Hepatic steatosis in chronic hepatitis C: baseline host and viral characteristics and influence on response to therapy with peginterferon alpha-2a plus ribavirin.

Hepatic steatosis is common in hepatitis C virus (HCV)-infected patients and may be associated with the metabolic syndrome. We studied steatosis in patients treated with peginterferonalpha-2a plus ribavirin. Forty-five of 207 patients (22%) had >5% hepatic steatosis at baseline. Significantly more patients with steatosis than without were HCV genotype 3 (51%vs 14%; P < 0.0001) had higher HCV-RNA (P = 0.0045), body weight (P = 0.0176), body mass index (BMI, P = 0.0352) and serum triglycerides (TG) (P = 0.0364), hypertriglyceridaemia (P = 0.0009), elevated blood pressure/history of hypertension (P = 0.0229) and lower cholesterol (P = 0.0009). Significant steatosis predictors were genotype 3 (OR 9.04, 95% CI 3.85-21.21, P < 0.0001), HCV-RNA (OR 2.96, 1.49-5.88, P = 0.0019) and triglycerides (OR 1.06, 1.02-1.11, P = 0.0071). In genotype 3 patients, HCV-RNA was the only significant predictor (OR 11.15, 2.60-47.81, P = 0.0012). In non-genotype 3 patients, hypertriglyceridaemia was the only significant predictor (OR 1.07, 1.02-1.12, P = 0.0041). 134 of 207 patients (65%) achieved an sustained virological response (SVR) with peginterferon alpha-2a plus ribavirin, similar to the overall response rate. In genotype 3 patients with an SVR, steatosis decreased from 48% to 13% (baseline to end-point). No change was seen in the steatosis rate in non-genotype 3 patients with an SVR. This large and comprehensive analysis of a large data base from a multinational trial further adds to the observations that chronic HCV is associated with hepatic steatosis in approximately a fifth of patients. Further, features of the metabolic syndrome are associated with hepatic steatosis in most of these patients. Steatosis is significantly more common in genotype 3 compared with other genotypes, and in these patients, an SVR is associated with steatosis clearance.

Selection of different 5' untranslated region hepatitis C virus variants during post-transfusion and post-transplantation infection.

BACKGROUND: Hepatitis C virus (HCV) translation is initiated in a cap-independent manner by an internal ribosome entry site (IRES) located within the 5' untranslated region (5'UTR). Sequence changes in this region could affect translation efficiency and presumably viral replication. AIM: To determine translation efficiency of 5'UTR variants developing during post-transfusion hepatitis C in two immunocompetent subjects and in two immunosuppressed liver recipients with recurrent HCV. METHODS: Sequential samples were screened for 5'UTR changes by single-strand conformation polymorphism followed by cloning and sequencing whenever band pattern suggested sequence changes. 5'UTR variants were tested for IRES activity using a bicistronic dual luciferase expression plasmid transfected into HepG2 and Huh7 cell-lines. RESULTS: In the transfused patients, translation efficiency of 5'UTR variants from early post-transfusion samples was 5.1- to 13.7-fold higher than that of predominant variants found in late follow-up samples. Post-transplant variants in the other two patients had 2.6- to 5.9-fold higher translation efficiency than those present only in pretransplant samples. CONCLUSION: In the immunocompetent host there may be selection of low translation efficiency HCV variants over the course of infection. However, in immunosuppressed subjects the opposite seems to be true as low translation efficiency variants are superseded by high translation efficiency variants.

Changes in hepatitis C virus population in serum and peripheral blood mononuclear cells in chronically infected patients receiving liver graft from infected donors.

