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Biomedical subjects

Michael W Fried

Publications and source records attributed to Michael W Fried.

At least 19 recordsLinked to original sources
PubMed2006

Neurocognitive functioning and HAART in HIV and hepatitis C virus co-infection.

OBJECTIVES: This study examined the effects of HAART on neurocognitive functioning in persons with hepatitis C virus (HCV) and HIV co-infection. DESIGN: A prospective study examining neurocognitive performance before and after HAART initiation. METHOD: Participant groups included a mono-infected group (45 HIV+/HCV- participants) and a co-infected group (20 HIV+/HCV+ participants). A neuropsychological battery (attention/concentration, psychomotor speed, executive functioning, verbal memory, visual memory, fine motor, and gross motor functioning) was used to evaluate all participants. After 6 months of HAART, 31 HIV+ mono-infected and 13 HCV+/HIV+ co-infected participants were reevaluated. RESULTS: Neurocognitive functioning by domain revealed significantly worse performance in the co-infected group when compared to the monoinfected group on domains of visual memory and fine motor functioning. Assessment of neurocognitive functioning after antiretroviral therapy revealed that the co-infected group was no longer performing worse than the monoinfected group. CONCLUSIONS: The findings of the current study suggest that persons with HCV+/HIV+ co-infection may have greater neurocognitive declines than persons with HIV infection alone. HCV+/HIV+ co-infection may accelerate the progression of HIV related neurocognitive decline.

Adult↗
PubMed2006

Optimizing treatment regimens in hepatitis C.

Scientists and clinicians have made tremendous advances in understanding the pathogenesis of hepatitis C virus (HCV) infection and have developed impressive strategies for treating this hepatotropic virus in the short time since its discovery in 1989. This article goes beyond the current guidelines for the treatment of HCV infection to examine the use of multiple pretreatment factors to predict response; the use of viral kinetics to guide length of treatment; higher dose ribavirin in genotype 1 infection; retreatment of non responders and relapsers; and improving adherence to therapy.

Antiviral Agents↗
PubMed2006

Chronic hepatitis B: a critical appraisal of current approaches to therapy.

BACKGROUND & AIMS: Treatment of chronic hepatitis B (CHB) involves a number of complex and controversial issues. Expert opinions may differ from those of practicing hepatologists and gastroenterologists. We aimed to explore this issue further after a critical review of the literature. METHODS: A panel of 14 international experts graded the strength of evidence for 16 statements addressing 3 content areas: patient selection, therapeutic end points, and treatment options. Available data relating to the statements were reviewed critically in 3 small work groups. After discussion of each statement with the entire panel, the experts voted anonymously to accept or reject statements based on the strength of evidence and their experience. A total of 241 members of the American Association for the Study of Liver Diseases (AASLD) responded to the same statements and their responses were compared with those of the experts. A discordant response was defined as a difference of more than 20% in any of the 5 graded levels of response (accept or reject) between the 2 groups. RESULTS: With the exception of 2 statements, the experts' responses were relatively uniform. However, the responses of the AASLD members were discordant from the experts in 12 statements, spanning all 3 content areas. CONCLUSIONS: Several areas of disagreement on the management of CHB exist between experts and AASLD members. Our results indicate a potential knowledge gap among practicing hepatologists. Better educational efforts are needed to meet the challenge of managing this complex disorder in which even expert opinion occasionally may disagree.

Adenine↗
PubMed2006

Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1.

