There is no time to waste in planning the South African rollout of cabotegravir (CAB LA), the long-lasting antiretroviral injection approved for use in the United States in December 2021, say local health experts.

The jab, which could transform HIV pre-exposure prophylaxis (PrEP) regimes from a daily oral pill to injections administered every two months, is currently under review by the South African Health Products Regulatory Authority (Sahpra). PrEP refers to people who are not living with HIV taking antiretroviral medicine to prevent HIV infection.

While marketing approval could take anything from several months to several years, experts from advocates to researchers say planning for effective health service delivery of CAB LA should start now.

“We should definitely not wait for approval to plan injectable PrEP rollout,” Yvette Raphael, executive director of the organisation Advocacy for Prevention of HIV and Aids (Apha) says. “We must start distribution, education and physical planning to ensure all South Africans who need HIV prevention are able to access it.”

Shadow of stigma

In 2017, South Africa became the first country on the continent to approve a daily pill containing the antiretrovirals tenofovir and emtricitabine for HIV prevention. The pill, like the CAB LA injectable, can be used by any sexually active person who might be exposed to HIV regardless of sex, gender, or sexual orientation.

Government at the time implemented a rollout plan that initially targeted sex workers, with distribution at a limited number of sites. The strategy may have provided key insights into delivery prior to scaling up but may also have contributed to stigmatisation.

“It was originally brought out for sex workers and men having sex with men, populations who were largely stigmatised,” says Professor Linda-Gail Bekker, executive director of the Desmond Tutu HIV Foundation. “Oral PrEP is still trying to break out of this mould, where it’s seen as something used by people who are promiscuous or unfaithful.”

This stigma casts a shadow over PrEP users and healthcare service delivery that may extend to the injectable. Indeed, Raphael says that in some clinics, there are reports of healthcare workers denying people access to PrEP pills.

“Injectable rollout should be situated in clinics, where people are being tested for HIV and can be immediately offered the injection,” she says. “But if we don’t include the right education and engagement with healthcare workers, then we’re fighting a losing battle.”

Expand service delivery

While progress has been made in getting oral PrEP available at over 2,000 public sector facilities, Saiqa Mullick, director of implementation science at the Wits Reproductive Health and HIV Institute (RHI), says there is scope to make CAB LA more widely accessible than this.

“We need to continue to integrate new methods into services such as family planning, mobile health services, school-based sexual and reproductive health services, and prevention of mother-to-child-transmission services,” she says.

For that to be feasible, however, researchers must start now with implementation studies. This work will help answer key questions about administration, demand, and testing that can’t be answered through the oral PrEP experience.

Significantly, the need for a nurse to administer the CAB LA jab raises questions around already overburdened clinics. Is it feasible for them to offer the injection versus a pill that can be delivered in the post? What associated training and staffing costs will be required?

“We’re just getting our heads around service delivery of pills to be taken daily,” says Bekker. “This will be different and there are questions we need to urgently answer so we can tell implementers and users how to do this safely.”

Communicating with communities

One question is whether communities want a long-acting injectable. Early reports described by Spotlight suggest there is user demand, but not everyone will opt for the jab.

That choices may differ was underlined by a study presented at last week’s Conference on Retroviruses and Opportunistic Infections (CROI 2022) examining whether women prefer prevention pills or a vaginal ring.

Half the women in the study were given the pill for the first six months and the other half were given the ring. In the second six months, the groups switched around, and in the third six months, women could decide for themselves which of the two methods to use.

Two-thirds opted for the ring, while just under a third picked the pill. Similar studies have yet to be done for HIV prevention injections.

“We’ve seen with Covid vaccination that people still have a lot of concerns about what’s being put in their body,” says Bekker. “We need to get into people’s heads and understand what they know about the injectable so we can be very clear in our messaging.”

Where those messages are delivered should also be considered. Existing national platforms, such as the MyPrep website, are already trusted sources of information developed alongside the oral PrEP campaign. But these options can be expanded, says Mullick.  

“We need to continue to invest in expanding and learning the most effective ways of creating awareness and demand for new products and socialising PrEP for everyone whilst reaching out to those who need it,” she says.

Establishing guidelines

The risk of drug resistance with CAB LA must also be explored. Trials have shown the potential for those who test negative with a rapid test to start on CAB LA, then to seroconvert while on the drug and develop resistance.

