the next best thing to an H.I.V. vaccine? lenacapavir
NY TIMES
Published June 21, 2024Updated June 24, 2024
“I got cold shivers,” said Dr. Linda-Gail Bekker, an investigator in the trial of the drug, lenacapavir, describing the startling sight of a line of zeros in the data column for new infections. “After all our years of sadness, particularly over vaccines, this truly is surreal.”
Yvette Raphael, the leader of a group called Advocacy for Prevention of H.I.V. and AIDS in South Africa, said it was “the best news ever.”
The randomized controlled trial,
called Purpose 1, was conducted in Uganda and South Africa. It tested whether
the every-six-months injection of lenacapavir, made by Gilead Sciences, would
provide better protection against H.I.V. infection than two other drugs in wide
use in high-income countries, both daily pills.
The results were so convincing that the trial was halted early at the recommendation of the independent data review committee, which said all participants should be offered the injection because it clearly provided superior protection against the virus.
None of the 2,134 women in the arm of the trial who received lenacapavir contracted H.I.V.
By comparison, 16 of the 1,068 women (or 1.5 percent) who took Truvada, a daily pill that has been available for more than a decade, and 39 of 2,136 women (1.8 percent) who received a newer daily pill called Descovy were infected.
A second trial, conducted in six other countries, including Brazil and the United States, is assessing the effectiveness of lenacapavir in men who have sex with men, in transgender people and in those who use injection drugs.
New England Journal of Medicine November 27, 2024.
Among 3265 participants HIV infections occurred
in 2 participants given lenacapavir (0.10
per 100 person-years;) and in 9 participants in the people given HIV
medication: emtricitabine–tenofovir disoproxil fumarate (0.93 per 100 person-years.)
While Truvada, taken daily, provides high levels of protection against H.I.V. infection and has been widely used by gay men in the United States and other high-income countries for years, it has not proved to be a potent prevention tool in Africa, where uptake has been low, particularly among young African women, the group with the highest rates of new infection.
The hope is that a twice-a-year injection, which women can put on their calendars and then not think about for months, will prove more effective.
In general viruses are a chain of 4 nucleotides—DNA or RNA-- surrounded by a protein coat--the capsid. The protein shell transports and protects nucleotides. It also attaches the virus to a wall of a target cell and it has a way of getting viral nucleotides into a host cell. Inside the cell the strand of nucleotides uses the cell’s enzymes to create additional identical strands of nucleotides. It also uses the protein biosynthesis mechanism of the cell to create capsid proteins. Groups of these proteins then self assemble and form the three dimensional structure that surrounds the nucleotides.
Gilead researchers working in teams started a “capsid project” in 2006. They were looking for a small molecule that would prevent capsids from combining to form the protein shell that surrounds viruses. By 2010 they had screened over 4000 molecules and in 2016 they had their clinical candidate, Lenacapavir. Also called GS-6207 it binds to a pocket—binds directly to the interface between capsid protein subunits at multiple stages of the HIV replication lifecycle—and it thus prevents capsid formation. It was also highly efficacious in people with multi-drug resistant HIV. (1)
GS-6207 is a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site.
Drawing on X-ray crystallographic information, scientists designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs.(2).
In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. HIV GS-6207 was first used in humans in 2018.
The outstanding question is access:
Gilead charges $42,250 per patient per year for lenacapavir, in the United States, where it is approved as a treatment for H.I.V.
“Africa is excited, women are excited, we have waited long for this,” Ms. Mworeko said. “Now we need to know, how do we get this into the hands of people who need it? We need an answer to this yesterday.”
Gilead said it was committed to making large volumes of the drug available “at prices that enable widespread availability” as quickly as possible in low-income countries with H.I.V. incidence rates.
“On October 2, 2024 Gilead Sciences announced that it has signed non-exclusive, royalty-free voluntary licensing agreements with six pharmaceutical manufacturers to make and sell generic lenacapavir, (subject to required regulatory approvals, in 120 high-incidence, resource-limited countries, which are primarily low- and lower-middle income countries.) The agreements were signed in advance of any global regulatory submissions to enable these countries to quickly introduce generic versions of lenacapavir for HIV prevention, if approved.”
“The agreements advance Gilead’s strategy to enable broad, sustainable access to lenacapavir for pre-exposure prophylaxis (PrEP) globally and align with Gilead’s vision of ending the HIV epidemic for everyone, everywhere.”
“Gilead will support low-cost access to the drug in high-incidence, resource-limited countries through a two-part strategy: establishing a robust voluntary licensing program, and planning to provide Gilead-supplied product at no profit to Gilead until generic manufacturers are able to fully support demand. Additionally, the agreements cover not only lenacapavir for HIV prevention (pending approval), but also lenacapavir for HIV treatment in heavily treatment-experienced adults with multi-drug resistant HIV.
