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1.  Survey of Asian patients with Hepatitis B infection: limited knowledge of transmission and screening of family members 
Asian American families are disproportionately affected by Hepatitis B (HBV) infection. We aimed to assess the extent of screening family members of Asian patients with known HBV infection as well as patients’ knowledge of HBV disease.
A cross-sectional survey of established Asian patients with HBV-infection was performed at a university liver clinic. Outcome measures included the percentage of family members whose HBV serostatus was unknown and the percentage of patients who were able to correctly identify modes of transmission.
A total of 803 US-based family members were identified by 58 patients. Patients did not know the HBV serostatus of 50% of their family members and 28% of their immediate family members. Fifty percent of participants did not know how they had acquired HBV or stated unlikely transmission modes.
Though nationwide vaccination campaigns target this underrepresented population, screening family members of Asian patients with HBV remains a challenge.
PMCID: PMC3880640  PMID: 23913129
HBV; screening; knowledge; family testing; HCC
2.  Differences Between Caucasian, African American, and Hispanic Patients with Primary Biliary Cirrhosis in the United States 
Hepatology (Baltimore, Md.)  2007;46(3):769-775.
Primary biliary cirrhosis (PBC) is an uncommon chronic cholestatic liver disease that primarily afflicts young and middle-aged Caucasian women; there are limited data on the clinical presentation and disease severity among non-Caucasian patients with this disease. The goal of this study was to examine differences in the severity of liver disease between Caucasian and non-Caucasian patients with PBC screened for enrollment in a large national multicenter clinical trial. Demographic features, symptoms, physical findings, and laboratory tests obtained during screening were examined in 535 patients with PBC with respect to ethnicity, gender, and antimitochondrial antibody (AMA) status; 73 of 535 (13.6%) were non-Caucasian (21 were African American, and 42 were Hispanic). Non-Caucasians were more likely than Caucasians to be ineligible for participation in the clinical trial (46.5% versus 25.1%, P = 0.0001), primarily because of greater disease severity. African Americans and Hispanics were also more likely to have a lower activity level, more severe pruritus, and more advanced disease. However, the mean age, male-to-female ratio, and seroprevalence of AMA positivity were similar between the 2 groups.
Liver disease severity at clinical presentation is higher among non-Caucasians than Caucasians with PBC, and this cannot be explained by demographic or serologic features alone. Possible mechanisms underlying this health discrepancy are not clear, but increased awareness of PBC as a cause of chronic cholestatic liver disease is critical in evaluating non-Caucasian patients in the United States.
PMCID: PMC4167731  PMID: 17654740
3.  Alcohol Use and Hepatitis C 
Hepatology (Baltimore, Md.)  2002;36(5 0 1):S220-S225.
Excess alcohol consumption can worsen the course and outcome of chronic hepatitis C. It is important to distinguish between alcohol abuse, which must be treated on its own merits, and the effect of alcohol use on progression, severity, and treatment of hepatitis C. Most studies on the effects of alcohol on hepatitis C have focused on patients, with high levels of daily alcohol intake. Indeed, the adverse effects of light and moderate amounts of alcohol intake on hepatitis C virus (HCV) infection have not been clearly shown, and only limited studies have been performed. Sex differences exist in the effect of alcohol on fibrosis as well as on the severity of hepatitis C. Alcohol use has been reported to be associated with lower responses to therapy and, in some studies, higher HCV RNA levels and increased HCV quasi-species. Few studies address the treatment of hepatitis C in the alcoholic individual or determine the effect of continued light or moderate alcohol use on the outcome of treatment response. In summary, many critical questions remain regarding the interactions between alcohol and hepatitis C. Currently, the evidence from the literature shows that heavy alcohol intake worsens the outcome of HCV infection. The literature is inadequate to provide definitive recommendations regarding the effect of light to moderate alcohol use in patients with hepatitis C.
PMCID: PMC4123319  PMID: 12407597
4.  Assessing mortality in women with hepatitis C virus and HIV using indirect markers of fibrosis 
AIDS (London, England)  2012;26(5):599-607.
Co-infection with hepatitis C virus (HCV) is a major cause of morbidity and mortality in HIV-infected individuals. However, predictors of mortality are poorly defined and most studies have focused predominantly on co-infection in men. We evaluated whether two indirect markers of hepatic fibrosis, aspartate aminotransferase-to-platelet ratio index (APRI) and FIB-4 scores, were predictive of mortality in a well defined longitudinal cohort of HCV/HIV-co-infected women on HAART.
HCV/HIV-co-infected women on antiretroviral therapy enrolled in Women’s Interagency HIV Study (WIHS), a National Institutes of Health-funded prospective, multicenter, cohort study of women with and at risk for HIV infection were included. Using Cox regression analysis, associations between APRI and FIB-4 with all-cause mortality were assessed.
