编者按：HIV感染的儿科照护与治疗始终是抗击艾滋病的全球战役中的一个重要课题。近期，在AIDS2024大会上，英国伦敦大学学院Anna Turkova教授接受了《感染医线》专访，分享了HIV感染儿科照护领域的突破性进展。她指出，发现和诊断未确诊的HIV感染儿童患者是当前面临的主要挑战，需要持续不断的努力和投入。随着基于多替拉韦的三联口服疗法的应用，HIV儿科治疗取得了显著成效，但长效注射剂等创新疗法的研发与应用仍需时日。同时，社会心理支持在HIV感染儿科照护中同样至关重要。面对未来，Anna教授描绘了长效注射预防药物等愿景，为全球HIV感染儿科照护事业描绘了希望蓝图。
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《感染医线》：能否具体分享一些近年来在HIV感染儿科照护领域取得了哪些最令您兴奋的突破？
Anna教授：我认为最令人振奋的突破在于我们获得了一种非常有效的HIV治疗方法。多年来，儿童在接受最佳HIV治疗方面一直处于落后状态，但这一情况正在逐步得到改善。我们进行的一项研究已经持续了十年，主要是对一种名为多替拉韦的儿童药物制剂进行评估和持续研发。如今，多替拉韦无论是单独使用还是作为治疗方案的基础，都已成为最有效的治疗方法之一。我很高兴，我们的研究以及其他研究和所有利益相关者的共同努力都为这一疗法的推广和应用做出了贡献。目前，95个国家的99%的HIV感染儿童都可以购买并正在使用多替拉韦进行治疗，且我们已经观察到了更好的病毒学反应，这充分证明了我们的工作价值。
然而，尽管多替拉韦是一种良好的口服治疗方法，但我们也知道其耐药性也正在发展，因此急需寻找一种有效的二线治疗方法。同时，许多儿童和青少年在坚持治疗方面存在问题和困难，因此需要探索新的给药方法，比如注射剂。但遗憾的是，获得良好的二线治疗仍然具有挑战性，长效注射剂在儿童中的应用也尚未获得批准。因此，在实现与成人相同的治疗效果方面，我们仍然任重道远。
除此之外，个人认为最大的挑战在于找到那些尚未被诊断出的HIV感染儿童，因为这个差距是未知的，也是最难以弥补的。许多儿童尚未被诊断出感染HIV，因此我们无法让他们及时接受治疗并挽救他们的生命。特别是在生命的前几年，这些儿童的死亡率非常高。正如我在全体会议演讲中所引用的数据所示，如果儿童未被诊断出感染HIV，那么死亡高峰会发生在第一个月，而50%的儿童如果在两岁前未被诊断出，将会不幸死亡。另有50%的儿童虽然会存活下来，但他们可能没有任何症状。社会上存在一种误解，认为感染HIV的儿童一定会生病，但实际上他们中的许多人并没有生病，也没有出现任何症状。因此，我们需要制定策略来确定在何处以及如何进行大规模的人群检测，以便找到这些儿童。同时，我们还需要克服人们前来为儿童进行检测时可能遇到的污名和歧视问题，并努力解决政府不提供财政支持的问题。因此，找到那些尚未被诊断出的HIV感染儿童，并让他们及时接受必要的治疗——这才是我们当前面临的最大挑战。
IIDF: Could you elaborate on some of the most exciting breakthroughs achieved in recent years in paediatric HIV care that you find particularly noteworthy?
Dr Turkova: The most exciting breakthrough I think is access to a very effective treatment. For many years, and even still now, children are left behind in terms of the best treatment available for them. One of the studies we have done, that has been done for a decade, has been evaluation and continued development of a pediatric formulation of drugs called dolutegravir. Dolutegravir, not only alone but as dolutegravir-based treatment, is now currently one of the most effective treatments. I am really pleased that we have contributed to the rollout with our study, other studies and, of course, a huge amount of joint effort from all the different stakeholders. At the moment, there are 95 countries where 99% of children living with HIV reside can procure and are procuring dolutegravir. We have already seen a better virological response and we know that work has been worth it, however, there is still a way to go. It is a good oral treatment. We know resistance is developing, so we will need a good second-line. We also know that lots of children and adolescents have problems and difficulties with adherence, so novel methods of delivery, like injectables, are needed. Access to a good second-line therapy, particularly tenofovir alafenamide, is challenging, because there is no generic formulation, and access to the long-acting injectables is not approved yet, and there is no clear plan. So there is still a way to go in terms of achieving the same treatment outcomes as in adults, which means achieving 95% biological suppression and treatment. We have a gap there. I think the most significant gap is for us to find the missing children, because that gap is unknown. A lot of children out there have not been diagnosed, therefore we cannot start them on treatment and save their lives. There is a high mortality rate in the first few years of life. As I quoted in my Plenary speech, the peak of mortality happens in the first month if a child is undiagnosed, and 50% will die by two years of age if not diagnosed. The problem is that another 50% will survive and may not have symptoms. There is a myth that children with HIV need to be ill but many of them are not sick and have no symptoms. To find those children and have a strategy for where and how to test many people, and overcome stigma and discrimination of people coming forward to test their children, and governments not contributing financially - that is the problem. This is the biggest gap - finding undiagnosed children.