BACKGROUND: We have previously studied hepatitis C (HCV)-infected recipients of livers from HCV-infected donors and found that either the donor's strain or the recipient's strain predominate in serum. The current study was undertaken to determine whether these changes are complete and whether they are reflected in the population of virus associated with peripheral blood mononuclear cells (PBMCs). METHODS: We analyzed HCV ribonucleic acid from sequential serum and PBMC samples from 11 and 8 patients, respectively. The relatively stable NS5 region was chosen for analysis because it allowed for dependable identification of donor and recipient strains. Viral sequences were analyzed by direct sequencing and by sensitive strain-specific polymerase chain reaction assays. These assays were capable of detecting the minor sequence present at a concentration 1:104-10-7 below that of the major sequence. RESULTS: Five patients retained their original infecting strain; the donor strain was detected only transiently. In the remaining six patients, recipient strain was detected for the first few weeks, after which only the donor strain was consistently present. However, in one patient the second nondominant strain was detected from the background of the major strain on a single occasion 8 months after transplantation. All changes in serum were closely paralleled by those occurring in PBMCs. CONCLUSIONS: Viral population changes in the setting of liver transplantation from HCV-infected donors to HCV-infected recipients occur simultaneously in PBMCs and serum. The takeover of one strain by another in PBMC- and serum-derived viral populations seemed to be complete and long lasting.

Clinical significance of elevated alpha-fetoprotein in adults and children.

The aim of the current study is to identify underlying pathology associated with elevated serum alpha-fetoprotein (AFP; >20 ng/ml) among patients referred to a tertiary-care academic medical center with emphasis in liver diseases, hepatobiliary surgery, and liver transplantation. From May 1992 to April 1997, 386 patients (320 adults and 66 children) with elevated AFP (>20 ng/ml) were identified from the Medical Archival System (MARS) database at the University of Pittsburgh Medical Center. The medical records from all these patients were retrospectively reviewed. Radiological, pathological, and biochemical profiles were obtained at the time of documented elevated AFP. These patients included: 218 adults with malignancies, 102 adults without malignancies, 18 children and infants with malignancies, and 48 children and infants without malignancies. Thirty-two percent of adults were found to have raised AFP with liver disease and without hepatocellular carcinoma and 78% had some type of malignancy, predominantly hepatocellular carcinoma. Seventy-three percent of infants and children had elevated AFP without malignancy. Based on our findings, we recommend that all patients (adults, infants and children) with raised AFP of >20 ng/ml should undergo thorough evaluation to rule out malignant disease.

Exposure of hepatitis C virus (HCV) RNA-positive recipients to HCV RNA-positive blood donors results in rapid predominance of a single donor strain and exclusion and/or suppression of the recipient strain.

We have analyzed three cases of hepatitis C virus (HCV)-infected recipients who received blood from HCV-infected donors. Two recipients were exposed to two different HCV RNA-positive donors, and one was exposed to a single donor. All parental genomes from the actual infecting units of blood and the recipients were defined, and their presence in the follow-up serum samples was determined using sensitive strain-specific assays. The strain from one of the donors was found to predominate in all recipients' serum samples collected throughout the follow-up period of 10 to 30 months. In two recipients exposed to two infected donors, the strain from the second donor was occasionally found at very low level. However, the original recipients' strains were not detected. Our observations show that HCV-infected individuals can be superinfected with different strains, and this event may lead to eradication or suppression of the original infecting strain. Furthermore, our findings demonstrate that simultaneous exposure to multiple HCV strains may result in concomitant infection by more than one strain, although a single strain could rapidly establish its dominance. The results of the present study suggest the existence of competition among infecting HCV strains which determines the ultimate outcome of multiple HCV exposure.

A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B.

