get the jabs. In this Spotlight special briefing, Catherine Tomlinson looks at the difficult choices facing the country if we want to offer the injection to more people more quickly. The calls we make could have global implications.
New HIV infections in South Africa have declined dramatically over the last two decades - from highs of over half a million in the early 2000s to an estimated 149 000 in 2023, roughly a third of the peak. A group of leading researchers have found that the two key drivers of this decline are the use of condoms and antiretroviral treatment. The latter works for prevention because most people living with HIV who are stable on treatment become non-infectious.
Yet, new infections remain stubbornly above the levels required to bring an end to the HIV epidemic in the next decade. The number of new HIV infections in 2023 was almost three times higher than HIV-related deaths - 149 000 versus 50 000 (roughly another 50 000 people living with HIV died of non-HIV-related causes in 2023). The fact that the number of people becoming infected with HIV is higher than the number of people with HIV who are dying, means the absolute number of people living with the infection is increasing. In 2023, 7.8 million people were living with HIV in South Africa. By 2026, this number is projected to exceed eight million.
Without further steep reductions in new HIV infections, South Africa will not meet the United Nations' Sustainable Development Goal target to cut HIV infections by 90% by 2030 (compared to 2010). To reach this target, South Africa must bring new HIV infections down to around 40 000 per year.
New tools
The good news is that there are new, highly effective tools that South Africa can incorporate into its existing HIV prevention efforts. The existing package of HIV prevention services provided in public health facilities includes the free provision of condoms, oral PrEP (pills to prevent HIV), and medical male circumcision. New tools that can be rolled out to bolster HIV prevention efforts include an HIV injection and a vaginal ring - both containing antiretroviral medicines.
While both new products are important and have roles to play in preventing HIV, the injection - known as long-acting cabotegravir or CAB-LA - in particular, has been heralded as a potential "game changer" for reducing new HIV infections. This is because the injection, which must be administered every two months, essentially eliminates users risks of contracting HIV.
CAB-LA has the potential to prevent HIV transmission for millions in Africa! It is already being used in the Copperbelt and central provinces in Zambia. Different from the current available PREP, this injection is given every two months only and does not require daily pills. pic.twitter.com/6ddY6n9BZ3
-- Dr. Esperance Luvindao (@EsperanceMl) February 26, 2024
The bad news is that due to the high cost of CAB-LA and limited global supply, its rollout remains delayed. Supply will likely need to be rationed for at least the next few years. A rationed rollout will prevent the full benefits of the "game changing" HIV prevention product from being realised in South Africa - the country with the world's largest HIV epidemic.
"The consequences of rationing will be more infections," Doctors Without Borders' Helen Bygrave told Spotlight.
What is CAB-LA?
CAB-LA was registered by the South African Health Products Regulatory Authority in late 2022. The injection, which provides two months of protection per shot, contains the antiretroviral medicine cabotegravir.
CAB-LA was shown to be highly effective at preventing HIV infection in two large trials partially conducted in South Africa. Both trials, which were conducted in women, men who have sex with men and trans women, were stopped early after CAB-LA's effectiveness in preventing HIV became apparent.
The two trials showed that CAB-LA is even more effective than currently available oral PrEP - an already highly effective HIV prevention tool. This is understood to be because the injection, unlike oral PrEP, does not require users to remember or be able to take a pill daily.
In fact, the trials showed that CAB-LA virtually eliminates a person's risk of contracting HIV for the two months per shot. Research on jabs that provide four and six months of protection is under way.
Modelling work to assess the impact of introducing CAB-LA in South Africa suggests it has the potential to significantly reduce new HIV infections. It is estimated that, with broad rollout, CAB-LA could prevent up to 52 000 HIV infections per year - compared with up to 16 300 when only using oral PrEP.
The long wait for a price tag
One snag in the CAB-LA story has been uncertainty over its price. After years of advocacy by medicine access advocates for an affordable and transparent price, late last year the pharmaceutical company ViiV, that makes CAB-LA, finally shared the price that it would charge South Africa and other countries eligible to receive its "non-profit price".
After several behind-the-scenes price drops, ViiV settled on a price of around US$30 (ZAR570 at the current dollar to rand exchange rate) per injection. While ViiV has said that this is a non-profit price, the lack of public information about ViiV's production costs makes it impossible to judge whether this is actually ViiV's at-cost price.
