Since June 2024, all scholars around the world who care about AIDS prevention have focused their attention on Gilead's antiviral drug lenacapavir.

At that time, Gilead announced the latest data of the PURPOSE 1 trial conducted by lenacapavir, and the results showed that: in the case of head-to-head daily oral PrEP drugs, lenacapavir achieved 0 infection with 2 injections per year. This means that in the case of unfavorable vaccine development, lenacapavir is expected to replace the preventive effect of the vaccine with its ultra-persistent prevention characteristics.

Of course, is the result of the PURPOSE1 trial accidental or inevitable? No one can give an answer. But in September, Gilead continued to provide PURPOSE 2 trial data, indicating to the outside world that the possibility of inevitability is greater. The results showed that 99.9% of the participants in the Lenacapavir group were not infected with HIV, and the risk of infection was reduced by 96% compared with the placebo group. This may indicate that the era of efficient human AIDS prevention may be getting closer and closer.

The fight between humans and AIDS can be traced back to the 1980s. In 1983, two scholars from the United States and France independently isolated HIV, the pathogen of AIDS, and the world began to understand this evil virus. HIV attacks the commander-in-chief of the human immune system, CD4 immune cells. It is not enough to capture them. HIV also uses CD4 cells as its home base and breeds countless viruses. Eventually, fewer and fewer CD4 cells can function, and the immune system gradually collapses. Various common bacterial and viral infections have become fatal injuries, such as Candida albicans infection. Often, a small cold can cause AIDS patients to die due to immune system defects.

Although the medical community has enough knowledge about HIV, the prevention and treatment of HIV is still a big challenge: drugs still cannot cure HIV, and vaccines have not been available. In 1984, Margaret Heckler, then US Secretary of Health, announced at a press conference that HIV was the culprit of AIDS and optimistically predicted that the vaccine would be available within two years. However, in the nearly 40 years since then, scientists have tried multiple routes, including inactivated vaccines, attenuated live vaccines, protein subunit vaccines, viral vector vaccines, DNA vaccines and other new ideas, as well as "combined vaccines" combining different routes. Hundreds of billions of R&D costs and nearly 100 vaccines have all failed to succeed.

There is no way. HIV is so primitive and simple that it has almost unlimited mutation possibilities, which also leads to many challenges for vaccine entrants. In January last year, after a large-scale Phase 3 clinical failure, Johnson & Johnson completely stopped the operation of its infectious disease research and development department. In the global HIV vaccine battle, another strong player is close to withdrawal. This seems to tell the market that entering the field of HIV vaccine research and development must be cautious.

Of course, if you want to prevent AIDS, you don't just rely on vaccines. Antiviral drugs can also have a similar effect. For more than 30 years, oral antiretroviral drugs have been the cornerstone of HIV treatment. Their continuously improving safety and effectiveness have directly reversed the initial tragic process of the HIV epidemic.

For now, there are clear guidelines for both "prevention" before exposure and "blocking" after exposure. For example, for HIV-negative individuals, the recommended post-exposure prophylaxis regimen, including a 28-day course of two or three antiretroviral drugs combined within 72 hours of HIV exposure, can clearly reduce the probability of HIV infection. However, compliance is a great challenge for post-exposure prophylaxis. A meta-analysis showed that by the end of 2022, the overall compliance rate of post-exposure prophylaxis in healthy patients was only 58.4%, an increase of 1.8% from 2014. In other words, although most individuals will think of blocking therapy after exposure, less than 60% of them actually stick to the end of the course of treatment. In this case, it is even more unrealistic to continue taking the drug before exposure. This undoubtedly brings challenges to the prevention and control of AIDS.

The core reason for this problem is that the treatment regimen requires daily medication. On the one hand, the cumbersomeness will cause forgetting to take the medication, resulting in the suspension of blocking; on the other hand, the side effects caused by frequent administration will lead to discontinuation of medication. Due to a combination of factors, the market has an extremely urgent need for longer-acting HIV drugs. For this reason, the market has expectations for lenacapavir.

Now, with the release of two phase 3 clinical data, the potential of lenacapavir is being verified step by step. The PURPOSE 1 trial recruited more than 5,300 women in South Africa and Uganda. The treatment group was injected with lenacapavir twice a year, and the control group was daily oral PrEP drugs Descovy or Truvada.

The final results showed that among the more than 2,000 women in the lenacapavir group, no infection occurred during the trial, while the incidence rate in the Descovy group was 2.02 cases per 100 person-years and in the Truvada group was 1.69 cases. In other words, with two injections per year, lenacapavir can achieve zero HIV infection. The PURPOSE 2 trial is a supplement to the PURPOSE 1 trial, and the included subject population is richer.

In countries such as Argentina, Brazil, Mexico, Peru, South Africa, Thailand and the United States, the PURPOSE 2 trial included men who have sex with men, transgender men and women. Although two patients in the lenacapavir group were infected with HIV, overall the risk was still reduced by 96% compared with the control group. As the results of the PURPOSE 2 trial were announced, Ethel Weld, assistant professor of medicine at the Johns Hopkins University School of Medicine, said.

Indeed, lenacapavir has a high efficacy and reduces what individuals must do to protect themselves throughout their lives, which is closer to the field of other prevention paradigms (such as vaccination). Of course, whether lenacapavir can become a real game changer is still unknown. On the one hand, the indication of lenacapavir for the prevention of HIV requires regulatory approval. According to Gilead, the data from these two trials will be used to support a series of global regulatory filings, which are expected to begin at the end of 2024, and if approved, the time may be 2025.

However, in addition to whether it can be successfully approved, price will also be the key to whether lenacapavir can become a game changer. Currently, the cost of HIV treatment with lenacapavir in the United States is $42,000 in the first year and $39,000 per year thereafter. And its patent protection will continue for nearly 20 years. For less developed countries, patients obviously cannot afford such high costs. According to an analysis presented at the 24th International AIDS Conference, the cost of PrEP drugs for each patient in South Africa needs to be less than $54 per year to be affordable.

Lenacapavir's competitor, oral PrEP, may cost less than $4 per month because the patent has expired. Faced with the huge gap, whether lenacapavir can benefit more high-risk groups as scheduled remains to be seen. Therefore, people from all walks of life overseas called on Gilead to lower the price of the latest long-acting injection lenacapavir, and at the same time as launching it in wealthy countries, it is also necessary to ensure that HIV-infected or high-risk people in low-income and middle-income countries can obtain lenacapavir at the same time, such as through cooperation in the drug patent sharing pool and licensing the production of generic drugs. A Gilead spokesperson previously stated that the company's strategy is to provide high-quality, low-cost lenacapavir to countries that need it most. Perhaps, in the future we will witness the birth of a game changer.

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