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Yaron Rotman,
Mazen Noureddin, Jordan J Feld,
Jeremie Guedj,
Michael Witthaus,
Hwalih Han,
Yoon J Park,
Su-Hyung Park,
Theo Heller,
Marc G Ghany, [......],
Emmanuel Thomas,
Golo Ahlenstiel,
Birgit Edlich,
Rachel Titerence,
Leah Hogdal,
Barbara Rehermann,
Harel Dahari,
Alan S Perelson,
Jay H Hoofnagle,
T Jake Liang
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ABSTRACT: OBJECTIVE: Ribavirin improves treatment response to pegylated-interferon (PEG-IFN) in chronic hepatitis C but the mechanism remains controversial. We studied correlates of response and mechanism of action of ribavirin in treatment of hepatitis C. DESIGN: 70 treatment-naive patients were randomised to 4 weeks of ribavirin (1000-1200 mg/d) or none, followed by PEG-IFNα-2a and ribavirin at standard doses and durations. Patients were also randomised to a liver biopsy 24 h before or 6 h after starting PEG-IFN. Hepatic gene expression was assessed by microarray and interferon-stimulated gene (ISG) expression quantified by nCounter platform. Temporal changes in ISG expression were assessed by qPCR in peripheral-blood mononuclear cells (PBMC) and by serum levels of IP-10. RESULTS: After 4 weeks of ribavirin monotherapy, hepatitis C virus (HCV) levels decreased by 0.5±0.5 log(10) (p=0.009 vs controls) and ALT by 33% (p<0.001). Ribavirin pretreatment, while modestly augmenting ISG induction by PEG-IFN, did not modify the virological response to subsequent PEG-IFN and ribavirin treatment. However, biochemical, but not virological, response to ribavirin monotherapy predicted response to subsequent combination treatment (rapid virological response, 71% in biochemical responders vs 22% non-responders, p=0.01; early virological response, 100% vs 68%, p=0.03; sustained virological response 83% vs 41%, p=0.053). Ribavirin monotherapy lowered serum IP-10 levels but had no effect on ISG expression in PBMC. CONCLUSIONS: Ribavirin is a weak antiviral but its clinical effect seems to be mediated by a separate, indirect mechanism, which may act to reset IFN-responsiveness in HCV-infected liver.
Gut 02/2013; · 10.11 Impact Factor
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ABSTRACT: Natural killer (NK) cells exhibit a polarized phenotype with increased cytotoxicity and decreased interferon gamma (IFN-γ) production in chronic hepatitis C virus (HCV) infection. Here, we asked whether this is caused by type I interferon (IFN)-induced expression and phosphorylation levels of signal transducer and activator of transcription (STAT) molecules in NK cells and whether it affects the response and refractoriness of NK cells to IFN-α-based therapy of HCV. STAT1 levels in NK cells were significantly higher in patients with chronic HCV infection than in uninfected controls. STAT1 levels and induction of phosphorylated STAT1 (pSTAT1) increased further during IFN-α-based therapy with preferential STAT1 over STAT4 phosphorylation. Induction of pSTAT1 correlated with increased NK cytotoxicity (tumor necrosis factor-apoptosis-inducing ligand [TRAIL] expression and degranulation) and decreased IFN-γ production. NK cells from patients with a greater than 2 log(10) first-phase HCV RNA decline to IFN-α-based therapy (>99% IFN effectiveness) displayed strong pSTAT1 induction in vivo and were refractory to further stimulation in vitro. In contrast, NK cells from patients with a less than 2 log(10) first-phase HCV RNA decline exhibited lower pSTAT1 induction in vivo (P = 0.024), but retained greater IFN-α responsiveness in vitro (P = 0.024). NK cells of all patients became refractory to in vivo and in vitro stimulation by IFN-α during the second-phase virological response. CONCLUSION: These data show that IFN-α-induced modulation of STAT1/4 phosphorylation underlies the polarization of NK cells toward increased cytotoxicity and decreased IFN-γ production in HCV infection, and that NK cell responsiveness and refractoriness correlate to the antiviral effectiveness of IFN-α-based therapy.
Hepatology 08/2011; 55(1):39-48. · 11.66 Impact Factor
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ABSTRACT: Mathematical modeling of hepatitis C virus (HCV) kinetics indicated that cellular immune responses contribute to interferon (IFN)-induced clearance of HCV. We investigated a potential role of natural killer (NK) cells in this process.
Phenotype and function of blood and liver NK cells were studied during the first 12 weeks of treatment with pegylated IFN-alfa and ribavirin, the time period used to define the early virological response.
