Despite numerous efforts since the discovery of human immunodeficiency virus (HIV) as the causative agent of acquired immunodeficiency syndrome (AIDS ) in 1983, the HIV/AIDS epidemic remains a critical public health challenge. In December 2020, World Health Organization (WHO) and Joint United Nations Programme on HIV/AIDS (UNAIDS) initially proposed to achieve the 95-95-95 targets by 2025, i.e., 95% of people living with HIV (PLWHs) know their status, 95% of PLWH who know their status are on antiretroviral therapy (ART), and 95% of PLWH on ART are virally suppressed. Subsequently, WHO/UNAIDS set the goal of reducing the number of new HIV infections to less than 200 000 per year globally and thus ending the AIDS epidemic as a public health threat by 2030. It was estimated that by the end of 2023, 86% of PLWHs were aware of their HIV status, 89% of PLWHs who knew their status were on ART, and 93% of PLWHs on ART had achieved viral suppression. However, the fact that 39.9 million people were living with HIV globally at the end of 2023 and there are still 1.3 million new HIV infections suggested that realizing the 2030 goal requires significant effort in the coming 6 years [
1]. To achieve this “last mile,” innovative modalities and strategies are urgently needed to reduce the number of new HIV infections [
2] (Fig.1).
Recently,
Science selected the long-acting lenacapavir for HIV prevention as the top breakthrough of the year 2024. The invention of lenacapavir represents a significant advance in HIV treatment and prevention, adding to six established categories of anti-HIV drugs that act at different stages of the HIV life cycle, including nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), fusion inhibitors (FIs), and CCR5 antagonists. Unlike these existing six categories of anti-HIV drugs, lenacapavir is a novel and highly potent HIV capsid inhibitor, which can inhibit HIV replication by interfering with multiple essential steps of the virus lifecycle, including inhibiting the uptake, assembly, and release of HIV-1 provirus DNA mediated by the viral capsid, as well as the formation of the viral capsid core (Fig.2). More importantly, lenacapavir has a long pharmacokinetic half-life, allowing subcutaneous injection every six months. Due to its unique mechanism of action and as the first drug in this class by far, lenacapavir has no known cross-resistance to other existing anti-HIV drugs and has therefore been used to treat multidrug-resistant HIV-1 adults who cannot achieve virologic suppression with traditional ART regimens [
3]. A very recent study reported that a combination of lenacapavir therapy with an anti-CD4 domain 1 antibody achieved a sustained virological inhibition in a patient infected with multidrug-resistant HIV strains [
4]. Lenacapavir was first approved for marketing in Europe in August 2022 and then was approved by the US Food and Drug Administration (FDA) in December 2022. According to the latest announcement from the National Medical Products Administration (NMPA) of China, lenacapavir sodium tablets and lenacapavir sodium injections have just obtained marketing approval for ART in China on January 2, 2025.
Besides being used for the treatment of HIV patients, the most significant potential of lenacapavir is in preventing HIV infection in people with a high risk of HIV infection. The strategy, also known as pre-exposure prophylaxis (PrEP), is to take medication in advance to prevent infection. The term PrEP first appeared in the mid-2000s as a strategy to prevent or reduce HIV transmission in individuals at high risk of HIV exposure. By taking medication in advance, a protective barrier within the human body is established before coming into contact with HIV and thus prevents the establishment of infection. A multinational study conducted in 2010, named the Pre-exposure Prophylaxis Initiative (iPrEx) trial, showed that daily oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) conferred 44% additional protection from HIV acquisition among men who have sex with men (MSM), who also received daily behavioral prevention measures [
5]. Subsequently, multiple clinical trials and real-world studies worldwide have shown that the PrEP strategy effectively blocks and reduces the incidence of HIV infection in different risk populations. In July 2012, the US FDA approved FTC/TDF (Truvada) as the preferred medication for PrEP strategy. In 2015, WHO recommended PrEP strategy as a key measure for global AIDS prevention and control. On August 11, 2020, FTC/TDF regimen was approved for marketing in China for PrEP in populations at high risk of HIV infection. On December 5, 2020, the first expert consensus on HIV PrEP in China was released as a clinical technical guidance for PrEP implementation. As of the end of 2023, at least 144 countries and regions in the world have approved the clinic use of PrEP to prevent HIV infection [
6].
