Bradley E. Aouizerat

Abstract

Study Objective: To evaluate the association between use of methadone, other central nervous system (CNS) depressants, and QTc interval–prolonging medications and risk of mortality among human immunodeficiency virus (HIV)-infected and at-risk HIV-uninfected women. Design: Multicenter, prospective, observational cohort study (Women's Interagency HIV Study [WIHS]). Participants: A total of 4150 women enrolled in the WIHS study between 1994 and 2014 who were infected (3119 women) or not infected (1031 women) with HIV. Measurements and Main Results: Data on medication utilization were collected from all study participants via interviewer-administered surveys at 6-month intervals (1994–2014). Mortality was confirmed by National Death Index data. With age defining the time scale for the analysis, Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause mortality in HIV-infected and -uninfected women and non–acquired immunodeficiency syndrome (AIDS) deaths in HIV-infected women. A total of 1046 deaths were identified, of which 429 were considered non-AIDS deaths. Use of benzodiazepines, CNS depressants (excluding methadone), and number of medications with conditional QTc interval–prolonging effects were each associated with all-cause mortality in multivariate models of HIV-infected women: hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.01–1.60, p=0.037; HR 1.61, 95% CI 1.35–1.92, p<0.0001; and HR 1.15 per drug, 95% CI 1.00–1.33, p=0.047, respectively. Other explanatory variables for all-cause mortality in this model included HIV viral load, CD4+ cell count, renal function, hemoglobin and albumin levels, HIV treatment era, employment status, existence of depressive symptoms, ever use of injection drugs, and tobacco smoking. Of interest, use of CNS depressants (excluding methadone) was also associated with non-AIDS deaths (HR 1.49, 95% CI 1.49–2.2, p<0.0001). Although use of benzodiazepines and conditional QT interval–prolonging medications were associated with increased risk of non-AIDS mortality (HR 1.32 and 1.25, respectively), the effect was not statistically significant (p>0.05). Conclusion: In this cohort of HIV-infected and at-risk HIV-uninfected women, use of benzodiazepines, CNS depressants, and conditional QTc interval–prolonging medications were associated with a higher risk of mortality independent of methadone and other well-recognized mortality risk factors. Care must be taken to assess risk when prescribing these medications in this underserved and at-risk patient population.

Abstract

Objectives: Dental care is the most commonly cited unmet health-care service due to cost. Previous research has highlighted the unmet dental needs of people living with HIV (PLWH). Understanding associations among dental insurance availability, dental care utilization, and the presence of unmet dental needs among PLWH is a public health priority. Methods: Oral health surveys were collected cross-sectionally (April–October 2016) among 1,442 women living with HIV (WLWH) in the Women's Interagency HIV Study. Logistic regression models were used to analyze the association between having versus not having dental insurance by type (Ryan White, private, Medicaid/Medicare) and two primary outcomes: a) typical frequency of dental visits (at least annually, less than annually) and b) reporting an unmet dental need in the past 6 months. Results: All dental insurance types were associated with higher odds of receiving annual dental care and, for those with either Medicare/Medicaid or private insurance, lower odds of having an unmet dental need. When WLWH were asked to describe their oral health, poor self-reported condition was associated with both an unmet dental need (odds ratio [OR]: 4.52, 95 percent Confidence Interval [CI] [3.29–6.20]) and lower odds of annual dental care utilization (OR: 0.44, 95 percent CI [0.34–0.57]). Self-reported depressive symptom burden was also linked to having an unmet dental need (OR: 2.10, 95 percent CI [1.46–3.01]). Conclusions: Dental insurance coverage increases dental care utilization and is associated with better oral health among WLWH. In the era of health-care reform, dental insurance coverage may be instrumental for enhancing treatment outcomes.

Abstract

Increase of peripheral blood CD4 lymphocyte counts is a key goal of combined antiretroviral therapy (cART); most, but not all, recipients respond adequately and promptly. A small number of studies have examined specific genetic factors associated with the extent of CD4 recovery. We report a genome-wide examination of factors that predict CD4 recovery in HIV-infected women. We identified women in in a cohort study who were on cART with viral load below 400 copies, and drew racially and ethnically matched samples of those with good CD4 response over 2 years or poor response. We analyzed the exomes of those women employing next generation sequencing for genes associated with CD4 recovery after controlling for non-genetic factors identified through forward stepwise selection as important. We studied 48 women with good CD4 recovery and 42 with poor CD4 recovery during virologically-suppressive cART. Stepwise logistic regression selected only age as a statistically significant (p<0.05) non-genetic predictor of response type (each additional year of age reduced the odds of good recovery by 11% (OR = 0.89, CI = 0.84–0.96, p = 0.0009). After adjustment for age and genomic estimates of race and ethnicity, 41 genes harbored variations associated with CD4 recovery group (p0.001); 5 of these have been previously reported to be associated with HIV infection, 4 genes would likely influence CD4 homeostasis, and 13 genes either had known functions or were members of product families that had functions for which interactions with HIV or effects on lymphocyte homeostasis were biologically plausible. Greater age was the strongest acquired factor that predicted poor CD4 cell recovery. Sequence variations spanning 41 genes were independently predictive of CD4 recovery. Many of these genes have functions that impact the cell cycle, apoptosis, lymphocyte migration, or have known interactions with HIV. These findings may help inform new hypotheses related to responses to HIV therapy and CD4 lymphocyte homeostasis.