Four hundred and fifty HCV/HIV-co-infected women, of whom 191 women died, had a median follow-up of 6.6 years and 5739 WIHS visits. Compared with women with low APRI or FIB-4 levels, severe fibrosis was significantly associated with an increased risk of all-cause mortality {APRI: hazard ratio 2.78 [95% confidence interval (CI) 1.87, 4.12]; FIB-4: hazard ratio 2.58 (95% CI 1.68, 3.95)}. Crude death rates per 1000 patient-years increased with increasing liver fibrosis: 34.8 for mild, 51.3 for moderate and 167.9 for severe fibrosis as measured by FIB-4. Importantly, both APRI and FIB-4 increased during the 5 years prior to death for all women: the slope of increase was greater for women dying a liver-related death compared with nonliver-related death.
Both APRI and FIB-4 are independently associated with all-cause mortality in HCV/HIV-co-infected women and may have clinical prognostic utility among women with HIV and HCV.
PMCID: PMC3698040  PMID: 22156972
fibrosis markers; hepatitis C virus; HIV; longitudinal study; mortality
5.  Association of Chronic Hepatitis C Infection with T-Cell Phenotypes in HIV-Negative and HIV-Positive Women 
Hepatitis C virus (HCV) viremia is thought to have broad, systemic effects on the cellular immune system that go beyond its impact on just those T-cells that are HCV-specific. However, prior studies of chronic HCV and circulating T-cell subsets (activation and differentiation phenotypes) in HIV-negatives used general population controls, rather than a risk-appropriate comparison group. Studies in HIV-positives did not address overall immune status (total CD4+ count).
We used fresh blood from HIV-positive and at-risk HIV-negative women, with and without chronic HCV, to measure percentages of activated CD4+ and CD8+ T-cells, Tregs, and T-cell differentiation phenotypes (naïve, central memory (CM), effector memory (EM), and terminally differentiated effector). This included 158 HIV-negatives and 464 HIV-positives, of whom 18 and 63, respectively, were HCV viremic.
In multivariate models of HIV-negatives, HCV viremia was associated with 25% fewer naïve CD4+ (P=0.03), 33% more EM CD4+ (P=0.0002) and 37% fewer CM CD8+ (P=0.02) T-cells. Among HIV-positives we observed only one of these three relationships: higher percentage of EM CD4+ among HCV viremic women. Further, the association with EM CD4+ among HIV-positives was limited to individuals with diminished immune status (total CD4+ count ≤500 cells/μL), as were associations of HCV viremia with higher percentages of activated CD4+ and Tregs. Among HIV-positives with high CD4+ count, no significant associations were observed.
These data suggest that HCV viremia in HIV-negatives is associated with accelerated T-cell differentiation, but among HIV-positives the impact of HCV viremia is less straightforward and varies by total CD4+ count.
PMCID: PMC4197408  PMID: 25314250
hepatitis C virus; HIV; T-cell; phenotype; activation; differentiation
6.  Interferon Lambda 4 Genotype Is Not Associated with Recurrence of Oral or Genital Herpes 
PLoS ONE  2015;10(10):e0138827.
IFNL4-ΔG/TT (rs368234815) genotype is associated with hepatitis C virus clearance and may play a role in other infections. IFN-λ4 protein is generated only in individuals who carry the IFNL4-ΔG allele. The IFNL4 rs12979860-T allele, which is in strong linkage disequilibrium with IFNL4-ΔG, was recently reported to be associated with more frequent and severe oral herpes episodes. We investigated the association of IFNL4-ΔG/TT with herpes simplex virus (HSV)-related outcomes among 2,192 African American and European American participants in the Women’s Interagency HIV Study (WIHS). WIHS is a prospective cohort study of human immunodeficiency virus (HIV)–infected and at-risk women that began in 1994. This report includes follow-up through 2013. Available data included: HSV–1 and HSV–2 antibodies at study entry; bi-annually ascertained episodes of (self-reported) oral herpes, (self-reported) genital sores and (clinician-observed) genital ulcers; HSV–2 DNA in cervicovaginal lavage (CVL) specimens. IFNL4-ΔG/TT genotyping was determined by TaqMan. We compared women with IFNL4-ΔG/ΔG or IFNL4-TT/ΔG genotypes (i.e., IFNL4-ΔG carriers) to those with the IFNL4-TT/TT genotype, adjusting for age, race and HIV status. For outcomes with repeated measurements, the adjusted odds ratio (aOR), 95% confidence interval [CI] and p-value were determined using a generalized estimating equations approach. Median participant age at enrollment was 36 years; 81% were African American, 74% were HIV-infected. Among 1,431 participants tested for antibodies, 72.8% were positive for HSV–1 and 79.0% were positive for HSV–2. We observed no association between IFNL4-ΔG/TT genotype and any outcome: HSV–1 or HSV–2 antibody prevalence (p>0.1, all comparisons); oral herpes (aOR, 1.2; p = 0.35); genital sores (aOR, 1.0; p = 0.71); genital ulcers (aOR, 1.1; p = 0.53); detectable HSV–2 DNA in CVL (N = 322; aOR, 0.71; p = 0.49); HSV–2 DNA level (p = 0.68). In this large prospective study, IFNL4-ΔG/TT genotype was not associated with HSV-related outcomes, including episodes of oral or genital herpes.