BACKGROUND & AIMS: Compared with Caucasian Americans (CA), African Americans (AA) with chronic hepatitis C are less likely to respond to interferon-based antiviral therapy. METHODS: In a multicenter treatment trial, 196 AA and 205 CA treatment-naive patients with hepatitis C virus (HCV) genotype 1 infection were treated with peginterferon alfa-2a (180 microg/wk) and ribavirin (1000-1200 mg/day) for up to 48 weeks. The primary end point was sustained virologic response (SVR). RESULTS: Baseline features were similar among AA and CA, including HCV-RNA levels and histologic severity, but AA had higher body weights, a higher prevalence of diabetes and hypertension, and lower alanine transaminase levels (P < .001 for all). The SVR rate was 28% in AA and 52% in CA (P < .0001). Racial differences in viral responses were evident as early as treatment week 4. Breakthrough viremia was more frequent among AA than CA (13% vs 6%, P = .05); relapse rates were comparable (32% vs 25%, P = .30). Proportions of patients with serious adverse events and dose modifications and discontinuations were similar among AA and CA. In multiple regression analyses, CA had a higher SVR rate than AA (relative risk, 1.96; 95% confidence interval, 1.48-2.60; P < .0001). Other factors independently associated with higher SVR included female sex, lower baseline HCV-RNA level, less hepatic fibrosis, and more peginterferon taken. CONCLUSIONS: AA with chronic hepatitis C genotype 1 have lower rates of virologic response to peginterferon and ribavirin than CA. These differences are not explained by disease characteristics, baseline viral levels, or amount of medication taken.

Adolescent↗
PubMed2006

Hemophilic siblings with chronic hepatitis C: Familial aggregation of spontaneous and treatment-related viral clearance.

BACKGROUND & AIMS: Hemophilic siblings provide a unique population to explore the natural history of chronic hepatitis C. METHODS: From 3993 hemophilic patients with hepatitis C, 257 sibling pairs, of which both members had evidence of hepatitis C infection, were studied to evaluate the genetic contribution to spontaneous and treatment-induced clearance of hepatitis C infection and progression of liver disease. Familial aggregation was assessed by comparing observed probabilities of concordance for these disease characteristics within sibling pairs to those expected for randomly paired hemophilic subjects. Additional measures of familial aggregation, heritability, and sibling relative risk were also calculated. RESULTS: Among human immunodeficiency virus-negative subjects, concordance for spontaneous viral clearance was 2-fold higher in siblings compared with randomly paired subjects (8.8% vs 4.3%, respectively, P = .04). Similarly, the concordance rate for treatment-related viral clearance was over twice that among sibling pairs than among randomly paired hemophiliacs (31.3% vs 13.3%, respectively, P = ns). Heritability estimates for spontaneous and treatment-induced viral clearance were 0.24 +/- 0.14 (P = .04) and 0.43 +/- 0.42 (P = .10), respectively. The sibling relative risks for these respective characteristics were 1.6 and 1.7. Concordance for advanced liver disease was higher among siblings but did not reach statistical significance (4.0% vs 2.3%, respectively, P = ns). The heritability estimate was 0.29 +/- 0.13 (P = .02). CONCLUSIONS: Concordance rates and heritability estimates for spontaneous and treatment-related viral clearance indicate that genetic factors have a modest influence on the outcome of hepatitis C, although shared environmental factors cannot be excluded. Investigations to map candidate disease-susceptibility genes associated with these characteristics must be approached with caution.

Antiviral Agents↗
PubMed2006

Social stigmatization and hepatitis C virus infection.

