- Personalized medicine for HLA-associated drug-hypersensitivity reactions. [Journal Article]
- PMPer Med 2010; 7(5):495-516
- Multiple genetic and nongenetic factors can modify the action of a drug, resulting in varied responses to a particular drug across different individuals. Personalized medicine incorporates the compre...
Multiple genetic and nongenetic factors can modify the action of a drug, resulting in varied responses to a particular drug across different individuals. Personalized medicine incorporates the comprehensive knowledge of these factors to facilitate the selection of optimal therapy, reduce adverse drug reactions, increase patient compliance and increase the efficiency of therapy. Pharmacogenomics, which integrates the knowledge of an individual's genetic make-up for diagnostic decisions or therapeutic interventions is closely linked to personalized medicine, and is being increasingly used to prevent adverse drug reactions. There are various reports on genetic associations between particular HLA allotypes and drug hypersensitivities and the strongest associations reported thus far, are with the reverse transcriptase inhibitor, abacavir and HLA-B*5701, the gout prophylactic allopurinol and HLA-B*5801 and the antiepileptic carbamazepine and B*1502, providing a defined disease trigger and suggesting a general mechanism for these associations. Recognizing the strong HLA association, the US FDA has recommended genetic testing before starting abacavir and carbamazepine therapies. To incorporate HLA testing for other drug hypersensitivities and life-threatening reactions it is essential first to establish clear HLA associations, and second, to understand the immune-mechanism by which these drugs induce HLA-linked hypersensitivity. The latter will provide insight into the pathologic mechanisms of drug allergy allowing rational immunotherapy for these life-threatening reactions and the development of alternative drug therapies for hypersensitive patients.
- Increased dolutegravir peak concentrations in people living with HIV aged 60 and over and analysis of sleep quality and cognition. [Journal Article]
- CIClin Infect Dis 2018 May 16
- CONCLUSIONS: DTG Cmax was significantly higher in older PLWH. Our data provides clinicians with key information on the safety of prescribing DTG in older PLWH.
- Abacavir Use and Risk for Myocardial Infarction and Cardiovascular Events: Pooled Analysis of Data From Clinical Trials. [Journal Article]
- OFOpen Forum Infect Dis 2018; 5(5):ofy086
- CONCLUSIONS: This pooled analysis found comparable IRs for MI and CVEs among ABC-exposed and -unexposed participants, suggesting no increased risk for MI or CVEs following ABC exposure in a clinical trial population. Modifiable risk factors for MI and CVEs should be addressed when prescribing ART.
- Executive summary of the GeSIDA/National AIDS Plan consensus document on antiretroviral therapy in adults infected by the human immunodeficiency virus (updated January 2018). [Journal Article]
- EIEnferm Infecc Microbiol Clin 2018 May 11
- This update to the document on antiretroviral therapy (ART) in adults, which has been prepared jointly by GeSIDA and the Spanish National AIDS Plan for the last two decades, supersedes the document p...
This update to the document on antiretroviral therapy (ART) in adults, which has been prepared jointly by GeSIDA and the Spanish National AIDS Plan for the last two decades, supersedes the document published in 2017.1 The update provides physicians treating HIV-1-infected adults with evidence-based recommendations to guide their therapeutic decisions. The main difference with respect to the previous document concerns recommended initial ART regimens, only three of which are maintained as preferential. All three include dolutegravir or raltegravir, together with emtricitabine/tenofovir alafenamide or abacavir/lamivudine. Other differences concern the section on switching ART in patients with suppressed viral replication, which now includes new two- and three-drug regimens, and the antiretroviral drugs recommended for pregnant women and patients with tuberculosis. A recommendation has also been added for patients who present with acute HIV infection after pre-exposure prophylaxis.
- Emerging resistance mutations in PI-naive patients failing an atazanavir-based regimen (ANRS multicentre observational study). [Journal Article]
- JAJ Antimicrob Chemother 2018 Apr 27
- CONCLUSIONS: Resistance to atazanavir is rare in patients failing the first line of an atazanavir-based regimen according to the ANRS. Emergent NRTI resistance-associated mutations were reported in 18% of patients.
- Effect of aspirin treatment on abacavir-associated platelet hyperreactivity in HIV-infected patients. [Journal Article]
- IJInt J Cardiol 2018 Jul 15; 263:118-124
- CONCLUSIONS: Aspirin reduces ABC-induced in vivo platelet activation and platelet hyperreactivity in HIV-infected patients, however without normalizing them. Whether the observed reduction of platelet activation is sufficient to prevent cardiovascular events requires a prospective trial.
