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1.  Assessment of HIV antiretroviral therapy adherence by measuring drug concentrations in hair among children in rural Uganda 
AIDS care  2014;27(3):327-332.
Current tools for measuring medication adherence have significant limitations, especially among pediatric populations. We conducted a prospective observational study to assess the use of antiretroviral (ARV) drug levels in hair for evaluating antiretroviral therapy (ART) adherence among HIV-infected children in rural Uganda. Three-day caregiver recall, 30-day visual analog scale (VAS), Medication Event Monitoring System (MEMS), and unannounced pill counts and liquid formulation weights (UPC) were collected monthly over a one-year period. Hair samples were collected quarterly and analyzed for nevirapine (NVP) levels, and plasma HIV RNA levels were collected every six months. Among children with at least one hair sample collected, we used univariable random intercept linear regression models to compare log transformed NVP concentrations with each adherence measure, and the child’s age, sex, and CD4 count percentage (CD4%). 121 children aged 2–10 years were enrolled in the study; 74 (61%) provided at least one hair sample, and the mean number of hair samples collected per child was 1.9 (standard deviation [SD] 1.0). Three-day caregiver recall, VAS, and MEMS were found to be positively associated with increasing NVP concentration in hair, although associations were not statistically significant. UPC was found to have a non-significant negative association with increasing hair NVP concentration. In conclusion, NVP drug concentrations in hair were found to have non-significant, although generally positive, associations with other adherence measures in a cohort of HIV-infected children in Uganda. Hair collection in this population proved challenging, suggesting the need for community education and buy-in with the introduction of novel methodologies.
doi:10.1080/09540121.2014.983452
PMCID: PMC4305465  PMID: 25483955
2.  Antiretroviral concentrations in small hair samples as a feasible marker of adherence in rural Kenya 
Antiretroviral hair levels objectively quantify drug exposure over time and predict virologic responses. We assessed the acceptability and feasibility of collecting small hair samples in a rural Kenyan cohort. 95% of participants (354/373) donated hair. Although median self-reported adherence was 100% (IQR 96–100%), a wide range of hair concentrations likely indicates overestimation of self-reported adherence and the advantages of a pharmacologic adherence measure. Higher nevirapine (NVP) hair concentrations observed in women and older adults require further study to unravel behavioral versus pharmacokinetic contributors. In resource-limited settings, hair antiretroviral levels may serve as a low-cost quantitative biomarker of adherence.
doi:10.1097/QAI.0000000000000154
PMCID: PMC4146734  PMID: 24694932
Adherence; nevirapine; hair concentrations; resource-limited setting; feasibility and acceptability; pharmacologic measure
3.  Nevirapine Concentration in Hair Samples Is a Strong Predictor of Virologic Suppression in a Prospective Cohort of HIV-Infected Patients 
PLoS ONE  2015;10(6):e0129100.
Effective antiretroviral (ARV) therapy depends on adequate drug exposure, yet methods to assess ARV exposure are limited. Concentrations of ARV in hair are the product of steady-state pharmacokinetics factors and longitudinal adherence. We investigated nevirapine (NVP) concentrations in hair as a predictor of treatment response in women receiving ARVs. In participants of the Women’s Interagency HIV Study, who reported NVP use for >1 month from 2003–2008, NVP concentrations in hair were measured via liquid-chromatography-tandem mass-spectrometry. The outcome was virologic suppression (plasma HIV RNA below assay threshold) at the time of hair sampling and the primary predictor was nevirapine concentration categorized into quartiles. We controlled for age, race/ethnicity, pre-treatment HIV RNA, CD4 cell count, and self-reported adherence over the 6-month visit interval (categorized ≤ 74%, 75%–94% or ≥ 95%). We also assessed the relation of NVP concentration with changes in hepatic transaminase levels via multivariate random intercept logistic regression and linear regression analyses. 271 women contributed 1089 person-visits to the analysis (median 3 of semi-annual visits). Viral suppression was least frequent in concentration quartile 1 (86/178 (48.3%)) and increased in higher quartiles (to 158/204 (77.5%) for quartile 4). The odds of viral suppression in the highest concentration quartile were 9.17 times (95% CI 3.2–26, P < 0.0001) those in the lowest. African-American race was associated with lower rates of virologic suppression independent of NVP hair concentration. NVP concentration was not significantly associated with patterns of serum transaminases. Concentration of NVP in hair was a strong independent predictor of virologic suppression in women taking NVP, stronger than self-reported adherence, but did not appear to be strongly predictive of hepatotoxicity.
doi:10.1371/journal.pone.0129100
PMCID: PMC4460031  PMID: 26053176
4.  The Association of Self-perception of Body Fat Changes and Quality of Life in the Women’s Interagency HIV Study 
AIDS care  2013;25(12):10.1080/09540121.2013.793265.
