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Biomedical subjects

E B Keeffe

Publications and source records attributed to E B Keeffe.

At least 55 records · Page 3Linked to original sources
PubMed1999

Long-term follow-up after liver transplantation in patients with hepatic iron overload.

Patients with hepatic iron overload who undergo orthotopic liver transplantation (OLT) have a worse 1-year survival than those who undergo transplantation for other indications; the long-term outcome in this population is unknown. The purpose of this study is to report long-term follow-up after OLT in a cohort of patients with hepatic iron overload. Five liver transplant centers in the United States reported follow-up data on 37 patients receiving a first liver transplant who had severe hepatic iron overload in their native livers. Kaplan-Meier 5-year survival among these patients was compared with survival data from all age-matched liver transplantations reported to the United Network for Organ Sharing (UNOS) over the same time period (1987 to 1993). The 5-year survival rate after OLT was 40% in the hepatic iron overload group compared with an overall survival rate of 62% for all patient groups from the UNOS registry (P =.0009). Although sepsis was the cause of 53% of all deaths occurring within the first year after OLT, cardiac complications accounted for 50% of the late mortality in patients with hepatic iron overload. In conclusion, long-term survival after OLT is significantly decreased in patients with hepatic iron overload. Infectious and cardiac complications are the most common causes of death in these patients. Further studies are needed to define the relationship between hepatic iron overload and mortality and to examine the effect of iron depletion on outcome after OLT in this patient population.

Cause of Death↗
PubMed1999

Are infectious agents involved in primary biliary cirrhosis? A PCR approach.

BACKGROUND/AIMS: A variety of data suggest that microbial infections and, in particular, atypical mycobacteria infections, may either initiate and/or be associated with the pathogenesis of primary biliary cirrhosis. METHODS: To address this hypothesis, use was made of polymerase chain reaction techniques and primers specific for the 16s rRNA gene of Eubacteria, Archaeabacteria, Mycobacteria and Helicobacter to determine if such sequences were detectable in liver tissue specimens from 29 patients with primary biliary cirrhosis. Similar liver tissues from patients with primary sclerosing cholangitis, chronic hepatitis, alcoholic liver disease and otherwise normal donors were analyzed in parallel. Genomic DNA was extracted from each of these liver tissue specimens using sterile techniques to avoid possible laboratory contamination. The DNA was subjected to polymerase chain reaction amplification using bacterial genus specific primers and the amplified products cloned and sequenced. Sequence data were analyzed by searching for homology to existing genes. RESULTS: Sequences from primary biliary cirrhosis and control livers corresponded to those found in a variety of bacteria, but no consensus sequence was found in primary biliary cirrhosis specimens. Neither Archaeabacteria nor Mycobacteria products were detected in liver specimens of patients with primary biliary cirrhosis, and Helicobacter pylori DNA was detected in only one primary biliary cirrhosis patient. CONCLUSIONS: Although bacterial infection, particularly with intracellular organisms, has been suggested to play a role in the initiation of primary biliary cirrhosis, there is no evidence from this study to suggest an ongoing chronic infectious process.

Archaea↗
PubMed1999

Overview of interferon therapy for chronic hepatitis C.

The future therapy for chronic hepatitis C will probably include measures to decrease hepatocellular injury along with multidrug combinations, including inhibitors of the hepatitis C viral protease, helicase, or polymerase to reduce serum levels or eradicate HCV RNA. The results of recently concluded trials of IFN-alpha 2b plus ribavirin combination therapy have shown a twofold improvement in the biochemical and virologic response rates and superiority by other measures of efficacy with an acceptable safety profile. In view of these results, new guidelines for the management of chronic HCV infection are appropriate (Fig. 1).

Antiviral Agents↗
PubMed1999

Treatment strategies for chronic hepatitis C: update since the 1997 National Institutes of Health Consensus Development Conference.