“We don’t routinely do viral antigen tests, so we may need tightening around diagnosis to confirm that a person is indeed HIV negative before starting CAB-LA,” says Bekker.

Another option, she says, may be to start a person on oral PrEP for a period to ensure they are HIV negative before starting CAB LA. “The risk may be rare, but it is an example of the kinds of precautions we may need to put into place,” she says.

Guidance like this can come from the World Health Organization (WHO), which said it began the process of developing guidelines for long-acting prevention approaches in early 2022. It can also come from implementation studies where researchers have been licensed to use the jab in a research environment.

According to Bekker, her lab and others have applications for this access with the National Institutes of Health (NIH) in the US and the Gates Foundation. But there is a need to identify a leader for this process sooner than later. “If everyone is scrambling to find product to test, that’s great. But who can direct this and coordinate the kinds of pilots and research projects that are being done so we can quickly put the pieces together?” she asks.

Prioritising women

In South Africa, trials are currently underway at Wits RHI (Reproductive Health and HIV Institute) to establish the safety and efficacy of injectable PrEP for pregnant and breastfeeding women, according to Professor Sinead Delany-Moretlwe, director of research at Wits RHI.

Participants in those trials are now being offered the option to start CAB LA if they were in the daily oral pill group. The requirements for contraception have also been relaxed and women who become pregnant will be offered the option to continue with CAB LA during pregnancy.

The research could feed into the development of guidelines for CAB LA. “We learn more about safety, tolerability, and drug concentrations in pregnant women, which can accelerate access to effective HIV prevention in these populations,” says Delany-Moretlwe.

Indeed, the FDA approval of CAB LA was based in part on another study led by Delany-Moretlwe. It showed a 92% reduction in HIV infections among cis-gendered women receiving the CAB LA jab every eight weeks compared to the daily oral pill.

With women making up over 60% of all new HIV cases in SA, according to UNAIDS, this may be motivation for prioritising their access to the jab.

“PrEP is for all those that need it. However, in groups where we see the highest HIV incidence rates, such as adolescent girls and young women and key populations, it is important to specifically prioritise access for these groups,” says Mullick.

Modelling cost

Whether CAB LA is rolled out across the board to all those accessing PrEP or to priority groups will likely be determined by cost.

“Cost is going to drive this,” says Bekker. “Whether it goes to everyone or is saved for certain populations will be based on how much we can procure and how easily we can give it out.”

CAB LA is currently priced at $3,700 (R55,685) per dose in the US, where cost-effectiveness analysis presented at CROI 2022 has suggested the jab should be priced in line with generic oral daily PrEP. “The superiority of long-acting injectable PrEP notwithstanding, the presence of highly effective alternatives limits the additional price difference that payers should be willing to pay for CAB-LA,” that research said.

While CAB-LA’s manufacturer, Viiv Healthcare, says it is committed to making it accessible to low and middle-income countries, it is still unclear how much the jab will cost in South Africa.

That doesn’t mean we shouldn’t start modelling costs now, says Dr Tom Ellman, director of the Southern Africa Medical Unit (Samu) at Doctors without Borders (MSF).

“We should prepare as if we expect to deliver CAB LA well before the end of 2022, and budget platforms and implementation programmes while recognising the flaws and uncertainties,” he says.

All options on the table

Ellman says there is no doubt that CAB LA is a massive step forward that can save lives. “It should be seen as an incredibly urgent thing to move on,” he says.

With the incredible acceleration that’s been seen around Covid commodities including vaccines, treatments, and diagnostics, he says there is strong justification to speed up access and development of CAB LA.

However, he emphasises that oral PrEP is the gold standard of care, and that giving people a choice should be at the heart of South Africa’s HIV prevention strategy.

“Bearing in mind different lifestyles, differences in risk and changes in those risks, we must keep all options on the table inclining daily oral PrEP, condoms, behaviour, and the injectable,” he says.

Indeed, the potential of CAB LA shouldn’t overshadow the effectiveness of currently available PrEP, or that of the Dapivirine Vaginal Ring, which is still waiting for Sahpra approval.

“The injectable isn’t going to be the end-all, be-all of HIV prevention,” says Raphael. “We have to keep thinking about the methods that we have, and do a better job at rolling out oral PrEP and ensuring we get approval of methods, like the ring, that is further down the approval line.” DM/MC

This article was published by Spotlight – health journalism in the public interest.

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