Manufacturer’s plans for equitable access to twice-yearly PrEP under fire

While plans for global access to lenacapavir, the twice-yearly injectable PrEP product which demonstrated extraordinary efficacy last year, have progressed unusually quickly, critics say that the arrangements are riddled with inconsistencies and will not achieve Gilead Science’s stated goals of “ensuring broad, sustainable global access to lenacapavir for PrEP” and of “ending new HIV infections around the world”. Critics say that if the voluntary licenses to generic manufacturers are not improved, then countries should explore compulsory licensing instead.

Competing perspectives are presented in a pair of viewpoint articles published in Clinical Infectious Diseases this week. Dr Jared Baeten, senior vice president of clinical development at Gilead – and formerly an academic researcher running HIV prevention studies in African countries – articulates the position of the company which has developed lenacapavir. The critiques come from Drs Andrew Hill, Mark Siedner, Cassandra Fairhead, and Francois Venter, who conducted their analysis with support from the International Treatment Preparedness Coalition.

Two injectable PrEP products have been developed. ViiV Healthcare’s cabotegravir, which is dosed every two months, demonstrated highly impressive efficacy in 2020, but generic production has not yet started and the company’s licensing arrangements and pricing have faced much criticism.

Gilead reported even better results for lenacapavir, dosed every six months, in 2024. In the PURPOSE 1 study conducted with young women in South Africa and Uganda, HIV incidence was 100% lower with lenacapavir than with PrEP pills, while in the PURPOSE 2 study of gay and bisexual men and gender diverse people, incidence was 89% lower. Both types of injectable PrEP have probably demonstrated superiority over daily PrEP pills because people found them easier to take, rather than because the drugs are intrinsically more potent.

Speaking for Gilead, Baeten is also proud of several aspects of the research process for lenacapavir. The studies focused on some of the groups with the greatest need for improved HIV prevention and were shaped through engagement with advocates, scientists, regulators and policymakers. PURPOSE 1 was unusual in including adolescents and pregnant and breastfeeding women, while PURPOSE 2 had a notably diverse sample, including transgender men and non-binary people.

He says that planning for global access for lenacapavir began in 2022 and has involved extensive consultation. “Our planning for low- and lower-middle-income countries is guided by four priorities: delivering lenacapavir with speed, at sufficient volume to meet demand, at prices that enable widespread availability, and in partnership in a multisector ecosystem, if it is approved.”

Lenacapavir has rapidly advanced to submission for approval by drug regulators in the United States and Europe. As well as considering whether lenacapavir should be available in the European Union, the European Medicines Agency will also give a regulatory opinion on the use of lenacapavir in the global south. They will follow the same procedure that was used for the dapivirine vaginal ring, which can facilitate subsequent approval by the World Health Organization and national regulatory agencies in lower- and middle-income countries, many of which do not have the capacity to scrutinise all new medicines themselves.

Voluntary licensing agreements have already been signed with six generic manufacturers, and Beaten says this has happened more quickly than for any previous HIV drug. However, Dr Andrew Hill and colleagues say that the provisions of the licensing deal will undermine widespread access.

The devil is in the detail

Under the licensing deal, the six generic manufacturers are being supported to develop the technical expertise to produce lenacapavir themselves, which they will then be able to sell in 120 countries. The generic companies will not pay royalties to Gilead and will determine lenacapavir’s price themselves. In the rest of the world, Gilead will have the exclusive right to sell lenacapavir and decide its price.

Gilead have come up with a list of 120 “high-incidence, resource-limited countries”, but Hill points out they haven’t explained their criteria. Most are in Africa, Asia, the Caribbean and eastern Europe. While almost all countries classified as low-income or lower-middle-income by the World Bank are included, there’s inconsistency in the approach to upper-middle income countries. Those in sub-Saharan Africa will be covered by the deal, but most of those in Latin America are excluded. Thailand is included, but Malaysia and China are not. Hill notes that Brazil, Colombia, Guatemala and Algeria – which won’t have access to generic lenacapavir – have lower average incomes than some countries which are covered, such as Guyana and Kazakhstan.

And what about countries with a high incidence of HIV? Hill estimates that in 2023 there were over 200,000 new HIV infections in excluded middle-income countries – 23% of the global total. In many of the excluded countries, incidence is particularly high in key populations. It’s thought to be 9.2% for men who have sex with men and transgender women in Brazil, and 11.9% and 2.9% for those groups respectively in Peru. Annual incidence among people who inject drugs is 8.1% in China, 6.9% in Bulgaria, 4.5% in Iran and 3.5% in Mexico.