Within hours of treatment initiation, NK cells of patients that had an early virological response increased expression of activating receptors NKG2D, NKp30, and CD16 and decreased expression of NKG2C and 2B4, along with inhibitory receptors SIGLEC7 and NKG2A, resulting in NK cell activation. NK cell cytotoxicity, measured by degranulation and tumor necrosis factor-related apoptosis-inducing ligand production, peaked after 24 hours (P<.01), concomitant with an increase in alanine aminotransferase levels (P<.05), whereas IFN-γ production decreased within 6 hours and did not recover for more than 4 weeks (P<.05). NK cells from liver biopsies taken 6 hours after treatment initiation had increased numbers of cytotoxic CD16+NK cells (P<.05) and a trend toward increased production of tumor necrosis factor-related apoptosis-inducing ligand. Degranulation of peripheral blood NK cells correlated with treatment-induced, first-phase decreases in viral load (P<.05) and remained higher in early virological responders than in nonresponders for weeks.
IFN activates NK cells early after treatment is initiated. Their cytotoxic function, in particular, is strongly induced, which correlates to virologic response. Therefore, NK cell activation indicates responsiveness to IFN-α-based treatment and suggests the involvement of the innate immune cells in viral clearance.
Gastroenterology 07/2011; 141(4):1231-9, 1239.e1-2. · 11.68 Impact Factor
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Jordan J Feld,
Apurva A Modi,
Ramy El-Diwany,
Yaron Rotman,
Emmanuel Thomas,
Golo Ahlenstiel,
Rachel Titerence,
Christopher Koh,
Vera Cherepanov,
Theo Heller,
Marc G Ghany,
Yoon Park,
Jay H Hoofnagle,
T Jake Liang
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ABSTRACT: Less than half of patients infected with hepatitis C virus (HCV) achieve sustained viral clearance after pegylated interferon (peginterferon) and ribavirin therapy. S-adenosyl methionine (SAMe) improves interferon signaling in cell culture. We assessed the effect of SAMe on the kinetics of the early antiviral response and interferon signaling in nonresponders to previous antiviral therapy and investigated the mechanisms involved.
Nonresponders with HCV genotype 1 were given peginterferon alfa-2a and ribavirin for 2 weeks (course A, baseline/control). After 1 month, patients received SAMe (1600 mg daily) for 2 weeks and then peginterferon and ribavirin for 48 weeks (course B; completed by 21 of 24 patients). Viral kinetics and interferon-stimulated gene (ISG) expression in peripheral blood mononuclear cells (PBMCs) were compared between courses.
The decrease in HCV RNA from 0 to 48 hours (phase 1) was similar with and without SAMe. However, the second phase slope of viral decline was improved with SAMe (course A, 0.11 ± 0.04 log(10) IU/mL/wk; course B, 0.27 ± 0.06; P = .009); 11 patients (53%) achieved an early virological response, and 10 (48%) had undetectable HCV RNA by week 24. Induction of ISGs in PBMCs was significantly greater during course B. In cultured cells, SAMe increased induction of ISGs and the antiviral effects of interferon by increasing STAT1 methylation, possibly affecting STAT1-DNA binding.
The addition of SAMe to peginterferon and ribavirin improves the early viral kinetics and increases ISG induction in nonresponders to previous therapy. SAMe might be a useful adjunct to peginterferon-based therapies in chronic HCV infection.
Gastroenterology 03/2011; 140(3):830-9. · 11.68 Impact Factor
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ABSTRACT: The combination of pegylated interferon (PEG-IFN) and ribavirin is the standard treatment for chronic hepatitis C. Our recent clinical study suggests that ribavirin augments the induction of interferon-stimulated genes (ISGs) in patients treated for hepatitis C virus (HCV) infection. In order to further characterize the mechanisms of action of ribavirin, we examined the effect of ribavirin treatment on ISG induction in cell culture. In addition, the effect of ribavirin on infectious HCV cell culture systems was studied. Similar to interferon (IFN)-α, ribavirin potently inhibits JFH-1 infection of Huh7.5.1 cells in a dose-dependent manner, which spans the physiological concentration of ribavirin in vivo. Microarray analysis and subsequent quantitative polymerase chain reaction assays demonstrated that ribavirin treatment resulted in the induction of a distinct set of ISGs. These ISGs, including IFN regulatory factors 7 and 9, are known to play an important role in anti-HCV responses. When ribavirin is used in conjunction with IFN-α, induction of specific ISGs is synergistic when compared with either drug applied separately. Direct up-regulation of these antiviral genes by ribavirin is mediated by a novel mechanism different from those associated with IFN signaling and intracellular double-stranded RNA sensing pathways such as RIG-I and MDA5. RNA interference studies excluded the activation of the Toll-like receptor and nuclear factor κB pathways in the action of ribavirin. CONCLUSION: Our study suggests that ribavirin, acting by way of a novel innate mechanism, potentiates the anti-HCV effect of IFN. Understanding the mechanism of action of ribavirin would be valuable in identifying novel antivirals.
