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

由于医学的进步，艾滋病毒感染者（PLHIV）现在可以过上健康长寿的生活。为了保持健康，艾滋病毒感染者需要在余生中服用抗病毒药物（称为抗逆转录病毒药物）。抗逆转录病毒药物通常是安全的，但在某些人中会引起严重的副作用，特别是长期使用。常见的副作用是在临床试验中发现的;如果它们太严重或太常见，药物将无法通过试验。在临床试验中不可能测试足够多的人来发现不太常见的副作用。这些只能通过监测人们在真实的世界中服用药物来发现。记录哪些人有副作用并了解为什么会发生副作用对于使药物更安全至关重要。我们在乌干达工作，那里有150万人（3.5%）感染艾滋病毒。乌干达最近开始实施一项计划，迅速推出抗逆转录病毒组合，包括世界卫生组织（世卫组织）推荐的用于艾滋病毒感染者的新药dolutegravir（DTG）。乌干达还在推广异烟肼预防疗法，以预防活动性结核病-艾滋病毒感染者死亡的主要原因。乌干达最近才开发出监测药物相关副作用的系统，因此我们不了解乌干达艾滋病毒感染者中新艾滋病毒药物副作用的风险因素。这些风险因素包括“临床”风险因素，如患有其他疾病，或“遗传”风险因素，即增加副作用风险的人DNA的自然变异。某些DNA变异在特定种族的人群中更常见，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）了解哪些艾滋病毒感染者有DTG或DTG与IPT副作用的风险及其原因; 2）通过授权艾滋病毒感染者自行报告，加强报告药物相关副作用的系统。这些都是使我们能够在未来以正确的剂量用正确的抗逆转录病毒药物治疗每一个艾滋病毒感染者的重要步骤。我们将从乌干达的八个诊所招募10000名接受DTG或DTG加IPT的人，以调查：1）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有多常见; 3）是否有副作用的人有共同的临床风险因素; 4）这些最令人担忧的副作用（高血糖）是否存在遗传风险因素。我们还将招募15，000名接受DTG或DTG和IPT的人来调查是否存在移动的应用程序、'应用程序'、可以改善对乌干达艾滋病毒感染者药物相关副作用的监测。我们将测试Med Safety（R）移动的手机应用程序，该应用程序由欧洲药物安全项目开发。该应用程序已由英国药品和保健产品管理局（MHRA）为乌干达国家药品管理局（NDA）进行了调整，但尚未广泛使用。该应用程序将使艾滋病毒感染者能够直接向NDA报告副作用。作为回报，NDA将向艾滋病毒感染者提供有关药物安全的最新信息，并采取行动保障他们的健康。到项目结束时，我们将了解乌干达接受DTG或DTG联合IPT治疗的患者副作用的主要临床风险因素以及发生高血糖的遗传风险因素。这将成为未来个性化治疗的基础。从长远来看，我们的工作有可能造福撒哈拉以南非洲和其他地区的人民。在乌干达发现的药物相关副作用的风险因素可以让我们深入了解其他人群中临床、遗传和环境因素之间的复杂相互作用。我们从在包括大型发达城市和偏远农村地区在内的人群中部署Med Safety（R）应用程序中学到的知识，对于更广泛的全球药物安全监测工作将是非常宝贵的。我们与国家和国际机构，包括NDA，MHRA和世卫组织的密切联系将有助于确保我们的工作提高PLHIV的安全性。

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.