Body fat changes are of concern to HIV-seropositive adults on highly active antiretroviral therapy (HAART). Studies examining the association of body fat changes and quality of life (QOL) in the setting of HIV infection have been conducted predominately in men. We examined the relationship of self-perceived body fat change with QOL among 1,671 HAART-using HIV-seropositive women (mean age 40 ± 8 years; 54% African American, 24% reporting ≤ 95% HAART adherence) from the Women’s Interagency HIV Study. Self-perception of any fat loss was associated with lower overall QOL. Report of any peripheral fat loss was strongly associated with nearly all QOL domains (i.e., physical functioning, role functioning, energy/fatigue, social functioning, pain, emotional well-being, health perception, and perceived health index) except cognitive functioning, whereas report of any central fat loss was significantly associated with lower social and cognitive functioning. Report of any central fat gain was associated with lower overall QOL, but only physical functioning, energy/fatigue, and cognitive functioning were significantly affected. A significant association of report of any peripheral fat gain with overall QOL was not observed, however peripheral fat gain was significantly associated with lower physical functioning and pain. We found that any report of fat loss, especially in peripheral body sites is associated with lower QOL, as was any report of central fat gain. Ultimately health providers and patients need to be informed of these associations so as to better support HIV-seropositive women who live with these effects.
doi:10.1080/09540121.2013.793265
PMCID: PMC3769511  PMID: 23656440
body image perception; lipoatrophy; lipohypertrophy; Quality of life; HIV-seropositive women; HAART
5.  Strong Relationship between Oral Dose and Tenofovir Hair Levels in a Randomized Trial: Hair as a Potential Adherence Measure for Pre-Exposure Prophylaxis (PrEP) 
PLoS ONE  2014;9(1):e83736.
Background
Pre-exposure prophylaxis (PrEP) trials using tenofovir-based regimens have demonstrated that high levels of adherence are required to evaluate efficacy; the incorporation of objective biomarkers of adherence in trial design has been essential to interpretation, given the inaccuracy of self-report. Antiretroviral measurements in scalp hair have been useful as a marker of long-term exposure in the HIV treatment setting, and hair samples are relatively easy and inexpensive to collect, transport, and store for analysis. To evaluate the relationship between dose and tenofovir concentrations in hair, we examined the dose proportionality of tenofovir in hair in healthy, HIV-uninfected adults.
Methods
A phase I, crossover pharmacokinetic study was performed in 24 HIV-negative adults receiving directly-observed oral tenofovir tablets administered 2, 4, and 7 doses/week for 6 weeks, with a ≥3-week break between periods. Small samples of hair were collected after each six-week period and analyzed for tenofovir concentrations. Geometric-mean-ratios compared levels between each pair of dosing conditions. Intensive plasma pharmacokinetic studies were performed during the daily-dosing period to calculate areas-under-the-time-concentration curves (AUCs).
Results
Over 90% of doses were observed per protocol. Median tenofovir concentrations in hair increased monotonically with dose. A log-linear relationship was seen between dose and hair levels, with an estimated 76% (95% CI 60–93%) increase in hair level per 2-fold dose increase. Tenofovir plasma AUCs modestly predicted drug concentrations in hair.
Conclusions
This study found a strong linear relationship between frequency of dosing and tenofovir levels in scalp hair. The analysis of quantitative drug levels in hair has the potential to improve adherence measurement in the PrEP field and may be helpful in determining exposure thresholds for protection and explaining failures in PrEP trials. Hair measures for adherence monitoring may also facilitate adherence measurement in real-world settings and merit further investigation in upcoming PrEP implementation studies and programs.
Trial Registration
ClinicalTrials.gov +NCT00903084.
doi:10.1371/journal.pone.0083736
PMCID: PMC3885443  PMID: 24421901
6.  A Single-Nucleotide Polymorphism in CYP2B6 Leads to >3-Fold Increases in Efavirenz Concentrations in Plasma and Hair Among HIV-Infected Women 
The Journal of Infectious Diseases  2012;206(9):1453-1461.
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.
doi:10.1093/infdis/jis508
PMCID: PMC3466997  PMID: 22927450
7.  Influence of Cannabis Use on Severity of Hepatitis C Disease 
Background
Complications of hepatitis C virus (HCV) infection are primarily related to the development of advanced fibrosis.
Methods
Baseline data from a prospective community-based cohort study of 204 persons with chronic hepatitis C virus (HCV) infection were used for analysis. The outcome was fibrosis score on biopsy and the primary predictor evaluated was daily cannabis use.
