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Abacavir pharmacogenetics--from initial reports to standard of care.

ABSTRACT: Abacavir is a nucleoside analogue reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus infection as part of a multidrug, highly active antiretroviral therapy regimen. Despite its efficacy, approximately 5% of individuals who receive abacavir develop an immune-mediated hypersensitivity reaction (HSR) that warrants immediate discontinuation of abacavir and switching to an alternative antiretroviral regimen. Abacavir HSR is associated with individuals who carry the *57:01 variant in the human leukocyte antigen B (HLA-B) gene. There is a large volume of evidence to show that those who carry HLA-B*57:01 are at significantly increased risk of developing HSR and should not receive abacavir. Pharmacogenetic screening to ensure individuals who carry HLA-B*57:01 do not receive abacavir can reduce the incidence of HSR and is now considered the standard of care before prescribing abacavir. Genetic testing to prevent abacavir HSR is currently one of the best examples of integrating pharmacogenetic testing into clinical practice.

SUBMITTER: Martin MA

PROVIDER: S-EPMC3700656 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Abacavir pharmacogenetics--from initial reports to standard of care.

Martin Michael A MA Kroetz Deanna L DL

Pharmacotherapy 20130503 7

Abacavir is a nucleoside analogue reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus infection as part of a multidrug, highly active antiretroviral therapy regimen. Despite its efficacy, approximately 5% of individuals who receive abacavir develop an immune-mediated hypersensitivity reaction (HSR) that warrants immediate discontinuation of abacavir and switching to an alternative antiretroviral regimen. Abacavir HSR is associated with individuals who carr ...[more]

PMID: 23649914

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Project description:The use of fixed-dose combination nucleoside reverse-transcriptase inhibitors (NRTIs) with a nonnucleoside reverse-transcriptase inhibitor or a ritonavir-boosted protease inhibitor is recommended as initial therapy in patients with human immunodeficiency virus type 1 (HIV-1) infection, but which NRTI combination has greater efficacy and safety is not known.In a randomized, blinded equivalence study involving 1858 eligible patients, we compared four once-daily antiretroviral regimens as initial therapy for HIV-1 infection: abacavir-lamivudine or tenofovir disoproxil fumarate (DF)-emtricitabine plus efavirenz or ritonavir-boosted atazanavir. The primary efficacy end point was the time from randomization to virologic failure (defined as a confirmed HIV-1 RNA level > or = 1000 copies per milliliter at or after 16 weeks and before 24 weeks, or > or = 200 copies per milliliter at or after 24 weeks).A scheduled interim review by an independent data and safety monitoring board showed significant differences in virologic efficacy, according to the NRTI combination, among patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more. At a median follow-up of 60 weeks, among the 797 patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the time to virologic failure was significantly shorter in the abacavir-lamivudine group than in the tenofovir DF-emtricitabine group (hazard ratio, 2.33; 95% confidence interval, 1.46 to 3.72; P<0.001), with 57 virologic failures (14%) in the abacavir-lamivudine group versus 26 (7%) in the tenofovir DF-emtricitabine group. The time to the first adverse event was also shorter in the abacavir-lamivudine group (P<0.001). There was no significant difference between the study groups in the change from the baseline CD4 cell count at week 48.In patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the times to virologic failure and the first adverse event were both significantly shorter in patients randomly assigned to abacavir-lamivudine than in those assigned to tenofovir DF-emtricitabine. (ClinicalTrials.gov number, NCT00118898.)