Seventy-seven liver transplant candidates were enrolled in a multicenter study in which patients were treated with lamivudine (100 mg daily) without the adjunctive use of hepatitis B immune globulin. Treatment was begun while patients awaited liver transplantation and continued after transplantation. All were hepatitis B surface antigen (HBsAg) positive, and 61% had detectable hepatitis B e antigen (HBeAg) and HBV DNA when treatment was begun. Forty-seven underwent liver transplantation and 30 did not. Median study participation was 38 months (range, 2.7-48.5) in the transplanted patients and 26 months (range, 0.1-37) in the nontransplanted group. Twenty-five of 42 (60%) transplanted patients with 12 or more weeks of posttransplantation follow-up were HBsAg negative at the last study visit. At treatment week 156, 13 of 22 (59%) remained HBsAg negative, and all 9 reinfected patients were HBV-DNA positive before treatment. In the nontransplanted patients, HBeAg was initially detectable in 20 of 27 (74%) but this decreased to 3 of 17 (18%) after 104 weeks of treatment, and significant improvement in biochemical parameters was observed. HBV-DNA polymerase mutants were detected in 15 (21%) and 6 (20%) of the transplanted and nontransplanted patients, respectively. When compared with historical cohorts, lamivudine-treated patients appeared to have improved survival, and transplanted patients had a decrease in the rate of recurrent HBV infection. Lamivudine therapy was partially effective in preventing recurrent HBV infection when given before and after transplantation. Thus, future trials using a combination of HBIg and lamivudine are needed to assess the optimal prophylactic therapy.

Kidney transplantation for end-stage renal failure in liver transplant recipients with hepatitis C viral infection.

BACKGROUND: End-stage renal failure after successful liver transplantation (LTx) has been described in up to 5% of patients. Kidney transplantation (KTx) has been the treatment of choice in these cases. However, in recipients infected with hepatitis C virus (HCV), the augmentation of immunosuppression after KTx may result in an increased viral load. This, in turn, may adversely affect the liver allograft. METHOD: The present study retrospectively examined the outcome in 17 patients (3 females and 14 males, mean age 51.1+/-11.3 years) who received KTx after LTx. The mean interval from LTx to KTx was 57.6+/-32.1 months. The mean follow-up was 41.7+/-20.5 months after KTx, and 99.6+/-37.7 months after LTx. Sixteen of the 17 patients received tacrolimus-based immunosuppression at the time of KTx. RESULTS: During the follow-up period, one patient underwent combined liver and kidney retransplantation 3.7 years after KTx and 12.7 years after LTx. She subsequently died secondary to primary nonfunction. Four other patients died, two of lung cancer, one of pancreatitis/sepsis, and one of severe depression leading to noncompliance. A total of 29 episodes of biopsy-proven acute renal allograft rejection (1.7 episodes/ patient) were encountered and treated with steroids. Seven patients experienced a rise in liver function tests during the period of increased steroid dosage. Four patients received no treatment, and their liver function returned to baseline. The remaining three were treated with interferon. Overall 1- and 3-year actuarial patient and liver allograft survival was 88% and 71% (after renal transplantation); corresponding 1- and 3-year actuarial graft survival was 88% and 61%. Twelve patients are alive with normal liver function. One patient is on dialysis, because of renal allograft loss to noncompliance. CONCLUSION: In this series, LTx recipients with HCV infection were able to undergo KTx with a reasonable degree of success. KTx should be offered for end-stage renal failure after LTx, even in the presence of HCV infection, to individuals with stable liver function and no signs of liver failure.

Exposure of hepatitis C virus-negative recipients to > or =2 infected blood donors.

This study analyzed 4 cases of hepatitis C virus (HCV)-naive transfusion recipients who developed hepatitis after receiving blood from >1 HCV-infected donor. One recipient was exposed to 4 donors, 2 were exposed to 3 donors, and 1 was exposed to 2 donors. For 3 recipients, the strain from 1 of the donors predominated in all follow-up samples collected for 8-40 months. For 2 recipients, the strain from the second donor was occasionally detectable with sensitive strain-specific assays. For the fourth recipient, the initially dominant strain was later supplanted by a strain from the other donor. Simultaneous exposure to multiple HCV strains may result in concomitant infection by >1 strain, although a single strain rapidly establishes its dominance. These observations are compatible with the presence of competition among infecting HCV strains that results in the dominance of 1 strain and competitive exclusion or suppression of other strains.

Lamivudine after hepatitis B immune globulin is effective in preventing hepatitis B recurrence after liver transplantation.

