Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana.

2018

2018 Jun 01

1473-1150

<p>Inter-individual variability in efavirenz (EFV) pharmacokinetics and dynamics is dominantly driven by the polymorphism in cytochrome P450 (CYP) isoenzyme 2B6 516G&gt;T. We hypothesized that additional CYP polymorphisms mediate the relationship between CYP2B6 516G&gt;T, EFV metabolism, and clinical events. We investigated 21 SNPs in 814 HIV-infected adults initiating EFV-based therapy in Botswana for population pharmacokinetics, CNS toxicities, and treatment outcomes. Two SNPs (rs28399499 and rs28399433) showed reduced apparent oral EFV clearance. Four SNPs (rs2279345, rs4803417, rs4802101, and rs61663607) showed extensive clearance. Composite CYP2B-mediated EFV metabolism was significantly associated with CNS toxicity (p = 0.04), with extensive metabolizers reporting more and slow and very slow metabolizers reporting less toxicity after 1 month compared to intermediate metabolizers. Composite CYP2B6 metabolism was not associated with composite early treatment failure. In conclusion, our data suggest that CNS-related toxicities might not be solely the result of super-therapeutic parent EFV concentrations in HIV-infected individuals in patients of African ancestry.</p>

10.1038/s41397-018-0028-2

Pharmacogenomics J.

29855606

CYP2B6 genotypes and early efavirenz-based hiv treatment outcomes in botswana.

2017

2017 Jul 07

1473-5571

<p><strong>OBJECTIVES: </strong>To determine the association between cytochrome p450 2B6 genotypes and efavirenz-based HIV treatment outcomes.</p>

<p><strong>DESIGN: </strong>Observational cohort study of HIV infected adults initiating efavirenz-based regimens in Botswana.</p>

<p><strong>METHODS: </strong>The primary endpoint was a composite of death or loss to care or HIV RNA&gt;25 copies/ml at 6 months. CYP2B6 516G&gt;T and 983T&gt;C genotyping was done with Taqman Open Array platform. Adverse experiences were measured using the Subject Experience Questionnaire. Metabolism alleles were included in logistic regression models of the composite endpoint.</p>

<p><strong>RESULTS: </strong>801 individuals included 406 (51%) males, median age 37 years, median baseline CD4 count 195 cells/mm and plasma HIV RNA 4·9 log10 copies/ml. 277 (35%) reached the endpoint including 34 (4%) deaths, 151 (19%) lost to care, and 92 (11%) with plasma HIV RNA&gt;25 copies/ml. Metabolism variant alleles were common with 396 (49%) intermediate and 192 (24%) slow metabolizers. There were no statistically significant associations between metabolism and treatment endpoints. However, slower metabolism was associated with fewer adverse experiences.</p>

<p><strong>CONCLUSIONS: </strong>Slow metabolism alleles were associated with lower efavirenz clearance but not any of the treatment endpoints. Slow efavirenz metabolism did not exacerbate CNS toxicity. These results should allay concern that slow efavirenz metabolism adversely impacts individuals in sub-Saharan African settings in which these alleles are common.</p>

10.1097/QAD.0000000000001593

AIDS

28692529

CYP2B6 516G>T Minor Allele Protective of Late Virologic Failure in Efavirenz-treated HIV-Infected Patients in Botswana.

2017

2017 May 05

1944-7884

<p><strong>BACKGROUND: </strong>CYPB2B6 polymorphisms that affect efavirenz (EFV) concentrations are common, but the effect of this polymorphism on HIV virologic failure in clinical practice settings has not fully been elucidated. Our objective was to investigate the relationship between the CYPB2B6 516G&gt;T genotype and late virologic failure in patients treated with EFV in Gaborone, Botswana.</p>

<p><strong>SETTING: </strong>We performed a case-control study that included 1,338 HIV-infected black Batswana on EFV-based antiretroviral therapy (ART). Patients were approached for enrollment during regular visits at one of the outpatient HIV clinics between 7/2013-4/2014.</p>

<p><strong>METHODS: </strong>Cases experienced late HIV failure, defined as plasma HIV RNA &gt;1000 copies/mL after maintaining viral suppression (&lt;400 copies/mL) for at least 6 months. For each case, a total of 4 control patients were randomly sampled from the same population. Controls had plasma HIV RNA &lt;400 copies/mL on ART for at least 6 months. Logistic regression was used to determine the adjusted odds of late HIV failure by 516G&gt;T genotype.</p>

<p><strong>RESULTS: </strong>After adjustment for the confounding variables age and CD4 count, the CYPB2B6 516 T-allele was protective against late HIV virologic breakthrough, adjusted OR 0.70; 95%CI 0.50-0.97.</p>

<p><strong>CONCLUSION: </strong>The CYPB2B6 516 T-allele was protective against late virologic breakthrough in patients with initial (6 month) HIV RNA suppression on EFV-based ART. Future studies are needed to assess long-term viral benefits of identifying and offering EFV containing ART to black African HIV-infected patients with CYPB2B6 T-alleles, especially given the wider availability of a single pill EFV in this setting.</p>

10.1097/QAI.0000000000001442

J. Acquir. Immune Defic. Syndr.

28481785

Genomic architecture and treatment outcome in pediatric acute myeloid leukemia: a Children's Oncology Group report.

