One of the greatest successes of modern science is the development of effective antiretroviral therapy (ART) for control of HIV-1 infection. Arguably one of the more innovative responses to the ongoing HIV epidemic is the repurposing of ART for preventive efforts as preexposure prophylaxis (PrEP). This strategy has been critical in the face of approximately 1.7 million new infections in 2018 and in the absence of an effective HIV vaccine. Notwithstanding this advance, significant scientific challenges remain for the optimal implementation of PrEP, and novel approaches are still needed (1).

In the United States, currently approved PrEP consists of a single pill containing two antiretroviral drugs taken daily. While this regimen substantially reduces the risk of HIV-1 acquisition, PrEP has still not reached the majority of at-risk individuals, even in resource-rich settings (2). Comprehensive preventive services are a cornerstone of the Department of Health and Human Services’ strategic plan to end the HIV epidemic (3), and PrEP is the biomedical intervention currently available. Preventive interventions are at the intersection of medical and behavioral science, and their rollout can highlight disparities in health care access. PrEP is no different, requiring rigorous efforts to achieve its potential equitably across diverse groups.

We propose that PrEP offers a window into the efforts to end the HIV epidemic while also illuminating the tension between innovation in biomedical science and its application in public health efforts.

How effective is PrEP and for whom?

PrEP efficacy was initially demonstrated among men who have sex with men (MSM) with high-risk sexual behavior, reducing risk of HIV acquisition versus placebo (relative risk reduction [RRR] of 44%), with even greater protection (89% RRR) in a subgroup with confirmed presence of the study drug in blood (4). Similar results were seen in serodiscordant couples in which the partner with HIV was not on ART and the uninfected partner was randomized to receive PrEP: an overall RRR of 75% with PrEP, and 90% RRR with detectable drug levels (5).

Of note, initial studies done exclusively in women at risk of sexual acquisition were not as successful (6, 7); the apparent failures were driven predominantly by very low adherence (8). More recent studies have helped to clarify that PrEP is indeed effective in women, although because of differences in tissue site drug levels and other factors, daily adherence may be required to achieve full protection (8). Direct interactions between the vaginal microbiome and tenofovir may impact efficacy at least for topical therapy approaches (9), which suggests the need for caution when extrapolating data between populations. These concerns are highlighted by the recent FDA approval of a second drug for PrEP, emtricitabine/tenofovir alafenamide; this approval excludes women with vaginal receptive sex as their risk, as the formulation has not been studied in women. In sub-Saharan Africa, four in five new infections among adolescents aged 15–19 years are in girls, therefore appropriate testing and validation in women, and optimization of delivery and uptake are paramount (10). Testing PrEP in the context of conception, pregnancy, and the postpartum period is also important for meaningful risk mitigation, particularly given the high risk of transmission to the infant in the context of acute infection during pregnancy (11). Implementation and demonstration projects have highlighted that PrEP must be acceptable and accessible to people who need it; scientific demonstration of efficacy is inadequate to achieve full impact (12).

PrEP is also highly effective in preventing transmission via injection drug use (13), although implementation of PrEP in this population is minimal. This deficit in the use of PrEP is particularly relevant in regions where adjunctive harm reduction strategies (e.g., needle exchanges) are inadequate and drug use is highly criminalized. A cluster of HIV transmission through injection in the United States highlights the potential for an intersection between the opioid and HIV epidemics and the need to offer preventive options (3).

What are the risks of PrEP?

As with any medication, there is a small risk of idiosyncratic drug reaction and a risk of adverse effects, including modest declines in bone mineral density or renal impairment. However, with real-world implementation of PrEP, these risks have proven to be minimal (14). There are also scattered case reports of PrEP failure and a lingering concern for inadvertent initiation of PrEP in individuals already infected with HIV, but this has been a rare phenomenon overall. Perhaps a greater detriment to the adoption of PrEP has been a perceived risk that PrEP could lead to a rise in sexually transmitted infections (STIs) due to risky sexual practices. Increased STI incidence has been seen in a subset (~25%) of PrEP users, but this observation needs to be viewed in the context of increased frequency of testing for STIs (15, 16). The clinical decision-making impact of a perceived risk compensation must be directly addressed, as it is likely to bias providers away from PrEP prescription (17, 18).

What is limiting the effectiveness of PrEP?