PMCID: PMC4592222  PMID: 26431156
7.  Characteristics and Management of Patients with Chronic Hepatitis B in an Integrated Care Setting 
Digestive diseases and sciences  2014;59(9):2100-2108.
Few population-based studies have described characteristics and management of patients with chronic hepatitis B (CHB) in the USA.
We retrospectively studied adults with CHB in the Northern California Kaiser Permanente Medical Care Program (KPNC) from July 2009 to December 2010 (n = 12,016). Laboratory tests, treatment patterns, and hepatocellular carcinoma (HCC) surveillance were ascertained during a “recent” 18-month study window (July 2009–December 2010), or as “ever” based on records dating to 1995.
The mean age was 49 years; 51 % were men, 83 % Asian, and 87 % KPNC members >5 years. Overall, 51 % had ≥1 liver-related visit, 14 % with gastroenterology or infectious disease specialists, and 37 % with primary care providers (PCP) only. Less than 40 % of patients had both hepatitis B virus (HBV) DNA and ALT testing conducted recently, while 56 % of eligible patients had received HCC surveillance. Recent laboratory testing and HCC surveillance were more frequent in patients seen by a specialist versus PCP only (90 vs. 47 % and 92 vs. 73 %, respectively, p values <0.001). During the study period, 1,649 (14 %) received HBV treatment, while 5 % of untreated patients had evidence of treatment eligibility. Among 599 patients newly initiated on HBV therapy, 76 % had guideline-based indications for treatment.
Most patients initiated on HBV treatment met eligibility, and very few patients with evidence of needing treatment were left untreated. However, monitoring of ALT and HBV DNA levels, as well as HCC surveillance, were not frequent, underestimating the proportion of patients that warranted HBV therapy. Viral monitoring and cancer surveillance are therefore important targets for improving the scope of CHB care in the community setting.
PMCID: PMC4149592  PMID: 24728968
Community; Management; Provider; Treatment
8.  Direct and Indirect Serum Markers of Liver Fibrosis Compared with Transient Elastography among Women in the Women’s Interagency HIV Study 
The aim of this study was to determine the test characteristics of direct and indirect biomarkers for liver fibrosis compared with transient elastography (TE) among a group of human immunodeficiency virus (HIV)-infected and uninfected women with or without Hepatitis C virus (HCV) infection.
Women enrolled in the Women’s Interagency HIV Study (WIHS) from Washington DC, San Francisco, and Chicago with a body mass index (BMI)<35 underwent liver stiffness measurement using TE between October, 2010 and September, 2012. Serum samples were tested for hyaluronic acid to calculate the SHASTA and aspartate aminotransferase to platelet ratio index (APRI). Receiver operator characteristics (ROC) of significant liver fibrosis (liver stiffness ≥ 7.1 kPa by TE, correlating with a METAVIR fibrosis score of F2-F4) predicted by SHASTA and APRI were compared.
Among 308 women, the median age was 48 years, BMI was 25.6, 67% were non-Hispanic black, 27% HCV+, and 78% HIV+. The overall prevalence of significant liver fibrosis was 20%, and among HIV+ women, 22%. Overall, there was no statistically significant difference in the area under ROC curve (AUROC) between SHASTA and APRI relative to significant fibrosis by TE. Among HCV+ women (with or without HIV), the AUROC ranged from 0.70–0.73 for both the SHASTA and APRI compared to TE. Both SHASTA and APRI were associated with significant misclassification with a false negative rate of 33–40% for significant fibrosis compared with TE among women with HCV infection, with or without HIV.
Both the SHASTA and APRI, direct and indirect serum biomarkers of liver fibrosis respectively, are comparable at detection of significant liver fibrosis among women with HCV infection, regardless of HIV status. However, there was a high false negative rate in detection of significant liver fibrosis of up to 40% which is a significant limitation of use of these biomarkers.
PMCID: PMC4524652  PMID: 26251759
HIV; HCV; Biomarkers; SHASTA; APRI; Transient elastography; WIHS; Women
9.  Turnover Rates of Hepatic Collagen and Circulating Collagen-Associated Proteins in Humans with Chronic Liver Disease 
PLoS ONE  2015;10(4):e0123311.