- Pharmacogenomic information in the Warning section of drug labels: A comparison between labels in the United States and those in five other countries/regions. [Journal Article]
- JCJ Clin Pharm Ther 2018 Apr 22
- CONCLUSIONS: We selected six drugs, namely, clopidogrel, atomoxetine, irinotecan, mercaptopurine, abacavir and carbamazepine and compared the pharmacogenomic information in the "Warning" section of these drug labels in the United States and 5 other countries/regions.The pharmacogenomic information in drug labels is not well harmonized across countries/regions, possibly due to differences in population characteristics such as relevant allele frequencies, variable genetic test availability and differences in insurance coverage. Further and periodical investigations of this issue would be useful.
- Medical Genetics Summaries [BOOK]
- BOOKNational Center for Biotechnology Information (US): Bethesda (MD)
- Abacavir (brand name Ziagen) is used in the treatment of human immunodeficiency virus (HIV) infection. Abacavir is a nucleoside (and nucleotide) reverse transcriptase inhibitor (NRTI), and is used in...
Abacavir (brand name Ziagen) is used in the treatment of human immunodeficiency virus (HIV) infection. Abacavir is a nucleoside (and nucleotide) reverse transcriptase inhibitor (NRTI), and is used in combination with other medications as part of highly active antiretroviral therapy (HAART) (1). Hypersensitivity reactions associated with abacavir can be severe and potentially fatal. Symptoms include fever, rash, vomiting, and shortness of breath. They typically appear within the first 42 days of treatment (11 days median onset). HLA-B*57:01 significantly increases the risk of hypersensitivity reactions when abacavir is administered. Approximately 6% of Caucasians and 2-3% of African Americans carry this allele in the human leukocyte antigen B (HLA-B) gene. The HLA-B gene plays an important role in how the immune system recognizes and responds to pathogens, and mediates hypersensitivity reactions. HLA-B*57:01 has been found to be associated with abacavir hypersensitivity across different ethnicities, including Caucasians, Hispanics, and individuals of African origin (2, 3). Screening for the HLA-B*57:01 allele before starting abacavir therapy is recommended for all patients according to the FDA drug label for abacavir (Table 1). Even if previously tolerated, screening should happen before restarting abacavir therapy if HLA-B*57:01 status is unknown. Abacavir is contraindicated in HLA-B*5701-positive patients, and in patients with a prior hypersensitivity reaction to abacavir. Dosing guidelines from the professional societies, Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP), also recommend that HLA-B*57:01 screening should be performed prior to initiation of abacavir therapy and an alternate drug be administered for patients with the allele (Table 2, Table 3)(1, 3-5).
- Regimen durability in HIV-infected children and adolescents initiating first-line antiretroviral therapy in a large public sector HIV cohort in South Africa. [Journal Article]
- TMTrop Med Int Health 2018 Apr 15
- CONCLUSIONS: The decline in single-drug substitutions is associated with the introduction of tenofovir. Tenofovir use could improve regimen durability and treatment outcomes in resource-limited settings.
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- Adipocytes impair efficacy of antiretroviral therapy. [Journal Article]
- ARAntiviral Res 2018; 154:140-148
- Adequate distribution of antiretroviral drugs to infected cells in HIV patients is critical for viral suppression. In humans and primates, HIV- and SIV-infected CD4 T cells in adipose tissues have re...
Adequate distribution of antiretroviral drugs to infected cells in HIV patients is critical for viral suppression. In humans and primates, HIV- and SIV-infected CD4 T cells in adipose tissues have recently been identified as reservoirs for infectious virus. To better characterize adipose tissue as a pharmacological sanctuary for HIV-infected cells, in vitro experiments were conducted to assess antiretroviral drug efficacy in the presence of adipocytes, and drug penetration in adipose tissue cells (stromal-vascular-fraction cells and mature adipocytes) was examined in treated humans and monkeys. Co-culture experiments between HIV-1-infected CD4 T cells and primary human adipocytes showed that adipocytes consistently reduced the antiviral efficacy of the nucleotide reverse transcriptase inhibitor tenofovir and its prodrug forms tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). In HIV-infected persons, LC-MS/MS analysis of intracellular lysates derived from adipose tissue stromal-vascular-fraction cells or mature adipocytes suggested that integrase inhibitors penetrate adipose tissue, whereas penetration of nucleoside/nucleotide reverse transcriptase inhibitors such as TDF, emtricitabine, abacavir, and lamivudine is restricted. The limited distribution and functions of key antiretroviral drugs within fat depots may contribute to viral persistence in adipose tissue.