A 2019 study by the CDC examined the impact of targeted outreach to MSM about PrEP, with PrEP awareness increasing from 60% to 90% from 2014 to 2017 (2). However, despite this rise in awareness, active use of PrEP remained limited, increasing from 6% to 35% of eligible individuals over the same period. There is a notable racial disparity in PrEP uptake, with Black MSM using PrEP at approximately half the rate of White MSM (Figure 1). Moreover, PrEP use is also linked to higher educational attainment, income, and insurance status (2).

Figure 1

HIV infection risk and PrEP prescriptions in the United States. (A) Estimated proportions of people living in the United States at risk for HIV infection (2015 data) and distribution of PrEP prescriptions in 2016 among the subset for whom race/ethnicity data is available. (B) Risk versus prescription frequency among men and women (2015 data). Figure based on data in refs. 19, 21.

Of note, PrEP education efforts have primarily engaged MSM. Transgender women, who have a disproportionate risk of HIV infection, often have limited engagement with health care services. In the United States, women at risk for HIV infection are unlikely to self-identify or to be assessed to be at risk of HIV by health care providers. PrEP use among women has remained very low and static, at less than 5% of prescriptions and 2% of the women at risk during a period of expanding use among MSM (19). The best ways of reaching women at risk remains a topic of active investigation.

In addition to the challenges of identifying and engaging people at risk for HIV, continued adherence to the PrEP regimen is required. Recent studies have demonstrated that high levels of initial adherence are often not sustained over time (12).

Future strategies that address this challenge may include event-driven prophylaxis, proven effective among MSM (20); longer-acting formulations of PrEP; behaviorally congruent delivery methods; and other novel drugs and formulations (reviewed in ref. 21). A single PrEP modality, as is currently available, is unlikely sufficient for broad population-based impact, and consistent with the experience of contraception, offering a choice among an array of acceptable methods is likely to be a major driver of improved uptake (1).

Can PrEP interrupt the HIV epidemic?

Outside the rarefied setting of a clinical trial, PrEP has shown high preventive efficacy, and, in some cases, implementation and demonstration projects have shown decreases in local HIV incidence. Together with early treatment to prevent transmission (treatment as prevention) and in an era when patients on ART with undetectable viral loads have been shown not to transmit the virus (undetectable = transmissible), PrEP can bring us closer to the goal of ending the HIV epidemic, which has already claimed 35 million lives (3). However, even with more diverse implementation options, PrEP is not likely to be the only solution to the problem. As seen in the hepatitis C epidemic, even highly successful curative therapy will not be sufficient alone to end the epidemic, and an adjunctive vaccine would be highly impactful. Similarly, a vaccine is still urgently needed for HIV prevention. This need does not diminish the role of PrEP as an immediately available and effective intervention — one that further scientific innovation can certainly extend and improve.

Conclusions

The story of the development of PrEP is one of the astounding successes in medicine. The efficacy of this intervention has exceeded our best efforts to date at HIV vaccine design. But PrEP is also a story of barriers for both people at risk of HIV infection and providers, and an important illustration of how interventions are only successful when they can be effectively implemented. We would also argue that PrEP highlights the critical need for innovation from basic scientists and clinicians even after an initial “solution” has been achieved (1, 21). Although currently available PrEP is efficacious, the challenges of adherence and access emphasize the need for novel approaches to deliver therapies in ways that are acceptable, feasible, and available to the individuals at risk of HIV infection. Some of these strategies were highlighted at the recent 10th International AIDS Society Conference on HIV Science in Mexico City, and the recent call for new investigation in this arena from the NIH is an opportunity to expand and develop the science of prevention. Now more than ever, physicians and scientists have a critical role in developing new approaches, advocating for effective interventions, and translating the best possible science to at-risk populations as well as to providers and policy makers in order to realize the optimal benefits of PrEP.

Acknowledgments

We thank Craig Hendrix and Guido Massacessi for thoughtful comments on a draft of this article.

Footnotes

Conflict of interest: The authors have declared that no conflict of interest exists.

Copyright: © 2019, American Society for Clinical Investigation.

Reference information: J Clin Invest. 2019;129(12):5071–5073. https://doi.org/10.1172/JCI134389.