Results
The median age of the cohort was 46.8 years, 69.1% were male, 49.0% were Caucasian, and the presumed route of infection was injection drug use in 70.1%. The median lifetime duration and average daily use of alcohol were 29.1 years and 1.94 drink equivalents per day. Cannabis use frequency (within prior 12 months) was daily in 13.7%, occasional in 45.1%, and never in 41.2%. Fibrosis stage, assessed by Ishak method, was F0, F1–2 and F3–6 in 27.5%, 55.4% and 17.2% of subjects, respectively. Daily compared to non-daily cannabis use was significantly associated with moderate to severe fibrosis (F3–6 versus F1–2) in univariate [OR = 3.21 (95% CI, 1.20–8.56), p = 0.020] and multivariate analyses (OR = 6.78, (1.89–24.31), p=0.003). Other independent predictors of F3–6 were ≥11 portal tracts (compared to <5, OR = 6.92 (1.34–35.7), p=0.021] and lifetime duration of moderate and heavy alcohol use [OR per decade = 1.72 (1.02–2.90), p=0.044].
Conclusion
We conclude that daily cannabis use is strongly associated with moderate to severe fibrosis and that HCV-infected individuals should be counseled to reduce or abstain from cannabis use.
doi:10.1016/j.cgh.2007.10.021
PMCID: PMC3184401  PMID: 18166478
fibrosis; alcohol; viral load; marijuana; cirrhosis
8.  Citalopram is not Effective Therapy for Non-Depressed Patients with Irritable Bowel Syndrome 
Background & Aims
Data are conflicting on the benefit of selective serotonin reuptake inhibitors (SSRIs) for patients with irritable bowel syndrome (IBS); the role of visceral sensitivity in IBS pathophysiology is unclear. We assessed the effects of citalopram and the relationships between, symptoms, and quality of life (QOL), and rectal sensitivity in non-depressed patients with IBS.
Methods
Patients from primary, secondary and tertiary care centers were randomly assigned to groups given citalopram (20 mg/day for 4 weeks, then 40 mg/day for 4 weeks) or placebo. The study was double masked with concealed allocation. Symptoms were assessed weekly; IBS-QOL and rectal sensation were determined from barostat measurements made at the beginning and end of the study.
Results
Patients that received citalopram did not have a higher rate of adequate relief from IBS symptoms than subjects that received placebo (12/27, 44% vs 15/27, 56% respectively; P=0.59), regardless of IBS subtype. The odds ratio for weekly response to citalopram vs placebo was 0.80 (95% confidence interval [CI] 0.61–1.04). Citalopram did not reduce specific symptoms or increase IBS-QOL scores; it had no effect on rectal compliance and a minimal effect on sensation. Changes in IBS-QOL score and pressure-eliciting pain were correlated (r=0.33, 95% CI 0.03–0.57); changes in symptoms and rectal sensitivity or IBS-QOL scores were not correlated.
Conclusions
Citalopram was not superior to placebo in treating non-depressed IBS patients. Changes in symptoms were not correlated with changes in rectal sensation assessed by barostat; Any benefit of citalopram in non-depressed IBS patients is likely to be modest.
doi:10.1016/j.cgh.2009.09.008
PMCID: PMC2818161  PMID: 19765674
9.  Self-Perception of Body Fat Changes and HAART Adherence in the Women’s Interagency HIV Study 
AIDS and behavior  2008;13(1):53-59.
To determine the association of self-perceived fat gain or fat loss in central and peripheral body sites with adherence to highly active antiretroviral therapy (HAART) in HIV-seropositive women. 1,671 women from the Women’s Interagency HIV Study who reported HAART use between April 1999 and March 2006 were studied. Adherence was defined as report of taking HAART ≥ 95% of the time during the prior 6 months. Participant report of any increase or decrease in the chest, abdomen, or upper back in the prior 6 months defined central fat gain and central fat loss, respectively. Report of any increase or decrease in the face, arms, legs or buttocks in the prior 6 months defined peripheral fat gain or peripheral fat loss. Younger age, being African-American (vs. White non-Hispanic), a history of IDU, higher HIV RNA at the previous visit, and alcohol consumption were significant predictors of HAART non-adherence (P <0.05). After multivariate adjustment, self-perception of central fat gain was associated with a 1.5-fold increased odds of HAART non-adherence compared to no change. Perception of fat gain in the abdomen was the strongest predictor of HAART non-adherence when the individual body sites were studied. Women who perceive central fat gain particularly in the abdomen are at risk for decreased adherence to HAART despite recent evidence to suggest that HIV and specific antiretroviral drugs are more commonly associated with fat loss than fat gain.
doi:10.1007/s10461-008-9444-7
PMCID: PMC2902995  PMID: 18688706
Lipodystrophy; HIV; Women; HAART adherence; body image perception

Results 1-9 (9)