Accumulation and degradation of scar tissue in fibrotic liver disease occur slowly, typically over many years. Direct measurement of fibrogenesis, the rate of scar tissue deposition, may provide valuable therapeutic and prognostic information. We describe here results from a pilot study utilizing in vivo metabolic labeling to measure the turnover rate of hepatic collagen and collagen-associated proteins in plasma for the first time in human subjects. Eight subjects with chronic liver disease were labeled with daily oral doses of 2H2O for up to 8 weeks prior to diagnostic liver biopsy and plasma collection. Tandem mass spectrometry was used to measure the abundance and fractional synthesis rate (FSR) of proteins in liver and blood. Relative protein abundance and FSR data in liver revealed marked differences among subjects. FSRs of hepatic type I and III collagen ranged from 0.2–0.6% per day (half-lives of 4 months to a year) and correlated significantly with worsening histologic fibrosis. Analysis of plasma protein turnover revealed two collagen-associated proteins, lumican and transforming growth factor beta-induced-protein (TGFBI), exhibiting FSRs that correlated significantly with FSRs of hepatic collagen. In summary, this is the first direct measurement of liver collagen turnover in vivo in humans and suggests a high rate of collagen remodeling in advanced fibrosis. In addition, the FSRs of collagen-associated proteins in plasma are measurable and may provide a novel strategy for monitoring hepatic fibrogenesis rates.
PMCID: PMC4409311  PMID: 25909381
10.  Admixture Analysis of Spontaneous Hepatitis C Virus Clearance in Individuals of African-Descent 
Genes and immunity  2014;15(4):241-246.
Hepatitis C virus (HCV) infects an estimated 3% of the global population with the majority of individuals (75–85%) failing to clear the virus without treatment, leading to chronic liver disease. Individuals of African-descent have lower rates of clearance compared to individuals of European-descent and this is not fully explained by social and environmental factors. This suggests that differences in genetic background may contribute to this difference in clinical outcome following HCV infection. Using 473 individuals and 792,721 SNPs from a genome-wide association study (GWAS), we estimated local African ancestry across the genome. Using admixture mapping and logistic regression we identified two regions of interest associated with spontaneous clearance of HCV (15q24, 20p12). A genome-wide significant variant was identified on chromosome 15 at the imputed SNP, rs55817928 (P=6.18×10−8) between the genes SCAPER and RCN. Each additional copy of the African ancestral C allele is associated with 2.4 times the odds of spontaneous clearance. Conditional analysis using this SNP in the logistic regression model explained one-third of the local ancestry association. Additionally, signals of selection in this area suggest positive selection due to some ancestral pathogen or environmental pressure in African, but not in European populations.
PMCID: PMC4308959  PMID: 24622687
Hepatitis C; Chronic Infection; Admixture; African Ancestry
11.  Association of HIV Infection, Hepatitis C Virus Infection, and Metabolic Factors With Liver Stiffness Measured by Transient Elastography 
The Journal of Infectious Diseases  2013;208(11):1776-1783.
Background. Few studies have examined the relationship of human immunodeficiency virus (HIV) monoinfection and its associated perturbations with liver fibrosis.
Methods. Using multivariable linear regression, we examined the demographic, behavioral, metabolic and viral factors associated with transient elastography–measured liver stiffness in 314 participants (165 HIV positive/hepatitis C virus [HCV] negative, 78 HIV positive/HCV positive, 14 HIV negative/HCV positive, 57 HIV negative/HCV negative) in the Women's Interagency HIV Study.
Results. Compared with HIV negative/HCV negative women, HIV positive/HCV positive women had higher median liver stiffness values (7.1 vs 4.4 kPa; P < .001); HIV positive/HCV negative and HIV negative/HCV negative women had similar liver stiffness values (both 4.4 kPa; P = .94). HIV/HCV coinfection remained associated with higher liver stiffness values (74% higher; 95% confidence interval [CI], 49–104) even after multivariable adjustment. Among HCV positive women, waist circumference (per 10-cm increase) was associated with 18% (95% CI, 7.5%–30%) higher liver stiffness values after multivariable adjustment; waist circumference showed little association among HIV positive/HCV negative or HIV negative/HCV negative women. Among HIV positive/HCV negative women, history of AIDS (13%; 95% CI, 4% –27%) and HIV RNA (7.3%; 95% CI, 1.59%–13.3%, per 10-fold increase) were associated with greater liver stiffness.
Conclusions. HCV infection but not HIV infection is associated with greater liver stiffness when infected women are compared with those with neither infection. Our finding that waist circumference, a marker of central obesity, is associated with greater liver stiffness in HIV/HCV-coinfected but not HIV-monoinfected or women with neither infection suggests that in the absence of HCV-associated liver injury the adverse effects of obesity are lessened.