GOAL: Our aim was to assess stigmatization by evaluating the impact of hepatitis C virus (HCV) on social interactions, feelings of rejection, internalized shame, and financial insecurity, and behavior. BACKGROUND: HCV patients suffer from slowly progressive disease. Although much research has improved the long-term prognosis of chronic HCV, quality of life may be affected by perceived social stigmatization. STUDY: In a cross-sectional study, HCV patients without cirrhosis or significant comorbidities were recruited from the University of North Carolina viral hepatitis clinic. Subjects completed a questionnaire administered by a trained interviewer that assessed changes in sexual behavior, personal hygiene habits, social function, and interactions. Additionally, subjects completed validated, standardized questionnaires, the Health Status Questionnaire, and the SCL-90-R. Frequencies were calculated for the prevalence of stigmatization and altered social interaction. Correlations between education and behavior changes were assessed. A series of multivariate analyses controlling for age, sex, and education were performed to assess the association between HCV acquisition risk and stigmatization. RESULTS: One hundred seventy-five of 217 potential subjects (81%) participated in the survey. The average age was 45.2+/-7.7 years. Fifty-five percent were men and 53% were single. Twenty-nine percent had some college education. Risk factors for HCV acquisition included transfusion (21%) and injection drug use (29%), whereas 32% had an unknown mode of infection. Among common activities, 47% were less likely to share drinking glasses, 14% were less likely to prepare food, and one-third of subjects were less likely to share a towel. Thirty-five percent of respondents reported changes in their sexual practices. Decreased frequency of kissing and sexual intercourse was reported in 20% and 27% of individuals, respectively. Almost half of the single subjects reported increased use of condoms compared with only 20% among married couples. The majority of subjects perceived financial insecurity, internalized shame, and social rejection. Only 39% reported health impairment. Education level did not influence behavior change. CONCLUSION: The majority of HCV subjects alter common behaviors and report financial insecurity, internalized shame, and social rejection, regardless of the method of HCV acquisition or socioeconomic status. These findings indicate that all HCV individuals be counseled and encouraged to participate in educational programs at the time of diagnosis to reduce unnecessary behavioral changes and stigmatization perceptions to improve quality of life.

Cross-Sectional Studies↗
PubMed2005

Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.

BACKGROUND: Current treatments for chronic hepatitis B are suboptimal. In the search for improved therapies, we compared the efficacy and safety of pegylated interferon alfa plus lamivudine, pegylated interferon alfa without lamivudine, and lamivudine alone for the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. METHODS: A total of 814 patients with HBeAg-positive chronic hepatitis B received either peginterferon alfa-2a (180 microg once weekly) plus oral placebo, peginterferon alfa-2a plus lamivudine (100 mg daily), or lamivudine alone. The majority of patients in the study were Asian (87 percent). Most patients were infected with hepatitis B virus (HBV) genotype B or C. Patients were treated for 48 weeks and followed for an additional 24 weeks. RESULTS: After 24 weeks of follow-up, significantly more patients who received peginterferon alfa-2a monotherapy or peginterferon alfa-2a plus lamivudine than those who received lamivudine monotherapy had HBeAg seroconversion (32 percent vs. 19 percent [P<0.001] and 27 percent vs. 19 percent [P=0.02], respectively) or HBV DNA levels below 100,000 copies per milliliter (32 percent vs. 22 percent [P=0.01] and 34 percent vs. 22 percent [P=0.003], respectively). Sixteen patients receiving peginterferon alfa-2a (alone or in combination) had hepatitis B surface antigen (HBsAg) seroconversion, as compared with 0 in the group receiving lamivudine alone (P=0.001). The most common adverse events were those known to occur with therapies based on interferon alfa. Serious adverse events occurred in 4 percent, 6 percent, and 2 percent of patients receiving peginterferon alfa-2a monotherapy, combination therapy, and lamivudine monotherapy, respectively. Two patients receiving lamivudine monotherapy had irreversible liver failure after the cessation of treatment--one underwent liver transplantation, and the other died. CONCLUSIONS: In patients with HBeAg-positive chronic hepatitis B, peginterferon alfa-2a offers superior efficacy over lamivudine, on the basis of HBeAg seroconversion, HBV DNA suppression, and HBsAg seroconversion.

Adolescent↗
PubMed2005

Safety and antiviral activity of emtricitabine (FTC) for the treatment of chronic hepatitis B infection: a two-year study.

