Understanding adverse drug reactions to dolutegravir and isoniazid in HIV-positive Ugandans: incidence, risk factors, management and patient-reporting

了解乌干达 HIV 阳性患者对多替拉韦和异烟肼的不良药物反应：发生率、危险因素、管理和患者报告

• 批准号: MR/V030434/1
• 负责人: Ronald Kiguba
• 金额: $ 103.38万
• 依托单位: Makerere University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV030434%2F1
• 关键词: Understanding; adverse; drug; reactions; dolutegravir

Thanks to medical advances, people living with HIV (PLHIV) can now live long, healthy lives. To remain healthy, PLHIV will need to take drugs against the virus (called antiretrovirals) for the rest of their lives. Antiretrovirals are generally safe but cause serious side effects in some people, particularly with long-term use. Common side effects are discovered in clinical trials; if they are too severe or too common, the drug will fail the trial. It isn't possible to test enough people in a clinical trial to discover less common side effects. These can only be found by monitoring people taking the drug in the real world. Recording which people have side effects and understanding why they happen is essential for making drugs safer. We work in Uganda where 1.5 million people (3.5%) live with HIV. Uganda recently began a programme to rapidly roll-out antiretroviral combinations including dolutegravir (DTG), the new drug recommended by the World Health Organisation (WHO), to PLHIV. Uganda is also rolling-out Isoniazid Preventive Therapy (IPT) to prevent active tuberculosis - the main cause of death in PLHIV. Systems for monitoring drug-related side effects have only recently been developed in Uganda, so we do not understand the risk factors for side effects of the new HIV drugs in Ugandan PLHIV. These include 'clinical' risk factors, such as having other medical conditions, or 'genetic' risk factors, natural variations in a person's DNA that increase the risk of a side effect. Some DNA variations are more common in people of particular ethnicity, so it is essential that we record side effects across all ethnic groups. We aim to: 1) understand which PLHIV are at risk of a side effect to DTG or DTG with IPT and why; and 2) strengthen the systems for reporting drug-related side effects by empowering PLHIV to make their own reports. These are essential steps to enable us to treat each PLHIV with the right antiretrovirals at the right dose in the future. We will recruit 10000 people receiving DTG or DTG plus IPT from eight clinics across Uganda to investigate: 1) how the clinics currently aim to prevent, monitor and treat side effects in these people; 2) which side effects occur and how common they are; 3) whether there are common clinical risk factors across people with side effects; 4) whether there are genetic risk factors for the most concerning of these side effects, high blood sugar.We will also recruit 15,000 people receiving DTG or DTG and IPT to investigate whether mobile applications, 'apps', can improve monitoring of drug-related side effects in Ugandan PLHIV. We will test the Med Safety(R) mobile phone-based app, developed by a European drug safety project. The app has been adapted for Uganda's National Drug Authority (NDA) by the UK's Medicines and Healthcare products Regulatory Agency (MHRA) but isn't yet widely used. The app will enable PLHIV to report side effects directly to NDA. In return, NDA will provide PLHIV with updates on drug safety and take actions to safeguard their health. By the end of the project we will know the main clinical risk factors for side effects in people treated with DTG or DTG with IPT in Uganda and the genetic risk factors for developing high blood sugar. This will form the basis for personalised treatment in the future. In the longer term, our work has the potential to benefit those living throughout sub-Saharan Africa and beyond. The risk factors for drug-related side effects seen in Uganda could give insight into the complex interplay between clinical, genetic and environmental factors in other population groups. Our learning from deploying the Med Safety(R) app across a population that encompasses large, developed cities and isolated rural areas will be invaluable for wider global efforts in drug safety monitoring. Our strong links with National and International agencies including the NDA, MHRA and WHO will help to ensure that our work improves the safety of PLHIV.

得益于医疗进步，艾滋病毒（PLHIV）的人现在可以过着长寿，健康的生活。为了保持健康，PLHIV将需要在其余生中对病毒（称为抗逆转录病毒）服用毒品。抗逆转录病毒通常是安全的，但在某些人中会造成严重的副作用，尤其是长期使用。在临床试验中发现了常见的副作用。如果它们太严重或太常见，该药物将使试验失败。在临床试验中不可能测试足够多的人以发现较少的常见副作用。这些只能通过监视在现实世界中服用该药物的人们来找到。记录哪些人具有副作用并理解为什么会发生这种情况对于使毒品更安全至关重要。我们在乌干达工作，有150万人（3.5％）患有艾滋病毒。乌干达最近开始了一项计划，以迅速推出抗逆转录病毒组合，包括多卢特格雷韦（DTG），这是世界卫生组织（WHO）推荐的新药。乌干达还正在逐步推出异烟肼预防疗法（IPT），以防止活跃的结核病 - PLHIV死亡的主要原因。监测与药物相关的副作用的系统直到最近才在乌干达开发，因此我们不了解乌干达PLHIV新型HIV药物的副作用的危险因素。其中包括“临床”危险因素，例如患有其他医疗状况或“遗传”危险因素，一个人的DNA自然变化，增加了副作用的风险。某些DNA变异在特定种族的人中更为普遍，因此我们必须记录所有种族群体的副作用。我们的目标是：1）了解哪些PLHIV有可能与IPT对DTG或DTG产生副作用以及原因； 2）通过授权PLHIV发表自己的报告来加强报告与药物相关的副作用的系统。这些是使我们能够在未来使用正确剂量的正确抗逆转录病毒治疗每个PLHIV的重要步骤。我们将招募10000名从乌干达的八个诊所接受DTG或DTG Plus IPT的10000人进行调查：1）当前诊所目前如何预防，监测和治疗这些人的副作用； 2）发生哪些副作用以及它们的常见程度； 3）是否有副作用的人有共同的临床危险因素； 4）是否有最大的副作用遗传危险因素，高血糖。我们还将招募15,000名接受DTG或DTG的人，以及IPT来研究移动应用“应用程序”是否可以改善对乌干达PLHIV药物相关副作用的监测。我们将测试由欧洲药物安全项目开发的基于手机的Med Safety（R）基于手机的应用程序。该应用程序已由英国的药品和医疗保健产品监管机构（MHRA）改编为乌干达的国家药物管理局（NDA），但尚未广泛使用。该应用程序将使PLHIV能够直接向NDA报告副作用。作为回报，NDA将为PLHIV提供有关药物安全的最新消息，并采取行动来保护其健康。到该项目结束时，我们将知道在乌干达接受DTG或DTG治疗的人的副作用的主要临床风险因素，以及在乌干达的遗传危险因素。这将构成将来个性化治疗的基础。从长远来看，我们的工作有可能使生活在整个撒哈拉以南非洲及其他地区的人们受益。在乌干达看到的与药物相关的副作用的危险因素可以洞悉其他人群中临床，遗传和环境因素之间的复杂相互作用。我们从涵盖大型，发达的城市和孤立农村地区的人群中部署MED安全（R）应用程序中的学习对于全球在药物安全监测中的更广泛努力都是无价的。我们与包括NDA，MHRA以及将有助于确保我们的工作改善PLHIV的安全的国家和国际机构的紧密联系。