Bradley E. Aouizerat

Abstract

Background. Efavirenz exhibits marked interindividual variability in plasma levels and toxicities. Prior pharmacogenetic studies usually measure exposure via single plasma levels, examine limited numbers of polymorphisms, and rarely model multiple contributors. We analyzed numerous genetic and nongenetic factors impacting short-term and long-term exposure in a large heterogeneous population of human immunodeficiency virus (HIV)-infected women. Methods. We performed 24-hour intensive pharmacokinetic studies in 111 women receiving efavirenz under actual-use conditions and calculated the area-under-the-concentration-time curve (AUC) to assess short-term exposure; the efavirenz concentration in hair was measured to estimate long-term exposure. A total of 182 single-nucleotide polymorphisms (SNPs) and 45 haplotypes in 9 genes were analyzed in relationship to exposure by use of multivariate models that included a number of nongenetic factors. Results. Efavirenz AUCs increased 1.26-fold per doubling of the alanine aminotransferase level and 1.23-fold with orange and/or orange juice consumption. Individuals with the CYP2B6 516TT genotype displayed 3.5-fold increases in AUCs and 3.2-fold increases in hair concentrations, compared with individuals with the TG/GG genotype. Another SNP in CYP2B6 (983TT) and a p-glycoprotein haplotype affected AUCs without substantially altering long-term exposure. Conclusions. This comprehensive pharmacogenomics study showed that individuals with the CYP2B6 516TT genotype displayed >3-fold increases in both short-term and long-term efavirenz exposure, signifying durable effects. Pharmacogenetic testing combined with monitoring of hair levels may improve efavirenz outcomes and reduce toxicities.

Abstract

Background: Little is known about the relationships between sleep/wake circadian activity rhythms and fatigue in family caregivers (FCs) of oncology patients. Objectives: The objectives of this study were to describe values for nocturnal sleep/rest, daytime wake/activity, and circadian activity rhythm parameters measured using actigraphy and to evaluate the relationships between these subjective and objective measures of sleep disturbance and self-reported fatigue severity, in a sample of FCs of oncology patients. Methods: Family caregivers (n = 103) completed self-report measures for sleep disturbance (ie, Pittsburgh Sleep Quality Index, General Sleep Disturbance Scale) and fatigue (Lee Fatigue Scale) and wore wrist actigraphs for 48 hours prior to beginning radiation therapy. Spearman rank correlations were calculated between variables. Results: Approximately 40% to 60% of FCs experienced sleep disturbance depending on whether clinically significant cutoffs for the subjective or objective measures were used to calculate occurrence rates. In addition, these FCs reported moderate levels of fatigue. Only a limited number of significant correlations were found between the subjective and objective measures of sleep disturbance. Significant positive correlations were found between fatigue and subjective, but not objective measures of sleep disturbance. The amplitude of circadian activity rhythm was not related to any objective sleep measure but was correlated with self-report of longer sleep-onset latency. Conclusions: A significant percentage of FCs experience clinically meaningful disturbances in sleep-wake circadian activity rhythms. These disturbances occur primarily in sleep maintenance. Implications for Practice: Family caregivers need to be assessed, along with patients, for sleep disturbance, and appropriate interventions initiated for them and for the patient.

Abstract

Purpose: Anxiety is common in patients undergoing radiation therapy (RT) and in their family caregivers (FCs). Little is known about individual differences in anxiety trajectories during and after RT. This study aimed to identify distinct latent classes of oncology patients and their FCs based on self-reported anxiety symptoms from the beginning to four months after the completion of RT. Method: Using growth mixture modeling (GMM), longitudinal changes in Spielberger State Anxiety Inventory (STAI-S) scores among 167 oncology outpatients with breast, prostate, lung, or brain cancer and 85 FCs were evaluated to determine distinct anxiety symptom profiles. STAI-S scores were assessed just prior to, throughout the course of, and for four months following RT (total of 7 assessments). Baseline trait anxiety and depressive symptoms (during and after RT) were also assessed. Results: The GMM analysis identified three latent classes of oncology patients and FCs with distinct trajectories of state anxiety: Low Stable (n = 93, 36.9%), Intermediate Decelerating (n = 82, 32.5%), and High (n = 77, 30.6%) classes. Younger participants, women, ethnic minorities, and those with children at home were more likely to be classified in the High anxiety class. Higher levels of trait anxiety and depressive symptoms, at the initiation of RT, were associated with being in the High anxiety class. Conclusions: Subgroups of patients and FCs with high, intermediate, and low mean levels of anxiety during and after RT were identified with GMM. Additional research is needed to better understand the heterogeneity of symptom experiences as well as comorbid symptoms in patients and FCs.