Hepatology 01/2011; 53(1):32-41. · 11.66 Impact Factor
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Douglas B Kuhns,
W Gregory Alvord,
Theo Heller, Jordan J Feld,
Kristen M Pike,
Beatriz E Marciano,
Gulbu Uzel,
Suk See DeRavin,
Debra A Long Priel,
Benjamin P Soule,
Kol A Zarember,
Harry L Malech,
Steven M Holland,
John I Gallin
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ABSTRACT: Failure to generate phagocyte-derived superoxide and related reactive oxygen intermediates (ROIs) is the major defect in chronic granulomatous disease, causing recurrent infections and granulomatous complications. Chronic granulomatous disease is caused by missense, nonsense, frameshift, splice, or deletion mutations in the genes for p22(phox), p40(phox), p47(phox), p67(phox) (autosomal chronic granulomatous disease), or gp91(phox) (X-linked chronic granulomatous disease), which result in variable production of neutrophil-derived ROIs. We hypothesized that residual ROI production might be linked to survival in patients with chronic granulomatous disease.
We assessed the risks of illness and death among 287 patients with chronic granulomatous disease from 244 kindreds. Residual ROI production was measured with the use of superoxide-dependent ferricytochrome c reduction and flow cytometry with dihydrorhodamine oxidation assays. Expression of NADPH oxidase component protein was detected by means of immunoblotting, and the affected genes were sequenced to identify causal mutations.
Survival of patients with chronic granulomatous disease was strongly associated with residual ROI production as a continuous variable, independently of the specific gene affected. Patients with mutations in p47(phox) and most missense mutations in gp91(phox) (with the exception of missense mutations in the nucleotide-binding and heme-binding domains) had more residual ROI production than patients with nonsense, frameshift, splice, or deletion mutations in gp91(phox). After adolescence, mortality curves diverged according to the extent of residual ROI production.
Patients with chronic granulomatous disease and modest residual production of ROI have significantly less severe illness and a greater likelihood of long-term survival than patients with little residual ROI production. The production of residual ROI is predicted by the specific NADPH oxidase mutation, regardless of the specific gene affected, and it is a predictor of survival in patients with chronic granulomatous disease. (Funded by the National Institutes of Health.).
New England Journal of Medicine 12/2010; 363(27):2600-10. · 53.30 Impact Factor
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Lauren M Kucirka,
Homayoon Farzadegan, Jordan J Feld,
Shruti H Mehta,
Mark Winters,
Jeffrey S Glenn,
Gregory D Kirk,
Dorry L Segev,
Kenrad E Nelson,
Morgan Marks,
Theo Heller,
Elizabeth T Golub
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ABSTRACT: Most hepatitis delta virus (HDV) prevalence estimates from the United States are >10 years old, and HDV has shown significant temporal variation in other populations. HDV-hepatitis B virus (HBV) dual infection progresses rapidly, has more complications, and has a different treatment regimen than HBV infection alone. Accurate estimates of prevalence and risk factors are important to help clinicians decide who to screen.
Injection drug users in Baltimore, Maryland, who were positive for HBV serologic markers were tested for hepatitis delta antibody (HDAb) at 2 time periods: 1988-1989 (194 participants) and 2005-2006 (258 participants). Those who were HDAb positive in 2005-2006, plus a random sample of HDAb negative, HBV-positive participants were tested for HDV RNA, HBV DNA, and HCV RNA. Characteristics associated with HDV exposure and viremia were identified.
HDV prevalence declined from 15% in 1988-1989 to 11% in 2005-2006. Among those with chronic HBV infection, prevalence increased from 29% (14 of 48 participants) to 50% (19 of 38 participants) (P=.05). Visiting a "shooting gallery" (a location where people gather to inject illegal drugs) was a strong correlate of HDAb positivity (relative risk, 3.08; P=.01). Eight (32%) of those who were HDAb positive had HDV viremia. Viremic participants had elevated liver enzyme levels and more emergency room visits.
The temporal increase in HDV prevalence among those with chronic HBV infection is troubling; understanding this change should be a priority to prevent the burden from increasing.