The National Institutes of Health Consensus Development Conference on the management of hepatitis C, which took place in March 1997 and was published in September 1997, established guidelines for the diagnosis and management of chronic hepatitis C. The recommended treatment of chronic hepatitis C virus (HCV) infection is interferon alpha (or equivalent) 3 MIU three times per week for 12 months, in patients showing response to therapy after 3 months. Patients with the greatest risk for progression to cirrhosis (i.e. persistently elevated alanine aminotransferase levels, detectable serum HCV-RNA and liver biopsy showing portal or bridging fibrosis and at least moderate inflammation and necrosis) are recommended as candidates for therapy. The indication for therapy is less obvious in patients with milder histological changes, compensated cirrhosis and age less than 18 years or older than 60 years. Treatment is not indicated for patients with persistently normal aminotransferases or decompensated cirrhosis. This review outlines the background studies that led to the recommendations of the National Institutes of Health for the treatment of chronic hepatitis C and reviews newer evolving treatment strategies over the past year. In particular, the results of studies exploring treatment options for relapsers and non-responders to prior interferon therapy and the reported results to date on the safety and efficacy of combination therapy with interferon plus ribavirin are highlighted. Although aggressive suppression of HCV-RNA with induction therapy (daily and/or higher doses) or long-acting pegylated interferon preparations may improve the current results of therapy, few data are yet available. Finally, the treatment of chronic hepatitis C with protease inhibitors holds promise but has yet to reach the stage of clinical trials.

Adolescent↗
PubMed1999

Patient selection and listing policies for liver transplantation.

Liver transplantation expanded rapidly during the first three decades of its application but has undergone slower growth over the past few years because of a limited supply of donor organs. The growing discrepancy between available donor organs and patients listed for transplantation has fuelled recent debate regarding patient selection criteria and listing policies for liver transplantation. Allocation and distribution regulations of the United Network for Organ Sharing have also recently undergone changes to balance the principles of utility (i.e. the overall benefits of liver transplantation to society) and justice (i.e. the needs of the individual patient). The ideal geographical area over which organs can be distributed to balance utility and justice remains uncertain, although there are pressures to widen sharing of donor organs. The sickest patient who has been waiting the longest still receive the next available donor organ, but listing policies for the sickest patients, those with fulminant hepatic failure or acute decompensation of chronic liver disease, were recently revised. A uniform minimal listing criteria that proposes listing patients when their estimated survival with liver disease is less than that expected after liver transplantation was recently proposed and has generally been accepted. Finally, cost-outcome analyses and the reality of managed care with the transfer of financial risk from insurers to providers is beginning to have an influence on patient selection criteria.

Chronic Disease↗
PubMed1999

Does Asian race affect hepatitis B virus recurrence or survival following liver transplantation for hepatitis B cirrhosis?

To assess whether Asian race is an independent variable affecting survival and hepatitis B virus (HBV) recurrence after liver transplantation, the results of 27 consecutive liver transplants performed between June 1994 and April 1997 for HBV cirrhosis were analysed. In the group of 13 Asians, 38% had associated hepatocellular carcinoma and 62% had positive hepatitis B virus early antigen (HBeAg) or elevated HBV-DNA before transplant. Prophylactic hepatitis B immunoglobulin (HBIG) was administered perioperatively and long term at 4-6 weekly interval. Four patients with elevated HBV-DNA received lamivudine before transplantation. The 3 year actuarial patient survival rate was 100% in both Asian and non-Asian patients. Twenty-six patients remained seronegative for hepatitis B virus surface antigen after transplantation. The incidence of post-transplant HBV recurrence was similar: 0% in Asians compared with 7% in non-Asians. There was no recurrence in the group of 12 patients who were HBV-DNA or HBeAg negative pretransplant.

Adolescent↗
PubMed1999

Resection versus transplantation for hepatocellular carcinoma.

Hepatocellular carcinoma is responsible for more than 1 million deaths per year worldwide and thus remains a challenging medical problem. It causes few or no symptoms and the tumour frequently reaches an enormous size by the time of diagnosis in countries where screening is seldom used. It is generally resistant to commercially available anti-neoplastic agents and radiation therapy. The principal treatment continues to be resection, either partial or complete, with liver transplantation. However, less than one-third of patients are surgical candidates for either resection or transplantation at the time of clinical presentation. This review will address the results observed following resection or transplantation for hepatocellular carcinoma.