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《感染医线》：在儿童HIV感染中，早期诊断对于及时治疗和改善预后至关重要。目前，我们面临哪些主要挑战，以及有哪些创新的诊断工具或方法正在被开发或已应用于临床实践？
Anna教授：在全球范围内，针对HIV感染儿童问题的努力正以前所未有的规模进行。各国政府、非政府组织、研究机构以及国际机构如联合国儿童基金会（UNICEF）等，都在积极投入资源，探索并实践各种创新策略，以期能够更有效地发现和诊断未确诊的HIV感染儿童患者。UNICEF的关于寻找未确诊的HIV感染儿童的技术简报，不仅为这些努力提供了科学依据，还明确了方向，强调了早期发现和干预的重要性。全球联盟的成立更是彰显了国际社会对消除HIV感染儿童的坚定承诺，通过跨国合作，共同应对这一全球性挑战。
各国在应对HIV感染儿童问题时，根据自身的流行病学特点和资源状况，采取了多样化的策略。在高收入国家，由于医疗资源丰富，儿科诊所成为了HIV感染儿童检测的重要阵地。这些诊所不仅关注儿童的常规健康检查，还积极将艾滋病检测纳入其中，确保能够及时发现潜在病例。同时，急诊室和急救部门也被视为重要的检测渠道，以覆盖那些因急性疾病而就医的儿童。而在一些资源相对有限的国家，通过追踪已确诊艾滋病患者的家庭成员，特别是儿童，可以大大提高检测的针对性和效率。此外，儿童保健诊所也发挥了不可替代的作用，特别是在母亲可能感染HIV的情况下，对婴儿进行及时检测，可以有效阻断病毒的母婴传播。
对于年龄较大的未确诊儿童（特别是超过两岁的儿童），社区的参与变得尤为关键。通过社区服务和教育，提高居民对HIV感染儿童的认识和警惕性，鼓励家长和监护人带领孩子接受检测。在赞比亚等试点项目中，将艾滋病检测作为学龄前儿童入学要求的一部分，不仅提高了检测的覆盖率，还增强了社会对HIV感染儿童问题的关注。
对于青少年群体，由于其特殊的生理和心理特点，需要采取更加灵活和个性化的检测策略。通过整合他们正在接受的医疗服务（如生殖健康诊所、男性包皮环切诊所等），将艾滋病检测自然地融入其中，可以减少他们的抵触情绪，提高检测的接受度。同时，利用社交网络和同龄人的影响力，也可以有效扩大检测的覆盖面。
综上所述，当前全球范围内针对HIV感染儿童问题的努力正在取得积极进展。各种创新策略和模式的实施，为发现和诊断未确诊的HIV感染儿童患者提供了有力支持。然而，我们也应清醒地认识到，这一任务仍然艰巨而复杂，需要持续不断的努力和投入。
IIDF: Early diagnosis of HIV infection in children is crucial for timely treatment and improved outcomes. What are the major challenges we face currently, and what innovative diagnostic tools or methods are being developed or already in use in clinical practice to address these?
Dr Turkova: There has been a lot of effort and a lot of different initiatives ongoing across the world, exploring different ways and different modalities. Currently, there is a very nice document produced by UNICEF that is a technical brief on finding undiagnosed children. The Global Alliance has aimed to end pediatric HIV, signed by twelve African countries, also highlighting that finding children is one of the main strategies towards ending HIV in children.
