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，艾滋病毒携带者(PLHIV)现在可以健康长寿。为了保持健康，PLHIV将需要在其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，但在一些人身上会产生严重的副作用，特别是长期使用的话。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，药物将无法通过试验。在临床试验中测试足够多的人来发现不太常见的副作用是不可能的。只有在现实世界中监测吸毒者才能发现这些。记录哪些人有副作用并了解它们发生的原因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%)感染了艾滋病毒。乌干达最近开始了一项方案，以迅速推出抗逆转录病毒药物组合，包括世界卫生组织(WHO)向PLHIV推荐的新药多洛替格列韦(DTG)。乌干达还推出了异烟肼预防疗法(IPT)，以预防活动性结核病--PLHIV的主要死亡原因。乌干达最近才开发了监测与药物有关的副作用的系统，因此我们不了解乌干达艾滋病毒/艾滋病新药物副作用的风险因素。这些因素包括“临床”风险因素，如有其他医疗条件，或“遗传”风险因素，即一个人的DNA的自然变异，增加了副作用的风险。某些DNA变异在特定种族的人中更为常见，因此我们必须记录所有种族的副作用。我们的目标是：1)了解哪些PLHIV面临DTG或DTG与IPT的副作用风险，以及原因；2)通过授权PLHIV自己报告，加强报告药物相关副作用的系统。这些都是必要的步骤，使我们能够在未来用适当的抗逆转录病毒药物以适当的剂量治疗每一例艾滋病病毒感染者。我们将从乌干达各地的八家诊所招募10000名接受DTG或DTG加IPT治疗的人来调查：1)诊所目前旨在预防、监测和治疗这些人的副作用；2)发生哪些副作用，它们有多常见；3)副作用患者中是否存在常见的临床风险因素；4)这些副作用中最令人担忧的是否存在遗传风险因素，如高血糖。我们还将招募15,000名接受DTG或DTG和IPT治疗的人来调查移动应用程序是否可以改善对乌干达PLHIV中与药物相关的副作用的监测。我们将测试由一个欧洲药物安全项目开发的基于Med Safe(R)手机的应用程序。这款应用程序已经被英国药品和医疗保健产品管理局(MHRA)修改为乌干达国家药品管理局(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将向PLHIV提供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，我们将知道乌干达接受DTG或DTG加IPT治疗的人产生副作用的主要临床风险因素，以及导致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于生活在撒哈拉以南非洲和其他地区的人们。在乌干达看到的与毒品有关的副作用的风险因素可以深入了解其他人口群体的临床、遗传和环境因素之间的复杂相互作用。我们在包括大的发达城市和偏远的农村地区的人群中部署Med Safe(R)应用程序的经验将对全球药品安全监测的更广泛努力具有宝贵的价值。我们与包括NDA、MHRA和WHO在内的国家和国际机构的密切联系将有助于确保我们的工作改善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.