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1.  Interleukin-28b: A Key Piece of the Hepatitis C Virus Recovery Puzzle 
Gastroenterology  2010;138(4):1240-1243.
doi:10.1053/j.gastro.2010.02.033
PMCID: PMC3805379  PMID: 20184973
2.  Measuring biexponential transverse relaxation of the ASL signal at 9.4 T to estimate arterial oxygen saturation and the time of exchange of labeled blood water into cortical brain tissue 
The transverse decay of the arterial spin labeling (ASL) signal was measured at four inflow times in the rat brain cortex at 9.4 T. Biexponential T2 decay was observed that appears to derive from different T2 values associated with labeled water in the intravasculature (IV) and extravascular (EV) compartments. A two compartment biexponential model was used to assess the relative contribution of the IV and EV compartments to the ASL signal, without assuming a value for T2 of labeled blood water in the vessels. This novel methodology was applied to estimate the exchange time of blood water into EV tissue space and the oxygen saturation of blood on the arterial side of the vasculature. The mean exchange time of labeled blood water was estimated to be 370±40 ms. The oxygen saturation of the arterial side of the vasculature was significantly less than 100% (∼85%), which may have implications for quantitative functional magnetic resonance imaging studies where the arterial oxygen saturation is frequently assumed to be 100%.
doi:10.1038/jcbfm.2012.156
PMCID: PMC3564190  PMID: 23168531
arterial spin labeling; ASL; cerebral hemodynamics; exchange; functional MRI (fMRI); MRI
3.  Provisional Guidance on the Use of Hepatitis C Virus Protease Inhibitors for Treatment of Hepatitis C in HIV-Infected Persons 
In May 2011, hepatitis C virus (HCV) protease inhibitors (PIs) were approved by the US Food and Drug Administration to treat persons with genotype 1 chronic hepatitis C virus (HCV) infection, but not those dually infected with human immunodeficiency virus (HIV). Although critical safety and efficacy data are lacking, the availability of the drugs and substantial medical need justify the off-label use of HCV PIs in select HIV/HCV-coinfected persons. Pending results of ongoing investigations, this article represents provisional guidance on the use of HCV PIs in HIV-infected persons.
doi:10.1093/cid/cir882
PMCID: PMC3404695  PMID: 22173234
4.  Relationship of Liver Disease Stage and Antiviral Therapy With Liver-Related Events and Death in Adults Coinfected With HIV/HCV 
JAMA : the journal of the American Medical Association  2012;308(4):10.1001/jama.2012.7844.
Context
Human immunodeficiency virus (HIV) accelerates hepatitis C virus (HCV) disease progression; however, the effect of liver disease stage and antiviral therapy on the risk of clinical outcomes is incompletely understood.
Objective
To determine the incidence of end-stage liver disease (ESLD), hepatocellular carcinoma (HCC), or death according to baseline hepatic fibrosis and antiviral treatment for HIV/HCV coinfected individuals.
Design, Setting, and Participants
Prospective cohort of 638 coinfected adults (80% black, 66% men) receiving care at the Johns Hopkins HIV clinic and receiving a liver biopsy and who were prospectively monitored for clinical events between July 1993 and August 2011 (median follow-up, 5.82 years; interquartile range, 3.42–8.85 years). Histological specimens were scored for hepatic fibrosis stage according to the METAVIR scoring system.
Main Outcome Measure
Incidence of composite outcome of ESLD, HCC, or death.
Results
Patients experienced a graded increased risk in incidence of clinical outcomes based on baseline hepatic fibrosis stage (classification range, F0-F4): F0, 23.63 (95% CI, 16.80–33.24); F1, 36.33 (95% CI, 28.03–47.10); F2, 53.40 (95% CI, 33.65–84.76); F3, 56.14 (95% CI, 31.09–101.38); and F4, 79.43 (95% CI, 55.86–112.95) per 1000 person-years (P<.001). In multivariable negative binomial regression, fibrosis stages F2 through F4 and antiretroviral therapy were independently associated with composite ESLD, HCC, or all-cause mortality after adjustment for demographic characteristics, injection drug use, and CD4 cell count. Compared with F0, the incidence rate ratio (RR) for F2 was 2.31 (95% CI, 1.23–4.34; P=.009); F3, 3.18 (95% CI, 1.47–6.88; P=.003); and F4, 3.57 (95% CI, 2.06–6.19; P<.001). Human immunodeficiency virus treatment was associated with fewer clinical events (incidence RR, 0.27; 95% CI, 0.19–0.38; P<.001). For the 226 patients who underwent HCV treatment, the incidence of clinical events did not significantly differ between treatment nonresponders and untreated patients (incidence RR, 1.27; 95% CI, 0.86–1.86; P=.23). In contrast, no events were observed in the 51 patients with sustained virologic response (n= 36) and relapse (n= 15), including 19 with significant fibrosis.