Abstract

Background: We have a limited understanding of the biological underpinnings of symptoms in heart failure (HF), particularly in response to left ventricular assist device (LVAD) implantation. Objective: The aim of this study was to quantify the degree to which symptoms and biomarkers change in parallel from before implantation through the first 6 months after LVAD implantation in advanced HF. Methods: This was a prospective cohort study of 101 patients receiving an LVAD for the management of advanced HF. Data on symptoms (dyspnea, early and subtle symptoms [HF Somatic Perception Scale], pain severity [Brief Pain Inventory], wake disturbance [Epworth Sleepiness Scale], depression [Patient Health Questionnaire], and anxiety [Brief Symptom Inventory]) and peripheral biomarkers of myocardial stretch, systemic inflammation, and hypervolumetric mechanical stress were measured before implantation with a commercially available LVAD and again at 30, 90, and 180 days after LVAD implantation. Latent growth curve and parallel process modeling were used to describe changes in symptoms and biomarkers and the degree to which they change in parallel in response to LVAD implantation. Results: In response to LVAD implantation, changes in myocardial stretch were closely associated with changes in early and subtle physical symptoms as well as depression, and changes in hypervolumetric stress were closely associated with changes in pain severity and wake disturbances. Changes in systemic inflammation were not closely associated with changes in physical or affective symptoms in response to LVAD implantation. Conclusions: These findings provide new insights into the many ways in which symptoms and biomarkers provide concordant or discordant information about LVAD response.

Abstract

Objective: To determine the percentage of children with nonalcoholic fatty liver disease (NAFLD) in whom intervention for low-density lipoprotein cholesterol or triglycerides was indicated based on National Heart, Lung, and Blood Institute guidelines. Study design: This multicenter, longitudinal cohort study included children with NAFLD enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Nonalcoholic Steatohepatitis Clinical Research Network. Fasting lipid profiles were obtained at diagnosis. Standardized dietary recommendations were provided. After 1 year, lipid profiles were repeated and interpreted according to National Heart, Lung, and Blood Institute Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction. Main outcomes were meeting criteria for clinically actionable dyslipidemia at baseline, and either achieving lipid goal at follow-up or meeting criteria for ongoing intervention. Results: There were 585 participants, with a mean age of 12.8 years. The prevalence of children warranting intervention for low-density lipoprotein cholesterol at baseline was 14%. After 1 year of recommended dietary changes, 51% achieved goal low-density lipoprotein cholesterol, 27% qualified for enhanced dietary and lifestyle modifications, and 22% met criteria for pharmacologic intervention. Elevated triglycerides were more prevalent, with 51% meeting criteria for intervention. At 1 year, 25% achieved goal triglycerides with diet and lifestyle changes, 38% met criteria for advanced dietary modifications, and 37% qualified for antihyperlipidemic medications. Conclusions: More than one-half of children with NAFLD met intervention thresholds for dyslipidemia. Based on the burden of clinically relevant dyslipidemia, lipid screening in children with NAFLD is warranted. Clinicians caring for children with NAFLD should be familiar with lipid management.

Abstract

Background: We have a limited understanding of the biological underpinnings of symptoms in heart failure (HF). Objectives: The purpose of this paper was to compare relationships between peripheral biomarkers of HF pathogenesis and physical symptoms between patients with advanced versus moderate HF. Methods: This was a two-stage phenotype sampling cohort study wherein we examined patients with advanced HF undergoing ventricular assist device implantation in the first stage, and then patients with moderate HF (matched adults with HF not requiring device implantation) in the second stage. Linear modeling was used to compare relationships among biomarkers and physical symptoms between cohorts. Results: Worse myocardial stress, systemic inflammation and endothelial dysfunction were associated with worse physical symptoms in moderate HF (n=48), but less physical symptom burden in advanced HF (n=48). Conclusions: Where patients are in the HF trajectory needs to be taken into consideration when exploring biological underpinnings of physical HF symptoms.