Carcinoma, Hepatocellular↗
PubMed1999

Lamivudine therapy for chemotherapy-induced reactivation of hepatitis B virus infection.

A 54-yr-old man with lymphoma and serological evidence of prior hepatitis B virus (HBV) infection, with detectable anti-HBc and anti-HBs, was treated with intensive chemotherapy. He had reactivation of HBV infection with acute hepatitis B manifest by detectable HBsAg and elevated aminotransferase levels >1000 IU/L. He was treated with lamivudine 150 mg daily and had prompt resolution of acute hepatitis B with return of elevated aminotransferases to normal, and initial loss of HBeAg with later loss of HBsAg. Lamivudine was continued during the course of further chemotherapy as prophylaxis against repeat HBV reactivation. Lamivudine is a nucleoside analogue that is a potent inhibitor of HBV reverse transcriptase and HBV replication. Lamivudine therapy should be considered for the treatment of HBV reactivation and might play a future role as preemptive therapy of HBV reactivation in patients with prior hepatitis B or chronic hepatitis B with inactive viral replication.

Acute Disease↗
PubMed1999

Biochemical and viral response to consensus interferon (CIFN) therapy in chronic hepatitis C patients: effect of baseline viral concentration. Consensus Interferon Study Group.

OBJECTIVE: The effect of baseline viral concentration on response was assessed as part of a multicenter phase 3 trial evaluating the safety and efficacy of CIFN therapy for chronic HCV infection. METHODS: Patients (n = 472) received either CIFN 9 microg or IFN alpha-2b 3 MU subcutaneously t.i.w. for 24 wk, followed by 24 wk of observation. RESULTS: Efficacy was assessed by the percentage of patients who achieved normal ALT values or undetectable HCV RNA values (using RT-PCR with a sensitivity of 100 copies/ml). There was a clear relationship between baseline viral concentration and either ALT or HCV RNA response; patients with lower titer HCV RNA had better response rates. End-of-treatment HCV RNA responses were better for patients with low viral concentrations treated with CIFN (51%) than for patients treated with IFN a-2b (31%) (p = 0.03). ALT responses in patients with low viral concentrations were 60% for CIFN-treated patients and 27% for IFN alpha-2b-treated patients (p < 0.01) at the end of treatment. Patients with high titer HCV RNA were more likely to have a sustained HCV RNA response after treatment with CIFN 9 microg, compared with those treated with IFN alpha-2b (7% vs 0%, p = 0.03). CONCLUSIONS: Both genotype and baseline viral concentration were independent factors that affected response to interferon.

Adult↗
PubMed1999

Utility of hepatitis C virus serotypes in predicting response to treatment of chronic hepatitis C. Consensus Interferon Study Group.

Hepatitis C virus (HCV) genotyping has been shown to predict response to interferon, but is expensive. HCV serotyping is less expensive and simpler, and may be similarly useful. Using data from a large, randomized trial comparing consensus interferon (CIFN) and interferon alfa-2b (IFN alfa-2b) in patients with chronic HCV, we evaluated response rates based on HCV serotypes versus genotypes. Patients included in this analysis received subcutaneous injection of 9 microg CIFN (n = 232) or 3 MU IFN alfa-2b (n = 240) three times weekly for 24 weeks followed by 24 weeks of observation. Serum HCV RNA concentrations were measured regularly during treatment and at the end of both the treatment and post-treatment periods. Response to interferon was similar for HCV antibody types and their corresponding genotypes. The end-of-treatment HCV RNA rate of response (defined as undetectable serum on two consecutive assessments) was 29% for serotype 1 versus 24% for genotype 1 after CIFN; and 14% versus 15%, respectively, after IFN alfa-2b. Independently of treatment, patients infected with serotype or genotype 2 or 3 had a better therapeutic response than those infected with serotype or genotype 1. Similar results were obtained based on HCV antibody typing and genotyping, suggesting the potential of the former for predicting response to interferon.