Abstract

Context. Radiation therapy (RT) is a common treatment for prostate cancer. Despite available research, prostate cancer patients report that information about side effects is their most important unmet need. Additional research is needed that focuses on specific dimensions of the patient's symptom experience. Objectives. The study's purposes were to evaluate the trajectories of occurrence, severity, and distress of the six most prevalent symptoms reported by patients undergoing RT for prostate cancer and the effects of selected demographic and clinical characteristics on these trajectories. Methods. Patients completed the Memorial Symptom Assessment Scale 11 times before, during, and after RT. For problems with urination, pain, lack of energy, feeling drowsy, difficulty sleeping, and diarrhea, the trajectories of occurrence, severity, and distress were evaluated using multilevel generalized linear models. Results. Across all three dimensions, pain, lack of energy, feeling drowsy, and difficulty sleeping followed a decreasing linear trend. Problems with urination and diarrhea demonstrated more complex patterns of change over time. Conclusion. Although longitudinal data on pain, lack of energy, feeling drowsy, and difficulty sleeping are limited, they are highly prevalent symptoms in these patients. In addition, diarrhea becomes a significant problem for these patients over the course of RT. A number of demographic and clinical characteristics affect the trajectories of these common symptoms differentially.

Abstract

Objective: To characterize specific types of sleep problems experienced by adults with HIV. Method: The design was cross-sectional involving sleep questionnaires, diaries, and wrist actigraphy. The convenience sample included 290 adults living with HIV, 22-77 years of age. Measures included self-report for sleep onset latency, and wrist actigraphy estimates of total sleep time at night, wake after sleep onset, and daytime sleep. Results: Nearly half (45%) of the sample slept < 6 h per night. Difficulty falling asleep was reported by 34%, and 56% had fragmented sleep according to actigraphy; 20% had both problems, and 30% were good sleepers. Participants reporting difficulty falling asleep had actigraphy and clinical measures similar to the good sleepers, but subjectively they experienced greater sleep disturbance and symptom burden (particularly anxiety and morning fatigue) and reported more use of sleep medication. Participants with fragmented sleep reported low levels of sleep disturbance and symptom burden similar to the good sleepers, despite actigraphy measures indicating they obtained less sleep both at night and during the day. Sleep fragmentation was also associated with sociodemographic factors and slightly lower CD4+ T-cell counts. Participants reporting both sleep problems had actigraphy and clinical profiles similar to those who had only fragmented sleep, but their symptom experience was similar to participants with only sleep initiation difficulties. Conclusions: Findings support the need for targeting efforts to improve sleep for the majority of adults living with HIV/AIDS and tailoring interventions to the specific type of sleep problem regardless of the person's clinical and demographic profile.

Abstract

OBJECTIVE: CYP2B6 variation predicts pharmacokinetic characteristics of its substrates. Consideration for underlying genetic structure is critical to protect against spurious associations with the highly polymorphic CYP2B6 gene. DESIGN: The effect of CYP2B6 variation on response to its substrates, nonnucleoside reverse transcriptase inhibitors (NNRTIs), was explored in the Women's Interagency HIV Study. METHODS: Five putative functional polymorphisms were tested for associations with virologic suppression within 1 year after NNRTI initiation in women naive to antiretroviral agents (n=91). Principal components were generated to control for population substructure. Logistic regression was used to test the joint effect of rs3745274 and rs28399499, which together indicate slow, intermediate, and extensive metabolizers. RESULTS: Rs3745274 was significantly associated with virologic suppression [odds ratio=3.61, 95% confidence interval (CI) 1.16-11.22, P trend=0.03]; the remaining polymorphisms tested were not significantly associated with response. Women classified as intermediate and slow metabolizers were 2.90 (95% CI 0.79-12.28) and 13.44 (95% CI 1.66 to infinity) times as likely to achieve virologic suppression compared to extensive metabolizers after adjustment for principal components (P trend=0.005). Failure to control for genetic ancestry resulted in substantial confounding of the relationship between the metabolizer phenotype and treatment response. CONCLUSION: The CYP2B6 metabolizer phenotype was significantly associated with virologic response to NNRTIs; this relationship would have been masked by simple adjustment for self-reported ethnicity. Given the appreciable genetic heterogeneity that exists within self-reported ethnicity, these results exemplify the importance of characterizing underlying genetic structure in pharmacogenetic studies. Further follow-up of the CYP2B6 metabolizer phenotype is warranted, given the potential clinical importance of this finding.