Although the PrEP strategy is gradually gaining approval from more countries and regions, a big challenge is its low adherence due to the requirement for daily medication, which results in low or uneven protective efficiency among different populations. Therefore, developing safe and effective long-acting agents for PrEP has been put on the agenda to increase adherence. For example, an intramuscular injection of cabotegravir (CAB-LA, an integrase strand transfer inhibitor) every two months was superior to daily oral TDF/FTC in preventing HIV infection, supported by the HIV Prevention Trials Network (HPTN) 083 and HPTN 084 trials among MSM and transgender women in 2021 [
7]. The most exciting result came in 2024 from the PURPOSE 1 study, a phase 3, double-blind, randomized, controlled trial of using long-acting lenacapavir for HIV prevention [
8]. This study demonstrated that among 5338 initially HIV-negative participants involving adolescent girls and young women in Africa, there were 39 incidents of HIV infection among 2136 participants in the daily oral emtricitabine–tenofovir alafenamide (FTC/TAF) group (2.02 per 100 person-years), 16 incidents of HIV infection among 1068 participants in the daily oral FTC/TDF-group (1.69 per 100 person-years), but no HIV infections among 2134 participants in the group of subcutaneous lenacapavir every six months (0 per 100 person-years). These data showed that twice-yearly subcutaneous injections of lenacapavir achieved 100% protection in preventing new HIV infections. Subsequently, this exciting finding was further confirmed by another phase 3, double-blind, randomized, active-controlled trial (PURPOSE 2 study) in different populations with cisgender men, transgender women, transgender men, and gender-nonbinary persons [
9]. The results of PURPOSE 2 showed that there were only 2 cases of HIV infection among 2179 participants in the lenacapavir group (0.10 per 100 person-years), but 9 cases of HIV infection among 1086 participants in the FTC/TDF group (0.93 per 100 person-years). Again, the HIV incidence in the lenacapavir twice-yearly injection group was significantly lower than that in the daily oral FTC/TDF group (
P = 0.002). Based on these findings, the biannual lenacapavir injection has become a promising choice for the prevention of HIV infection (Tab.1).
Preventing new infections is critical to controlling the AIDS epidemic and achieving the 2030 targets. Long-acting lenacapavir significantly reduces medication frequency and will dramatically promote adherence among people who face stigma, discrimination, social inequalities, privacy, and time-consuming situations when taking daily oral PrEP. From this perspective, long-acting lenacapavir marks the arrival of a new era for HIV prevention and represents a game changer for ending the AIDS epidemic, especially in the circumstances before having an effective HIV vaccine to provide immunological prevention. A new PrEP regimen with high efficacy and good adherence will accelerate the goal of ending HIV epidemic. As such, it has been hailed by some experts as the top breakthrough of 2024. While the results from clinical trials of lenacapavir twice-yearly injections have been exciting, it remains to be seen how much this drug will accelerate the progress toward the 2030 goal of ending the AIDS epidemic [
10]. The safety and efficacy of lenacapavir and other PrEP regimens have been tested in high-risk populations of HIV infection, such as MSM, sex workers, transgender women or men, etc. So far, there is no such studies in the general population. It is unlikely that the general population will be willing to receive lenacapavir injections as a preventive measure. Even for people at high risk of HIV infection, the willingness and acceptance to take lenacapavir will also depend on its accessibility and affordability. The cost will significantly affect its scale-up scope in different countries and populations. It is reported that Gilead Sciences, the company that developed lenacapavir, has made voluntary licensing agreements with six generic drug companies, including three in India, one in Pakistan, one in Egypt, and one in the USA, to produce low-cost drug for 120 low- and lower-middle-income countries. However, several major issues need to be considered. First, it is unknown whether these manufacturers will produce and distribute large quantities of medicines in time to meet the 2030 AIDS control target. Secondly, a large