References

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现代科学最大的成功之一就是开发了用于控制HIV-1感染的有效抗逆转录病毒疗法（ART）。可以说，对正在发生的艾滋病毒流行病的更具创新性的应对措施之一是将抗逆转录病毒疗法重新用于预防工作，作为预防暴露前（PrEP）。面对2018年约170万例新感染病例以及缺乏有效的HIV疫苗，这一策略至关重要。尽管取得了这一进步，但PrEP的最佳实施仍然面临重大的科学挑战，并且仍然需要新颖的方法（1）。

在美国，目前批准的PrEP包含一个药丸，其中包含每日服用的两种抗逆转录病毒药物。尽管该方案大大降低了HIV-1感染的风险，但PrEP仍未达到大多数高危人群的要求，即使在资源丰富的环境中（2）。全面的预防服务是卫生和公共服务部结束艾滋病毒流行的战略计划的基石（3），而PrEP是目前可用的生物医学干预措施。预防性干预措施是医学和行为科学的交叉点，其推广可突出说明卫生保健获取方面的差距。PrEP也不例外，需要付出艰辛的努力才能在各个群体之间公平地发挥其潜力。

我们建议PrEP为结束HIV流行的努力提供一个窗口，同时也阐明了生物医学科学创新和其在公共卫生工作中的应用之间的张力。

PrEP有多有效？对谁有效？

PrEP功效最初在具有高风险性行为的男男性行为者（MSM）中得到证实，与安慰剂相比，降低了HIV感染的风险（相对风险降低[RRR]为44％），并且具有更高的保护作用（RRR为89％）在确认研究药物存在于血液中的亚组中（4）。在血清恶性伴侣中也观察到了类似的结果，其中艾滋病毒伴侣未进行抗逆转录病毒治疗，未感染的伴侣被随机分配接受PrEP：PrEP的总RRR为75％，药物水平可检测为90％的RRR（5）。

值得注意的是，仅针对有性征风险的女性进行的初步研究并不那么成功（6，7）; 明显的故障主要是由于极低的依从性造成的（8）。最近的研究有助于阐明PrEP确实对女性有效，尽管由于组织部位药物水平和其他因素的差异，可能需要每天坚持以实现全面保护（8）。阴道微生物组和替诺福韦之间的直接相互作用至少会影响局部治疗方法的疗效（9），这表明在总体之间推断数据时需要谨慎。FDA最近批准了用于PrEP的第二种药物恩曲他滨/替诺福韦alafenamide；这些问题使这些担忧更加突出。该批准不包括具有阴道接受性行为的女性作为其风险，因为该配方尚未在女性中进行研究。在撒哈拉以南非洲，年龄在15-19岁之间的青少年中有五分之四的新感染是女孩，因此，对妇女进行适当的测试和验证以及优化分娩和吸收至关重要（10）。在怀孕，妊娠和产后期间进行PrEP测试对于减轻风险具有重要意义，特别是考虑到在妊娠期间发生急性感染的情况下传播给婴儿的风险很高（11）。实施和示范项目强调，PrEP必须是可接受的，并且需要它的人可以使用。科学证明疗效不足以取得充分的影响（12）。

PrEP在预防通过注射毒品传播方面也非常有效（13），尽管在该人群中实施PrEP的可能性很小。PrEP使用中的这种缺陷在减少辅助伤害的措施（例如，更换针头）不充分且药物使用被高度定罪的地区尤其重要。在美国，大量艾滋病毒通过注射传播，突显出阿片类药物和艾滋病毒流行之间可能存在交叉点，以及提供预防措施的必要性（3）。

PrEP有哪些风险？

与任何药物一样，特异药物反应的风险很小，并且有不良反应的风险，包括骨矿物质密度的适度下降或肾功能不全。但是，在实际实施PrEP的情况下，这些风险已被证明是最小的（14）。也有零星的PrEP失败病例报告，以及对已经感染HIV的人无意中启动PrEP的持续关注，但这在总体上是罕见的现象。人们可能认为，对PrEP的采用有更大的危害，因为由于危险的性行为，PrEP可能导致性传播感染（STIs）上升。在部分PrEP用户中（约25％）发现STI发生率增加，但是需要在增加STI测试频率的背景下来观察这种观察（15，16）。必须直接解决风险感知补偿的临床决策影响，因为这可能会使提供者偏离PrEP处方（17，18）。

什么限制了PrEP的有效性？

疾病预防控制中心（CDC）于2019年进行的一项研究调查了针对性针对MSM的针对PrEP的影响，PrEP意识从2014年到2017年从60％上升至90％（2）。然而，尽管意识有所提高，但PrEP的积极使用仍然受到限制，在同一时期内，合格个人的比例从6％增加到35％。PrEP摄取存在明显的种族差异，使用PrEP的黑色MSM大约是白色MSM的一半（图1）。此外，PrEP的使用还与更高的学历，收入和保险地位相关（2）。