2017

3051-8

2017 Jun

1528-0020

<p>Childhood acute myeloid leukemia (AML) is frequently characterized by chromosomal instability. Approximately 50% of patients have disease relapse, and novel prognostic markers are needed to improve risk stratification. We performed genome-wide genotyping in 446 pediatric patients with de novo AML enrolled on Children's Oncology Group (COG) studies, AAML0531 (NCT01407757), AAML03P1 (NCT00070174), and CCG2961 (NCT00003790). Affymetrix and Illumina Omni 2.5 platforms were used to evaluate copy number alterations (CNAs) and determine their associations with treatment outcome. Data from Affymetrix and Illumina studies were jointly analyzed with ASCAT and GISTIC software. An average of 1.14 somatically acquired CNAs per patient were observed. Novel reoccurring altered genomic regions were identified, and the presence of CNAs was found to be associated with decreased 3-year overall survival (OS), event-free survival (EFS), and relapse risk from the end of induction I (HR 1.7, 95%CI 1.2-2.4, HR 1.4, 95%CI 1.0-1.8, and HR 1.4, 95%CI 1.0-2.0, respectively). Analyses by risk group demonstrated decreased OS and EFS in the standard risk group only (HR 1.9, 95%CI 1.1-3.3, and HR 1.7, 95%CI 1.1-2.6, respectively). Further studies are required to test the prognostic significant of CNA presence in disease relapse in AML patients.</p>

10.1182/blood-2017-03-772384

Blood

28411282

Comparing Analytic Methods for Longitudinal GWAS and a Case-Study Evaluating Chemotherapy Course Length in Pediatric AML. A Report from the Children's Oncology Group.

2016

139

2016

1664-8021

<p>Regression analysis is commonly used in genome-wide association studies (GWAS) to test genotype-phenotype associations but restricts the phenotype to a single observation for each individual. There is an increasing need for analytic methods for longitudinally collected phenotype data. Several methods have been proposed to perform longitudinal GWAS for family-based studies but few methods are described for unrelated populations. We compared the performance of three statistical approaches for longitudinal GWAS in unrelated subjectes: (1) principal component-based generalized estimating equations (PC-GEE); (2) principal component-based linear mixed effects model (PC-LMEM); (3) kinship coefficient matrix-based linear mixed effects model (KIN-LMEM), in a study of single-nucleotide polymorphisms (SNPs) on the duration of 4 courses of chemotherapy in 624 unrelated children with de novo acute myeloid leukemia (AML) genotyped on the Illumina 2.5 M OmniQuad from the COG studies AAML0531 and AAML1031. In this study we observed an exaggerated type I error with PC-GEE in SNPs with minor allele frequencies &lt; 0.05, wheras KIN-LMEM produces more than expected type II errors. PC-MEM showed balanced type I and type II errors for the observed vs. expected P-values in comparison to competing approaches. In general, a strong concordance was observed between the P-values with the different approaches, in particular among P &lt; 0.01 where the between-method AUCs exceed 99%. PC-LMEM accounts for genetic relatedness and correlations among repeated phenotype measures, shows minimal genome-wide inflation of type I errors, and yields high power. We therefore recommend PC-LMEM as a robust analytic approach for GWAS of longitudinal data in unrelated populations.</p>

10.3389/fgene.2016.00139

Front Genet

27547214

Associations between genetic variants in folate and drug metabolizing pathways and relapse risk in pediatric acute lymphoid leukemia on CCG-1952.

2015

47-50

2015

2213-0489

<p>Genetic variation in drug detoxification pathways may influence outcomes in pediatric acute lymphoblastic leukemia (ALL). We evaluated relapse risk and 24 variants in 17 genes in 714 patients in CCG-1961. Three TPMT and 1 MTR variant were associated with increased risks of relapse (rs4712327, OR 3.3, 95%CI 1.2-8.6; rs2842947, OR 2.7, 95%CI 1.1-6.8; rs2842935, OR 2.5, 95%CI 1.1-5.0; rs10925235, OR 4.9, 95%CI 1.1-25.1). One variant in SLC19A1 showed a protective effect (rs4819128, OR 0.5, 95%CI 0.3-0.9). Our study provides data that relapse risk in pediatric ALL is associated with germline variations in TPMT, MTR and SLC19A1.</p>

10.1016/j.lrr.2015.05.005

Leuk Res Rep

26605150

TPMT and MTHFR genotype is not associated with altered risk of thioguanine-related sinusoidal obstruction syndrome in pediatric acute lymphoblastic leukemia: a report from the Children's Oncology Group.

2014

2086-8

2014 Nov

1545-5017

<p>Sinusoidal obstruction syndrome is a complication of therapy for pediatric ALL and may be modified by thiopurine methyltransferase activity as well as by MTHFR genotype. We assessed TPMT *3A, *3B, *3C, and MTHFR C677T and A1298C germline genetic polymorphisms among 351 patients enrolled in the thioguanine treatment arm of CCG-1952 clinical trial. TPMT and MTHFR C677T genotypes were not associated with SOS risk. The combination of MTHFR and TPMT variant genotypes was not associated with SOS risk. These suggest that germline genetic variation in TPMT and MTHFR do not significantly alter SOS risk in patients exposed to thioguanine.</p>

10.1002/pbc.25057

Pediatr Blood Cancer

24737678

Patient and hospital factors associated with induction mortality in acute lymphoblastic leukemia.