There are lots of interesting modalities. It depends on the country’s epidemiology. It depends on a country’s HIV prevalence. It depends on the age of estimated distribution of undiagnosed children in that country. So countries need to know their own epidemiology, and then they can combine different modalities to ensure resources are used wisely. You can test children in high income countries in pediatric clinics, along with TB and malnutrition, but also have access to emergency wards and casualty departments. If a child comes in with a broken arm and nothing to do with HIV, if you still test, it has been shown to have a high yield for picking up children who have no symptoms yet, therefore giving the option for an early diagnosis. If you diagnose them when they already have symptoms of advanced HIV, the outcomes are poor, mortality is high, and recovery is not that great. So we try to pick them up before developing symptoms. The other modality is to diagnose children though the family index case findings. For example, if an adult is diagnosed with HIV, we ask if they have children in the family, and then try to reach out to those children, and try to persuade adults to test children. Even, for example, if there are families that look after children who are orphans, they are at high risk because there is the potential that their parents died with HIV and that is why they are orphaned. So it is important to know your community situation, and know how to read that community and use the community knowledge to reach out to these sometimes hard-to-reach populations and families. There are well child clinics. I explained in my Plenary, that around a quarter of new mothers will acquire new HIV during pregnancy or while breastfeeding, so even if you test mothers during pregnancy sometimes you might still be missing quite a few who acquire HIV during the last trimester of pregnancy or during breastfeeding. So we can pick up cases by testing in so-called well child clinics. When a mother brings a child in for vaccination, for example, or medical checkup, we should check a mother’s status if she doesn’t know her status already, and then pick up an infant potentially at risk. If the mother is not around, and a carer comes, you could get consent to test the infant. That is for younger children, under one year or two years old, because these are the ages that tend to be seen at well child clinics.
We know the majority of undiagnosed children are well over 2 years of age and 60% are aged above 5 years. So how do we pick up those children? That is a big question. That is why community input is really important, and getting testing done through the community services. There was an interesting project in Zambia, for example, where they were developing a pilot for doing HIV tests as a requirement for preschool, so as a medical examination and part of medical assessment, HIV could be tested. They don’t need to disclose the result of the test, but there is a way to say this child was tested. I understand this hasn’t been piloted yet, but the idea was developed. For adolescents, for example, different ways might be through reproductive health clinics, or through male circumcision clinics, or any other health services. They can integrate HIV testing through any health services that adolescents are attending. Apart from health services, you could reach them through social networks, through their peers. There is also mobile testing as well.
There are many interesting initiatives ongoing that are showing promise. So I think we are living in a very interesting time. We know we have a lot of tools that can work. We need more implementation to indicate which approach in which country works best. We need to encourage that, and of course, funding is important.
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《感染医线》：在药物治疗方面，针对儿童HIV感染者的治疗方案有哪些最新的进展？特别是那些旨在简化治疗方案、减少副作用并提高患儿生活质量的药物或疗法。
Anna教授：从公共卫生的角度来看，我们确实需要一个适用于所有人的更普遍的治疗方案。到目前为止，我们采用的是基于多替拉韦的三联口服疗法。所谓简化，就是将这三种药物组合成一种片剂，即儿科用阿巴卡韦/拉米夫定/多替拉韦。这是首选的一线HIV感染儿科治疗方案。这种方案简化了医护人员的治疗过程，因为用药变得非常简单——只需根据患者的体重范围调整片剂数量即可。同时，它也简化了照护过程，大大降低了出错的可能性。我们认为这是最佳的方法——一种我们知道对大多数人非常有效的固定剂量三联组合药物。
此外，我们还在评估双联治疗的效果。研究表明，这种治疗方法对成人效果显著，可以简化病毒载量受到抑制的成人的治疗过程，也可以作为成人的一线起始治疗方案。为此，我们开展了一项名为D3的研究——D代表多替拉韦，3代表拉米夫定。这是一种双联药物，将两种药物合二为一。双联疗法的优势在于，首先，药片的体积更小；其次，减少了一种药物，这可能使长期安全性更好。这项研究正在进行中，招募工作已接近完成。我们有望在2026年公布研究结果。
当然，我们非常期待在儿童中使用注射剂，因为很多家庭在坚持治疗和每天服用口服片剂方面存在问题。我认为注射剂会有很大的帮助，尤其是对于每天服药有困难的家庭。但遗憾的是，我们目前还没有这种药物。相关研究正在进行中，但要确保大多数儿童都能使用，还需要一段时间。实际上，在这个领域我们还有很长的路要走。
IIDF: Regarding pharmacotherapeutics, what are the latest advancements in treatment regimens for paediatric HIV-infected individuals? Particularly, those aimed at simplifying treatment, reducing side effects, and enhancing the quality of life for these children.