The prevention of recurrent hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT) with hepatitis B immunoglobulin (HBIG) is expensive and requires indefinite parenteral administration. Lamivudine is a nucleoside analogue capable of inhibiting HBV replication. The aim of this study is to determine the efficacy of lamivudine in the prevention of recurrent HBV infection after a course of HBIG in patients who were hepatitis B surface antigen (HBsAg) positive and hepatitis Be antigen (HBeAg) negative before OLT. Patients at high risk for recurrent HBV infection (HBeAg positive and HBV DNA positive) were excluded. Thirty HBsAg-positive, HBeAg-negative patients underwent OLT from January 1993 to June 1997. All 30 patients were administered HBIG after OLT and, after 2 years, were given the option of continuing with HBIG or switching to lamivudine. Five patients were excluded: 3 patients were lost to follow-up and 2 patients died of technical complications. Three patients terminated HBIG therapy at 8, 24, and 29 months after OLT, and reinfection with HBV occurred in 1 patient. Six patients elected to continue HBIG therapy for life; 1 patient died of melanoma and the remaining 5 patients are HBsAg negative, with an average follow-up of 73 months. Sixteen patients were converted to lamivudine after a course of HBIG, and all 16 patients are HBsAg negative, with an average follow-up of 51 months after OLT. Five patients have been on lamivudine monotherapy for more than 24 months. These results suggest that lamivudine administered after a posttransplantation course of HBIG can effectively prevent the recurrence of HBV infection in patients who are HBsAg positive and HBeAg negative before OLT.

Detection of active hepatitis C virus and hepatitis G virus/GB virus C replication in bone marrow in human subjects.

We have analyzed the presence of hepatitis C virus (HCV) and hepatitis G virus (HGV) sequences in bone marrow and serum samples from 48 patients of a hematologic outpatient clinic. HCV RNA was detected in 18 (38%) and 15 (31%) and HGV RNA was detected in 6 (13%) and 9 (19%) of serum and bone marrow samples, respectively. In 3 patients, HGV RNA was detectable in bone marrow but not in the serum; 2 of these patients were negative for the presence of specific antibodies. Using a highly strand-specific Tth-based reverse transcriptase-polymerase chain reaction (RT-PCR), the presence of HCV RNA and HGV RNA negative strand was demonstrated in 4 and 5 bone marrow samples, respectively. Our study shows that HCV and HGV can replicate in bone marrow; in the case of HGV, analysis of serum may underestimate the true prevalence of infection. (Blood. 2000;95:3986-3989)

Late-onset renal failure after liver transplantation: role of posttransplant alcohol use.

BACKGROUND: Late-onset renal failure is being increasingly recognized as a complication in patients undergoing liver transplantation for hepatitis C virus (HCV). However, its precise incidence, predisposing risk factors, and impact on outcome after liver transplantation, have not been defined. METHODS: The development of late-onset renal failure (defined as serum creatinine persistently >2.0 mg/dl, occurring more than 6 months posttransplant) was assessed in 120 consecutive liver transplant recipients who survived at least 6 months after transplantation. Fifty-seven percent (68/120) of the patients had undergone transplantation for liver disease due to HCV. The median follow-up was 5 years. RESULTS: Late-onset renal failure developed in 28% (33/120)of the patients. Posttransplant alcohol use (P=0.0001), posttransplant diabetes (P=0.0042), and recurrent HCV hepatitis (P=0.019) were significantly associated with late onset renal failure. In multivariate analysis, alcohol use (O.R. 10.7, 95%; CI 2.4-35.9, P=0.001) and diabetes (O.R. 2.1, 95%; CI 1.1-9.9, P=.03) were independently significant predictors of late onset renal failure. When only patients transplanted for HCV were analyzed, posttransplant alcohol use (P=0.004) was the only significant independent predictor of late-onset renal failure. HCV genotype 1b, as compared with other HCV genotypes, was associated with a higher rate of late-onset renal failure in patients with HCV; 70% of the patients with genotype 1b versus 32% of those with 1a and 33% of those with 2b, developed late onset renal failure (P=0.03). At a median follow up of 5 years, mortality in patients with HCV with late-onset renal failure was 52% as compared with 2% in those without renal failure (P=.0001). CONCLUSION: Late-onset renal failure in patients with HCV portended a grave outcome. Alcohol use was an independent predictor of late-onset renal failure in patients with HCV and represents a potentially modifiable risk factor for late-onset renal failure in these patients.