Conclusion
In this cohort of patients with HIV/HCV coinfection, hepatic fibrosis stage was independently associated with a composite outcome of ESLD, HCC, or death.
doi:10.1001/jama.2012.7844
PMCID: PMC3807214  PMID: 22820790
5.  Hepatic steatosis associated with increased central body fat by dual-energy X-ray absorptiometry and uncontrolled HIV in HIV/hepatitis C co-infected persons 
AIDS (London, England)  2010;24(6):811-817.
Objective
To evaluate the relationship between regional body composition and liver disease (fibrosis or steatosis) in HIV/HCV co-infected individuals.
Methods
Whole body dual-energy X-ray absorptiometry (DXA) was performed in 173 HIV/HCV co-infected persons within 12 months of a liver biopsy. Significant fibrosis was defined as a METAVIR stage greater than 1. Steatosis was graded as: 0, none; 1, steatosis involving less than 5% of hepatocytes; 2, 5–29%; 3, 30–60%; 4 greater than 60%, and was defined as more than 0. Poisson regression with robust variance was used to estimate prevalence ratios of the outcome measures.
Results
The population was 62% male and 84% black with a median body mass index of 25.2 kg/m2 (interquartile range 22.5, 29.3 kg/m2). No differences in regional body fat or fat distribution were observed in 42 patients with significant fibrosis compared to others with less fibrosis. However, the 77 individuals (45%) with steatosis had greater central fat than those without steatosis [prevalence ratio 1.04 per kg trunk fat; 95% confidence interval (CI) 1.04, 1.11], after adjusting for hepatic fibrosis (prevalence ratio 1.77; 95% CI 1.29, 2.42), uncontrolled HIV replication (viral load >400 copies/ml) (prevalence ratio 1.57; 95% CI 1.12, 2.22), age, sex, race and diabetes mellitus.
Conclusions
In HIV/HCV co-infected individuals, measures of regional body fat or fat distribution were not associated with hepatic fibrosis. In contrast, increased central adiposity by DXA, as well as concomitant fibrosis and uncontrolled HIV, were associated with hepatic steatosis. The extent to which weight loss and effective antiretroviral therapy can reduce the risk of steatosis deserves further investigation.
doi:10.1097/QAD.0b013e3283333651
PMCID: PMC3800050  PMID: 20186036
body composition; hepatic fibrosis; hepatitis C; HIV; steatosis
6.  Development of a high-resolution fat and CSF-suppressed optic nerve DTI protocol at 3T: application in multiple sclerosis 
Functional Neurology  2013;28(2):93-100.
Summary
Clinical trials of neuroprotective interventions in multiple sclerosis require outcome measures that reflect the disease pathology. Measures of neuroaxonal integrity in the anterior visual pathways are of particular interest in this context, however imaging of the optic nerve is technically challenging. We therefore developed a 3T optic nerve diffusion tensor imaging protocol incorporating fat and cerebrospinal fluid suppression and without parallel imaging. The sequence used a scheme with six diffusion-weighted directions, b=600smm−2 plus one b≈0 (b0) and 40 repetitions, averaged offline, giving an overall scan time of 30 minutes. A coronal oblique orientation was used with voxel size 1.17mm×1.17mm×4mm, We validated the sequence in 10 MS patients with a history of optic neuritis and 11 healthy controls: mean fractional anisotropy was reduced in the patients: 0.346(±0.159) versus 0.528(±0.123), p<0.001; radial diffusivity was increased: 0.940(±0.370)×10−6mm2s−1 compared to 0.670(± 0.221)×10−6mm2s−1 (p<0.01). No significant differences were seen for mean diffusivity or mean axial diffusivity.
PMCID: PMC3812733  PMID: 24125558
3T; diffusion; multiple sclerosis; optic nerve; optic neuritis
7.  Human Immunodeficiency Virus and Liver Disease Forum 2010: Conference Proceedings 
Hepatology (Baltimore, Md.)  2011;54(6):2245-2253.
Liver disease continues to represent a critical mediator of morbidity and mortality in those with human immunodeficiency virus (HIV) infection. The frequent presence and overlap of concomitant injurious processes, including hepatitis C virus and hepatitis B virus infections, hepatoxicity associated with antiretroviral therapeutic agents, alcohol, and other toxins, in the setting of immunosuppression lead to rapid fibrotic progression and early development of end-stage liver disease. This conference summary describes the proceedings of a state-of-the-art gathering of international experts designed to highlight the status of current research in epidemiology, natural history, pathogenesis, and treatment of HIV and liver disease.
doi:10.1002/hep.24651
PMCID: PMC3795389  PMID: 21898501
8.  Vitamin D deficiency and its relation to bone mineral density and liver fibrosis in HIV–HCV coinfection 
Antiviral therapy  2012;18(2):237-242.