BACKGROUND/AIMS: The aim of this study was to evaluate long term safety and antiviral activity of different doses of emtricitabine given once daily to patients chronically infected with hepatitis B. METHODS: Eligible patients were randomized in a double-blind, parallel study to evaluate 25, 100 or 200 mg once daily doses of emtricitabine for 48 weeks. Patients were then followed for an additional 48 weeks on open-label 200 mg emtricitabine. Serum HBV DNA, ALT, and hepatitis B serology were measured at regular intervals over the 2 years. Resistance surveillance was performed after 1 and 2 years on viremic samples, i.e. > 4700 copies/mL. RESULTS: Emtricitabine was well tolerated and produced a dose proportional antiviral response. After 2 years, 53% of the patients had serum HBV DNA < or = 4700 copies/mL, 33% seroconverted to anti-HBe and 85% had normal ALT. Eighteen percent of the patients who had received 200 mg emtricitabine for 2 years developed resistance mutations. CONCLUSIONS: Emtricitabine was well tolerated and demonstrated a potent antiviral response for up to 2 years in patients with chronic hepatitis B infection. Based on these data, 200 mg emtricitabine once daily was chosen as the optimal dose for future hepatitis B studies.

Adult↗
PubMed2005

Pantoprazole reduces the size of postbanding ulcers after variceal band ligation: a randomized, controlled trial.

Elective esophageal variceal ligation (EVL) is performed to decrease the risk of variceal hemorrhage. Side effects of EVL include hemorrhage, chest pain, dysphagia, and odynophagia. Because gastric acid may exacerbate postbanding ulcers and delay healing, proton pump inhibition may decrease side effects associated with EVL. The aim of this study was to assess the efficacy of pantoprazole, a proton pump inhibitor, as an adjunct to elective EVL. We performed a double-blinded, randomized, placebo-controlled trial of pantoprazole after elective EVL. Subjects in the pantoprazole arm received 40 mg pantoprazole intravenously after EVL followed by 40 mg oral pantoprazole for 9 days. Control subjects received intravenous and oral placebo. Subjects underwent upper endoscopy 10 to 14 days after banding. Primary outcomes included the size and number of ulcers and the subjects' reports of dysphagia, chest pain, and heartburn. Forty-four subjects were randomized: 42 completed the protocol. At follow-up endoscopy, the mean number of ulcers was similar in the two groups. However, the ulcers in the pantoprazole group were on average half as large as in the placebo group (37 mm(2) vs. 82 mm(2), P < .01). Chest pain, dysphagia, and heartburn scores were not significantly different. Four subjects, all in the placebo group, had adverse outcomes, including 3 who bled from postbanding ulcers and 1 with sepsis. In conclusion, subjects receiving pantoprazole after elective EVL had significantly smaller postbanding ulcers on follow-up endoscopy than subjects receiving placebo. However, the total ulcer number and patient symptoms were not different between the groups.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2005

Early hepatic stellate cell activation is associated with advanced fibrosis after liver transplantation in recipients with hepatitis C.

Recurrent hepatitis C after liver transplantation is a serious problem faced by liver transplant recipients. Activation of hepatic stellate cells is an early step in hepatic fibrogenesis. The aim of this study was to evaluate hepatic stellate cell activation, early after liver transplantation, as a predictor for the subsequent development of advanced fibrosis. Forty-six patients who underwent liver transplantation for hepatitis C and protocol liver biopsies were divided into rapid fibrosers (n = 21), defined as recipients who developed bridging fibrosis or cirrhosis within 2 years of liver transplantation, and slow fibrosers (n = 25). The protocol liver biopsy obtained 4 months after transplantation was stained and quantitated for hepatic stellate cell activation with antibody to alpha smooth muscle actin. Hepatic stellate cell activity was independently associated with rapid fibrosis (odds ratio: 1.6 [95% CI: 1.1,2.2], P = 0.013). The c-statistics for the receiver operating characteristic curve for stellate cell activity and fibrosis were 0.78 and 0.67, respectively, P = 0.36. The receiver operating characteristic curve for a model including stellate cell activity, histology activity index, and alanine aminotransferase. obtained at month 4 had the best c-statistic (0.88). In recipients with stage 0 or 1 fibrosis on the month 4 liver biopsy who subsequently developed advanced fibrosis, the c-statistic for the receiver operating characteristic curves was significantly better for stellate cell activity than for stage of fibrosis (0.77 and 0.51, respectively; P = 0.004). In conclusion, hepatic stellate cell activation early after liver transplantation complements traditional testing for identifying liver transplant recipients with hepatitis C at greatest risk for developing advanced fibrosis.