Prognostic value of abdominal CT scanning and hepatic histopathology in patients with acute liver failure.

Acute liver failure has extremely high mortality without liver transplantation. We attempted to determine the value of abdominal CT scanning and liver biopsy in its management. A retrospective analysis of patients with acute liver failure was performed; demographic, clinical, radiologic and histopathologic features were noted. Over a period of 13 years, 177 patients were evaluated. The mean age was 39 years and 63% were females. The patients were divided into three groups. Fourteen percent survived with medical management (group I), 37% died (group II), and 49% had liver transplantation (group III). Most patients showed diffuse low density of the liver on CT scanning and the proportions were similar in the three groups. Moderate to large ascites was not present in group I but occurred in 31% of patients in group II and in 15% in group III. Mean hepatic volumes were similar in the three groups; however, 97% of the patients with a liver volume of less than 1000 ml either died or required liver transplantation. Liver biopsies among patients with spontaneous recovery (group I) were distinguished by the presence of regenerative changes and a hepatic parenchymal necrosis of less than 50%. These results suggest that in patients with acute liver failure a liver volume of less than 1000 ml and/or hepatic parenchymal necrosis of greater than 50% is indicative of a poor prognosis. This information may assist decision making in such patients, in particular, regarding the need for liver transplantation.

Acute liver failure: clinical features, outcome analysis, and applicability of prognostic criteria.

Acute liver failure (ALF) is an uncommon condition associated with high morbidity and mortality. We performed a retrospective analysis of patients evaluated for ALF. The aim of our study is to determine the clinical features and outcome of such patients and to assess the validity of King's College Hospital (KCH) prognostic criteria. One hundred seventy-seven patients were evaluated for ALF during a period of 13 years. Mean age was 39 years, and 63% were women. The causes included viral hepatitis (31%), acetaminophen toxicity (19%), idiosyncratic drug reactions (12%), miscellaneous causes (11%), and an indeterminate group (28%). Twenty-five patients (14%) recovered with medical therapy (group I), 65 patients (37%) died without orthotopic liver transplantation (OLT; group II), and 87 patients (49%) underwent OLT (group III). Patients in group II were older and often had advanced encephalopathy, whereas those in group I had less hyperbilirubinemia and often had hyperacute failure. KCH criteria had high specificity and positive predictive value but low negative predictive value for a poor outcome. We conclude that early prognostication is needed in patients with ALF to assist decision making regarding OLT. The fulfillment of KCH criteria usually predicts a poor outcome, but a lack of fulfillment does not predict survival.

Hepatitis C virus in lymphoid cells of patients coinfected with human immunodeficiency virus type 1: evidence of active replication in monocytes/macrophages and lymphocytes.

It has been reported that hepatitis C virus (HCV) may be lymphotropic in the setting of human immunodeficiency virus type 1 (HIV-1) coinfection. The present study was undertaken to determine the phenotype of lymphoid cells harboring replicating HCV in HIV-1-positive subjects. By means of highly strand-specific thermostable enzyme Tth-based reverse-transcriptase polymerase chain reaction, the presence of viral RNA-negative strand was sought in different subpopulations of peripheral blood mononuclear cells from 10 HIV-positive patients. HCV RNA-negative strand was most commonly present in monocytes/macrophages (4 cases), followed by CD8+ and CD4+ lymphocytes (2 cases) and CD19+ cells (1 case). In 2 cases that were further analyzed, viral-negative strand remained detectable in monocytes/macrophages cultured for 3 weeks. Moreover, monocyte/macrophage- and serum-derived viral sequences differed in the 5' untranslated region. These findings imply that, in HIV-infected subjects, HCV may replicate in the same cells as HIV-1, which raises the possibility of direct interactions between these pathogens.