Background
Fractures and cirrhosis are major causes of morbidity and mortality among HIV–HCV-coinfected individuals. It is not known whether vitamin D deficiency is associated with these outcomes.
Methods
Between 2005 and 2007, 116 HIV–HCV- coinfected individuals underwent dual-energy X-ray absorptiometry within 1 year of a liver biopsy. 25-Hydroxy-vitamin D (25OHD) and parathyroid hormone were measured from archived samples. Low bone mineral density (BMD) was defined as BMD≥2 standard deviations lower than age-, sex- and race-matched controls (Z-score ≤−2.0) at the total hip, femoral neck or lumbar spine. Histological fibrosis staging was assessed according to the METAVIR system (0 [no fibrosis] to 4 [cirrhosis]).
Results
The cohort was 87% African-American and 63% male. The median age (IQR) was 49.9 years (46.5–53.3). A total of 89% had a CD4+ T-cell count >200 cells/mm3 and 64% were receiving HAART. The median 25OHD was 19 ng/ ml (IQR 11.0–26.0). Hypovitaminosis D (25OHD≤15 ng/ml) was present in 41% and secondary hyperparathyroidism, defined by parathyroid hormone >65 pg/ml, was present in 24%. In total, 27% had low BMD (Z-score ≤−2) at the spine, femoral neck or total hip, and 39% had significant hepatic fibrosis (METAVIR≥2). In multivariate analysis, vitamin D deficiency was not associated with significant fibrosis or with BMD at any site.
Conclusions
Vitamin D deficiency was highly prevalent in this mostly African-American HIV–HCV-coinfected population, but was not related to BMD or liver disease severity. These data suggest that efforts to increase vitamin D levels in this population may not improve bone or liver outcomes.
doi:10.3851/IMP2264
PMCID: PMC3790468  PMID: 22910231
9.  Laser Captured Hepatocytes Show Association of BCHE Loss and Fibrosis Progression in Hepatitis C Infected Drug Users 
Hepatology (Baltimore, Md.)  2012;56(2):544-554.
Chronic hepatitis C virus (HCV) infection is complicated by hepatic fibrosis. Hypothesizing that early fibrogenic signals may originate in cells susceptible to HCV infection, hepatocyte gene expression was analyzed from persons with chronic HCV at different stages of liver fibrosis. Four HCV-infected subjects with pre-cirrhotic liver fibrosis (Ishak fibrosis 3–5) were matched for age, race, and gender to five HCV-infected subjects with no evidence of fibrosis (Ishak fibrosis 0). Hepatocytes from each subject were isolated from liver biopsies using laser capture microdissection. Transcriptome profiling was performed on hepatocyte RNA using hybridization arrays. We found that hepatocytes in pre-cirrhotic fibrosis were depleted for genes involved in small molecule and drug metabolism, especially butyrylcholinesterase (BCHE), a gene involved in the metabolism of drugs of abuse. Differential expression of BCHE was validated in the same tissues and cross-sectionally in an expanded cohort of 143 HCV-infected individuals. In a longitudinal study, serum BCHE activity were already decreased at study inception in 19 fibrosis progressors compared to 20 fibrosis non-progressors (p<0.05). Non-progressors also had decreased BCHE activity over time compared to initial values, but these evolved a median (range) 8.6 (7.8–11.4) years after the study period inception(p<0.05). Laser captured portal tracts were enriched for immune related genes when compared to hepatocytes but pre-cirrhotic livers lost this enrichment.
Conclusion
Overall, we found that chronic HCV is associated with hepatocyte BCHE loss years before hepatic synthetic function is impaired. These results indicate that BCHE may be involved in the pathogenesis of HCV-related fibrosis among injection drug users.
doi:10.1002/hep.25655
PMCID: PMC3388175  PMID: 22331678
butyrylcholinesterase; Hepacivirus; chronic HCV infection; laser capture microdissection; portal tract
10.  Highly active anti-hepatitis C therapy: seven lessons from HIV 
Antiviral therapy  2012;17(6 0 0):1183-1188.
Summary
The hepatitis C virus (HCV) direct antiviral treatment era is underway. Although there are some important differences, it is likely that the experience with HCV will be similar in many respects to what already occurred with HIV. This paper considers seven important lessons learned with HIV and the degree to which they should be anticipated with HCV.
doi:10.3851/IMP2429
PMCID: PMC3715614  PMID: 23186629
11.  HIV, Age, and the Severity of Hepatitis C Virus–Related Liver Disease 
Annals of internal medicine  2013;158(9):658-666.