The Journal of Infectious Diseases 09/2010; 202(6):845-52. · 6.41 Impact Factor
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Jordan J Feld,
Glen A Lutchman,
Theo Heller,
Koji Hara,
Julie K Pfeiffer,
Richard D Leff,
Claudia Meek,
Maria Rivera,
Myung Ko,
Christopher Koh,
Yaron Rotman,
Marc G Ghany,
Vanessa Haynes-Williams,
Avidan U Neumann,
T Jake Liang,
Jay H Hoofnagle
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ABSTRACT: The therapeutic mechanisms of ribavirin for hepatitis C are unclear. Microarray analyses have shown that ribavirin increases induction of interferon-stimulated genes. We evaluated viral kinetics, serum cytokine expression, and viral mutagenesis during early stages of peginterferon therapy with and without ribavirin.
Fifty patients with chronic hepatitis C virus (HCV) infection genotype 1 were randomly assigned to groups that were given peginterferon alpha-2a, with or without ribavirin, for 4 weeks; all patients then received an additional 44 weeks of combination therapy. First- and second-phase viral kinetics were evaluated. Serum levels of interferon-gamma-inducible protein-10 (IP10), monokine induced by interferon-gamma, and monocyte chemoattractant protein 1 were quantified as measures of the interferon-stimulated genes response. NS5A and NS5B were partially sequenced, and mutation rates were calculated.
The first-phase decrease in HCV RNA was similar between groups. Patients who received ribavirin had a more rapid second-phase decrease, compared with patients who did not receive ribavirin-particularly those with an adequate first-phase decrease (0.61 vs 0.35 log10 IU/mL/week; P = .018). At 12 hours, fold induction of serum IP10 was higher in patients given the combination therapy than those given peginterferon only (7.6- vs 3.8-fold; P = .01); however, the difference was greatest in patients with an adequate first-phase decrease in HCV RNA. IP10-induction correlated with first- and second-phase kinetics and with ribavirin serum concentrations on day 3. HCV mutation rates were similar between groups.
Ribavirin improves the kinetics of the early response to therapy in patients with an adequate initial response to peginterferon. Induction of interferon-stimulated cytokines correlates with viral kinetics following ribavirin therapy, suggesting that ribavirin promotes interferon signaling.
Gastroenterology 07/2010; 139(1):154-62.e4. · 11.68 Impact Factor
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ABSTRACT: PURPOSE An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO) offers timely clinical direction to ASCO's membership following publication or presentation of potentially practice-changing information. This PCO addresses recommendations for chronic hepatitis B virus (HBV) infection screening in patients receiving cytotoxic or immunosuppressive chemotherapy for treatment of malignant diseases. CLINICAL CONTEXT: The Centers for Disease Control and Prevention (CDC) issued Recommendations for Identification and Public Health Management of Persons with Chronic Hepatitis B Virus Infection, recommending screening for hepatitis B infection (hepatitis B surface antigen [HBsAg], antihepatitis B core antigen [anti-HBc], and antibodies to HBsAg [anti-HBs]) for "persons receiving cytotoxic or immunosuppressive therapy (eg, chemotherapy for malignant diseases...)." PROVISIONAL CLINICAL OPINION: The evidence is insufficient to determine the net benefits and harms of routine screening for chronic HBV infection in individuals with cancer who are about to receive cytotoxic or immunosuppressive therapy or who are already receiving therapy. Individuals with cancer who undergo certain cytotoxic or immunosuppressive therapies and have HBV infection or prior exposure to HBV may be at elevated risk of liver failure from HBV reactivation. As such, HBV screening requires clinical judgment. Physicians may consider screening patients belonging to groups at heightened risk for chronic HBV infection or if highly immunosuppressive therapy is planned. Highly immunosuppressive treatments include, but are not limited to, hematopoietic cell transplantation and regimens including rituximab. Screening based on a high risk of prior HBV exposure or risk of reactivation due to planned therapeutic regimens should include testing for HBsAg as a serologic marker for HBV infection. In some populations, testing for anti-HBc should also be considered. There is no evidence to support serologic testing for anti-HBs in this context. When evidence for chronic HBV infection is found, antiviral therapy before and throughout the course of chemotherapy may be considered to reduce the risk of HBV reactivation, although evidence from controlled trials of this approach is limited. Screening and/or treating HBV infection should not delay the initiation of chemotherapy. NOTE: ASCO's provisional clinical opinions (PCOs) reflect expert consensus based on clinical evidence and literature available at the time they are written, and are intended to assist physicians in clinical decision-making and identify questions and settings for further research. Due to the rapid flow of scientific information in oncology, new evidence may have emerged since the time a PCO was submitted for publication. PCOs are not continually updated and may not reflect the most recent evidence. PCOs address only the topics specifically identified in the PCO and are not applicable to interventions, diseases or stages of disease not specifically identified. PCOs cannot account for individual variation among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine the best course of treatment for the patient. Accordingly, adherence to any PCO is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances. ASCO PCOs describe the use of procedures and therapies in clinical practice and cannot be assumed to apply to the use of these interventions in the context of clinical trials. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO's PCOs, or for any errors or omissions.