And while South Africa and other countries eligible to receive ViiV's non-profit price now know what they will have to pay for CAB-LA, countries in Latin America and Asia that are not eligible to receive this price are still waiting for price clarity from ViiV, Doctors Without Borders' Access Campaign pharmacist, Jess Burry, told Spotlight.
There is no private sector price yet for CAB-LA in South Africa.
A tough price to swallow
The good news is that South Africa finally knows what ViiV will charge the South African government for CAB-LA. The bad news is that the price is far above what the South African government says it can pay.
The country's National Essential Medicines List Committee published a budget impact analysis in February 2023, stating that the cost of CAB-LA could not exceed more than twice the cost of two months of oral PrEP for it to be cost effective and procured by government. Subsequently, the health department has said that in order to be affordable, the cost of CAB-LA must be within the range of what South Africa pays for two months of oral PrEP, which is R130.
Earlier cost-effectiveness analysis conducted by local academics came to a similar conclusion.
Out of budget
In addition to exceeding South Africa's threshold price, the cost of making CAB-LA broadly available in the public sector may simply be unaffordable given the country's already strained health budget.
Assessing potential cost is particularly tricky for preventative medicines where uptake is highly unpredictable. When assessing the budget required to procure a therapeutic medicine, buyers like the South African government consider how many people have a condition requiring the medicine. But for a preventative product, which targets the general population, it is impossible to know how many people will actually choose to use the product.
Researchers at the University of Witwatersrand's Health Economics and Epidemiology Research Office (HE2RO) have been grappling with the issue. Depending on how many people start CAB-LA and how long they stay on it, the researchers estimate it will cost the South African government between R3.9 billion and R11.4 billion per year.
🆕 WHO guidelines encouraging countries to deliver long-acting injectable cabotegravir (CAB-LA) - a key to preventing #HIV infection among people at substantial risk.
📌 https://t.co/nBklLQboDZ pic.twitter.com/EKMcEwSTZf
-- World Health Organization (WHO) (@WHO) July 28, 2022
Prices are however anticipated to drop substantially when generics enter the market in three or four years' time. There is thus an argument that the high price might nevertheless be worth paying given that it would only be for a few years.
Even so, in an overstretched health budget that is probably facing yet more cuts, it is hard to envision where the money to buy CAB-LA could come from. The hope is that, at least for the next few years while we await availability of more-affordable generic CAB-LA, global donors will help the South African government cover the costs of providing CAB-LA.
"Short-term affordability is difficult," says Professor Linda-Gail Bekker, CEO of the Desmond Tutu HIV Foundation.
"I think the reality is we're going to need help and that's where PEPFAR [the United States President's Emergency Plan for AIDS Relief] and other agencies come into the mix."
Spotlight understands that the South African government is in communication with PEPFAR regarding potentially receiving donations of CAB-LA from PEPFAR.
PEPFAR has procured around 300 000 vials of CAB-LA from ViiV for use in select low- and middle-income countries through 2025, Mitchell Warren, CEO of New York-based NGO AVAC, tells Spotlight. PEPFAR will focus its rollout in select African countries, which may include South Africa.
ViiV has indicated that around 1.2 million doses of CAB-LA will be available for procurement for use in low- and middle-income countries through 2025, which includes the 300 000 doses procured by PEPFAR. The 1.2 million doses would allow for 200 000 people to take CAB-LA for one year (one person would require six doses for a year's worth of protection). The number of people who could benefit from the shots in low- and middle-income countries are likely in the millions.
Will the price go down?
A challenge for CAB-LA's market viability is that the product's cost-effectiveness is judged against the cost of oral PrEP. The medicines used for oral PrEP are also used for HIV treatment and, with enormous manufacturing scale and broad generic competition, extremely cheap.
While ViiV currently maintains a market monopoly on CAB-LA and can unilaterally set its price, ViiV yielded to advocacy pressure and licensed three generic companies to manufacturer CAB-LA in March 2023.
The introduction of generic competition is expected to bring the cost of CAB-LA down, but generic availability is still several years away as the licensed generic companies must still establish manufacturing capacity and gain regulatory approval for their products.
But, when generic versions of CAB-LA does enter the market, its price may fall significantly. A costing analysis conducted by the Clinton Health Access Initiative found that generic CAB-LA injections can be manufactured and sold at prices equivalent to those for oral PrEP.