Background
Persons with HIV infection have been reported to develop age-related diseases at younger ages than those without HIV. Whether this finding is related to HIV infection or failure to control for other risk factors is unknown.
Objective
To investigate whether persons with HIV infection develop hepatitis C virus (HCV)–related liver disease at younger ages than similar persons without HIV.
Design
Comparison of the severity of liver fibrosis by age among persons who have HCV with and without HIV followed concurrently in the same protocol.
Setting
Observational cohort from Baltimore, Maryland, participating in the ALIVE (AIDS Linked to the IntraVenous Experience) study.
Participants
1176 current and former injection drug users with antibodies to HCV.
Measurements
Liver fibrosis assessed semiannually from 2006 to 2011 by elastography (FibroScan, Echosens, Paris, France) and using previously validated thresholds for clinically significant fibrosis and cirrhosis; concurrent assessment of medical history, alcohol and illicit drug use, HCV RNA levels, hepatitis B virus surface antigen level, body mass index, and (for those with HIV) CD4+ lymphocyte count and HIV RNA levels.
Results
Among 1176 participants with antibodies to HCV, the median age was 49 years and 34% were coinfected with HIV and HCV. Participants contributed 5634 valid liver fibrosis measurements. The prevalence of clinically significant fibrosis without cirrhosis (12.9% vs. 9.5%) and of cirrhosis (19.5% vs. 11.0%) was greater in persons coinfected with HIV and HCV than in those with only HCV (P < 0.001). Increasing age and HIV infection were independently associated with liver fibrosis, as were daily alcohol use, chronic hepatitis B virus infection, body mass index greater than 25 kg/m2, and greater plasma HCV RNA levels. When these factors were kept constant, persons with HIV had liver fibrosis measurements equal to those of persons without HIV, who were, on average, 9.2 years older.
Limitation
The process of liver fibrosis began before the study in most persons.
Conclusion
In this cohort, persons who have HCV with HIV have liver fibrosis stages similar to those without HIV who are nearly a decade older.
doi:10.7326/0003-4819-158-9-201305070-00604
PMCID: PMC3708651  PMID: 23440167
12.  Screening for HCV Infection in Jails 
doi:10.1001/jama.2012.374
PMCID: PMC3701941  PMID: 22453565
13.  Stability of liver fibrosis among HCV-infected injection drug users 
Antiviral therapy  2012;17(5):813-821.
Background
There are few published data characterizing patterns of liver stiffness measurements (LSMs) among HCV-infected persons and their potential impact on clinical decisions (for example, deferring treatment and hepatocellular carcinoma surveillance).
Methods
A total of 591 HCV-infected injection drug users (IDUs) in a community-based cohort had four LSMs. We used semi-parametric latent class growth modelling to identify patterns, which then became a gold standard against which we characterized validity of information from the initial measurements.
Results
Median age was 49, 68% were male, 92% African-American and 33% HIV-coinfected. The median LSM at visit 1 was 6.7 kPa (IQR 5.3–8.8). Over a median 1.75 years, LSM measures were stable; median change between visits was 0 kPa (IQR -1.4–1.7). Only 3% had evidence of fibrosis progression. Other groups included stable patterns of 1) no fibrosis (59%), 2) moderate fibrosis (21%), 3) severe fibrosis (7%) and 4) cirrhosis (9%). Individuals with fibrosis progression were more likely to be HIV-infected than those with stable low fibrosis (P<0.001). The diagnostic accuracy of the first LSM for identification of need for cancer surveillance (cirrhosis ≥12.3 kPa) was high (positive predictive value = 97%). Although no single low LSM had high negative predictive value for significant fibrosis (metavir <2), individuals with two or more low results rarely had progression.
Conclusions
These data underscore the stability of liver fibrosis in a cohort of predominantly African-American HCV-infected persons over 1.75 years, support using LSMs to monitor untreated persons at risk for progression and assess need for hepatocellular carcinoma surveillance.
doi:10.3851/IMP2085
PMCID: PMC3699312  PMID: 22418880
14.  Discordance Between CD4+ T-Lymphocyte Counts and Percentages in HIV-Infected Persons With Liver Fibrosis 
In cross-sectional analysis of 287 human immunodeficiency virus–infected persons with high hepatitis C virus prevalence, liver fibrosis defined by elastography was associated with higher CD4+ T-cell percentages relative to absolute CD4+ number; this discordance was most apparent in persons with marked lymphopenia.
Background. Cirrhosis of the liver can induce splenic sequestration of peripheral blood cells, recently suggested to reduce the number but not percentage of circulating CD4+ T cells in persons uninfected with human immunodeficiency virus (HIV). We investigated whether earlier stages of liver fibrosis prior to cirrhosis were associated with discordance between CD4 count (CD4N) and CD4 percentage (CD4%) in HIV-infected patients.