number of people at high risk of HIV infection in middle-income countries, which include the majority of countries in Latin America and Asia, are not covered in the current agreements. These people may not have the capability to pay for the high-cost branded drug, which range from 20 000 to 40 000 US dollars per person per year. The cumulative cost to a young person over a lifetime will be enormous. Thirdly, a country’s socio-economic situation, social stability and governance, health infrastructure, logistics, and transport capacity will all affect the delivery of lenacapavir and other PrEP to people in need. Many efforts need to be strengthened at a country level before scaling up the use of long-acting drugs at the global level. Fourthly, the use of lenacapavir may carry the risk of “risk compensation,” where reduced fear of HIV leads to increased engagement in unprotected sex and higher rates of other sexually transmitted infections (STIs). Finally, although new HIV infections will be reduced if the rapid deployment of lenacapavir injections can be achieved in high-risk populations, sporadic cases (but with a large absolute number) in the general population are likely to be a challenge for completing the final step in ending the HIV epidemic.
Since efforts in developing HIV vaccines have been unsuccessful for the past 40 years, some people may wonder if long-acting antiviral drugs can be a substitute for vaccines to prevent HIV. One viewpoint suggests that the twice-yearly lenacapavir injection is comparable to the protective efficacy of a preventive vaccine, thereby obviating the need to continue HIV vaccine research. However, lenacapavir and other PrEP drugs cannot substitute for an effective HIV vaccine. Lenacapavir will have a tremendous positive impact on people at high risk of HIV infection if made widely available to people in need. However, due to the challenges mentioned above, including uncertain drug manufacture capacity, limited pricing policy, disparities in socio-economic situations, health infrastructure, culture, and behaviors, as well as the recent United States withdrawal from the WHO, can all hinder the application of lenacapavir injections in time in the world to reduce HIV infection to achieve the ending HIV/AIDS goal by 2030. If the HIV vaccines could be developed, manufacturing enough vaccines and scaling up their usage to all people in need would be more affordable and feasible, which has been proved by the COVID-19 pandemic experience with 13 billion doses of COVID-19 vaccines administered globally within two years. An effective HIV vaccine would provide long-lasting immunity, reduce the incidence of new infections, and alleviate the need for continuous medication. Vaccination usually requires just a few doses and is much more cost-effective than life-long lenacapavir twice-yearly injections. Even after we reach the goal of ending AIDS by 2030 through the global application of lenacapavir and other PrEP regimens, we will still need sustainable and long-term strategies that prioritize cost-effectiveness, adherence, and quality of life. HIV vaccines are the best option for achieving this aim. Because humans are the only natural host for HIV other than chimpanzees, a successful HIV vaccine that can stop HIV transmission and infection could ultimately eradicate HIV from humans in the future. One example of a successful global vaccination effort is the eradication of smallpox, a disease caused by the varicella virus that only infects humans. Therefore, the pursuit of an effective HIV vaccine must not be overshadowed by the excitement surrounding lenacapavir, but must be strengthened. The rollout of lenacapavir can be used as a complementary measure until an effective HIV vaccine is successfully developed. Advancements in vaccine technologies, including viral vectors, mRNA vaccines, germline-targeted antigen design, and artificial intelligence assistance, are revitalizing a field previously hindered by HIV’s genetic diversity and immune evasion tactics. These innovative technologies, coupled with the lessons learned from past HIV vaccine failures and the experience of developing and deploying the COVID-19 vaccine, underscore the feasibility of breakthroughs in the future with sufficient investment and political will. Success in achieving an effective HIV vaccine will be a genuine breakthrough that will benefit the whole humanity.
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