Doctors Without Borders' Burry notes, however, that to achieve these lower prices more generic manufacturers should be licensed to bolster competition. Bygrave adds that if generic companies had been licensed sooner, in earlier stages of drug development, generic products would be available much sooner than the current expectation of 2027.
What happens if South Africa doesn't buy CAB-LA?
If South Africa does not procure CAB-LA, says Warren, it may have a dampening effect on the global market for the product, which he says may in turn discourage or delay generic companies from investing in establishing and building up manufacturing capacity.
This is because, in the HIV market, South Africa is an influential buyer. PEPFAR, the Global Fund and the South African government are the three largest buyers of HIV treatment globally. And, despite the relatively low levels of oral PrEP uptake and coverage in South Africa, the country has still put more people on oral PrEP than any other country.
Of the estimated 6.2 million people who have ever been started on oral PrEP globally, 1.3 million are based in South Africa, according to AVAC's PrEP tracker. By comparison, only 441 000 people in the United States have taken oral PrEP.
Warren tells Spotlight "2024/2025 is a pivotal moment to build a market for CAB-LA... to show that there is indeed demand". If we don't demonstrate demand, he says, generic producers will ask "why should I spend my money to build [manufacturing] capacity if no one is buying the product?".
Seen in this light, the case for paying R570 per injection for three or so years starts to look more reasonable, especially if donors like PEPFAR can help pick up the tab. Decision-makers might still baulk at the price tag, but they should at least take the potential opportunity cost of not purchasing CAB-LA into account.
A rationing conundrum
CAB-LA is currently only available in South Africa through implementation studies. These studies are reaching only a minuscule fraction of the people that could benefit from CAB-LA but will provide important lessons to guide its broader rollout across the public health sector. As with oral PrEP and COVID-19 vaccines, the eventual level of uptake will in part depend on how easy the jabs are to get and how they are promoted. The doses used in the implementation studies were donated by ViiV.
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When CAB-LA will be rolled out more broadly, that is to say outside of implementation studies, remains a big unanswered question. It will largely depend on whether and how much of the drug we purchase and whether we receive donations from PEPFAR and how large those donations are.
What is clear is that, over the next few years, until more supply is available at more affordable prices, South Africa will need to ration its rollout of CAB-LA. As a result, far fewer new HIV infections will be prevented than would be the case without rationing.
Great news! Cabotegrivir-long acting injections to prevent HIV infection are on the way! #HIVPrevention #LongActingInjections #CABLA pic.twitter.com/ICIIm17DX8
-- Research Connect - Wits RHI (@ResearchConnec1) December 21, 2021
Rationing also raises difficult questions of who the limited supply should go to. A rationed rollout could involve piloting the rollout in public health facilities outside of implementation study settings in certain areas with high HIV rates or limiting eligibility for the product to certain populations and/or people who have been unable to adhere to daily oral PrEP tablets.
While limiting eligibility can ensure the product gets to the most high-risk groups, it has the drawback of potentially stigmatising use of the product. The oral PrEP rollout in South Africa initially restricted eligibility to sex workers and men who have sex with men, before expanding to the general population. This created the idea in some quarters that oral PrEP is meant for sex workers and gay men, groups that face ongoing prejudice in South Africa, which are sadly often reinforced by healthcare workers providing HIV prevention services.
Bekker tells Spotlight that, given that a rationed approach will likely be necessary over the next few years, the messaging must be carefully tailored to try prevent stigmatising CAB-LA or making people feel targeted. "If we have to do this, we are going to have to do it carefully", she says.
Lost opportunities
If South Africa does not receive donated CAB-LA or declines to procure it at ViiV's price, then the product will likely remain unavailable in the country (outside of implementation studies) for the next few years and many avoidable new HIV infections will occur.
This would be an incredibly sad conclusion to the years of research and the participation of communities, including South African ones in clinical trials that delivered CAB-LA. It would make a mockery of the years of calls and commitments to provide people at risk of HIV, and in particular young women and girls, with a choice of products to protect themselves from HIV.
"We've got innovation for the first time in prevention, it is a time when we so badly need primary prevention to move us towards... [our] goals," says Bekker. "It just feels just so dreadful that when the innovation is here, cost and availability is the reason we are unable to get the maximum benefit out of them."
