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1.  Insulin Sensitivity and Variability in Hepatitis C Virus Infection Using Direct Measurement 
Digestive diseases and sciences  2012;58(4):1141-1148.
Background & Aims
Studies investigating insulin resistance (IR) in chronic hepatitis C virus (HCV) infection have used surrogate measures of IR that have limited reliability. We aimed to describe the distribution and risk factors associated with IR and its change over time in HCV using direct measurement.
One hundred and two non-cirrhotic, non-diabetic, HCV-infected subjects underwent clinical, histologic, and metabolic evaluation, and 27 completed repeat evaluation at 6 months. Insulin-mediated glucose uptake was measured by steady-state plasma glucose (SSPG) concentration during the insulin suppression test.
Three subjects with diabetes were excluded and 95 completed all testing. SSPG ranged from 39 to 328 mg/dL (mean 135 mg/dL) and was stable over time (mean SSPG change -0.3 mg/dL). SSPG was associated with Latino ethnicity (Coef 67, 95%CI 37-96), BMI (Coef 19 per 5 kg/m2, 95%CI 5-32), ferritin (Coef 1.4 per 10 ng/ml, 95%CI 0.2-2.5), male gender (Coef -48, 95%CI -80 to -16), and HDL (Coef -16, 95%CI -28 to -5 mg/dL). Current tobacco use (Coef 55, 95%CI 19-90), steatosis (Coef -44, 95%CI -86 to -3), and increases in BMI (Coef 30 per 5 kg/m2, 95%CI 6-53) and triglyceride (Coef 3.5 per 10 mg/dL, 95%CI 0.3-6.7) predicted change in SSPG.
There was a wide spectrum of insulin resistance in our HCV population. Host factors, rather than viral factors, appeared to more greatly influence insulin action and its change in HCV.
PMCID: PMC3566265  PMID: 23086116
Diabetes; HCV; Insulin Resistance; Oral Glucose Tolerance Test
2.  Lower Liver-Related Death in African American Women With HIV/HCV Co-Infection Compared to Caucasian and Hispanic Women 
Hepatology (Baltimore, Md.)  2012;56(5):1699-1705.
Among individuals with and without concurrent human immunodeficiency virus (HIV), racial/ethnic differences in the natural history of hepatitis C virus (HCV) have been described. African-Americans have lower spontaneous HCV clearance than Caucasians, yet slower rates of liver fibrosis once chronically infected. It is not clear how these differences in the natural history of hepatitis C affect mortality, in either HIV positive or negative individuals. We conducted a cohort study of HIV/HCV co-infected women followed in the multicenter, NIH-funded Women’s Interagency HIV Study (WIHS) to determine the association of self-reported race/ethnicity with all-cause and liver-related mortality. Survival analyses were performed using Cox proportional hazards models. The eligible cohort (n=794) included 140 Caucasians, 159 Hispanics, and 495 African Americans. There were 438 deaths and 49 liver-related deaths during a median follow-up of 8.9 years and maximum follow-up of 16 years. African American co-infected women had significantly lower liver-related mortality compared to Caucasian (HR 0.41 95% CI 0.19–0.88, p=0.022) and Hispanic co-infected women (HR 0.38 95% CI 0.19–0.76, p=0.006). All-cause mortality was similar between racial/ethnic groups (HRs for all comparisons 0.82–1.03, logrank p=0.8).
African American co-infected women were much less likely to die from liver disease as compared to Caucasians and Hispanics, independent of other causes of death. Future studies are needed to investigate the reasons for this marked racial/ethnic discrepancy in liver-related mortality.
PMCID: PMC3440547  PMID: 22618868
race; ethnicity; viral hepatitis; mortality; gender
3.  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.
PMCID: PMC3466997  PMID: 22927450
4.  Hematopoietic Precursor Cells Isolated From Patients on Long-term Suppressive HIV Therapy Did Not Contain HIV-1 DNA 
Background. We address the key emerging question of whether Lin−/CD34+ hematopoietic precursor cells (HPCs) represent an important latent reservoir of human immunodeficiency virus type 1 (HIV-1) during long-term suppressive therapy.
Methods. To estimate the frequency of HIV-1 infection in bone marrow, we sorted Lin−/CD34+ HPCs and 3 other cell types (Lin−/CD34−, Lin−/CD4+, and Lin+/CD4+) from 8 patients who had undetectable viral loads for 3–12 years. Using a single-proviral sequencing method, we extracted, amplified, and sequenced multiple single HIV-1 DNA molecules from these cells and memory CD4+ T cells from contemporaneous peripheral blood samples.