Adult↗
PubMed2005

Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin.

BACKGROUND/AIMS: Prediction of sustained virological response (SVR) during treatment would allow clinicians to identify patients most likely to benefit from therapy. METHODS: Retrospective analysis of data from 1121 adults with chronic hepatitis C treated for 48 weeks with peginterferon alfa-2a (40 KD) 180 microg/week plus placebo or ribavirin (1000/1200 mg/day), or interferon alfa-2b 3 MIU three times/week plus ribavirin in a randomized, multinational, study. RESULTS: 67% of patients treated with peginterferon alfa-2a (40 KD)/ribavirin with early virological responses (HCV RNA negative or > or = 2 log10 decrease) at week 12 had SVRs at week 72 (HCV RNA < 50 IU/mL). The negative predictive value (NPV) was 97%. The probability of an SVR increased with the rapidity of HCV RNA suppression. The highest SVR rates were achieved in patients with rapid virological responses at week 4, but the corresponding NPV (74%) is too low for a decision criterion. In patients with early virological responses by week 12, the SVR rate was approximately 20% lower in those who received <80% compared with patients who received > or = 80% of the planned ribavirin dose. CONCLUSIONS: Early, sustained suppression of HCV replication portends an SVR. Cessation of treatment may be contemplated in patients without a > or = 2 log10 reduction in HCV RNA after 12 weeks.

Antiviral Agents↗
PubMed2004

Patient and graft survival in hepatitis C recipients after adult living donor liver transplantation in the United States.

End stage liver disease from chronic hepatitis C is the leading indication for liver transplantation in the United States. Small studies suggest that recurrent hepatitis C may be more common and occur earlier after living donor liver transplantation compared to deceased donor liver transplantation. The objective of our study was to analyze the United Network for Organ Sharing liver transplant database to compare patient and graft survival in recipients transplanted for chronic hepatitis C who received a living donor organ and deceased donor organ between 1999 and 2002. We identified 279 living donor recipients and 3955 deceased donor recipients. Living donor recipients were less ill at the time of transplant, more likely to be female, and received grafts from younger donors. In the living donor group and deceased donor group, 1-year graft survival was 77% and 82%, respectively, and 2-year graft survival was 72% and 75%, respectively, P =.11. One-year patient survival was 87% in both groups and 2-year patient survival was 83% and 81% in the living donor group and deceased donor group, respectively, P =.68. Short-term patient and graft survival are similar between living donor and deceased donor liver transplant recipients with hepatitis C suggesting that recurrent hepatitis C does not seem to affect short-term outcomes.

Female↗
PubMed2004

Liver transplantation for acute liver failure from drug induced liver injury in the United States.

Studies of acute liver failure from drugs have included cases mostly attributed to acetaminophen (APAP) but have reported limited data on other drugs. We used the United Network for Organ Sharing (UNOS) liver transplant database from 1990 to 2002 to identify recipients and estimate a U.S. population-based rate of liver transplantation due to acute liver failure from drugs. Patients were identified if their diagnosis was acute hepatic necrosis from an implicated drug at the time of transplant. Liver transplantation for drug hepatotoxicity accounted for 15% of liver transplants for acute liver failure over the study period. In our cohort (n = 270), 206 (76%) recipients were female. APAP alone, or in combination with another drug, accounted for 133 (49%) cases. In the non-acetaminophen (non-APAP) group (n = 137), the most frequently implicated drugs were: isoniazid, n = 24 (17.5%); propylthiouracil, n = 13 (9.5%); and phenytoin and valproate in 10 (7.3%) cases each. One-year patient and graft survival for the entire cohort was 77 and 71%, respectively. Among Caucasians (n = 206) and African-Americans (n = 48), APAP only was implicated in 110 (53%) patients and 12 (25%) patients, respectively, and non-APAP drugs were implicated in 96 (47%) patients and 36 (75%) patients, respectively (P =.0004). Among African-Americans in the non-APAP group, 28 (78%) were women. In conclusion four drugs were implicated in 42% of patients undergoing liver transplantation for acute liver failure due to drugs other than APAP. The increased frequency of African-American women undergoing liver transplantation for non-APAP drug induced liver injury warrants further study.