Antiviral Agents↗
PubMed1999

Genotype does not affect pattern of HCV RNA decrease among responders during interferon treatment of chronic hepatitis C. Consensus Interferon Study Group.

We assessed differences in the pattern of HCV RNA decrease for HCV genotypes 1, 2, and 3 during interferon treatment to determine if the lower response rates observed among genotype 1 patients were related to a slower decrease in HCV clearance. Serum HCV RNA values of 472 chronic hepatitis C patients treated with either consensus interferon (CIFN) or interferon alfa-2b (IFN alfa-2b) were evaluated. Neither virological sustained responders nor relapsers differed in the pattern of serum HCV RNA decrease based on genotype. Virological sustained responders infected with genotype 1 cleared HCV RNA as rapidly as sustained responders who were infected with genotype 2 or 3. Relapsers had a slower rate of serum HCV RNA decrease than did virological sustained responders. Nonresponders differed in the pattern of serum HCV RNA decrease based on genotype: HCV genotype 3 patients had the greatest decrease in serum HCV RNA; genotype 2 patients had an intermediate decrease; and genotype 1 patients had the least serum HCV RNA decrease. HCV genotype 1 patients treated with CIFN had a greater decrease in serum HCV RNA during therapy than did patients treated with IFN alfa-2b. However, there was no difference in the magnitude of serum HCV RNA decrease between the two interferon treatments for patients infected with genotype 2 or 3. In summary, both genotype and ultimate response to treatment are determinants of the pattern and rate of serum HCV RNA change during interferon therapy of chronic hepatitis C.

Antiviral Agents↗
PubMed1998

Identification and precursor frequency analysis of a common T cell epitope motif in mitochondrial autoantigens in primary biliary cirrhosis.

The immunodominant antimitochondrial antibody response in patients with primary biliary cirrhosis (PBC) is directed against the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Based on our earlier observations regarding peripheral blood mononuclear cell (PBMC) T cell epitopes, we reasoned that a comparative analysis of the precursor frequencies of PDC-E2 163-176-specific T cells isolated from PBMC, regional hepatic lymph nodes, and from the liver of PBC patients would provide insight regarding the role of T cells in PBC. Results showed a disease-specific 100-150-fold increase in the precursor frequency of PDC-E2 163-176-specific T cells in the hilar lymph nodes and liver when compared with PBMC from PBC patients. Interestingly, autoreactive T cells and autoantibodies from PBC patients both recognize the same dominant epitope. In addition, we demonstrated cross-reactivity of PDC-E2 peptide 163-176-specific T cell clones with PDC-E2 peptide 36-49 and OGDC-E2 peptide 100-113 thereby identifying a common T cell epitope "motif" ExETDK. The peptide 163-176-specific T cell clones also reacted with purified native PDC-E2, suggesting that this epitope is not a cryptic determinant. These data provide evidence for a major role for PDC-E2 peptide 163-176 and/or peptides bearing a similar motif in the pathogenesis of PBC.

Adult↗
PubMed1998

Safety and immunogenicity of hepatitis A vaccine in patients with chronic liver disease.

Acute hepatitis A superimposed on chronic liver disease (CLD) has been associated with severe or fulminant hepatitis. An open, multicenter study was performed to compare the safety and immunogenicity of an inactivated hepatitis A vaccine in patients with CLD with that in healthy subjects. A secondary objective was to compare the safety of the hepatitis A vaccine with that of a commercial hepatitis B vaccine in subjects with chronic hepatitis C. A total of 475 subjects over the age of 18 years were enrolled into 1 of 5 groups according to history, serological data, and previous diagnosis. Patients in groups 1 (healthy adults), 2 (chronic hepatitis B), 3 (chronic hepatitis C), and 5 (other CLD not caused by viral hepatitis) were vaccinated with two doses of inactivated hepatitis A vaccine, 6 months apart. Patients in group 4 (chronic hepatitis C) received 3 doses of a recombinant hepatitis B vaccine, according to a 0-, 1-, and 6-month schedule. Local injection-site symptoms were the most common reactions reported following vaccination in all groups (35.5% of all doses), with the hepatitis B vaccine eliciting fewer injection-site symptoms than the hepatitis A vaccine (19.8% compared with 37.5%). Although a higher percentage of healthy subjects (93%) seroconverted after a single dose of the hepatitis A vaccine than did subjects with chronic hepatitis C (73.7%) or CLD of nonviral etiologies (83.1%), more than 94% of all vaccinees were seropositive for anti-HAV after the complete vaccination course. At each time point, a lower geometric mean concentration of anti-HAV was observed for each group of CLD patients compared with the healthy control subjects. In conclusion, hepatitis A vaccine was well tolerated and induced a satisfactory immune response in patients with chronic hepatitis B, chronic hepatitis C, and miscellaneous CLD.