Quality of life in long-term survivors after liver transplantation: impact of recurrent viral hepatitis C virus hepatitis.

Post liver transplant recurrence of infection with hepatitis C virus (HCV) occurs in approximately 50% of patients transplanted because of HCV-related liver disease. The aim of this study was to assess long-term quality of life, psychologic distress, and coping in patients with recurrent HCV after liver transplantation in comparison to patients transplanted for other etiologies of underlying liver disease. All liver transplant recipients transplanted at a University affiliated Veterans Affairs Medical Center who had greater than 6 months follow-up were sent a questionnaire investigating quality of life (assessed by Medical Outcomes study health survey SF-36), depression (assessed by Beck Depression Inventory), total mood disturbance (assessed by Profile of Mood States scale), coping (assessed by Billing and Moos Inventory of coping with illnesses), and employment status. Lower Beck Depression Inventory score (p = 0.001), lower mood disturbance score (p = 0.0001), overall satisfaction with present work (p = 0.0001), and lesser use of avoidant coping (p = 0.06) were predictors of better quality of life in long-term survivors of liver transplantation. At a mean follow-up of 4 yr after liver transplantation, patients with histopathologically diagnosed recurrent viral HCV hepatitis had significantly lower global quality of life score (mean score of 76.4 versus 86.2, p = 0.011) and physical functioning score (mean score 20 versus 25, p = 0.015), as compared to all other patients. In summary, quality of life and physical functioning were significantly impaired in liver transplant recipients with histopathologically diagnosed recurrent HCV hepatitis, as compared to those whose HCV hepatitis had not recurred or those transplanted for other reasons.

Uneven distribution of hepatitis C virus quasispecies in tissues from subjects with end-stage liver disease: confounding effect of viral adsorption and mounting evidence for the presence of low-level extrahepatic replication.

We have found differences among the populations of hepatitis C virus sequences in serum, peripheral blood mononuclear cells (PBMCs), and various tissues in patients with chronic hepatitis C. These results are compatible with the existence of independent viral compartments in the infected host. Our results also suggest that PBMCs, and probably various tissues, can selectively adsorb viral subpopulations differing in the E2 region.

Clinical and virologic outcomes of hepatitis B and C viral coinfection after liver transplantation: effect of viral hepatitis D.

Hepatitis B (HBV) and C viral (HCV) dual-infection-associated liver disease is an uncommon indication for liver transplantation. The clinical and virologic outcomes in such patients have not been well studied. We retrospectively studied 13 patients with hepatitis B surface antigen (HBsAg) and antibody to HCV positivity who underwent orthotopic liver transplantation (OLT) and survived at least 30 days post-OLT. Antibody to hepatitis delta virus (HDV) was negative in 8 patients (group I) and positive in 5 patients (group II). Eleven of the 13 patients received standard hepatitis B immune prophylaxis, and they all remained HBsAg negative. All group I patients were HCV RNA positive after transplantation; in contrast, all group II patients were HCV RNA negative. Serum alanine aminotransferase levels were elevated in 88% (7 of 8) of the patients in group I compared with 20% (1 of 5 patients) in group II. None of the patients had graft loss from chronic rejection or recurrent hepatitis. Three patients had unsuspected hepatocellular carcinoma in the explant. We conclude that among liver transplant recipients with HBV and HCV coinfection, HDV infection is associated with the suppression of HCV replication and mild inflammatory activity after OLT.

Liver transplantation for Wilson's disease: a single-center experience.