Abstract

Purpose: To examine the psychometric properties of the 9-item Fatigue Severity Scale (FSS) using a Rasch model application. Methods: A convenience sample of HIV-infected adults was recruited, and a subset of the sample was assessed at 6-month intervals for 2 years. Socio-demographic, clinical, and symptom data were collected by self-report questionnaires. CD4 T-cell count and viral load measures were obtained from medical records. The Rasch analysis included 316 participants with 698 valid questionnaires. Results: FSS item 2 did not advanced monotonically, and items 1 and 2 did not show acceptable goodness-of-fit to the Rasch model. A reduced FSS 7-item version demonstrated acceptable goodness-of-fit and explained 61.2% of the total variance in the scale. In the FSS-7 item version, no uniform Differential Item Functioning was found in relation to time of evaluation or to any of the socio-demographic or clinical variables. Conclusion This study demonstrated that the FSS-7 has better psychometric properties than the FSS-9 in this HIV sample and that responses to the different items are comparable over time and unrelated to socio-demographic and clinical variables.

Abstract

Our knowledge of pharmacogenetic variability in diverse populations is scarce, especially in sub-Saharan Africa. To bridge this gap in knowledge, we characterised population frequencies of clinically relevant pharmacogenetic traits in two distinct South African population groups. We genotyped 211 tagging single nucleotide polymorphisms (tagSNPs) in 12 genes that influence antiretroviral drug disposition, in 176 South African individuals belonging to two distinct population groups residing in the Western Cape: the Xhosa (n = 109) and Cape Mixed Ancestry (CMA) (n = 67) groups. The minor allele frequencies (MAFs) of eight tagSNPs in six genes (those encoding the ATP binding cassette sub-family B, member 1 [ABCB1], four members of the cytochrome P450 family [CYP2A7P1, CYP2C18, CYP3A4, CYP3A5] and UDP-glucuronosyltransferase 1 [UGT1A1]) were significantly different between the Xhosa and CMA populations (Bonferroni p < 0.05). Twentyseven haplotypes were inferred in four genes (CYP2C18, CYP3A4, the gene encoding solute carrier family 22 member 6 [SLC22A6] and UGT1A1) between the two South African populations. Characterising the Xhosa and CMA population frequencies of variant alleles important for drug transport and metabolism can help to establish the clinical relevance of pharmacogenetic testing in these populations.

Abstract

Aim: Endothelial lipase (EL) is a key enzyme in lipid metabolism, and a polymorphism in the EL gene may be a candidate for modulating lipid parameters in type 2 diabetic (T2D) patients. Methods: In 396 T2D patients (age: 59.5±10.7 years; BMI: 28.9±5.3kg/m2; HbA1c: 8.2±1.9%), the c.584C>T polymorphism (rs2000813, p.Thr111Ile) was studied in 225 men (frequency of c.584T: 0.351) and 171 women (frequency of c.584T: 0.304). Patients' metabolic parameters, and macrovascular and microvascular complications, were assessed at baseline and at follow-up (mean: 4.2 years). Results: Patients who were homozygous for the minor allele displayed modestly decreased low-density lipoprotein (LDL) cholesterol and raised apolipoprotein B at baseline, and raised systolic blood pressure and high-density lipoprotein (HDL) cholesterol on follow-up. Homozygosity for the minor allele was significantly associated with frequency of retinopathy (P=0.025), with TT homozygous patients more likely to have diabetic retinopathy (OR: 3.505; 95% CI: 1.491-8.239) both initially and at follow-up. Conclusion: The c.584C > T EL polymorphism is associated with a higher risk of diabetic retinopathy that could be linked to modifications in HDL-cholesterol metabolism and blood pressure levels.