Abstract

We previously demonstrated an association between lipoprotein (a) [Lp(a)] levels and atherosclerosis in human immunodeficiency virus (HIV)-seropositive women. The effects of antiretroviral therapy (ART) on Lp(a) levels in relation to apo(a) size polymorphism remain unclear. ART effects on allele-specific apo(a) level (ASL), an Lp(a) level associated with individual apo(a) alleles within each allele-pair, were determined in 126 HIV-seropositive women. ART effects were tested by a mixed-effects model across pre-ART and post-ART first and third visits. Data from 120 HIV-seronegative women were used. The mean age was 38 years; most were African-American (∼70%). Pre-ART ASLs associated with the larger (4.6 mg/dl vs. 8.0 mg/dl, P = 0.024) or smaller (13 mg/dl vs. 19 mg/dl, P = 0.041) apo(a) sizes were lower in the HIV-seropositive versus HIV-seronegative group, as was the prevalence of a high Lp(a) level (P = 0.013). Post-ART ASL and prevalence of high Lp(a) or apo(a) sizes and frequency of small size apo(a) (≤22 kringles) did not differ between the two groups. ART increased Lp(a) level (from 18 to 24 mg/dl, P < 0.0001) and both ASLs (P < 0.001). In conclusion, regardless of genetic control, Lp(a) can be modulated by HIV and its treatment. ART initiation abrogates HIV-induced suppression of Lp(a) levels and ASLs, contributing to promote CVD risk in HIV-seropositive individuals.

Abstract

Higher exposure to tenofovir (TFV) increases the risk for kidney function decline, but the impact of genetic factors on TFV exposure is largely unknown. We investigated whether single-nucleotide polymorphisms (SNPs, n=211) in 12 genes are potentially involved in TFV exposure. Participants (n=91) from the Women's Interagency HIV Study, underwent a 24 h intensive pharmacokinetic sampling of TFV after witnessed dose and TFV area under the time-concentration curves (AUCs) were calculated for each participant. SNPs were assayed using a combination of array genotyping and Sanger sequencing. Linear regression models were applied to logarithmically transformed AUC. Those SNPs that met an a priori threshold of P<0.001 were considered statistically associated with TFV AUC. ABCG2 SNP rs2231142 was associated with TFV AUC with rare allele carriers displaying 1.51-fold increase in TFV AUC (95% confidence interval: 1.26, 1.81; P=1.7 × 10 -5 ). We present evidence of a moderately strong effect of the rs2231142 SNP in ABCG2 on a 24 h TFV AUC.

Abstract

Pain is frequent and underreported among HIV+ women. We determined occurrence and severity of pain, and types of pain treatments used among HIV+ and HIV− women. Cross-sectional analyses of pain as measured by the Brief Pain Inventory Short Form, and related pain therapies nested in the Women’s Interagency HIV Study (WIHS). Multiple variable linear regression models examined differences by HIV status in pain severity and pain interference in general activity, mood, ability to walk, work, relationships with others, sleep, and enjoyment of life. Among 1393 HIV+ and 587 HIV− participants with median age 47–48 years, there was no statistically significant difference in pain reported within the past week by HIV status (HIV+ 50% vs. 49% HIV−, p = 0.70). Ratings of pain severity and interference were similar between HIV+ and HIV− women, as was receipt of pain medication (58% HIV+ vs. 56% HIV−). Pain medications most frequently used were: NSAIDS (90% HIV+, 96% HIV−), opioids (65% HIV+, 67% HIV−), topical anesthetics (46% HIV+, 56% HIV−), muscle relaxants (23% HIV+, 14% HIV−), and anticonvulsants (23% HIV+, 14% HIV−). Nearly half of predominantly low income, minority women reported pain in the past week, and two-thirds reported opioid use for pain management. The occurrence, severity, and treatment of pain did not differ by HIV status, nor did report of pain interference with mood or function. Additional research is needed to better characterize pain etiology among HIV+ women in the era of potent antiretroviral therapy, and determine the extent to which pain severity and type of medication used for pain treatment impact HIV disease outcomes.

Abstract

Hair provides a direct measure of long-term exposure of atazanavir (ATV). We report the results of the first genome-wide association study (GWAS) of ATV exposure measured in hair in an observational cohort representative of US women living with HIV; the Women's Interagency HIV Study. Approximately 14.1 million single nucleotide polymorphisms (SNPs) were analyzed in linear regression-based GWAS, with replication, adjusted for nongenetic predictors collected under conditions of actual use of ATV in 398 participants. Lastly, the PharmGKB database was used to identify pharmacogene associations with ATV exposure. The rs73208473, within intron 1 of SORCS2, resulted in a 0.46-fold decrease in ATV exposure, with the strongest association (P = 1.71×10−8) in GWAS. A priori pharmacogene screening did not identify additional variants statistically significantly associated with ATV exposure, including those previously published in ATV plasma candidate pharmacogene studies. The findings demonstrate the potential value of pharmacogenomic GWAS in ethnically diverse populations under conditions of actual use.