Project description:ImportanceThe coronavirus disease 2019 (COVID-19) pandemic has caused major disruptions in the US health care system.ObjectiveTo estimate frequency of and reasons for reported forgone medical care from March to mid-July 2020 and examine characteristics of US adults who reported forgoing care.Design, setting, and participantsThis survey study used data from the second wave of the Johns Hopkins COVID-19 Civic Life and Public Health Survey, fielded from July 7 to July 22, 2020. Respondents included a national sample of 1337 individuals aged 18 years or older in the US who were part of National Opinion Research Center's AmeriSpeak Panel.ExposuresThe initial period of the COVID-19 pandemic in the US, defined as from March to mid-July 2020.Main outcomes and measuresThe primary outcomes were missed doses of prescription medications; forgone preventive and other general medical care, mental health care, and elective surgeries; forgone care for new severe health issues; and reasons for forgoing care.ResultsOf 1468 individuals who completed wave 1 of the Johns Hopkins COVID-19 Civic Life and Public Health Survey (70.4% completion rate), 1337 completed wave 2 (91.1% completion rate). The sample of respondents included 691 (52%) women, 840 non-Hispanic White individuals (63%), 160 non-Hispanic Black individuals (12%), and 223 Hispanic individuals (17%). The mean (SE) age of respondents was 48 (0.78) years. A total of 544 respondents (41%) forwent medical care from March through mid-July 2020. Among 1055 individuals (79%) who reported needing care, 544 (52%) reported forgoing care for any reason, 307 (29%) forwent care owing to fear of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, and 75 (7%) forwent care owing to financial concerns associated with the COVID-19 pandemic. Respondents who were unemployed, compared with those who were employed, forwent care more often (121 of 186 respondents [65%] vs 251 of 503 respondents [50%]; P = .01) and were more likely to attribute forgone care to fear of SARS-CoV-2 transmission (78 of 186 respondents [42%] vs 120 of 503 respondents [24%]; P = .002) and financial concerns (36 of 186 respondents [20%] vs 28 of 503 respondents [6%]; P = .001). Respondents lacking health insurance were more likely to attribute forgone care to financial concerns than respondents with Medicare or commercial coverage (19 of 88 respondents [22%] vs 32 of 768 respondents [4%]; P < .001). Frequency of and reasons for forgone care differed in some instances by race/ethnicity, socioeconomic status, age, and health status.Conclusions and relevanceThis survey study found a high frequency of forgone care among US adults from March to mid-July 2020. Policies to improve health care affordability and to reassure individuals that they can safely seek care may be necessary with surging COVID-19 case rates.

Project description:Tacrolimus, an immunosuppressant used in solid organ transplantation, has a narrow therapeutic index and exhibits inter-individual pharmacokinetic variability. Achieving and maintaining a therapeutic level of the drug by giving appropriate doses is crucial for successful immunosuppression, especially during the initial post-transplant period. We studied the effect of CYP3A5, CYP3A4, and ABCB1 gene polymorphisms on tacrolimus trough concentrations in South Indian renal transplant recipients from Kerala to formulate a genotype-based dosing equation to calculate the required starting daily dose of tacrolimus to be given to each patient to attain optimal initial post-transplant period drug level. We also investigated the effect of these genes on drug-induced adverse effects and rejection episodes and looked into the global distribution of allele frequencies of these polymorphisms. One hundred forty-five renal transplant recipients on a triple immunosuppressive regimen of tacrolimus, mycophenolate mofetil, and steroid were included in this study. Clinical data including tacrolimus daily doses, trough levels (C0) and dose-adjusted tacrolimus trough concentration (C0/D) in blood at three time points (day 6, 6 months, and 1-year post-transplantation), adverse drug effects, rejection episodes, serum creatinine levels, etc., were recorded. The patients were genotyped for CYP3A5*3, CYP3A4*1B, CYP3A4*1G, ABCB1 G2677T, and ABCB1 C3435T polymorphisms by the PCR-RFLP method. We found that CYP3A5*3 polymorphism was the single most strongly associated factor determining the tacrolimus C0/D in blood at all three time points (p < 0.001). Using multiple linear regression, we formulated a simple and easy to compute equation that will help the clinician calculate the starting tacrolimus dose per kg body weight to be administered to a patient to attain optimal initial post-transplant period tacrolimus level. CYP3A5 expressors had an increased chance of rejection than non-expressors (p = 0.028), while non-expressors had an increased risk for new-onset diabetes mellitus after transplantation (NODAT) than expressors (p = 0.018). Genotype-guided initial tacrolimus dosing would help transplant recipients achieve optimal initial post-transplant period tacrolimus levels and thus prevent the adverse effects due to overdose and rejection due to inadequate dose. We observed inter-population differences in allele frequencies of drug metabolizer and transporter genes, emphasizing the importance of formulating population-specific dose prediction models to draw results of clinical relevance.

Dataset Information

Abacavir pharmacogenetics--from initial reports to standard of care.

Publications

Abacavir pharmacogenetics--from initial reports to standard of care.

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