Results. We analyzed 100 000–870 000 bone marrow Lin−/CD34+ HPCs from the 8 patients and found no HIV-1 DNA. We did isolate HIV-1 DNA from their bone marrow Lin+/CD4+ cells that was genetically similar to HIV-1 DNA from lymphoid cells located in the peripheral blood, indicating an exchange of infected cells between these compartments.
Conclusions. The absence of infected HPCs provides strong evidence that the HIV-1 infection frequency of Lin−/CD34+ HPCs from bone marrow, if it occurred, was <.003% (highest upper 95% confidence interval) in all 8 patients. These results strongly suggest that Lin−/CD34+ HPCs in bone marrow are not a source of persistent HIV-1 in patients on long-term suppressive therapy.
PMCID: PMC3415927  PMID: 22536001
5.  Racial/Ethnic Differences in Spontaneous HCV Clearance in HIV Infected and Uninfected Women 
Digestive diseases and sciences  2012;58(5):1341-1348.
Among individuals without human immunodeficiency virus (HIV), African Americans have lower spontaneous clearance of hepatitis C virus (HCV) than Caucasians, and women have higher clearance than men. Few studies report racial/ethnic differences in acute HCV in HIV infected, or Hispanic women. We examined racial/ethnic differences in spontaneous HCV clearance in a population of HCV mono- and co-infected women.
We conducted a cross sectional study of HCV seropositive women (897 HIV infected and 168 HIV uninfected) followed in the US multicenter, NIH-funded Women's Interagency HIV Study (WIHS), to determine the association of race/ethnicity with spontaneous HCV clearance, as defined by undetectable HCV RNA at study entry.
Among HIV and HCV seropositive women, 18.7 % were HCV RNA negative, 60.9 % were African American, 19.3 % Hispanic and 17.7 % Caucasian. HIV infected African American women were less likely to spontaneously clear HCV than Hispanic (OR 0.59, 95 % CI 0.38–0.93, p = 0.022) or Caucasian women (OR 0.57, 95 % CI 0.36–0.93, p = 0.023). Among HIV uninfected women, African Americans had less HCV clearance than Hispanics (OR 0.18, 95 % CI 0.07–0.48, p = 0.001) or Caucasians (OR 0.26, 95 % CI 0.09–0.79, p = 0.017). There were no significant differences in HCV clearance between Hispanics and Caucasians, among either HIV infected (OR 0.97, 95 % CI 0.57–1.66, p = 0.91) or uninfected (OR 1.45, 95 % CI 0.56–3.8, p = 0.45) women.
African Americans were less likely to spontaneously clear HCV than Hispanics or Caucasians, regardless of HIV status. No significant differences in spontaneous HCV clearance were observed between Caucasian and Hispanic women. Future studies incorporating IL28B genotype may further explain these observed racial/ethnic differences in spontaneous HCV clearance.
PMCID: PMC3663918  PMID: 23179159
African American; Hispanic; Acute hepatitis C; Female
6.  Impact of Insulin Resistance on HCV Treatment Response and Impact of HCV Treatment on Insulin Sensitivity Using Direct Measurements of Insulin Action 
Diabetes Care  2012;35(5):1090-1094.
Insulin resistance, as measured by surrogate markers, is associated with lower response to hepatitis C virus (HCV) therapy and may improve with HCV eradication. We prospectively evaluated the impact of directly measured insulin resistance and abnormal glucose metabolism on achieving sustained virologic response (SVR) with HCV therapy and assessed whether SVR results in improved insulin sensitivity and fasting glucose.
A total of 50 noncirrhotic, nondiabetic, HCV-infected patients (27 untreated, 23 treated with pegylated interferon/ribavirin, nonrandomized) underwent clinical and histologic evaluation and 75-g oral glucose tolerance test. Insulin sensitivity was assessed directly with insulin suppression test by measuring steady-state plasma glucose (SSPG) concentration during a 240-min infusion of octreotide, glucose, and insulin. Of the subjects, 43 had at least one follow-up evaluation.
Patient characteristics were median age 48, 57% male, and 52% white. SVR was achieved in 61% (14 of 23) of treated subjects. SVR was independently associated with HCV genotypes 2 and 3 (odds ratio 8.8 [95% CI 1.2–61.7]) but was not strongly associated with insulin sensitivity. When controlling for elapsed time between measurements, being on interferon, and BMI, SSPG decreased by 36 mg/dL (−88 to 16) in those with SVR and decreased by 28 mg/dL (−93 to 38) in those without SVR, compared with the untreated group. BMI (coefficient 9.1 per 5 units; 95% CI 5.3–12.9) and interferon use (coefficient 56; 95% CI 6.8–105) were associated with SSPG.
