Immune-mediated adverse drug reactions to HIV and TB treatments in South Africa: predict, prevent and improve long-term outcomes (IMARI SA study)
南非艾滋病毒和结核病治疗的免疫介导药物不良反应:预测、预防和改善长期结果(IMARI SA 研究)
基本信息
- 批准号:10382256
- 负责人:
- 金额:$ 33.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-21 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AIDS preventionAdultAdverse reactionsAffectAfricanAgeAllelesAreaAutoimmune DiseasesBiologicalBlindnessBullaCD4 Lymphocyte CountCD4 Positive T LymphocytesCarbamazepineCaringCause of DeathCell CountCellsChildCollaborationsCollectionComplexConsentCountryCutaneousDNADiseaseDrug ToleranceDrug resistance in tuberculosisDrug usageEarly DiagnosisEarly treatmentEconomic BurdenEosinophiliaEthambutolEtiologyEuropeEuropeanGenesGeneticGenetic RiskGenotypeHIVHIV/TBHLA-A geneHLA-B AntigensHLA-C AntigensHealth Care CostsHigh PrevalenceHospitalizationHypersensitivityImmuneImmunologic FactorsImmunologicsImpairmentIndividualInfrastructureIngestionInternationalLiquid substanceMeasurementMeasuresMediatingMental HealthMental disordersMorbidity - disease rateNevirapineNorth AmericaOrganOther GeneticsOutcomePatientsPeripheral Blood Mononuclear CellPersonsPharmaceutical PreparationsPhenotypePlasmaPopulationPredispositionPreventionPrevention strategyPreventiveProceduresPyrazinamideQuality of lifeRaceReactionRecurrenceRegimenRegistriesResearchResolutionResource-limited settingResourcesRifampinRisk FactorsSalivarySamplingSkinSouth AfricaSouth AfricanSputumStevens-Johnson SyndromeSymptomsTestingTherapeuticTimeToxic Epidermal NecrolysisTranslationsTreatment ProtocolsTreatment outcomeTrimethoprim-SulfamethoxazoleTuberculosisUniversitiesValidationViralViral Load resultVirus DiseasesVisionabacaviradjudicationadverse drug reactionbiobankco-infectioncohortcomorbidityconstrictiondisabilityefavirenzexperiencefollow-upgenetic associationgenetic risk factorimprovedisoniazidlong-term sequelaemembermortalitymulti-ethnicnovelphysical conditioningpreventprospectiverisk variantscreeningsexsoutheast Asiansuccesstooltreatment optimizationtreatment strategytuberculosis drugstuberculosis treatment
项目摘要
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.
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。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。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Graeme Ayton Meintjes其他文献
Graeme Ayton Meintjes的其他文献
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{{ truncateString('Graeme Ayton Meintjes', 18)}}的其他基金
HIV-associated Tuberculosis Training Program (HATTP)
HIV 相关结核病培训计划 (HATTP)
- 批准号:
10472830 - 财政年份:2017
- 资助金额:
$ 33.01万 - 项目类别:
HIV-associated Tuberculosis Training Program (HATTP)
HIV 相关结核病培训计划 (HATTP)
- 批准号:
9337925 - 财政年份:2017
- 资助金额:
$ 33.01万 - 项目类别:
HIV-associated Tuberculosis Training Program (HATTP)
HIV 相关结核病培训计划 (HATTP)
- 批准号:
10595639 - 财政年份:2017
- 资助金额:
$ 33.01万 - 项目类别:
HIV-associated Tuberculosis Training Program (HATTP)
HIV 相关结核病培训计划 (HATTP)
- 批准号:
10252833 - 财政年份:2017
- 资助金额:
$ 33.01万 - 项目类别:
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