图1

美国的HIV感染风险和PrEP处方。（A）2016年估计有可能感染HIV的美国人口比例（2015年数据）以及2016年PrEP处方在可获得种族/族裔数据的子集中的分布情况。（B）男性风险与处方频率的关系（2015年数据）。该图基于参考中的数据。19，21。

值得注意的是，PrEP教育工作主要涉及MSM。跨性别女性感染艾滋病毒的风险不成比例，她们参与医疗保健服务的机会通常很有限。在美国，有感染艾滋病毒风险的妇女不太可能自我识别或被卫生保健提供者评估为有感染艾滋病毒的风险。妇女中使用PrEP的比例仍然很低且保持不变，在MSM扩大使用期间，只有不到5％的处方和2％的有风险的妇女使用（19）。接触处于危险中的妇女的最佳方法仍然是积极调查的话题。

除了确定和吸引有艾滋病毒感染风险的人的挑战外，还需要继续遵守PrEP方案。最近的研究表明，高水平的初始依从性通常不会随着时间的流逝而持续（12）。

应对这一挑战的未来策略可能包括事件驱动的预防，在MSM中被证明是有效的（20）；PrEP的长效制剂；行为上一致的交付方式；以及其他新药和制剂（参考文献21）。目前可用的单一PrEP方式不足以产生广泛的以人群为基础的影响，并且与避孕的经验相一致，在一系列可接受的方法中进行选择很可能是吸收率提高的主要驱动力（1）。

PrEP可以打断艾滋病流行吗？

在临床试验的稀缺环境之外，PrEP表现出很高的预防功效，并且在某些情况下，实施和示范项目显示出本地艾滋病毒发生率下降。结合早期预防传播的治疗方法（预防性治疗），以及在ART病患者中发现病毒载量无法检测（不能检测=可以传播）的情况下，PrEP可以使我们更接近终结艾滋病毒的目标流行病，已经夺去了3500万人的生命（3）。但是，即使采用了更多不同的实施方案，PrEP也不可能是该问题的唯一解决方案。正如在丙型肝炎流行中看到的那样，即使仅是成功的治愈疗法也不足以结束该流行，而辅助疫苗将具有很大的影响力。同样，仍然迫切需要疫苗来预防艾滋病毒。这种需求并不会削弱PrEP作为立即可用的有效干预措施的作用-进一步的科学创新无疑可以扩展和改善这种干预措施。

结论

PrEP的发展故事是医学上惊人的成功之一。迄今为止，这种干预措施的有效性超出了我们在HIV疫苗设计方面的最大努力。但是，PrEP也是一个面临艾滋病毒感染者和提供者的障碍的故事，并且是干预措施只有在有效实施的情况下才能成功的重要例证。我们还认为，即使实现了最初的“解决方案”，PrEP仍强调了基础科学家和临床医生对创新的迫切需求（1，21）。尽管目前可用的PrEP是有效的，但是依从性和获取的挑战强调了需要新颖的方法来以易受HIV感染的个人可接受，可行和可用的方式进行治疗。在最近于墨西哥城举行的第10届国际艾滋病学会关于艾滋病科学的会议上，其中一些策略得到了强调，而美国国立卫生研究院最近要求在这一领域进行新的调查，则是扩展和发展预防科学的机会。如今，医生和科学家比以往任何时候都扮演着至关重要的角色，它在开发新方法，倡导有效的干预措施以及将最佳科学转化为高危人群以及提供者和政策制定者方面，以实现PrEP的最佳利益。 。

致谢

我们感谢Craig Hendrix和Guido Massacessi对本文的草稿提出了深思熟虑的评论。

脚注

利益冲突：作者已经声明不存在利益冲突。

版权： ©2019，美国临床研究学会。

参考信息：J Clin Invest。2019; 129（12）：5071-5073。https://doi.org/10.1172/JCI134389。

参考

1. 亨德里克斯·CW。艾滋病毒抗逆转录病毒暴露前预防：发展挑战和发展前景。临床药理学。2018; 104（6）：1082–1097。查看此文章，网址为：PubMedCrossRefGoogle Scholar
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6. Marrazzo JM等。基于替诺福韦的非洲妇女艾滋病毒感染前预防措施。新英格兰医学杂志。2015; 372（6）：509–518。查看此文章，网址为：PubMedCrossRefGoogle Scholar
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