Journal of Clinical Oncology 07/2010; 28(19):3199-202. · 18.37 Impact Factor
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ABSTRACT: Although coffee consumption has been associated with reduced frequency of liver disease, it is unclear whether the effect is from coffee or caffeine and whether there is an effect on hepatic fibrosis specifically. This study was undertaken to use a food-frequency instrument for dietary caffeine consumption to evaluate the relationship between caffeine intake and liver fibrosis. Patients undergoing liver biopsy completed a detailed caffeine questionnaire on three occasions over a 6-month period. Caffeine intake was compared between patients with mild and advanced liver fibrosis (bridging fibrosis/cirrhosis). Logistic regression was used to evaluate the association between caffeine consumption and hepatic fibrosis. One hundred seventy-seven patients (99 male, 104 white, 121 with chronic hepatitis C virus [HCV] infection) undergoing liver biopsy completed the caffeine questionnaire on up to three occasions. Results from repeated questionnaires were consistent. Daily caffeine consumption above the 75(th) percentile for the cohort (308 mg = approximately 2.25 cups of coffee equivalents) was associated with reduced liver fibrosis (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.14-0.80; P = 0.015) and the protective association persisted after controlling for age, sex, race, liver disease, body mass index, and alcohol intake in all patients (OR, 0.25; 95% CI, 0.09-0.67; P = 0.006), as well as the subset with HCV infection (OR, 0.19; 95% CI, 0.05-0.66; P = 0.009). Despite a modest trend, consumption of caffeine from sources other than coffee or of decaffeinated coffee was not associated with reduced liver fibrosis. A reliable tool for measurement of caffeine consumption demonstrated that caffeine consumption, particularly from regular coffee, above a threshold of approximately 2 coffee-cup equivalents per day, was associated with less severe hepatic fibrosis.
Hepatology 01/2010; 51(1):201-9. · 11.66 Impact Factor
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Golo Ahlenstiel,
Rachel H Titerence,
Christopher Koh,
Birgit Edlich, Jordan J Feld,
Yaron Rotman,
Marc G Ghany,
Jay H Hoofnagle,
T Jake Liang,
Theo Heller,
Barbara Rehermann
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ABSTRACT: Patients with chronic hepatitis C virus (HCV) infection display great variability in disease activity and progression. Although virus-specific adaptive immune responses have been characterized extensively and found to be impaired in chronic hepatitis C, the role of innate immune responses in disease activity and progression of chronic hepatitis C is not well understood.
We studied 42 HCV-infected patients and 12 healthy uninfected controls.
We found an increased frequency of natural killer (NK) cells expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), NKp44, NKG2C, and CD122 in chronic hepatitis C as compared with healthy controls (P < .05 for all markers) and stronger activation of NK cells in the liver than in the blood (P < .05). This NK cell phenotype was associated with polarization of NK cell function toward CD107a expression as a marker of degranulation, but with not increased interferon (IFN)-gamma production of CD56(dim) NK cells. The polarized NK cell phenotype correlated with alanine aminotransferase levels (r(2) = 0.312, P = .03). To investigate whether in vivo exposure of NK cells to HCV-induced type I IFN was causing this NK cell phenotype, peripheral blood mononuclear cells from 10 healthy controls and 8 HCV-infected patients were stimulated in the presence of IFN-alfa, which resulted in increased NK cell expression of TRAIL and CD107a (P < .001), but not IFN-gamma.
Collectively, these results describe a polarized NK cell phenotype induced by chronic exposure to HCV-induced IFN-alfa. This phenotype may contribute to liver injury through TRAIL expression and cytotoxicity, whereas the lacking increase in IFN-gamma production may facilitate the inability to clear HCV.
Gastroenterology 09/2009; 138(1):325-35.e1-2. · 11.68 Impact Factor
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Tara N Palmore,
Neeral L Shah,
Rohit Loomba,
Brian B Borg,
Uri Lopatin, Jordan J Feld,
Farooq Khokhar,
Glen Lutchman,
David E Kleiner,
Neal S Young,
Richard Childs,
A John Barrett,
T Jake Liang,
Jay H Hoofnagle,
Theo Heller
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ABSTRACT: HBV infection may reactivate in the setting of immunosuppression, although the frequency and consequences of HBV reactivation are not well known. We report 6 patients who experienced loss of serologic markers of hepatitis B immunity and reappearance of HBsAg in the serum as a result of a variety of acquired immune deficiencies.