Methods. In cross-sectional analysis of 287 HIV-infected participants of the AIDS Linked to the Intravenous Experience cohort, we evaluated CD4N, CD4%, and transient elastography staging of liver fibrosis. High CD4+ lymphocyte discordance was defined as higher CD4% relative to CD4N based on accepted clinical cutoffs; multivariable logistic regression was used to determine covariates associated with discordance.
Results. Of 287 participants, 99 (34.4%) had high CD4+ discordance, which increased to 76% of 114 participants with marked lymphopenia (total lymphocyte count [TLC] ≤1200 cells/μL). In multivariable analysis, the odds of having high CD4+ discordance was increased in persons with significant liver fibrosis compared to those without fibrosis (odds ratio, 1.69; 95% confidence interval [CI], .95–2.96); the odds ratio of discordance increased to 2.66 (95% CI, 1.11–6.40) among the subset of participants with TLC ≤1200 cells/μL. The odds for discordance associated with cirrhosis were of similar magnitude as those observed with significant fibrosis.
Conclusions. In HIV-infected persons, liver fibrosis is associated with discordant peripheral CD4+ lymphocyte results, especially in the setting of marked lymphopenia. Clinicians should also consider CD4% when interpreting absolute CD4+ counts of HIV-infected persons with known or suspected liver disease, particularly if TLC is <1200 cells/μL.
doi:10.1093/cid/cis294
PMCID: PMC3404711  PMID: 22460963
15.  Spontaneous Clearance of Primary Acute Hepatitis C Virus Infection Correlated with High Initial Viral RNA Level and Rapid HVR1 Evolution 
Hepatology (Baltimore, Md.)  2012;55(6):1684-1691.
Objective/Aims
To determine whether early viral dynamics and evolution predict outcome of primary acute hepatitis C virus (HCV) infection.
Methods
HCV- and HIV-negative injection drug users were enrolled prospectively and followed monthly to identify acute HCV infection using RNA detection. Subjects with more than one month between HCV RNA negative and positive visits were excluded to ensure stringent acute infection. Differences in medians of log-transformed viral RNA levels and evolutionary rates in each gene of a 5’-hemigenomic amplicon were assessed using the Mann-Whitney Rank Sum test. Correlation coefficient was calculated using Spearman Rank Order.
Results
Initial viremia level was 50-fold higher in subjects with spontaneous clearance (compared with persistence) of primary acute HCV infection (median 7.1 versus 5.4 log10 IU/mL, P=0.002). Initial viremia level in subjects with IL-28B-C allele and clearance was higher than that in subjects with IL-28B-T allele and persistence (P=0.001). Evolutionary rates in the hypervariable region 1 (HVR1) region of E2 gene were significantly higher in self-resolvers than those in persistence subjects during early infection, whereas other genes/regions had comparable rates. All major substitutions in HVR1 in persistence subjects were convergent changes whereas over the same time interval clearance subjects displayed divergent evolution, indicating different immune responses between the two groups.
Conclusions
Spontaneous clearance of acute HCV infection is predicted by high initial viremia as well as favorable IL-28B genotype, and associated with rapid envelope sequence evolution. This linkage of host genetics, viral dynamics, and evolution provides new directions for mechanistic studies.
doi:10.1002/hep.25575
PMCID: PMC3330174  PMID: 22234804
16.  Using High Angular Resolution Diffusion Imaging Data to Discriminate Cortical Regions 
PLoS ONE  2013;8(5):e63842.
Brodmann’s 100–year–old summary map has been widely used for cortical localization in neuroscience. There is a pressing need to update this map using non–invasive, high–resolution and reproducible data, in a way that captures individual variability. We demonstrate here that standard HARDI data has sufficiently diverse directional variation among grey matter regions to inform parcellation into distinct functional regions, and that this variation is reproducible across scans. This characterization of the signal variation as non–random and reproducible is the critical condition for successful cortical parcellation using HARDI data. This paper is a first step towards an individual cortex–wide map of grey matter microstructure, The gray/white matter and pial boundaries were identified on the high–resolution structural MRI images. Two HARDI data sets were collected from each individual and aligned with the corresponding structural image. At each vertex point on the surface tessellation, the diffusion–weighted signal was extracted from each image in the HARDI data set at a point, half way between gray/white matter and pial boundaries. We then derived several features of the HARDI profile with respect to the local cortical normal direction, as well as several fully orientationally invariant features. These features were taken as a fingerprint of the underlying grey matter tissue, and used to distinguish separate cortical areas. A support–vector machine classifier, trained on three distinct areas in repeat 1 achieved 80–82% correct classification of the same three areas in the unseen data from repeat 2 in three volunteers. Though gray matter anisotropy has been mostly overlooked hitherto, this approach may eventually form the foundation of a new cortical parcellation method in living humans. Our approach allows for further studies on the consistency of HARDI based parcellation across subjects and comparison with independent microstructural measures such as ex–vivo histology.