PMCID: PMC3814832  PMID: 23901097
HIV; HCV; liver fibrosis; transient elastography; obesity; women
12.  Viral Hepatitis in HIV Infection 
The New England journal of medicine  2007;356(14):1445-1454.
PMCID: PMC4144044  PMID: 17409326
13.  Role of αvβ6 Integrin in Acute Biliary Fibrosis 
Hepatology (Baltimore, Md.)  2007;46(5):1404-1412.
Acute biliary obstruction leads to periductal myofibroblasts and fibrosis, the origin of which is uncertain. Our study provides new information on this question in mice and humans. We show that bile duct obstruction induces a striking increase in cholangiocyte αvβ6 integrin and that expression of this integrin is directly linked to fibrogenesis through activation of transforming growth factor beta (TGF-β). Administration of blocking antibody to αvβ6 significantly reduces the extent of acute fibrosis after bile duct ligation. Moreover, in β6-null mice subjected to the injury, fibrosis is reduced by 50% relative to that seen in wild-type mice, whereas inflammation occurs to the same extent. The data indicate that αvβ6, rather than inflammation, is linked to fibrogenesis. It is known that αvβ6 binds latent TGF-β and that binding results in release of active TGFβ. Consistent with this, intracellular signaling from the TGFβ receptor is increased after bile duct ligation in wild-type mice but not in β6−/− mice, and a competitive inhibitor of the TGFβ receptor type II blocks fibrosis to the same extent as antibody to αvβ6. In a survey of human liver disease, expression of αvβ6 is increased in acute, but not chronic, biliary injury and is localized to cholangiocyte-like cells.
Cholangiocytes respond to acute bile duct obstruction with markedly increased expression of αvβ6 integrin, which is closely linked to periductal fibrogenesis. The findings provide a rationale for the use of inhibitors of αvβ6 integrin or TGFβ for down-regulating fibrosis in the setting of acute or ongoing biliary injury.
PMCID: PMC4144397  PMID: 17924447
15.  Randomized Controlled Study of Tenofovir and Adefovir in Chronic Hepatitis B Virus and HIV Infection: ACTG A5127 
Hepatology (Baltimore, Md.)  2006;44(5):1110-1116.
Chronic hepatitis B virus (HBV) infection is an important cause of morbidity and mortality in subjects coinfected with HIV. Tenofovir disoproxil fumarate (TDF) and adefovir dipivoxil (ADV) are licensed for the treatment of HIV-1 and HBV infection, respectively, but both have in vivo and in vitro activity against HBV. This study evaluated the anti-HBV activity of TDF compared to ADV in HIV/HBV-coinfected subjects. ACTG A5127 was a prospective randomized, double-blind, placebo-controlled trial of daily 10 mg of ADV versus 300 mg of TDF in subjects with HBV and HIV coinfection on stable ART, with serum HBV DNA ≥ 100,000 copies/mL, and plasma HIV-1 RNA ≤ 10,000 copies/mL. This study closed early based on results of a prespecified interim review, as the primary noninferiority end point had been met without safety issues. Fifty-two subjects were randomized. At baseline, 73% of subjects had a plasma HIV-1 RNA < 50 copies/mL, 86% were HBeAg positive, 94% were 3TC resistant, median serum ALT was 52IU/L, and 98% had compensated liver disease. The mean time-weighted average change in serum HBV DNA from baseline to week 48 (DAVG48) was −4.44 log10 copies/mL for TDF and −3.21 log10 copies/mL for ADV. There was no difference in toxicity between the 2 treatment arms, with 11 subjects (5 ADV and 6 TDF) experiencing elevations of serum ALT on treatment. In conclusion, over 48 weeks, treatment with either ADV or TDF resulted in clinically important suppression of serum HBV DNA. Both drugs are safe and efficacious for patients coinfected with HBV and HIV.
PMCID: PMC4114764  PMID: 17058225
17.  Addition of Nitazoxanide to PEG-IFN and Ribavirin to Improve HCV Treatment Response in HIV-1 and HCV Genotype 1 Coinfected Persons Naïve to HCV Therapy: Results of the ACTG A5269 Trial 
HIV clinical trials  2013;14(6):274-283.
We hypothesized that nitazoxanide (NTZ) added to pegylated inter-feron alfa-2a (PEG-IFN) and weight-based ribavirin (WBR) would improve hepatitis C virus (HCV) virologic responses in HCV treatment-naïve HIV-1/HCV genotype 1 coin-fected persons.
Prospective, single-arm study in which subjects received 4-week lead-in (NTZ 500 mg twice daily) followed by 48 weeks of NTZ, PEG-IFN, and WBR. We compared the HCV virologic responses of these subjects to his­torical controls from the completed ACTG study A5178 who received PEG-IFN and WBR and had similar subject characteristics. Primary endpoints were early virologic response and complete early virologic response (EVR and cEVR).