Between 2000 and 2005, six patients with reactivation of hepatitis B were seen in consultation by the Liver Diseases Branch at the Clinical Center, National Institutes of Health. The course and outcome of these 6 patients were reviewed.
All 6 patients developed reappearance of HBsAg and evidence of active liver disease after stem cell transplantation (n = 4), immunosuppressive therapy (n = 1), or change in human immunodeficiency virus antiretroviral regimen (n = 1), despite having antibody to HBsAg (anti-HBs) or antibody to hepatitis B core antigen (anti-HBc) without HBsAg before. All 6 patients developed chronic hepatitis B, 2 patients transmitted hepatitis B to their spouses, and 1 patient developed cirrhosis. The diagnosis of hepatitis B reactivation was frequently missed or delayed and often required interruption of the therapy for the underlying condition. None of the patients received antiviral prophylaxis against HBV reactivation.
Serologic evidence of recovery from hepatitis B infection does not preclude its reactivation after immunosuppression. Screening for serologic evidence of hepatitis B and prophylaxis of those with positive results by using nucleoside analogue antiviral therapy should be provided to individuals in whom immunosuppressive therapy is planned.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 08/2009; 7(10):1130-7. · 5.64 Impact Factor
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ABSTRACT: The slow progression of hepatitis C virus (HCV) infection could ultimately negatively impact pediatric patients during their lifespan. This study describes the symptomatic and pathophysiologic presentation of HCV infection in a cohort of pediatric outpatients.
HCV-positive patients were identified by diagnosis codes from outpatient visits. Demographic and pathophysiologic indicators (comorbidities, reported symptoms, alanine transaminase, aspartate transaminase, gamma glutamyl transpeptidase, HCV viral load, genotype, and liver biopsy results) were collected and analyzed.
We reviewed 62 patients with HCV infection who were from 3 months and 19 years of age (M +/- SD, 12.5 +/- 5.8 years). Sixty percent presented with clinical symptoms of fatigue, joint-abdominal pain, bruising/bleeding, or other non-specific symptoms. On liver biopsy (n = 35) 80% had evidence of inflammation, 57% had fibrosis, and 9% had steatosis. All patients with steatosis or cirrhosis reported symptoms. Males were significantly more likely than women to be symptomatic (58.3% vs. 41.7%, P = 0.04). Patients with symptoms were significantly older (M = 13.5 +/- 5.2 vs. 8.9 +/- 5.5 years, P = 0.003). There was a significant inverse relationship between viral load and symptoms (chi = 4.75, P = 0.03). Patients with low viral load (<2 million copies) were 5 times more likely to have symptoms than those with high viral loads (P = 0.03). Significance was also noted between HCV genotype and ALT levels (chi = 3.72, P = 0.05). There were no significant relationships between symptom status and race, comorbidities, alanine transaminase, aspartate transaminase, gamma glutamyl transpeptidase, HCV genotype, or liver histology.
Pediatric patients with HCV can have significant symptoms and physiologic liver changes related to HCV.
The Pediatric Infectious Disease Journal 08/2009; 28(8):724-7. · 3.58 Impact Factor
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ABSTRACT: Because clearance of hepatitis B virus (HBV) infection is rarely, if ever, achievable, the goals of therapy necessarily focus on prevention of bad clinical outcomes. Ideally, therapies would be shown to prevent tangible clinical endpoints like development of cirrhosis, end-stage liver disease and hepatocellular carcinoma. However, these endpoints typically take years or decades to occur and are therefore impractical targets for clinical trials which last only 1-2 years. As a result, surrogate biomarkers that are believed to correlate with long-term outcome are used to evaluate therapy. Of the clinical, biochemical, serological, virological, and histological endpoints that have been evaluated, none has been shown to be ideal on its own. Symptoms are uncommon and aminotransferase levels fluctuate spontaneously. Loss of hepatitis B e antigen (HBeAg) has been the traditional therapeutic endpoint; however, the indefinite durability off treatment and the emergence of HBeAg-negative disease have made it inadequate as the sole goal of therapy. Loss of hepatitis B surface antigen is associated with improved clinical outcomes, but it is rarely achieved with current therapies. Suppression of viral replication, as measured by serum HBV DNA levels, has become the major goal of therapy, particularly if maintained off therapy. Although useful, the significance of viral levels depends on the stage of disease, degree of liver damage, and the type of therapy. Finally, liver biopsy, often considered the gold standard, is invasive, prone to sampling error, and may take years to change significantly.At present, there is no ideal biomarker for evaluation of therapies for hepatitis B. Future research should be directed at development and validation of surrogate markers that accurately predict or reflect clinically relevant outcomes of chronic hepatitis B.