doi:10.1371/journal.pone.0063842
PMCID: PMC3656939  PMID: 23691102
17.  3D MDEFT imaging of the human brain at 4.7 T with reduced sensitivity to radiofrequency inhomogeneity 
A modification to the 3D modified driven equilibrium Fourier transform (MDEFT) imaging technique is proposed that reduces its sensitivity to RF inhomogeneity. This is especially important at high field strengths where RF focusing effects exacerbate B1 inhomogeneity, causing significant signal nonuniformity in the images. The adiabatic inversion pulse used during the preparation period of the MDEFT sequence is replaced by a hard (nonadiabatic) pulse with a nominal flip angle of 130°. The spatial inhomogeneity of the hard pulse preparation compensates for the inhomogeneity of the excitation pulses. Uniform signal intensity is obtained for a wide range of B1 amplitudes and the high CNR characteristic of MDEFT is retained. The new approach was validated by numerical simulations and successfully applied to human brain imaging at 4.7 T, resulting in highquality T1-weighted images of the whole human brain at high field strength with uniform signal intensity and contrast, despite the presence of significant RF inhomogeneity.
doi:10.1002/mrm.20482
PMCID: PMC1633717  PMID: 15906308
high field MRI; T1-weighted imaging; RF inhomogeneity; human brain imaging; structural brain imaging
18.  High Plasma Interleukin-18 Levels Mark the Acute Phase of Hepatitis C Virus Infection 
The Journal of Infectious Diseases  2011;204(11):1730-1740.
Background. Proinflammatory cytokines play a critical role in antiviral immune responses. Large-scale genome studies have found correlations between single-nucleotide polymorphisms (SNPs) in the interleukin (IL) 18 promoter and spontaneous control of hepatitis C virus (HCV), suggesting a role in clearance.
Methods. Plasma IL-18, IL-1β, IL-6, IL-8, IL-12, interferon-γ, tumor necrosis factor–α, alanine aminotransferase (ALT), and HCV RNA levels were assessed longitudinally in subjects with known dates of HCV acquisition and analyzed according to IL-18 SNPs and outcome, either spontaneous clearance (SC) (n = 13) or persistent infection (PI) (n = 25).
Results. No significant change in plasma proinflammatory cytokine expression was observed with the exception of IL-18, which increased in every subject with initial detection of HCV RNA. In every SC subject, IL-18 returned to the preinfection baseline concomitant with HCV control. In PI subjects, IL-18 declined following the acute phase of infection but remained above the preinfection baseline throughout chronic infection and did not correlate with HCV RNA or ALT levels.
Conclusions. Plasma IL-18 was an early and the most reliably detected host response to HCV infection measured in blood. Reduced IL-18 production with transition to chronic infection without correlation with HCV RNA or ALT levels suggests modulation of the innate response with persistent infection.
doi:10.1093/infdis/jir642
PMCID: PMC3203233  PMID: 21984735
19.  Genetic Polymorphism in IL28B Is Associated With Spontaneous Clearance of Hepatitis C Virus Genotype 4 Infection in an Egyptian Cohort 
The Journal of Infectious Diseases  2011;204(9):1391-1394.
Single-nucleotide polymorphisms (SNPs) around IL28B are associated with spontaneous hepatitis C virus (HCV) clearance of genotypes 1 and 3 in white and African-American populations. This study investigated whether the IL28B SNP (rs12979860) is associated with spontaneous clearance of HCV, principally genotype 4, in 162 Egyptians (80 with clearance). The protective C allele was more common in those with spontaneous clearance (76.3% vs 57.9%; P = .0006). Individuals with clearance were 3.4 (95% confidence interval, 1.8–6.5) times more likely to have C/C genotype. Thus, IL28B plays a role in spontaneous clearance of HCV genotype 4 in North Africa.
doi:10.1093/infdis/jir536
PMCID: PMC3182308  PMID: 21933876
20.  Controlled HIV Viral Replication, Not Liver Disease Severity Associated with Low Bone Mineral Density in HIV/HCV Co-Infection 
Journal of hepatology  2011;55(4):770-776.
Objective
To evaluate the prevalence and risk factors for low bone mineral density (BMD) in persons co-infected with HIV and Hepatitis C.
Methods
HIV/HCV co-infected study participants (n=179) were recruited into a prospective cohort and underwent dual-energy X-ray absorptiometry (DXA) within 1 year of a liver biopsy. Fibrosis staging was evaluated according to the METAVIR system. Osteoporosis was defined as a T-score ≤ −2.5. Z-scores at the total hip, femoral neck, and lumbar spine were used as the primary outcome variables to assess the association between degree of liver disease, HIV-related variables, and BMD.