Dr Turkova: For the public health approach, we need to understand that the pediatric population is very small compared to adults. If you start to introduce an individualized approach, it is very difficult to then deliver that approach consistently when reaching out to all children in rural and urban settings and so on. We really need a more universal regimen that works for all. So far, it is a triple oral therapy, dolutegravir-based triple therapy. What simplification means is that there is a tablet combining the three agents into one. We call it pALD - pediatric abacavir/lamivudine/dolutegravir. It is a triple fixed combination which provides the preferred recommended pediatric treatment regimen for first-line. This simplifies treatment for healthcare professionals, because the dosing is very simple - you adjust the number of tablets according to weight band. It is simpler for carers because they don’t need to have 2 or 3 bottles at home and to remember how many of each tablet is needed. It is one bottle, one label. Much fewer errors. We think this is the best way to go - a fixed dose triple combination that we know works very well for the majority.
We are also evaluating dual treatment. It has been shown that this works very well for adults as a simplification for virologically suppressed adults and also as first-line starting therapy for adults. There is a study called D3 - D stands for dolutegravir, 3 stands for 3TC. It is dual - two drugs in one. It is a randomized controlled trial comparing triple dolutegravir to dual dolutegravir in children who are virologically suppressed. The idea is, first of all, it is a smaller tablet; and secondly, it is one drug less, which potentially leads to better safety in the long term. This study is ongoing. It is nearly completely recruited. We will hopefully be presenting the results in 2026.
Of course, we are very much looking forward to injectables in children, because a lot of families have issues with adherence and difficulties in giving in oral tablets every day. I think it will work, especially for the families having difficulty administering medicines every day. But we don’t have them yet. The studies are ongoing evaluating this, but it will still be a bit of a wait to ensure they are accessible for most kids. There is actually quite a long way to go.
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《感染医线》：除了药物治疗，您如何看待社会心理支持在HIV感染儿科照护中的作用？有哪些成功的案例或项目值得分享，以展示社会心理支持对儿童患者及其家庭的重要性？
Anna教授：在全体会议上，我强调仅靠治疗是远远不够的。事实上，治疗其实是所有环节中最简单的一环，相比之下，其他所有方面的工作都要更为复杂和艰巨。我们已经多次证明，如果没有实际的心理社会支持作为后盾，治疗效果往往不尽如人意。从患者年幼时，我们就能观察到这一现象。尽管早期治疗确实能带来一定的益处，比如降低死亡率，但这种益处往往会逐渐消失。这是因为大多数相关家庭都来自弱势背景，他们缺乏额外的营养支持、生计支持、食物支持以及治疗依从性支持。同时，我们还需要关注母亲们的心理健康问题、家庭暴力问题以及生活环境的改善。因此，我们需要提供全方位的支持，以确保这些孩子能够健康地活下去。然而，即便开始了治疗，到了两岁左右，死亡率仍然居高不下。进入青春期后，更是多次证明，如果没有心理社会支持的辅助，治疗效果往往比成人更差。
举例来说，有一项名为“SEARCH YOUTH”的研究，这是一项随机集群试验，专注于非治疗性的干预措施。研究发现，这些干预措施主要包含四个组成部分。其中，第一个组成部分就是与年轻人深入讨论他们想要分享的生活事件以及生活中发生的重要事情。这与抗逆转录病毒治疗的依从性并无直接关系，而是更多地关注他们的家庭生活、大学经历、最近的婚姻状况或关系破裂等话题。这样做不仅改善了青少年与医护人员之间的关系，还被证明能够显著提高治疗的依从性。同时，它也被证实能够提高病毒学抑制率，因为当患者感受到被关注和理解时，他们更有可能更好地遵循治疗方案。尤为重要的是，这一方法已经被证明能够有效地提高那些可能失去随访的患者重新参与治疗的比例。此外，研究还显示，接受这一干预措施的青少年在抑郁的症状和体征方面也明显减少，这对于他们的心理健康具有极其重要的意义。这就是一个有代表性的成功案例。虽然这并不是我亲自参与的试验，但它无疑是我非常欣赏和推崇的一项研究。
IIDF: Apart from pharmacotherapy, how do you view the role of psychosocial support in paediatric HIV care? Are there any successful case studies or programs that you can share to demonstrate the significance of psychosocial support for HIV-infected children and their families?