Acetaminophen↗
PubMed2004

Guidelines for stopping therapy in chronic hepatitis C.

Tremendous progress has been made in the treatment of chronic hepatitis C. Over 50% of patients treated with pegylated interferon and ribavirin experience permanent eradication of the hepatitis C virus. The indications for therapy have been expanded based on evolving data concerning the safety and efficacy of these agents. Although awareness of which patients in whom to initiate therapy is important, a thorough understanding of features of the antiviral response is also necessary so that treatment can be discontinued when the chances of sustained response are nil. Recent studies have defined virologic milestones that are useful for managing patients during antiviral therapy. Pretreatment genotype and response to therapy measured at weeks 12 and 24 of treatment have been identified as key determinants in decisions about continuing treatment. Progress in defining early treatment stopping points has reduced adverse events in patients who are unlikely to respond to therapy.

Antiviral Agents↗
PubMed2004

Treatment of chronic hepatitis C infection with peginterferons plus ribavirin.

Interferon monotherapy provided the first hope for patients with chronic hepatitis C that the virus could be permanently eradicated. An important development in treating this disease was the recognition that the effects of interferon could be greatly enhanced by combining it with ribavirin, a nucleoside analogue. This combination regimen essentially doubled the sustained virological response rates seen with interferon alone. Recently, modified forms of interferon have been developed that-when used in combination with ribavirin-demonstrate even better efficacy. Thus, peginterferon alfa-2a (Hoffman La-Roche, Nutley, NJ) and peginterferon alfa-2b (Schering-Plough, Kenilworth, NJ) are the latest innovations for the treatment of chronic hepatitis C. The addition of a polyethylene glycol molecule to the native interferon protein favorably alters the pharmacokinetic profile, allowing for once-weekly administration, and leads to superior efficacy compared to standard interferon preparations. This article reviews the data from clinical trials of peginterferon alfa-2a and peginterferon alfa-2b.

Antiviral Agents↗
PubMed2004

Efficacy and safety of two-dose regimens of peginterferon alpha-2a compared with interferon alpha-2a in chronic hepatitis C: a multicenter, randomized controlled trial.

OBJECTIVES: This study compared the efficacy and safety of peginterferon alpha-2a 135 microg/wk, peginterferon alpha-2a 180 microg/wk and interferon alpha-2a in patients with chronic hepatitis C. METHODS: A total of 639 patients received peginterferon alpha-2a 135 microg or 180 microg once weekly, or interferon alpha-2a 3 MIU thrice weekly for 48 wk. RESULTS: Sustained virological responses were significantly higher with peginterferon alpha-2a than with interferon alpha-2a 3 MIU (28% in the 135 microg and 180 microg peginterferon alpha-2a groups vs 11% with interferon alpha-2a, p = 0.001). The proportion of patients with clinically significant histological improvement was lower in the peginterferon alpha-2a 135 microg (48%) than the 180 microg group (58%, p = 0.035 vs peginterferon alpha-2a 135 microg), but similar to that in the interferon alpha-2a group (45%, p = 0.820 vs peginterferon alpha-2a 135 microg and p = 0.017 vs peginterferon alpha-2a 180 microg, respectively). The overall safety profiles were similar for the three treatments. In patients with chronic hepatitis C, peginterferon alpha-2a 135 microg/wk and 180 microg/wk produced similar sustained virological response rates, both of which were significantly higher than that achieved with interferon alpha-2a thrice weekly. A significantly higher proportion of patients treated with the 180 microg dose of peginterferon alpha-2a had clinically significant histological improvement.

Adult↗