Results
The population was 65% male, 85% Black with mean age 50.3 years. The prevalence of osteoporosis at either at the total hip, femoral neck, or lumbar spine was 28%, with 5% having osteoporosis of the total hip, 6% at the femoral neck, 25% at the spine. The mean Z-scores (standard deviation) were −0.42 (1.01) at the total hip, −0.16 (1.05) at the femoral neck, and −0.82 (1.55) at the lumbar spine. In multivariable models, controlled HIV replication (HIV RNA < 400 copies/mL vs ≥400 copies/mL) was associated with lower Z-scores (mean ± standard error) at the total hip (−0.44±0.17, p=0.01), femoral neck (−0.59±0.18, p=0.001), and the spine (−0.98±0.27, p=0.0005). There was no association between degree of liver fibrosis and Z-score.
Conclusion
Osteoporosis was very common in this population of predominately African-American HIV/HCV co-infected patients, particularly at the spine. Lower BMD was associated with controlled HIV replication, but not liver disease severity.
doi:10.1016/j.jhep.2011.01.035
PMCID: PMC3113457  PMID: 21338640
hepatitis C; bone mineral density; hepatic fibrosis; HIV
21.  Exceeding the limits of liver histology markers 
Journal of hepatology  2008;50(1):36-41.
Background/Aims
Alternatives to liver biopsy for staging liver disease caused by hepatitis C virus (HCV) have not appeared accurate enough for widespread clinical use. We characterized the magnitude of the impact of error in the “gold standard” on the observed diagnostic accuracy of surrogate markers.
Methods
We calculated the area under the receiver operating characteristic curve (AUROC) for a surrogate marker against the gold standard (biopsy) for a range of possible performances of each test (biopsy and marker) against truth and a gradient of clinically significant disease prevalence.
Results
In the ‘best’ scenario where liver biopsy accuracy is highest (sensitivity and specificity of biopsy are 90%) and the prevalence of significant disease 40%, the calculated AUROC would be 0.90 for a perfect marker (99% actual accuracy) which is within the range of what has already been observed. With lower biopsy sensitivity and specificity, AUROC determinations > 0.90 could not be achieved even for a marker that perfectly measured disease.
Conclusions
We demonstrate that error in the liver biopsy result itself makes it impossible to distinguish a perfect surrogate from ones that are now judged by some as clinically unacceptable. An alternative gold standard is needed to assess the accuracy of tests used to stage HCV-related liver disease.
doi:10.1016/j.jhep.2008.07.039
PMCID: PMC2637134  PMID: 19012989
liver disease; biopsy; hepatitis C virus; validity; surrogate markers
22.  CXCL9 and CXCL10 Chemokines as Predictors of Liver Fibrosis in a Cohort of Primarily African-American Injection Drug Users With Chronic Hepatitis C 
The Journal of Infectious Diseases  2011;204(6):832-836.
CXCL9 (monokine induced by IFN γ [Mig]) and CXCL10 (interferon [IFN] γ−inducible protein 10 [IP-10]) have been associated with hepatic fibrosis in predominantly white hepatitis C virus (HCV)–infected patients. We investigated their potential as noninvasive markers of hepatic fibrosis and fibrosis progression in African-American patients. Peripheral chemokine levels were measured in 115 HCV-infected patients within 4 months of liver biopsy; patients underwent a second biopsy after 3–5 years. CXCL10 levels appeared to be higher in patients with advanced fibrosis on the contemporaneous biopsy and were significantly higher in patients with advanced fibrosis compared with those with minimal fibrosis on the later biopsy (P = .0045). Therefore, CXCL10 has potential as a marker of fibrosis progression in African-American HCV-infected patients.
doi:10.1093/infdis/jir424
PMCID: PMC3156920  PMID: 21849280
23.  Predictors and effects of alcohol use on liver function among young HCV-infected injection drug users in a behavioral intervention 
Journal of hepatology  2010;55(1):45-52.
Background & Aims
Hepatitis C virus (HCV) screening can provide opportunities to reduce disease progression through counseling against alcohol use, but empirical data on this issue are sparse. We determined the efficacy of a behavioral intervention in reducing alcohol use among young, HCV-infected injection drug users (IDUs) (n=355) and assessed whether changes in liver enzymes were associated with changes in alcohol consumption.
Methods
Both the intervention and attention-control groups were counseled to avoid alcohol use, but the intervention group received enhanced counseling. Logistic regression, ANOVA, and continuous time Markov models were used to identify factors associated with alcohol use, changes in mean ALT and AST levels and change in alcohol use post-intervention.