Among 67 subjects (78% male; 48% Black; median age, 50 years), EVR was achieved in 65.7% (90% CI, 55.0%–75.3%), cEVR in 38.8% (28.8%–49.6%). and SVR in 32.8% (23.4%–43.5%). EVR was higher with NTZ (51.4% in A5178; P = .03), but the sustained virologic response (SVR) proportion was similar (27.3% in A5178; P = .24). In contrast to A5178, SVR was similar across IL28B genotypes. Overall, NTZ was safe and well-tolerated.
Whereas EVR proportion improved significantly in this pilot study, the addition of NTZ to PEG-IFN/WBR did not significantly improve SVR compared to historical controls. NTZ may be associated with an attenuation of the effect of IL28B on HCV treatment response.
PMCID: PMC4113390  PMID: 24334180
genotype 1; hepatitis C; HIV; nitazoxanide; pegylated interferon; ribavirin
18.  Peginterferon Alfa-2a plus Ribavirin versus Interferon Alfa-2a plus Ribavirin for Chronic Hepatitis C in HIV-Coinfected Persons 
The New England journal of medicine  2004;351(5):451-459.
Chronic hepatitis C virus (HCV) infection is a cause of major complications in persons who are also infected with the human immunodeficiency virus (HIV). However, the treatment of HCV infection in such persons has been associated with a high rate of intolerance and a low rate of response. We conducted a multicenter, randomized trial comparing peginterferon plus ribavirin with interferon plus ribavirin for the treatment of chronic hepatitis C in persons coinfected with HIV.
A total of 66 subjects were randomly assigned to receive 180 μg of peginterferon alfa-2a weekly for 48 weeks, and 67 subjects were assigned to receive 6 million IU of interferon alfa-2a three times weekly for 12 weeks followed by 3 million IU three times weekly for 36 weeks. Both groups received ribavirin according to a dose-escalation schedule. At week 24, subjects who did not have a virologic response (those who had an HCV RNA level greater than or equal to 60 IU per milliliter) underwent liver biopsy, and medications were continued in subjects with either a virologic response or histologic improvement.
Treatment with peginterferon and ribavirin was associated with a significantly higher rate of sustained virologic response (an HCV RNA level of less than 60 IU per milliliter 24 weeks after completion of therapy) than was treatment with interferon and ribavirin (27 percent vs. 12 percent, P=0.03). In the group given peginterferon and ribavirin, only 14 percent of subjects with HCV genotype 1 infection had a sustained virologic response (7 of 51), as compared with 73 percent of subjects with an HCV genotype other than 1 (11 of 15, P<0.001). Histologic responses were observed in 35 percent of subjects with no virologic response who underwent liver biopsy.
In persons infected with HIV, the combination of peginterferon and ribavirin is superior to the combination of interferon and ribavirin in the treatment of chronic hepatitis C. These regimens may provide clinical benefit even in the absence of virologic clearance. The marked discrepancy in the rates of sustained virologic response between HCV genotypes indicates that strategies are needed to improve the outcome in persons infected with HCV genotype 1.
PMCID: PMC4113392  PMID: 15282352
19.  Effects of HCV Treatment on Cytokine Expression During HCV/HIV Coinfection 
There is growing evidence that cytokine expression is linked to hepatitis C virus (HCV) pathogenesis and treatment response rates among HCV-monoinfected persons. However, because of the profound effects of human immunodeficiency virus (HIV) coinfection on HCV, it is not clear if these observations are also true for HCV/HIV-coinfected individuals. Serum expression of the proinflammatory cytokines interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α) and the fibrogenic cytokine transforming growth factor-β1 (TGF-β1) were measured in HCV/HIV-coinfected persons at baseline and at week 24 of HCV therapy. Higher levels of IL-8 and TGF-β were demonstrated among nonwhite subjects at baseline. Increases in TNF-α and IL-8 expression were found at week 24 of HCV therapy, suggesting that enhanced proinflammatory cytokine production may occur during HCV treatment. However, cytokine levels were not predictive of HCV virologic, biochemical, or histologic response. Although previous studies conducted among HCV-monoinfected individuals have suggested that cytokine levels could predict the virologic response to therapy, no such associations were observed among HCV/HIV-coinfected persons, suggesting that they may respond differently to treatment than do their HCV-monoinfected counterparts.
PMCID: PMC4113398  PMID: 17115902
20.  Novel Model of Antigen-Specific Induction of Bile Duct Injury 
Gastroenterology  2006;131(6):1899-1906.
Background & Aims
Biliary-directed inflammation is an important cause of acute and chronic liver disease. We developed and characterized a transgenic mouse model of immunemediated hepatobiliary injury.