“Given the transformative potential of lenacapavir for prevention, our focus is on making it available as quickly and broadly as possible where the need is greatest,” said Daniel O’Day of Gilead.
“In selecting the licensees, Gilead listened to global health advocates and organizations that advised partnering with manufacturers from multiple countries and continents.
To provide Gilead-supplied lenacapavir until generic versions are available, Gilead is prioritizing registration in 18 countries that represent about 70% of the HIV burden.”
South Africa’s current budget for oral PrEP is about $40 per patient per year.
Oral anti-retroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis--However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multi-drug resistance.
In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment—which contributes to virologic failure, resistance generation and viral transmission—as well as of pre-exposure prophylaxis, leading to new infections.
Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence.
From Yale school of Medicine bulletin:
Onyema Ogbuagu, a Yale infectious diseases specialist cares for patients who are affected by or at risk for HIV/AIDS. He recently “studied people whose HIV infection is resistant current HIV treatment. Some had acquired HIV from people who already had developed resistance to multiple HIV medications. Others were ‘typically people who were on HIV treatments and, because they were put on the wrong medication, or they didn't take the medication as prescribed had developed resistance.
“To conduct the third phase of the drug trial, his group treated three groups of patients with lenacapavir tablets, and with injections that went under the skin.
People in the study were immediately switched off failing treatments and placed on lenacapavir, along with at least one or more additional HIV drugs.
Early on researchers randomly gave lenacapavir to one group and a placebo to the other in a 2:1 ratio for two weeks. Those who received lenacapavir tablets for the first two weeks took weekly doses. After the two weeks, researchers added new drugs to replace the current therapy the person was on that had not been effective. Subsequently, they tested people to check the amount of viral copies they had in their bloodstream.
“We found that we had suppressed 88% of viral copies in the arm where people had received lenacapavir, and suppressed only 17% in people who received the placebo in the arm,” Ogbuagu noted, “and then we followed them out to a year.”
“The drug managed to suppress the virus in over 80% of individuals. “That’s incredible,” he said.
The clinical trials were done with a relatively small group of people since only 8% or less of all the HIV patient population has multi-drug resistance and met that definition in the study, When the study, which was done with FDA oversight, met research goals, the agency approved 927 milligrams of lenacapavir injections, separated into two doses, to be received twice per year. Lenacapavir tablets of 300 milligrams were approved for use only as a loading dose—for an initial lead-in option before switching to the injection in the study. The efficacy of long term treatment is still being evaluated.
The U.S. Food and Drug Administration (FDA) approved lenacapavir (Sunlenca) on December 22, 2022
addendum by jon cohen in science july 2026
In October 2024, Gilead announced it would license LEN PrEP
to six generic companies that could sell it at steep discounts to 120 low and
middle-income countries. Until they were ready to deliver, Gilead promised to
provide the drug itself at no profit—reportedly for $60 a dose instead of the
$14,000 it charges in wealthy nations. And in December 2024, the U.S.
President’s Emergency Plan for AIDS Relief (PEPFAR) and the Global Fund to
Fight AIDS, Tuberculosis and Malaria announced they would provide LEN PrEP to 2
million people in 3 years.
“We were incredibly optimistic in 2024,” Bekker says. “It
looked like everything was falling into place.”
Then Trump took office, quickly dismantling the U.S. Agency
for International Development (USAID), which managed about half of PEPFAR’s
funding. The administration also halted all aid to South Africa because of what
it called “egregious actions” by its government, including the supposed
seizures of Afrikaner-owned farms. Last month, the U.S. Department of State
said it would phase South Africa out of PEPFAR altogether by 2027. The country
was PEPFAR’s single largest beneficiary, receiving $435 million in 2024. South
Africa buys its own HIV drugs, but the aid helped it pay health care workers
and pharmacists, provide counseling, reach marginalized communities, and
evaluate progress.
A different dispute has disrupted aid to Zambia, which received more than $4 billion in support from PEPFAR over the past decade. In return for health aid, the U.S. now requires countries to sign a memorandum of understanding in which they commit to support health programs themselves and wean off aid by 2030. Negotiations with Zambia have stalled, reportedly because the U.S. wants access to health data, pathogen sequences and samples, and Zambia’s vast mineral deposits. The country currently receives only a dribble of U.S. aid.
1. https://longactinghiv.org/LEAPWRKSHP2023-Text_Summary-MartinR
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2771126/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7
2. Nature 584, 614 (2020), doi: 10.1038/s41586-020-2443-1.
Mol Pharm. 2023 Dec 4;20(12):6213-6225. doi:
Twice-Yearly Lenacapavir or Daily F/TAF
for HIV Prevention in Cisgender Women
by Linda-Gail Bekker, M.B., Ch.B., Ph.D. et al.
Published July 24, 2024
N Engl J Med 2024;391:1179-1192
https://www.nejm.org/doi/abs/10.1056/NEJMoa2411858
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