Results
Six months post-intervention, alcohol abstinence increased 22.7% in both groups, with no difference by intervention arm. Transition from alcohol use to abstinence was associated with a decrease in liver enzymes, with a marginally greater decrease in the intervention group (p=0.05 for ALT; p=0.06 for AST). In multivariate Markov models, those who used marijuana transitioned from alcohol abstinence to consumption more rapidly than non-users (RR=3.11); those who were homeless transitioned more slowly to alcohol abstinence (RR=0.47); and those who had ever received a clinical diagnosis of liver disease transitioned more rapidly to abstinence (RR=1.88).
Conclusions
Although, behavioral counseling to reduce alcohol consumption among HCV-infected IDUs had a modest effect, reductions in alcohol consumption were associated with marked improvements in liver function. Interventions to reduce alcohol use among HCV-infected IDUs may benefit from being integrated into clinical care and monitoring of HCV infection.
doi:10.1016/j.jhep.2010.10.028
PMCID: PMC3094600  PMID: 21145862
24.  Changes in Blood-borne Infection Risk Among Injection Drug Users 
The Journal of Infectious Diseases  2011;203(5):587-594.
(See the editorial commentary by Grebely and Dore, on pages 571–4.)
Background. Population-level hepatitis C virus (HCV) infection incidence is a surrogate for community drug-related risk.
Methods. We characterized trends in human immunodeficiency virus (HIV) and HCV infection incidence and HCV infection prevalence among injection drug users (IDUs) recruited over 4 periods: 1988–1989, 1994–1995, 1998, and 2005–2008. We calculated HIV and HCV infection incidence within the first year of follow-up among IDUs whose test results were negative for these viruses at baseline (n = 2061 and n = 373, respectively). We used Poisson regression to compare trends across groups.
Results. HIV infection incidence declined significantly from 5.5 cases/100 person-years (py) in the 1988–1989 group to 2.0 cases/100 py in the 1994–1995 group to 0 cases/100 py in the 1998 and 2005–2008 groups. Concurrently, HCV infection incidence declined but remained robust (22.0 cases/100 py in the 1988–1989 cohort to 17.2 cases/100 py in the 1994–1995 cohort, 17.9 cases/100 py in the 1998 cohort, and 7.8 cases/100 py in the 2005–2008 cohort; P = .07). Likewise, HCV infection prevalence declined, but chiefly in younger IDUs. For persons aged <39 years, relative to the 1988–1989 cohort, all groups exhibited significant declines (adjusted prevalence ratio [PR] for the 2005–08 cohort, .73; 95% confidence interval [CI], .65–.81). However, for persons aged ≥39 years, only the 2005–2008 cohort exhibited declining prevalence compared with the 1988–1989 cohort (adjusted PR, .87; 95% CI, .77–.99).
Conclusions. Although efforts to reduce blood-borne infection incidence have had impact, this work will need to be intensified for the most transmissible viruses, such as HCV.
doi:10.1093/infdis/jiq112
PMCID: PMC3072736  PMID: 21282191
25.  Incidence and risk factors for steatosis progression in adults coinfected with HIV and hepatitis C virus 
Gastroenterology  2010;140(3):809-817.
Background and Aims
Hepatic steatosis is a common histological finding in patients that are co-infected with HIV and hepatitis C virus (HCV), although little is known about its natural history. We prospectively examined the natural history of steatosis in patients co-infected with HIV and HCV that attended an urban HIV clinic.
Methods
The study cohort consisted of 222 co-infected patients (87% African American, 94% with HCV genotype 1 infection) who had at least 2 liver biopsies performed between 1993 and 2008. Biopsies were scored by a single pathologist; samples were classified as having trivial (< 5% of hepatocytes affected) or significant (>5%) levels of fat (steatosis). We characterized progression to significant levels of fat among patients whose first biopsy samples had no or trivial levels of fat, and regression among those with significant fat, using logistic regression.
Results
Initial biopsies from most patients (88%) had no or trivial amounts of fat. Among second biopsy samples, 74% had no or trivial fat and 13% had significant amounts of fat. The strongest risk factors for steatosis progression were alcohol abuse and overweight/obesity; cumulative exposure to anti-retroviral therapy between biopsies and high counts of CD4+ T cells were associated with reduced progression of steatosis. Among the 28 patients whose initial biopsy had significant fat levels, most (75%) regressed.
Conclusions
Antiretroviral therapy and high counts of CD4+ T cells are associated with reduced progression of steatosis in patients co-infected with HIV and HCV. Efforts to diagnose and prevent steatosis should focus on persons with high body mass index and excessive alcohol intake.
doi:10.1053/j.gastro.2010.11.052
PMCID: PMC3073565  PMID: 21134375
pathology; cirrhosis; AIDS; liver disease

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