Ovalbumin (OVA)-BIL mice were developed using 3.0 kilobase of the rat apical sodium-dependent bile acid transporter promoter to drive aberrant expression of a membrane form of ovalbumin (OVA) on biliary epithelium. Liver inflammation resulted from adoptive transfer of OVA-specific T cells. Liver immune cells were characterized to determine the mechanism of the response by assessing activation, proliferation, and intracellular cytokine expression.
OVA-BIL transgenic mice were tolerant to OVA, without evidence of liver disease. Adoptive transfer of OVA-specific CD4+ and CD8+ T cells into naïve OVA-BIL mice led to biliary-centered necroinflammatory damage in a dose-dependent manner. This inflammation absolutely required CD8+ T cells and was augmented by CD4+ T cells. Adoptively transferred OVA CD8+ cells homed to and proliferated in the liver but not the spleen. These activated, adoptively transferred cytotoxic T lymphocytes produced elevated levels of tumor necrosis factor α and interferon γ.
T-cell recognition of antigen aberrantly expressed on bile duct epithelium induced an acute necroinflammatory response specific to the liver, with activation, proliferation, and cytokine production predominantly by the OVA-specific cytotoxic T cells. Thus, OVA BIL represents an antigen-specific animal model of inflammatory bile duct injury.
PMCID: PMC4113411  PMID: 17087941
21.  Hematologic Toxicity Assocated with Interferon-Based Hepatitis C Therapy in HIV Type 1-Coinfected Subjects 
This study investigates whether dose modifications for adverse hematologic effects or the use of hematopoietic growth factors influenced the outcome of therapy for hepatitis C virus (HCV) infection in patients who were coinfected with HCV and human immunodeficiency virus (HIV) and who were participants in a randomized, controlled trial.
Subjects were randomized to receive ribavirin plus interferon-alfa-2a (IFN-alfa-2a) or pegylated IFN-alfa-2a for a total of 48 weeks. Doses were modified for a number of adverse effects (including hematologic toxicity), and hematopoietic growth factors were administered at the discretion of the physician. Associations of dose modifications or initiation of hematopoietic growth factor support with treatment outcomes were determined by standard statistical methods.
One hundred thirty-three subjects were included in this study. Subjects treated with pegylated IFN-alfa-2a were more likely to have had dose modifications (dose reduction or discontinuation) than were those treated with IFN-alfa-2a. By multivariate analysis, treatment with pegylated IFN-alfa-2a is associated with higher sustained virologic and/or histologic response. Dose modifications for nonhematologic toxicity are independently associated with lower sustained virologic and/or histologic responses. Although hematologic toxicity was not directly associated with clinical outcome in this analysis, use of hematopoietic growth factors was associated with an increased sustained virologic and/or histologic response.
Dose modifications for anti-HCV therapy may adversely affect the outcome of treatment of HCV in individuals who are coinfected with HIV. The use of hematopoietic growth factor support may be associated with an improved clinical response to therapy.
PMCID: PMC4075655  PMID: 17443478
22.  Viral Factors Associated with Cytokine Expression During HCV/HIV Co-Infection 
Co-infection with human immunodeficiency virus (HIV) is associated with reduced hepatitis C virus (HCV) treatment response and accelerated HCV disease. Cytokines, as mediators of immune responses, inflammation, and fibrogenesis, may underlie important differences in HCV pathogenesis during HIV co-infection. We previously found that serum interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α) increased after HCV therapy with interferon (IFN) in HCV/HIV co-infected patients; however, cytokine levels were not predictive of HCV therapeutic response. Here, we examined viral factors associated with expression of IL-8, TNF-α, and transforming growth factor-β1 (TGF-β1) in uninfected, HCV mono-infected, HIV mono-infected, and HCV/HIV co-infected persons. HIV co-infection was associated with decreased IL-8 detection but not TNF-α detection. A significant interaction effect demonstrated that HIV infection was associated with elevated TGF-β1 in HCV-positive individuals but not in HCV-negative individuals. The induction of a sustained profibrotic signal, such as TGF-β1, by HIV may cause accelerated liver fibrosis during HCV/HIV co-infection and may hinder the host’s ability to mount an effective HCV-specific immune response. Further studies are warranted to identify noninvasive markers of liver disease for the clinical management of HCV disease, particularly when liver biopsies have not been performed or are contraindicated.
PMCID: PMC4066618  PMID: 17477814
23.  De novo malignancies following liver transplantation: a case–control study with long-term follow-up 
Clinical transplantation  2006;20(5):617-623.
Long-term survival data on de novo malignancy are limited following orthotopic liver transplantation (OLT) when compared with controls without malignancies.