Adolescent↗
PubMed1998

Re-treatment of chronic hepatitis C with consensus interferon .

A multicenter, open-label, phase 3 study was conducted in 337 patients with chronic hepatitis C virus (HCV) infection who had either not responded to previous interferon therapy or had relapsed after discontinuation of therapy with either consensus interferon (9 microg) or interferon alpha-2b (3 million U) three times a week for 24 weeks. Patients were randomized to receive a higher dose of consensus interferon (15 microg) administered subcutaneously three times a week for 24 or 48 weeks and then were observed for an additional 24 weeks. Patients who had relapsed after prior interferon therapy were more likely to have a sustained alanine aminotransferase response and HCV RNA response (as measured by reverse transcription-polymerase chain reaction with a sensitivity of < 100 copies/mL) than were patients who had not responded to prior interferon therapy. For relapsers, the sustained HCV RNA response rate was 58% (48 weeks) and 28% (24 weeks). The sustained alanine aminotransferase response for relapsers was 52% (48 weeks) and 39% (24 weeks). The sustained HCV RNA response rate among prior nonresponders was 13% (48 weeks) and 5% (24 weeks), and the sustained alanine aminotransferase response rate for nonresponders was 17% (48 weeks) and 12% (24 weeks). The administration of 15 microg of consensus interferon was well tolerated and was not associated with an increase in the incidence of side effects. These data demonstrate that re-treatment with 15 microg of consensus interferon is safe and effective therapy for patients with chronic hepatitis C who have either not responded to previous interferon therapy or relapsed after discontinuation of interferon therapy.

Adult↗
PubMed1998

Allograft rejection after liver transplantation for autoimmune liver diseases.

Autoimmune liver diseases (AILD) may progress to liver failure, requiring liver transplantation as definitive therapy, and these immune-mediated disorders may predispose the patient to more frequent graft rejection. The objective of this study was to determine the effect of preexisting AILD on the incidence of allograft rejection after liver transplantation. Sixty-three patients who underwent liver transplantation between March 1988 and December 1994 for AILDs that included autoimmune hepatitis (AIH; n = 33) and primary biliary cirrhosis (PBC; n = 30) were retrospectively compared with 47 patients who underwent liver transplantation for alcoholic cirrhosis during the same time period. There was a lower incidence of acute allograft rejection in patients with AILD who received tacrolimus-based compared with cyclosporine-based immunosuppression (50% v 85.5%; P = .02). However, patients with AILDs overall had a higher incidence of acute rejection than patients with alcoholic cirrhosis (81% v 46.8%; P < .001), regardless of the type of immunosuppression. In addition, steroid-resistant rejection occurred more frequently in patients with AILDs than in patients with alcoholic cirrhosis (38.1% v 12.8%; P = .003). There was also a trend toward a higher incidence of chronic rejection in patients with AILDs compared with patients with alcoholic cirrhosis (11.1% v 2.1%), but this difference did not reach statistical significance. Patient and graft survivals at 1 and 3 years were similar between patients with AILDs and alcoholic liver disease. Compared with alcoholic cirrhosis, preexisting AILDs are associated with a higher incidence of acute allograft rejection and a trend toward more frequent chronic rejection.

Adult↗