And even though over half of all PURPOSE 2 study participants were recruited in Brazil, Peru, Argentina and Mexico, none of these countries will have access to generic PrEP. Unless Gilead sets a cost-effective price for its own lenacapavir product in these countries, Hill says that the company risks violating the Declaration of Helsinki ethical guidelines on conducting research. These state that vulnerable populations should only be enrolled in research if they “will be able to benefit from the knowledge, practices or interventions resulting from the research”.

2028 is seen as the most likely date for generics to be widely available, but Hill believes that making agreements with more than six generic manufacturers would allow large volumes of lenacapavir to be produced more quickly. While three of the generic companies are based in India, other experienced Indian manufacturers were excluded. The remaining three companies are based in Pakistan, Egypt and the US – many experts say that not including any manufacturers from sub-Saharan Africa is a missed opportunity to support regional self-sufficiency.

Affordability is key to access

The price of lenacapavir will be a crucial determinant of the impact twice-yearly PrEP will have on the global epidemic. Jared Baeten of Gilead does give some general indications of the company’s approach to pricing, without ever giving any figures. In the 120 countries which will be covered by the voluntary licenses, he says they will price lenacapavir at no profit to the company. This will apply in the period between approval by drug regulators and generic products actually being available, so Gilead’s price will probably matter most in 2026 and 2027. After that, prices will be determined by each generic manufacturer, and he hopes that prices will lower over time, as has happened with generic PrEP pills.

But in the countries that are excluded from the licensing deal, Gilead will continue to determine the price. Baeten says the company is “exploring several innovative strategies to support access to lenacapavir for PrEP for upper-middle income countries, including tiered pricing” – this refers to a strategy in which the same medicine is sold at different prices in different countries, typically based on income levels or market conditions. In the Latin American countries where the PURPOSE 2 study was done, he says that consultation and planning are ongoing.

Lenacapavir was originally developed for HIV treatment, has great efficacy against HIV that is resistant to existing antiretrovirals, and is currently only licensed by drug regulators for the treatment of people with extensive drug resistance. Gilead charges around $40,000 per year for this niche product in high-income countries, but Beaten explicitly says that this will not be the reference point for PrEP pricing, in any country. A lower price would allow a larger injectable PrEP market to develop, but it remains unclear how low Gilead is prepared to go.

According to Hill’s calculations, generic manufacturers could produce lenacapavir for around $95 per year, assuming there are one million PrEP users, with the price dropping to $40 if the size of the market increased to ten million PrEP users. All of this assumes that voluntary licences are in place and there is strong competition between generic companies. At the same time, a modelling study found that for lenacapavir to be cost-effective in the upper-middle income country of South Africa, it would need to cost less than $106 a year, while in lower-middle income Zimbabwe, it could not be any more than $21.

Baeten also states that Gilead is committed to making their own production of lenacapavir available in low- and middle-income countries until the generic manufacturers are ready, that they will be able to supply two million people during this time, and that people who took part in the PURPOSE 1 and 2 studies will continue to receive the drug until it is routinely available.

Much of Baeten’s article describes what the company is doing to cover the period until generic lenacapavir is produced under the licensing deal, but he does not directly engage with the criticisms of the license itself, many of which have been previously raised by advocacy groups and by UNAIDS, the United Nations HIV programme.

Both articles were written before Donald Trump returned to the White House and most of the United States’ global health programmes were fed into the woodchipper. This will have a profound impact on the prospects for lenacapavir, as it takes away major players who might have been ready to place large orders for the product with generic manufacturers, which would give the manufacturers confidence to invest in production and would help lower prices. In the scale-up of oral PrEP over the last decade, over 90% of PrEP was funded by PEPFAR, the US President’s Emergency Plan for AIDS Relief. But PrEP programmes have been specifically excluded from any continuation of PEPFAR, and other key players like The Global Fund have also been weakened by recent events, as a significant proportion of their funding came from the US government. It’s unclear whether national governments will be willing or able to step in and pay for PrEP pills themselves, never mind pay for injectable PrEP.

Hill says that if Gilead does not make changes to the voluntary license, compulsory licences may need to be invoked. A compulsory license is a legal mechanism that allows governments to authorise companies to produce or import patented drugs without the consent of the patent holder. It is typically invoked due to a public health emergency, anti-competitive practices, or when patented medicines are unaffordable or inaccessible. Several countries including Brazil, Thailand and Malaysia used compulsory licenses to force access to antiretrovirals between 2001 and 2007, but few countries have dared to do so in recent years. One notable exception is Colombia, an upper-middle income country that was excluded from the voluntary licensing agreement for dolutegravir and which issued a compulsory license for this key HIV treatment medication in 2024. The threat of a compulsory license can also work to bring prices down.

“A coordinated response from governments, donors, civil society, and the private sector including Gilead is urgently required to ensure lenacapavir access is wide enough to eliminate HIV transmission worldwide,” Hill and colleagues conclude. “Unless crucial changes to the current license are made, compulsory licences may be required.”