In South Africa, HIV treatment means taking one or more antiretroviral tablets a day. People in some other countries have the additional option of treatment in the form of two injections administered every two months. We unpack why long-acting HIV treatment is not available in South Africa and ask why the push for HIV prevention jabs has been so much stronger than that for HIV treatment jabs.
HIV prevention injections have recently been making headlines around the world but there has been much less noise about antiretroviral injections to treat HIV. Though not available in South Africa, such long-acting injectable HIV treatments exist and are being used in some places.
There is a clear front-runner in this field. Monthly injections of the antiretrovirals cabotegravir and rilpivirine for the treatment of HIV was approved by the United States Food and Drug Administration (FDA) in January 2021. A year later, this approval was expanded to allow for jabs to be administered only every second month. The cabotegravir and rilpivirine combination is roughly as safe and effective as the daily tablets used to treat HIV.
The FDA has also approved six-monthly lenacapavir injections, but only for tough to treat HIV.
Why no cabotegravir/rilpivirine in SA?
As pointed out by Professor Francois Venter, head of Ezintsha at Wits University, neither the combination of cabotegravir and rilpivirine nor rilpivirine injections on their own have been registered with the country's medicines regulator, the South African Health Products Regulatory Authority (SAHPRA). Cabotegravir injections for use as HIV prevention have been approved by SAHPRA, but supply of the jabs is very limited.
In countries where rilpivirine has been registered, Venter says it is very expensive and the price is limiting access.
There are also practical difficulties when it comes to how cabotegravir and rilpivirine jabs might be rolled out, said Venter.
The first is that healthcare workers would need specialised training to administer both injections - the jabs are administered to the buttocks using special needles. Secondly, they also need to keep track of the patient's injection points because the jab can't be given in the same location during follow-up visits.
This means that anyone receiving the cabotegravir and rilpivirine combination for HIV treatment would need to go to a specialised site where a specially trained healthcare worker who has access to the right needles is able to give them the two shots. This makes it an intervention, said Venter, that can't simply be "rolled out in primary healthcare tomorrow or be available from your general practitioner".
Another concern is drug resistance. Venter explained that rilpivirine is in a class of antiretrovirals called Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). Another NNRTI called efavirenz has been taken by millions of South Africans living with HIV and formed part of standard first-line HIV treatment in the country until a few years ago. "We used efavirenz for many, many years", said Venter, "and there was lots of circulating background resistance".
Because of this, he explained there is concern that if the combination of cabotegravir and rilpivirine is used in the country it will set up many people to fail that regimen.
"For lots and lots of reasons, people are a little bit worried or very worried about these drugs being used in the general population. So even internationally, only a tiny, tiny, tiny fraction of people with HIV are being treated with this combination," Venter said.
Nevertheless an option for some
Despite these challenges for the general population, there are certain groups of people living with HIV who could benefit from long-acting cabotegravir and rilpivirine injections.
Venter said there are some people living with HIV who for a variety of reasons are unable to take daily oral treatment but are able to keep their clinic appointments. He said that various studies and demonstration projects have shown that long-acting injections, including the cabotegravir and rilpivirine combination, work really well in these populations.
"It's important to remember that if those patient populations are not able to swallow their tablets every day, they're going to die," Venter said. "This combination of these two injections is lifesaving. It may not be optimal for all those reasons I mentioned," he added. "But if the alternative is they are going to die, this is all we have to offer them - but it's completely unavailable."
Patents and supply
As with most HIV medicines, questions have been asked about the prices charged for cabotegravir and rilpivirine and about the possibility of generic competition. Prices usually drop substantially once a few generic manufacturers enter the market. Having multiple suppliers can also result in a more reliable supply.
At the 25th International AIDS Conference (AIDS 2024) in Munich, Germany, Professor Chloe Orkin, Director of the SHARE Research Collaborative for health equity, read out a statement on how people in Sub-Saharan Africa and other low-and-middle income countries cannot access long-acting cabotegravir and rilpivirine. "Johnson and Johnson hold the marketing right for long acting cabotegravir and rilprivirine in these countries, but they have not yet been brought to market," she said. "The Medicines Patent Pool [MPP] can only do deals with generic companies to develop drugs, if companies developing the drugs authorise them with a license. MPP does not have the rights to rilpivirine. So, unless this happens, cabotegravir and rilpivirine treatment can't be rolled out in these countries."
Johnson & Johnson took issue with these comments when approached by Spotlight. "We would like to correct the statements made at AIDS 2024," said a spokesperson. "Engagement with the Medicines Patent Pool is unnecessary as Johnson & Johnson has taken actions related to rilpivirine long-acting patents in 90 low- and middle-income countries, allowing generic manufacturers to produce and market their own versions."
The details here are not straight-forward. Johnson & Johnson hold the patent rights on rilpivirine, while ViiV Healthcare hold the patent rights on cabotegravir.
