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.
HIV and associated co-morbidities are prevalent in South Africa, with immunologically mediated adverse drug reactions (IM-ADRs) affecting one in five people treated for HIV and associated complications, such as tuberculosis (TB). We will establish the largest South African network of phenotype and causality adjudicated cases of severe IM-ADRs paired with a biorepository of DNA, PBMCs, blister fluid cells, plasma and skin from adults and children. This will be used to 1) identify HLA and other genetic risk factors associated with these IM- ADRs related to prevalent drugs used to treat HIV and its complications; and 2) elucidate the impact of IM-ADRs on HIV and TB treatment outcomes, as well as long-term complications of IM-ADRs.
