A call for urgent action in navigating the complex landscape of long-acting HIV medications

26 Nov 2024

HIV prevention injections that can provide two, or even six, months of protection per shot have arguably been the biggest HIV story of the year. Ahead of World Aids Day, Professor Francois Venter assesses the state of play and the critical next steps with these potentially game-changing new tools in the fight against HIV.

There has been a wave of articles, interviews and reports on new medications given every few weeks or months, with new research unfolding, coupled with demands for access to these exciting agents, in an often bewildering and overwhelming flood of information.

The revolution comes against a background in drug delivery development where smart biochemists are able to work out ways to get old drugs or new formulations to release more slowly into the body. The approach is not new, and people in South Africa will be very familiar with contraceptives given into a muscle as an injection every two to three months, as an implant under the skin in the inner arm every three years, or even as an intra-uterine device that can stay in place for several years.

This approach of using different ways of administering a long-acting drug is now being extended to many other areas of medication. For chronic illnesses that require taking tablets or injections every day, an Achilles heel for everything from hypertension to HIV, this solves a major problem.

As for what all this means for HIV, it helps to take prevention and treatment in turn, as they differ by availability timelines for new long-acting products, who immediately needs the medication, and how it will be deployed. There are also specific politics around each new drug, that circle around pharmaceutical company commercial interests and international patent debates, that often trump the needs of everyday people who need the medication.

Long-acting HIV prevention

HIV prevention has been electrified by two new injectable drugs given to people at risk: cabotegravir given into a muscle every two months, and the new arrival, lenacapavir, given just under the skin every six months. There is a ton of detail we can’t unpack here, but in a nutshell, both drugs give near 100% protection from HIV, with very few side effects.

It is important to remember that there is also a highly effective and safe prevention tablet that has to be taken daily. It is nearly 100% effective if taken perfectly; however, practical effectiveness is reduced in the real world, as some people forget to take their tablets as prescribed. A less effective vaginal ring, a choice for women who don’t or can’t take tablets, is now being rolled out in South Africa.

The uptake of the oral prevention option across the world has been very poor, for complex reasons, including poor advocacy, poor education, lack of accessible services, and overly complicated processes to get medication. South Africa in fact accounts for about 40% of the world’s population taking HIV prevention tablets, but even here only a minority of people who need it are getting it.

So why isn’t everyone who needs prevention getting the new injectables? Wading through company, activist, health worker, guideline and researcher input on the issue, it seems (at least from what I can discern) that the two companies who make cabotegravir and lenacapavir didn’t plan very well for the success of their medications. Scaling of manufacturing was almost an afterthought once the studies reported the amazing results, especially for cabotegravir. Both companies have shown opaque approaches to communications.

ViiV, the company making cabotegravir, showed a bewildering lack of understanding of the scale of the need for their drug, judging by their initial commitment to supply the world’s need, and then realising they could not even supply a fraction of this. This was followed by a ponderous licensing process to generic manufacturers, a disappointing result considering the company had previously been key in facilitating access to transformative HIV treatment drugs.

Gilead, the company making lenacapavir, has been a little faster on the licensing front, although not through the commonly accepted mechanism of the Medicines Patent pool, opting instead to license generic manufacturers directly. They’ve also provided precious little detail on critical issues like the price they will charge until generics eventually come online.

We are left with a distressing situation for HIV prevention – vanishingly small amounts of cabotegravir relative to what we need, drip fed into the country by the company, with supply only likely to ease into 2028, many years after we found out the drug worked. For lenacapavir, we have no clue what it will cost, and it looks, at best, like we are facing a similar timeline to that of cabotegravir.

Both drugs were tested on people in South Africa. This is something to celebrate since we far too often only find out efficacy and safety in our own populations far too late. But, that the two drugs will probably only be introduced at scale here a decade after they were tested is certainly not something to celebrate.

Long-acting HIV treatment

For HIV treatment, where combinations of antiretrovirals are used rather than a single drug as with prevention, the situation is simpler but timelines are far longer.

