If you grew up in the middle of the early AIDS epidemic as I did, something I've written about firsthand, the results of a study on a twice-yearly injection from Gilead seem almost too good to be true.
Over the past four decades, the progress against HIV/AIDS has been nothing short of miraculous. Here's a quick look at the taming of a death sentence by the discovery and use of better and better drugs.
- 1980s: The first published report of AIDS infections by the CDC in 1981. AZT (zidovudine) becomes the first FDA-approved drug for AIDS. But it is toxic and ineffective.
- 1990s: Major turning point with the introduction of highly active antiretroviral therapy (HAART) in 1996, reducing AIDS-related deaths for the first time. However, the pill burden is oppressive; patients must take up to 40 pills per day at regular intervals. The combination therapy is effective, but the side effects could be brutal.
- 2000s: More efficacious and less toxic antiretroviral drugs, sometimes combined in one pill, improve patient compliance, outcomes, and quality of life. First progress in preventing mother-to-child transmission of HIV. AIDS becomes a manageable chronic condition.
- 2010s: Pre-exposure prophylaxis (PrEP) drugs prevent transmission of the virus.
Another major milestone. And then some.
A June 20th press release from Gilead Sciences Inc. summarized the results of the company's PURPOSE 1 trial, which examined the efficacy of injectable lenacapavir (Sunlenca) in Sub-Saharan Africa, where women and adolescent girls make up almost 60% of all new HIV infections globally. Although PrEP drugs would have prevented most (1) of these infections, access and adherence to a regular schedule were sometimes problematic, especially in Africa.
The PURPOSE 1 trial, a Phase 3, double-blind, randomized study that began in 2021, evaluated the efficacy of lenacapavir – a capsid inhibitor – given by subcutaneous injection twice per year (!) against two commonly used PrEP drugs, Truvada and Descovy, both nucleoside reverse-transcriptase inhibitors (2). The results were astounding:
- 5,300 female study participants, aged 16-25, across 25 sites in South Africa and Uganda
- 2,134 received lenacapavir (two injections per year)
- 1,068 received Truvada (one pill per day)
- 2,136 received Descovy (one pill per day)
- 16 of the 1,068 women (1.5%) of the women who took Truvada became infected
- 39 of the 2,136 women who received Descovy (1.8%) became infected
- There were ZERO infections in the 2,134 women who received the lenacapavir injections
If someone projected this back in the early 1990s when people were dying miserable (and inevitable) deaths, I would have suggested a psych evaluation. (When preliminary results became available, the trial was stopped early, and all the women switched to lenacapavir.)
The first capsid inhibitors
Capsid inhibitors, the newest class of HIV replication inhibitors, are unique in that they disrupt the function of three targets in the HIV life cycle.; the other eight classes target only one. In virology, inhibition of multiple molecular targets, traditionally by combining several drugs that work by different mechanisms, is the best way to address suppress resistance.
The chemical structure of lenacapavir is nothing short of insane. But the name is even more so: Sodium;[4-chloro-7-[2-[(1S)-2-(3,5-difluorophenyl)-1-[[2-[(2S,4R)-5,5-difluoro-9-(trifluoromethyl)-7,8-diazatricyclo[4.3.0.02,4]nona-1(6),8-dien-7-yl]acetyl]amino]ethyl]-6-(3-methyl-3-methylsulfonylbut-1-ynyl)pyridin-3-yl]-1-(2,2,2-trifluoroethyl)indazol-3-yl]-methylsulfonylazanide. Try using this in Scrabble.
How does lenacapavir work?
To understand this you need to know what a viral capsid is. In short, it's the molecular "suitcase" that carries all the goodies – the proteins and genetic material that enable the virus to infect host cells and replicate. Capsids, just like all other viral components, are necessary for a "healthy" virus.
(Left) The HIV capsid (purple) contains all the components required for a functional virus. The envelope (red) is an extra coating, which is found in HIV, but not all viruses. Image: ClinicalInfo.AIDS.gov (Right) HIV capsid formation and budding. (Image: Gilead)
Lenacapavir, which binds to the capsid protein, shuts down viral replication by disrupting:
- Viral Assembly: It prevents the proper formation of new viral particles.
- Maturation: It blocks the processing of viral proteins, producing defective, non-infectious viruses (3).
- Reverse Transcription: Interferes with DNA synthesis from viral RNA (4).
These inhibitors bind to the capsid protein, disrupting the assembly and maturation of new viral particles and interfering with the reverse transcription process, where viral RNA is converted into DNA within the host cell. By hindering these critical stages of the HIV lifecycle, capsid inhibitors effectively prevent the replication and spread of the virus within the body, offering a potent mechanism for treating and potentially preventing HIV.
Bottom line
Short of an AIDS vaccine, which has been the target of countless failed attempts over four decades, this is about as good as it gets. Gilead is collaborating with a number of regulatory agencies, including the European Medicines Agency and the World Health Organization to develop programs to speed the delivery of the drug to poorer countries with underdeveloped healthcare systems.
NOTES:
(1) Truvada, when used as directed, is about 99% effective in preventing transmission.
(2) Because effective PrEP options already exist, there is broad consensus in the AIDS field that using a placebo group would be unethical. I fully agree.
(3) HIV protease inhibitors also block maturation, but by a different mechanism. Lenacapavir does not inhibit HIV protease.
(4) Lenacapavir does not inhibit HIV polymerases; it indirectly inhibits their action by a mechanism that is different from NRTs and NNRTs.
Josh Bloom
Director of Chemical and Pharmaceutical Science
Dr. Josh Bloom, the Director of Chemical and Pharmaceutical Science, comes from the world of drug discovery, where he did research for more than 20 years. He holds a Ph.D. in chemistry.