Insulin resistance does not appear to be strongly associated with SVR. HCV therapy may improve insulin resistance regardless of virologic response; however, BMI and interferon use were clearly associated with insulin resistance.
PMCID: PMC3329815  PMID: 22399695
7.  Insulin Resistance and Cognition Among HIV-Infected and HIV-Uninfected Adult Women: The Women's Interagency HIV Study 
Cognitive impairment remains prevalent in the era of combination antiretroviral therapy (cART) and may be partially due to comorbidities. We postulated that insulin resistance (IR) is negatively associated with cognitive performance. We completed a cross-sectional analysis among 1547 (1201 HIV+) women enrolled in the Women's Interagency HIV Study (WIHS). We evaluated the association of IR with cognitive measures among all WIHS women with concurrent fasting bloods and cognitive testing [Trails A, Trails B, and Symbol Digit Modalities Test (SDMT)] using multiple linear regression models. A smaller subgroup also completed the Stroop test (n=1036). IR was estimated using the Homeostasis Model Assessment (HOMA). Higher HOMA was associated with poorer performance on the SDMT, Stroop Color-Naming (SCN) trial, and Stroop interference trial, but remained statistically significant only for the SCN in models adjusting for important factors [β=3.78 s (95% CI: 0.48–7.08), p=0.025, for highest vs. lowest quartile of HOMA]. HIV status did not appear to substantially impact the relationship of HOMA with SCN. There was a small but statistically significant association of HOMA and reduced neuropsychological performance on the SCN test in this cohort of women.
PMCID: PMC3332367  PMID: 21878059
8.  Fetal Outcomes in Pregnancies Complicated by Intrahepatic Cholestasis of Pregnancy in a Northern California Cohort 
PLoS ONE  2012;7(3):e28343.
Intrahepatic cholestasis of pregnancy (ICP) has important fetal implications. There is increased risk for poor fetal outcomes, including preterm delivery, meconium staining of amniotic fluid, respiratory distress, fetal distress and demise.
One hundred and one women diagnosed with ICP between January 2005 and March 2009 at San Francisco General Hospital were included in this study. Single predictor logistic regression models were used to assess the associations of maternal clinical and biochemical predictors with fetal complications. Clinical predictors analyzed included age, race/ethnicity, gravidity, parity, history of liver or biliary disease, history of ICP in previous pregnancies, and induction. Biochemical predictors analyzed included serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, direct bilirubin, albumin, total protein, and total bile acids (TBA).
The prevalence of ICP was 1.9%. Most were Latina (90%). Labor was induced in the majority (87%) and most were delivered by normal spontaneous vaginal delivery (84%). Fetal complications occurred in 33% of the deliveries, with respiratory distress accounting for the majority of complications. There were no statistically significant clinical or biochemical predictors associated with an increased risk of fetal complications. Elevated TBA had little association with fetal complications until reaching greater than 100 µmoL/L, with 3 out of 5 having reported complications. ICP in previous pregnancies was associated with decreased risk of fetal complications (OR 0.21, p = 0.046). There were no cases of late term fetal demise.
Maternal clinical and laboratory features, including elevated TBA, did not appear to be substantial predictors of fetal complications in ICP.
PMCID: PMC3293870  PMID: 22403605
9.  The Calm Mouse: An Animal Model of Stress Reduction 
Molecular Medicine  2012;18(1):606-617.
Chronic stress is associated with negative health outcomes and is linked with neuroendocrine changes, deleterious effects on innate and adaptive immunity, and central nervous system neuropathology. Although stress management is commonly advocated clinically, there is insufficient mechanistic understanding of how decreasing stress affects disease pathogenesis. Therefore, we have developed a “calm mouse model” with caging enhancements designed to reduce murine stress. Male BALB/c mice were divided into four groups: control (Cntl), standard caging; calm (Calm), large caging to reduce animal density, a cardboard nest box for shelter, paper nesting material to promote innate nesting behavior, and a polycarbonate tube to mimic tunneling; control exercise (Cntl Ex), standard caging with a running wheel, known to reduce stress; and calm exercise (Calm Ex), calm caging with a running wheel. Calm, Cntl Ex and Calm Ex animals exhibited significantly less corticosterone production than Cntl animals. We also observed changes in spleen mass, and in vitro splenocyte studies demonstrated that Calm Ex animals had innate and adaptive immune responses that were more sensitive to acute handling stress than those in Cntl. Calm animals gained greater body mass than Cntl, although they had similar food intake, and we also observed changes in body composition, using magnetic resonance imaging. Together, our results suggest that the Calm mouse model represents a promising approach to studying the biological effects of stress reduction in the context of health and in conjunction with existing disease models.
PMCID: PMC3388136  PMID: 22398685

Results 1-9 (9)