Hepatology 05/2009; 49(5 Suppl):S96-S102. · 11.66 Impact Factor
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ABSTRACT: Antimitochondrial antibodies (AMAs) are the serological hallmark for primary biliary cirrhosis (PBC). When AMAs are detected in patients with chronic hepatitis, they negatively impact on the autoimmune hepatitis (AIH) scoring system. The purpose of this study was to determine if AMAs detected in the sera of patients with overt AIH have clinical or pathological significance. All patients with a clinicopathologic diagnosis of AIH from one center were reviewed. Only those meeting the criteria for probable or definite AIH according to the International Autoimmune Hepatitis Group were included. Patients found to be consistently AMA-positive via enzyme-linked immunosorbent assay (ELISA) for pyruvate dehydrogenase complex E2 subunit were reviewed in detail. Fifteen of 126 patients with typical features of AIH (pretreatment AIH score >10) had detectable AMAs in serum. None had any histologic features suggestive of PBC. None had detectable anti-liver-kidney-microsomal antibodies. Of these 15 patients, all have remained persistently AMA-positive via ELISA. All 15 patients have been followed long-term, and their clinical course remained typical for AIH. No bile duct damage typical of PBC was seen on initial or follow-up liver biopsies. CONCLUSION: Patients with overt AIH who test positive for AMAs at initial presentation and are treated with corticosteroid therapy have shown no clinical or histologic evidence of PBC despite the continued detection of AMAs over a follow-up of up to 27 years.
Hepatology 09/2008; 48(2):550-6. · 11.66 Impact Factor
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Jordan J Feld,
Nadeem Hussain,
Elizabeth C Wright,
David E Kleiner,
Jay H Hoofnagle,
Sushil Ahlawat,
Victoria Anderson,
Dianne Hilligoss,
John I Gallin,
T Jake Liang,
Harry L Malech,
Steven M Holland,
Theo Heller
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ABSTRACT: Chronic granulomatous disease (CGD) is a rare genetic disorder, predisposing affected individuals to recurrent infectious complications and shortened survival. Liver involvement in CGD includes vascular abnormalities, which may lead to noncirrhotic portal hypertension.
To evaluate the impact of noncirrhotic portal hypertension on survival in CGD, all records from 194 patients followed up at the National Institutes of Health with CGD were reviewed. Cox proportional hazards regression was used to determine factors associated with mortality.
Twenty-four patients died, all from infectious complications. By Cox regression, factors associated with mortality were as follows: (1) decreases in platelet count (>9000/microL/y; hazard ratio, 4.7; P = .007), (2) alkaline phosphatase level increases (>0.25/y; hazard ratio, 4.5; P = .01) and (3) history of liver abscess (hazard ratio, 3.1; P = .03). By regression analysis, decreasing platelet count was associated with increasing portal vein diameter, splenomegaly, increased serum immunoglobulin G level, and increasing number of alanine aminotransferase increases; greater number of alkaline phosphatase level increases and abscess were both associated with increasing age and number of infections. Prospective evaluation revealed increased hepatic-venous pressure gradients in 2 patients with progressive thrombocytopenia, suggestive of portal hypertension.
These data suggest mortality in patients with CGD is associated with the development of noncirrhotic portal hypertension, likely owing to injury to the microvasculature of the liver from repeated systemic and hepatic infections. The slope of decline in platelet count may be a useful measure of progression of portal hypertension over time. Furthermore, the data illustrate the potential independent effect of portal hypertension on clinical outcome outside the setting of cirrhosis.
Gastroenterology 06/2008; 134(7):1917-26. · 11.68 Impact Factor
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Annals of internal medicine 01/2008; 147(11):806-8. · 16.73 Impact Factor
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Jordan J Feld,
Santosh Nanda,
Ying Huang,
Weiping Chen,
Maggie Cam,
Susan N Pusek,
Lisa M Schweigler,
Dickens Theodore,
Steven L Zacks,
T Jake Liang,
Michael W Fried
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ABSTRACT: The reasons for hepatitis C treatment failure remain unknown but may be related to different host responses to therapy. In this study, we compared hepatic gene expression in patients prior to and during peginterferon and ribavirin therapy. In the on-treatment group, patients received either ribavirin for 72 hours prior to peginterferon alpha-2a injection or peginterferon alpha-2a for 24 hours, prior to biopsy. The patients were grouped into rapid responders (RRs) with a greater than 2-log drop and slow responders (SRs) with a less than 2-log drop in hepatitis C virus RNA by week 4. Pretreatment biopsy specimens were obtained from a matched control group. The pretreatment patients were grouped as RRs or SRs on the basis of the subsequent treatment response. Gene expression profiling was performed with Affymetrix microarray technology. Known interferon-stimulated genes (ISGs) were induced in treated patients. In the pretreatment group, future SRs had higher pretreatment ISG expression than RRs. On treatment, RRs and SRs had similar absolute ISG expression, but when it was corrected for the baseline expression with the pretreatment group, RRs showed a greater fold change in ISGs, whereas SRs showed a greater change in interferon (IFN)-inhibitory pathways. The patients pretreated with ribavirin had heightened induction of IFN-related genes and down-regulation of genes involved in IFN inhibition and hepatic stellate cell activation. CONCLUSION: These data suggest that ISG inducibility is important for the treatment response and that ribavirin may improve outcomes by enhancing hepatic gene responses to peginterferon. Collectively, these mechanisms may provide a molecular basis for the improved efficacy of combination therapy.