When asked how the companies work together, ViiV Healthcare told Spotlight they have had a formalised collaboration with Johnson & Johnson for the "investigation and commercialisation" of the cabotegravir and rilpivirine combination since 2015. "In this collaboration, each partner manufactures its own product (ViiV Healthcare manufactures cabotegravir and J&J manufactures rilpivirine) to make up the complete treatment regimen," the company told Spotlight. "That said, Johnson & Johnson is the lead company for cabotegravir+rilpivirine long-acting in low- and middle-income countries and is better positioned to answer questions about cabotegravir+rilpivirine long-acting in these settings."
ViiV has granted voluntary licenses via the UN-backed MPP that allow generic manufacturers to produce cabotegravir injections for HIV prevention. ViiV has however confirmed to Spotlight that the existing MPP deal does not cover use of long-acting cabotegravir for HIV treatment and that this would require a separate agreement. "When negotiating the voluntary license with the Medicines Patent Pool, it was made clear that the prevention indication was the key priority for impact in low- and middle-income countries," ViiV stated.
Mounting evidence
Meanwhile, some new data on long-acting cabotegravir and rilpivirine was presented at AIDS 2024. While the combination has already been proven to be roughly as safe and effective as the daily tablets used to treat HIV, there is ongoing research on use of the treatment in different populations.
In a promising development for potentially expanding long-acting HIV treatment options for adolescents, the week 48 results from a Phase 3 study called IMPACT 2017 showed the regimen performed mostly the same in this age group as in adults.
The researchers looked at a cohort of adolescents living with HIV who were virologically suppressed on HIV treatment taken as tablets, and then switched to the two-monthly cabotegravir and rilpivirine injections. They were given a similar dose to what is given to adults. There were no unexpected safety signals in the study, according to Dr Aditya Gaur, who oversees the Translational Trials Center at St. Jude Children's Research Hospital in the United States and who presented the findings.
The majority of adverse events, Gaur said, were injection site reactions which occurred in a third of the participants. Most of them were mild. As seen in many studies of long-acting injections, the number of reported injection site reactions reduced as subsequent injections were given. More than half of the adolescents who were asked said they prefer the injections to pills.
HIV remained suppressed in everyone in the study who received the jabs.
In other positive news, two studies presented at AIDS 2024 showed that so far, the real-world outcomes of giving cabotegravir and rilpivirine injections every two months as treatment are similar to what was seen in clinical trials. The studies, called CARLOS and BEYOND, conducted in Germany and the United States respectively, monitored what happened to people in the real world who switched from antiretroviral tablets to the injections.
On a less positive note, there was some bad news for the development of more convenient injections. Researchers investigated the potential of giving an every two-monthly dose of cabotegravir and rilpivirine for HIV treatment injected just under the skin on the stomach (subcutaneous) instead of deep into the muscles (intramuscular).
The subcutaneous injection showed similar efficacy against HIV than intramuscular injections. But there were more injection site reactions in the 93 people who received the subcutaneous injections and more than half said they prefer the intramuscular injection. Because of this, the subcutaneous regimen will not be pursued any further, said Ronald D'Amico, associate medical director at ViiV Healthcare, who presented the study at the conference.
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Even longer-acting cabotegravir
Spotlight previously reported on results from a Phase 1 study that showed a new formulation of cabotegravir - called cabotegravir ultra-long-acting - could potentially provide four months of protection against HIV infection per shot. This same formulation is being considered for HIV treatment.
Dr Kimberley Brown, ViiV Healthcare's Global Medical Affairs Leader for Cabotegravir, explained that the use of the ultra-long-acting regimen in treatment is on a similar path as with prevention, where different combinations of cabotegravir ultra-long-acting paired with another long-acting compound needs to be evaluated.
"We would need to go through a very, very thorough development programme to ensure some of those options are being thought of and plans are underway to make this available as a treatment option as well - but again, it would have to be paired with another product to make a complete regimen," she said.
According to ViiV, two long-acting options are being considered for HIV treatment. The first option is the new double formulation of cabotegravir (cabotegravir ultra-long-acting) combined with rilpivirine. The second option looks at using the new formulation alongside the broadly neutralising antibody VH109 (bNAb N6LS).
Treatment with long-acting pills
Another potential alternative to daily antiretroviral tablets that is being researched is long-acting tablets, that could for instance be taken once a week.
Results from a study on such a long-acting pill containing the antiretrovirals islatravir and lenacapavir was presented earlier this year at the Conference of Retroviruses and Opportunistic Infections (CROI). 104 people participated in the study. Half were given the weekly oral tablet and the other half continued taking the daily antiretrovirals they were already on.
Based on the week 24 data, the weekly pill was well tolerated and safe, with no serious adverse events. The most common complaint was nausea and a dry mouth. No one discontinued the study due to side effects.
The data presented at CROI formed part of an ongoing Phase 2 study, Dr Nkosiphile Ndlovu, a Senior Research Clinician at the Clinical Trials Division at the Wits Reproductive Health and HIV Institute (Wits RHI) Research Centre, told Spotlight. He said longer-term data will be presented at a future scientific conference.
