Immune-mediated adverse drug reactions to HIV and TB treatments in South Africa: predict, prevent and improve long-term outcomes (IMARI SA study)

项目摘要 免疫介导的药物不良反应（IM-ADR）是成功治疗这两种疾病的主要障碍 艾滋病毒和结核病（TB）在国际上。它们对管理复杂性和经济负担的贡献是 南非（SA）的一个特殊问题是，人口中有四分之一的人感染艾滋病毒，五分之一的人感染艾滋病毒。 HIV患者在治疗过程中出现皮肤药物不良反应。Stevens-Johnson综合征 和中毒性表皮坏死松解症（SJS/TEN）和药物反应伴嗜酸性粒细胞增多和全身症状（DRESS） 是死亡率超过40%并导致住院时间延长的严重IM-ADR， 医疗保健成本和显著受限的治疗选择。这些IM-ADR对以下方面的具体影响 艾滋病毒治疗的成果尚未得到充分衡量。此外，IM-ADR本身是已知的 与严重的长期残疾和身心健康并发症有关， 在艾滋病毒和艾滋病毒/结核病合并感染人群中进行了测量。严重IM-ADR的预防措施，例如 DRESS和SJS/TEN受到了有希望的发现的推动，例如， HLA I类等位基因HLA-B*15：02和卡马西平SJS/TEN，这导致了治疗前的HLA- B*15：02在一些东南亚国家的卡马西平处方前。我们小组的成员是 负责翻译HLA-B*57：01筛查，以防止阿巴卡韦过敏，我们最近 描述了HLA-C*04：01和奈韦拉平SJS/TEN在SA中的强相关性，表明HLA类 I关联对于用于治疗和预防艾滋病毒的药物也很重要。然而，基因 非洲艾滋病毒感染人群中IM-ADR的风险因素尚未完全了解， 在了解非洲艾滋病毒/结核合并感染者常用药物中IM-ADR风险因素方面存在差距 人口数量。在南非和其他资源贫乏的非洲环境中，鉴于艾滋病毒和结核病的高负担， 迫切需要确定有助于改善预防工作的IM-ADR管理战略， 诊断和治疗方案。我们的假设是，我们将确定HLA和其他遗传 SJS/TEN以及DRESS与用于预防、治疗和管理艾滋病毒的药物之间的关联及其共同作用， 病态在具体目标1中，我们将创建一个DNA和其他IM-ADR病例样本的生物储存库 与用于治疗艾滋病毒和结核病的药物有关的药物，包括南非服务不足的地区。现有和 新的IM-ADR病例将接受特定表型验证和因果关系裁定。在具体目标2中， 将定义HLA和其他遗传风险因素与IM-ADR在艾滋病毒/结核病流行的设置。在 具体目标3，我们将确定短期和长期并发症和结果之间的队列， 经历过IM-ADR的患者以及对HIV护理的具体影响。使用的协同增益 根据现有的美国和南非合作，我们预测我们的发现将为非洲的发展创造一个路线图。 预防和管理国际资源匮乏环境中复杂艾滋病毒人群的IM-ADR。

PROJECT SUMMARY Immune-mediated adverse drug reactions (IM-ADRs) are a major obstacle to the successful treatment of both HIV and tuberculosis (TB) internationally. Their contribution to management complexity and economic burden is a particular problem in South Africa (SA) where 1 in 4 individuals in the population is HIV-infected and 1 in 5 patients with HIV develops a cutaneous adverse drug reaction during treatment. Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) are severe IM-ADRs that have mortalities that can exceed 40% and lead to prolonged hospitalization, higher healthcare costs and significantly constricted treatment options. The specific effect that these IM-ADRs have on HIV treatment outcomes has not been adequately measured. In addition, the IM-ADRs themselves are known to be associated with significant long-term disability and physical and mental health complications that have not been measured in HIV and HIV/TB co-infected populations. Preventive efforts for severe IM-ADRs such as DRESS and SJS/TEN have been fueled by promising discoveries such as the strong association between the HLA class I allele HLA-B*15:02 and carbamazepine SJS/TEN which has led to pre-treatment screening for HLA- B*15:02 before carbamazepine prescription in some Southeast Asian countries. Members of our group were responsible for the translation of HLA-B*57:01 screening to prevent abacavir hypersensitivity and we recently described a strong association between HLA-C*04:01 and nevirapine SJS/TEN in SA suggesting that HLA class I associations are also important for drugs used in the treatment and prevention of HIV. However, the genetic risk factors for IM-ADRs in African HIV-infected populations are incompletely understood and there are significant gaps in understanding the risk factors for IM-ADRs in drug commonly used in African HIV-TB co-infected populations. In SA and other resource poor African settings, given the high burden of HIV and TB, there is an urgent need to identify management strategies for IM-ADRs that will help improve prevention efforts, earlier diagnosis and treatment protocols. Our hypothesis tested will be that we will identify HLA and other genetic associations between SJS/TEN as well as DRESS and drugs used to prevent, treat and manage HIV and its co- morbidities. In specific aim 1 we will create a biorepository of DNA and other samples from IM-ADR cases related to drugs used to treat HIV and TB that includes underserviced areas in South Africa. Existing and new IM-ADR cases will undergo specific phenotype validation and causality adjudication. In specific aim 2 we will define HLA and other genetic risk factors associated with IM-ADRs in HIV/TB endemic settings. In specific aim 3 we will determine short and long-term complications and outcomes amongst a cohort of patients who have experienced IM-ADR and the specific impacts on HIV care. Using the synergistic gain of an existing US-South African collaboration we predict that our discoveries will create a roadmap for the prevention and management of IM-ADRs in complex HIV populations in resource poor settings internationally.