It is simpler as only one long-acting combination is available, using one of the drugs mentioned above, cabotegravir, with another, rilpivirine, with two separate injections in the buttocks given every two months. Administration is fiddly, needing training and expertise to administer the injection, and in different parts of the buttock every cycle, with special needles for people with obesity, and with rilpivirine needing refrigeration. This complexity and the expense even if prices drop from their current high levels, and the tiny amounts of available drugs, even in high income countries, mean that calls from people with HIV for this to replace their current highly successful oral tablet are unlikely to be heeded in government programmes or even in medical aid options any time soon.

ViiV has not extended its cabotegravir access programme for HIV prevention to the use of the drug for treatment. Janssen, the company producing rilpivirine, has made a verbal commitment to make rilpivirine available, but in the absence of any formal written commitments, and subsequent work on ensuring sufficient volumes of the drug, this commitment carries no weight.

So what about other injectables for treatment? There is a case for combining cabotegravir with lenacapavir, but the two companies are fierce commercial rivals, and so far trying to get them to contribute their medication to independent studies has proved unsuccessful, and making the medication through third parties is very complex to negotiate.

The road after this — to the end goal of widely available cost-effective medication available in readily accessible injection sites — is a long one, probably measured over a decade. At this stage, the start button is firmly in control of the two companies, and they seem reluctant to press it.

Additional injectables are still in the earlier stages of development. No doubt they will become available in time, but again, these are many years away, and as with most drug development, many will fail along the way.

One interesting future HIV treatment option, that may be registered in the next two to three years, is a weekly tablet that combines lenacapavir with another new antiretroviral, islatravir, made by yet another company, MSD. Early data is very encouraging, the combination may be cheap to produce, and it is interesting to think about whether this may be the first widely available long-acting combination available (imagine being given the same number of tablets for six months as you would be for a single month). However, negotiations with the companies have not yet started, and a gauntlet of obstacles could still slow this down. There are also other promising long-acting oral options in earlier stages of development.

So, people starting HIV treatment, and those on treatment, are not going to see significant change soon, and unless a more active approach to drug access and the necessary research studies are undertaken, this will probably remain the case for decades. Luckily, the currently available first line oral daily antiretroviral therapy is pretty amazing in terms of safety and potency. But a significant group of people would benefit from long-acting medications, and many people on stable therapy would simply like to benefit from the lower hassle factor that comes with this new treatment option.

A large amount of work needs to be done after the drugs become available, including finding the best place to administer the injections, and how to remind people to come back, as resistance may develop or immune damage occur if they start missing doses. Even in high-income countries, HIV clinicians complain about how difficult this is, and South African systems, even in the private sector, have proved poor at finding people who disappear from their care systems. Finding a convenient, efficient and responsible way to get these drugs to people will take implementation experience, and that takes time and effort. We also need to adapt these regimens for children and adolescents, an ongoing challenge when there is little commercial incentive for pharmaceutical companies to do this.

‘Multiple obstacles’

However, we cannot even start with much of this while pharmaceutical companies throw up multiple obstacles to doing the necessary research, implementation and other projects necessary to get these exciting agents into the next phase of assessment, and the coalface implementers start using them in pilot studies.

A certain level of blame for our current impasse could be laid at the feet of the researchers concerned, agencies, HIV activists, our government (which has never pushed on compulsory licences), and the broader HIV community, for not paying attention at an international level to these drugs from the get-go.

The drug development world is complex, but constant monitoring of the landscape and moving forward with relevant research has meant that previously we have been more on top of things. This no longer seems to be the case, whether it is the move away from HIV in favour of other priorities, the distraction of Covid-19, or the new power of the international companies in patent discussions at the expense of people’s health.

The pharmaceutical companies have never been more powerful — witness the casual bullying of the South African government around the Covid-19 vaccines. We have witnessed the weakening of key allies, including attacks on civil society, a lack of funding for activist organisations, the defunding of HIV education agencies, and the decimation of Doctors without Borders’ critical Medicines Access Campaign.

Our country has a proud history of access to world-class HIV medications. Allowing the current impasse to persist would mean this is no longer the case. We need focus, activism and partnerships. There is no reason to accept the current lack of progress. DM

*Venter is Executive Director of Ezintsha, a multidisciplinary research centre at the University of the Witwatersrand.

*This article was first published by Spotlight — health journalism in the public interest. Sign up to the Spotlight newsletter.

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Long-acting HIV prevention

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‘Multiple obstacles’