Over a 12 yr period at our institution, 50 of 1043 patients (4.8%) who underwent OLT were identified to have 53 de novo malignancies. The clinical characteristics and survival of these patients were retrospectively reviewed and compared with a control cohort of 50 OLT recipients without malignancy matched with the incidence cases by age, year of OLT, sex, and type of liver disease.
Chronic hepatitis C, alcohol and primary sclerosing cholangitis were the three leading causes of liver disease. Skin cancer was the most common malignancy (32%), followed by gastrointestinal (21%), including five small bowel tumors, and hematologic malignancies (17%). The cases and controls were not significantly different in the immunosuppressive regimen (p = 0.42) or the number of rejection episodes (p = 0.92). The five- and 10-year Kaplan–Meier survival rates for the cases were 77% and 34%, respectively, vs. 84% and 70%, respectively, for the controls (p = 0.02 by log-rank test). Patients with skin cancers had survival similar to the controls, but significantly better than non-skin cancers (p = 0.0001). The prognosis for patients with gastrointestinal tumors was poor, with a median survival of 8.5 months after the diagnosis.
In this single institutional study, de novo malignancies after OLT were uncommon. Patients with non-skin cancer after OLT had diminished long-term survival compared with the controls. Our results differ from other reports in the high incidence of gastrointestinal malignancies with attendant poor prognosis.
PMCID: PMC4050657  PMID: 16968488
de novo malignancies; orthotopic liver transplantation
24.  Recurrent Primary Biliary Cirrhosis: Peritransplant Factors and Ursodeoxycholic Acid Treatment Post-Liver Transplant 
Primary biliary cirrhosis (PBC) recurs after orthotopic liver transplantation (OLT) in up to one-third of patients. These patients are typically asymptomatic, can be identified by abnormal liver biochemistries, and have evidence of histologic recurrence on liver biopsy. The effect of treatment on recurrence has not been determined. This pilot study evaluates the factors associated with recurrent PBC and describes our experience using ursodeoxycholic acid treatment in this patient population. Forty-eight patients with PBC were followed for at least 1 yr post-OLT, and 27 patients (56%) developed abnormal serum alkaline phosphatase. Seventeen patients (35%) had evidence of recurrent PBC by liver biopsy. Patients with recurrent PBC had a trend toward longer warm ischemia times and more episodes of acute cellular rejection in the first year posttransplant, but this was not significant in multivariate analysis. Donor or recipient age, donor and recipient cytomegalovirus status, and dose of immunosuppression did not correlate with recurrence of PBC. Those patients diagnosed with recurrent PBC were placed on ursodeoxycholic acid, 15 mg/kg daily, with improvement in serum alkaline phosphatase in the majority. In conclusion, recurrent PBC is not infrequent post-OLT, and ursodeoxycholic acid can be used with some benefit post-OLT. Treatment effects on long-term survival are not known.
PMCID: PMC4050662  PMID: 16184542
25.  Viral Kinetics in Hepatitis C or Hepatitis C/Human Immunodeficiency Virus–Infected Patients 
Gastroenterology  2005;128(2):313-327.
Background & Aims
Kinetic modeling of hepatitis C virus (HCV) response to interferon (IFN)-based therapy provides insights into factors associated with treatment outcomes. HCV/human immunodeficiency virus (HIV)–co-infected patients show lower response rates vs. HCV-monoinfected patients. Reasons for this remain unclear. This study evaluated kinetic parameters and treatment responses in co-infected vs monoinfected patients.
Co-infected patients were randomized within a US multicenter trial (ACTG 5071) to receive pegylatedinterferon (PEG-IFN) alfa-2a + ribavirin vs. IFN alfa-2a + ribavirin. Monoinfected controls were matched prospectively for treatment, genotype, age, sex, race, and histology. Quantitative HCV-RNA testing was performed at hours 0, 6, 12, 24, 48, and 72; days 7, 10, 14, 28, and 56; and weeks 12, 24, 48, and 72.
Twelve HCV/HIV–co-infected and 15 HCV-monoinfected patients underwent viral kinetic sampling. Among HIV-positive patients the mean CD4+ count was 325 cells/mm3. Seventy-five percent of patients were genotype 1. The HCV-RNA level was undetectable at 72 weeks in 25% and 40% of co-infected and monoinfected patients, respectively. Phase 1/2 declines, free virus clearance rate, and infected hepatocyte death rate were not affected by co-infection status but differed by treatment. Efficiency (∈) ≥ 90% at 60 hours was associated with viral clearance (P = .02). Modeling with pooled parameters suggests baseline viral load is a key factor in time to response in this cohort. Predicted clearance time increased by 28% in co-infected patients.
Co-infection status did not affect key kinetic parameters. Among kinetic parameters, efficiency was associated significantly with viral clearance. Co-infected patients may require longer treatment duration than monoinfected patients given their generally higher baseline viral loads.
PMCID: PMC4036101  PMID: 15685543

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