Wilson's disease is a hereditary defect in copper excretion leading to the accumulation of copper in the tissues, with subsequent tissue damage. The most serious sequela is that of progressive central nervous system involvement. The use of orthotopic liver transplantation (OLT) has been controversial for those patients with neurological symptoms attributed to Wilson's disease. The aim of this study is to determine the effectiveness of OLT for patients with Wilson's disease, including those with neurological involvement attributed to copper accumulation in the central nervous system. OLT was performed in 45 patients (19 men [42.2%], 26 women [57.8%]) with Wilson's disease between 1971 and 1993 who were followed up for at least 4 years. The age at diagnosis of Wilson's disease ranged from 3 to 41 years (mean, 17.7 +/- 7.4 years). The age at OLT ranged from 8 to 52 years (mean, 22.3 +/- 9.4 years). Nineteen patients (42.2%) were aged younger than 18 years at OLT. The indications for OLT included chronic hepatic failure in 15 patients (33.3%) and fulminant (FHF) or subfulminant hepatic failure in 30 patients (66. 6%). All but 1 of the 19 pediatric patients (94.7%) were in the latter group. Twenty-five patients (55.5%) were receiving D-penicillamine, 9 patients for more than 1 year; none of the patients treated long term presented as FHF. Thirty-three patients (73.3%) survived more than 5 years after OLT. Fourteen patients (31%) died during the posttransplantation period; 7 of the 14 patients (50%) were aged younger than 18 years. Twelve patients died during the first 3 months after OLT of complications of disease and surgery, 10 of whom underwent transplantation for FHF. The other 2 patients died 6 and 9 years after transplantation of infectious problems. Eleven patients (24.4%) required retransplantation because of a primary nonfunctioning graft (n = 6), chronic rejection (n = 4), and hepatic artery thrombosis (n = 1). Seventeen patients (37.7%) presented with neurological abnormalities; 14 patients with Wilsonian neurological manifestations and 3 patients with components of increased intracranial pressure. Ten of the 13 surviving patients with hepatic insufficiency and neurological abnormalities at OLT showed significant neurological improvement. Our experience shows OLT is a life-saving procedure in patients with end-stage Wilson's disease and is associated with excellent long-term survival. The neurological manifestation of the disease can improve significantly after OLT. Earlier transplantation in patients with an unsatisfactory response to medical treatment may prevent irreversible neurological deterioration and less satisfactory improvement after OLT.

Cytomegalovirus PP65 antigenemia monitoring as a guide for preemptive therapy: a cost effective strategy for prevention of cytomegalovirus disease in adult liver transplant recipients.

BACKGROUND: The aim of the study was to assess the incidence of cytomegalovirus (CMV) infection and disease in adult liver transplant recipients, using routine preemptive therapy guided by the pp65 antigenemia test. METHODS: Antigenemia was monitored weekly after liver transplantation (OLTX) for the first 3 months, and once a month for another 3 months. CMV seronegative recipients were treated preemptively for the first positive antigenemia. Seropositive recipients were treated only when their antigenemia count reached a threshold of > or =100 positive cells per 200,000 leukocytes. RESULTS: A total of 144 patients were included between June 1994 and April 1995, of which 137 (95%) were primary OLTX. The percentage of positive antigenemia and CMV disease was 55 and 8%, respectively. Seventy-eight (54%) patients were protocol-monitored for the entire follow-up (group 1) and received appropriate preemptive therapy, although 66 (46%) patients had protocol violation by having missed blood samples or blood drawn at unscheduled times (group 2). Using Cox's proportional hazards model, patients with a first antigenemia count of >11 leukocytes had a significantly higher rate of CMV disease compared to patients with an antigenemia count < or =11 leukocytes (RR = 7.3, 95% confidence interval = 2.2 to 24.5). In a multivariate Cox regression analysis, adjustments were made to control for: group 1 versus group 2, use of OKT3, and serology risk categories. This analysis showed that the relative rate of CMV disease was still significantly higher among patients with antigenemia count >11 leukocytes (adjusted RR = 4.9, 95% confidence interval = 1.3 to 18.1). The estimated cost of preemptive therapy was less than that of prophylaxis with i.v. (14-day course) or oral (90-day course) ganciclovir. CONCLUSIONS: Preemptive therapy guided by pp65 antigenemia is a useful and cost effective strategy for prevention of CMV disease.