Hepatology 12/2007; 46(5):1548-63. · 11.66 Impact Factor
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ABSTRACT: After hepatitis B e antigen (HBeAg) seroconversion, hepatitis B may become inactive or progress to HBeAg-negative hepatitis with persistent or intermittent alanine aminotransferase (ALT) elevation. The aim of this study was to prospectively identify factors predictive of the clinical course in HBeAg-negative chronic hepatitis B (CHB). Patients were stratified by ALT and HBeAg status and followed every 3 months for up to 5 years. Kaplan-Meier and Cox regression analysis using the change from normal ALT to elevated ALT as endpoints were performed to determine factors associated with ALT elevation/normalization. Seventy-four HBeAg-negative and 32 HBeAg-positive patients were prospectively evaluated. For HBeAg-negative patients, hepatitis B virus (HBV) DNA was predictive of future ALT. Only 1 patient with normal ALT and an HBV DNA value lower than 10,000 copies/mL developed an elevated ALT within the subsequent year, whereas 67% with an HBV DNA value greater than 100,000 copies/mL had a rise in ALT above normal within 1 year. Patients with a previous history of ALT elevation and longer follow-up at all levels of HBV DNA were more likely to experience ALT elevations. For HBeAg-negative patients with elevated ALT and all HBeAg-positive patients, HBV DNA did not predict future ALT. Other viral and host factors were not predictive of future ALT. CONCLUSION: HBeAg-negative CHB has a fluctuating course. HBV DNA values lower than 10,000 copies/mL predict persistently normal ALT for at least 1 year. Patients with HBV DNA values between 10,000 and 100,000 copies/mL can safely be followed at 6 monthly intervals, whereas HBV DNA values greater than 100,000 copies/mL are highly predictive of future ALT elevation and should prompt regular follow-up.
Hepatology 11/2007; 46(4):1057-70. · 11.66 Impact Factor
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Nadeem Hussain, Jordan J Feld,
David E Kleiner,
Jay H Hoofnagle,
Reyes Garcia-Eulate,
Sushil Ahlawat,
Deloris E Koziel,
Victoria Anderson,
Dianne Hilligoss,
Peter Choyke,
John I Gallin,
T Jake Liang,
Harry L Malech,
Steven M Holland,
Theo Heller
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ABSTRACT: Chronic granulomatous disease (CGD) is a rare congenital disorder characterized by repeated bacterial and fungal infections. Aside from a high incidence of liver abscess, little is known about hepatic involvement in CGD. The aim of this study was to describe the spectrum of liver abnormalities seen in CGD. The charts of 194 patients with CGD followed at the NIH were reviewed, with a focus on liver abnormalities. Liver enzyme elevations occurred on at least one occasion in 73% of patients during a mean of 8.9 years of follow-up. ALT elevations were generally transient. Although transient alkaline phosphatase (ALP) elevations were also common, persistent ALP elevations lasting up to 17.6 years were seen in 25% of patients. Liver abscess occurred in 35% of patients. Drug-induced hepatotoxicity was documented in 15% of patients but likely occurred more frequently. Hepatomegaly was found in 34% and splenomegaly in 56% of patients. Liver histology showed granulomata in 75% and lobular hepatitis in 90% of specimens. Venopathy of the portal vein was common (80%) and associated with splenomegaly. Venopathy of the central vein was also common (63%) and was associated with the number of abscess episodes. Nodular regenerative hyperplasia (NRH) was seen in 9 patients, including 6 of 12 autopsy specimens. CONCLUSION: Liver enzyme abnormalities occur frequently in patients with CGD. In addition to liver abscesses and granulomata, drug hepatotoxicity is likely underappreciated. Vascular lesions such as venopathy and--to a lesser extent--NRH are common. The cause and clinical consequences of venopathy await prospective evaluation.
Hepatology 04/2007; 45(3):675-83. · 11.66 Impact Factor