Dr Turkova: In my Plenary, I said that treatment alone is not enough. We see it again and again. When I was trained and learned how to treat and manage children with HIV, the treatment is the simplest thing out of everything else. Everything else is much more difficult. We have shown again and again that without actual psychosocial support, outcomes are not great. We see this starting from an early age. If you start treatment early, there is a little bit of benefit from early treatment. There is less mortality with early treatment, but the benefit disappears, because most of the families involved come from vulnerable backgrounds, and without extra support with nutrition, with livelihood, with food, with adherence support, with supporting the mothers, there are mental health issues, addressing domestic violence, addressing the living environment, the treatment alone is not enough. You need to provide support to keep these kids alive. Even once starting treatment, the mortality is still very high by two years of age.
There have been studies, for example, SEARCH Youth, which was a randomized cluster trial looking at non-therapeutic, so non-treatment, intervention. What they found was there are four components to these interventions. The first component was discussion about life events that young people want to talk about, the important things that happen in their lives. It is not about adherence to ART. It is about what is happening at home, what is happening in college, a recent marriage, a recent broken relationship. The program gives you a structure for what to cover, how to prepare questions, and then to focus on those questions. This improves the rapport between the adolescent and the healthcare provider, and his been shown to improve retention in care. It has been shown to improve virological suppression, because being engaged and understood can translate into being better with your medicine. Especially, this has been shown to lead to higher rates of re-engagement for those who might be lost to follow-up. It has also shown to have lower symptoms and signs of depression, which is really important for mental health. So yes, that is one the real examples you asked about. It is not my trial, but one of my favorite trials.
05
《感染医线》：展望未来，您对HIV感染儿科照护领域的发展有何愿景？您认为未来几年内，我们可能看到的最大变革或突破是什么？
Anna教授：首先，我的梦想是在HIV高流行率国家，为处于风险中的育龄妇女，尤其是孕妇，提供长效注射药物，以防止她们感染HIV，因为她们属于高风险群体。对于婴儿产后预防，我们离实现这一目标还有很长的路要走，但也许可以考虑每年注射两次的方案。在多数情况下，几乎所有的儿童HIV感染都是母婴传播，即我们所说的垂直传播。预防的重点在于保护母亲，进而在哺乳期间保护婴儿。我们只需要2-3次注射就可以覆盖整个哺乳期，而这也是该方案影响最大的时期。
许多青少年表示，他们需要选择权。当然，并不是所有人都会选择注射药物，因为有些人可能不喜欢这种方式。很多人反映，每天服药难以坚持。在这种情况下，长效注射药物是一个很好的选择，尤其是对于那些可以做出选择的人来说。这可能会帮助到很多人。
我希望我们能够找到每一个尚未确诊的孩子，确保他们有接受治疗的选择。我渴望有一种真正成功且有效的预防方法，而且这种方法不依赖于人们每天服用口服药物。如果每年只需注射两次，那就太理想了。对青少年来说，选择权非常重要。他们真的渴望长效注射药物。我们相信这一天会到来。
IIDF: Looking into the future, what is your vision for the development of paediatric HIV care? What are the most significant changes or breakthroughs you foresee in this field in the coming years?
Dr Turkova: First of all, my dream is that long-acting injectables be available for prevention for women of reproductive age who are at risk in high prevalence countries in order not to acquire HIV. And for pregnant women in particular, because they are at high risk. For infants for postnatal prophylaxis, we are far away from being there, but potentially we could be looking at twice yearly injections. This is when many cases, nearly all, are getting infected, during pregnancy and breastfeeding, with a little transmission occurring through other routes (healthcare settings, horizontal transmission, sexual abuse). It is mostly mother-to-child transmission, what we call vertical transmission. Prevention is about protecting mothers and then protecting infants during breastfeeding. We would only need 2 or 3 injections to cover the breastfeeding period, but that is when it would have the most impact. Many adolescent say they need a choice. Probably not 100% will say they want injectables, because some people may not like injectables. Many say it is just too difficult to take tablets every day. It is a problem that their tablets remind them of their HIV status. For adolescents finding out about their diagnosis, it takes time to accept their diagnosis. You need time, and oral daily treatment is a reminder. There is also a stigma. You see your friends, you are going out, having sleepovers and attending parties - you don’t want to carry your tablets around. It is a way to provide them freedom. So long-acting injectables are the way to go, especially for those who can make that choice. This may help a lot of people. If you really want to achieve targets and end pediatric HIV, we need these new modalities. I hope that we could find every single child who is yet undiagnosed to make sure there is an option for them to be on treatment. I would like to have really successful effective prevention that doesn’t depend on people taking oral drugs. Twice a year injections would be fantastic. Choice for adolescents is very important. They really want the long-acting injectables. We will see it. It will be nice to see more new ideas and more implementation.