2014

846-52

2014 May

1545-5017

<p><strong>BACKGROUND: </strong>Deaths during induction chemotherapy for pediatric acute lymphoblastic leukemia (ALL) account for one-tenth of ALL-associated mortality and half of ALL treatment-related mortality. We sought to ascertain patient- and hospital-level factors associated with induction mortality.</p>

<p><strong>PROCEDURE: </strong>We performed a retrospective cohort analysis of 8,516 children ages 0 to &lt;19 years with newly diagnosed ALL admitted to freestanding US children's hospitals from 1999 to 2009 using the Pediatric Health Information System database. Induction mortality risk was modeled accounting for demographics, intensive care unit-level interventions, and socioeconomic status (SES) using Cox regression. The association of ALL induction mortality with hospital-level factors including volume, hospital-wide mortality and payer mix was analyzed with multiple linear regression.</p>

<p><strong>RESULTS: </strong>ALL induction mortality was 1.12%. Race and patient-level SES factors were not associated with induction mortality. Patients receiving both mechanical ventilation and vasoactive infusions experienced nearly 50% mortality (hazard ratio 122.30, 95% CI 66.56-224.80). Institutions in the highest induction mortality quartile contributed 27% of all patients but nearly half of all deaths (47 of 95). Hospital payer mix was associated with ALL induction mortality after adjustment for other hospital-level factors (P = 0.046).</p>

<p><strong>CONCLUSIONS: </strong>The overall risk of induction death is low but substantially increased in patients with cardio-respiratory and other organ failures. Induction mortality varies up to three-fold across hospitals and is correlated with hospital payer mix. Further work is needed to improve induction outcomes in hospitals with higher mortality. These data suggest an induction mortality rate of less than 1% may be an attainable national benchmark.</p>

10.1002/pbc.24855

Pediatr Blood Cancer

24249480

Assembly of a cohort of children treated for acute myeloid leukemia at free-standing children's hospitals in the United States using an administrative database.

2013

508-11

2013 Mar

1545-5017

<p>Pediatric Health Information System data were used to establish a multi-center cohort of 1,686 children treated for newly diagnosed acute myeloid leukemia (AML). The cohort assembly process, which included myeloid leukemia ICD-9 discharge diagnosis codes and manual review of induction chemotherapy, was validated by chart review at a single institution. The use of ICD-9 codes alone resulted in a poor positive predictive value (PPV; 31%). Inclusion of the results from the chemotherapy review improved the PPV to 100% without compromising sensitivity (95.7%). This cohort provides a reliable source for future comparative effectiveness and clinical epidemiology studies in pediatric AML.</p>

10.1002/pbc.24402

Pediatr Blood Cancer

23192853

Induction mortality and resource utilization in children treated for acute myeloid leukemia at free-standing pediatric hospitals in the United States.

2013

1916-23

05/2013

1097-0142

<p><strong>BACKGROUND: </strong>Clinical trials in pediatric acute myeloid leukemia (AML) determine induction regimen standards. However, these studies lack the data necessary to evaluate mortality trends over time and differences in resource utilization between induction regimens. Moreover, these trials likely underreport the clinical toxicities experienced by patients.</p>

<p><strong>METHODS: </strong>The Pediatric Health Information System database was used to identify children treated for presumed de novo AML between 1999 and 2010. Induction mortality, risk factors for induction mortality, and resource utilization by induction regimen were estimated using standard frequentist statistics, logistic regression, and Poisson regression, respectively.</p>

<p><strong>RESULTS: </strong>A total of 1686 patients were identified with an overall induction case fatality rate of 5.4% that decreased from 9.8% in 2003 to 2.1% in 2009 (P = .0023). The case fatality rate was 9.0% in the intensively timed DCTER (dexamethasone, cytarabine, thioguanine, etoposide, and rubidomycin [daunomycin]/idarubicin) induction and 3.8% for ADE (cytarabine, daunomycin, and etoposide) induction (adjusted odds ratio = 2.2, 95% confidence interval = 1.1-4.5). Patients treated with intensively timed DCTER regimens had significantly greater antibiotic, red cell/platelet transfusion, analgesic, vasopressor, renal replacement therapy, and radiographic resource utilization than patients treated with ADE regimens. Resource utilization was substantially higher than reported in published pediatric AML clinical trials.</p>

<p><strong>CONCLUSIONS: </strong>Induction mortality for children with AML decreased significantly as ADE use increased. In addition to higher associated mortality, intensively timed DCTER regimens had a correspondingly higher use of health care resources. Using resource utilization data as a proxy for adverse events, adverse event rates reported on clinical trials substantially underestimated the clinical toxicities of all pediatric AML induction regimens.</p>

10.1002/cncr.27957

Cancer

23436301