Preliminary experience with alpha-2b-interferon therapy of viral hepatitis in liver allograft recipients.

Currently, alpha interferon is the only recognized therapy for chronic viral hepatitis. As a result of its success in several multicenter trials, the agent was approved recently by the FDA for use in the clinical management of patients with chronic hepatitis C. FDA approval for its use in chronic hepatitis B is anticipated. Based upon this experience in nonimmunosuppressed individuals, the efficacy of alpha interferon therapy in patients who are recipients of liver allografts and are receiving chronic immunosuppression was assessed in a preliminary trial of the agent in 30 patients (13 with HBV, 11 with HCV, and 6 with hepatitis non A, non B, non C). Therapy was initiated at a dose of 3 X 10(6) units three times per week and continued for 6 months. Dose reduction in the amount of the alpha interferon administered was determined by a preestablished protocol. Nine percent of those with HCV and 18% of those with hepatitis non A, non B, non C experienced a full response to alpha interferon therapy. No full responses to alpha interferon therapy. No full responses were seen in those with HBV disease. Partial responses were common in all three groups but were most frequent in those with hepatitis non A, non B, non C and least frequent in those with HCV-related disease. This preliminary experience demonstrates the following: 1. Viral hepatitis following OLTx can be treated with alpha-2b-interferon. 2. The complications of alpha-2b-interferon therapy utilized prior to OLTx can be avoided by giving the therapy following successful OLTx. 3. The high rate of partial responses noted suggests that future studies should utilize either higher doses or longer durations of therapy or both. 4. The response rate was greatest for those having non A, non B, non C hepatitis and least for those with HCV hepatitis. 5. In this small preliminary series, no episodes of liver graft rejection could be ascribed to the use of alpha-2b-interferon in the patients so treated.     

Impact of hepatitis C viral infection in primary cadaveric liver allograft versus primary living-donor allograft in 100 consecutive liver transplant recipients receiving tacrolimus

BACKGROUND: There has been concern that adult living-donor liver transplantation (LLTx) for hepatitis C virus (HCV) infection may lead to recurrent disease that is more severe compared with the results of cadaveric LTx (CLTx), because the smaller sized graft in LLTx regenerates and may increase viral replication. This study examines the survival outcome and HCV recurrence in CLTx versus LLTx performed at a single institution. METHOD: A total of 100 consecutive adult recipients (75 men and 25 women; mean age 49.9+/-8.4 years) of LTx (65 CLTxs and 35 LLTxs performed July 2000-July 2002) who tested positive for HCV by polymerase chain reaction were examined retrospectively until October 2003. All patients received tacrolimus-based immunosuppression with mycophenolate mofetil and steroids. RESULTS: The overall actual patient survival was 85% (83.1% for CLTx vs. 88.6% for LLTx). The 39-month Kaplan-Meier actuarial patient survivals were 75.1% for CLTx and 88.6% for LLTx. Of 15 deaths, 6 were the result of recurrent HCV (five CLTxs and one LLTx), and of 10 retransplants, 2 were related to recurrent HCV (one CLTx and one LLTx). The rates of recurrence were 72.3% and 77.1%, the hepatitis activity indices were 5.4 + 2.4 and 6.2 + 2.8, the fibrosis scores were 1.4+/-1.4 and 1.5+/-1.3, and the times to recurrence were 318+/-269 days and 394+/-250 days for CLTx and LLTx, respectively. None of the differences between the two groups were significant. CONCLUSION: No detrimental effect of HCV infection was found in LLTx recipients when compared with contemporaneous CLTx recipients. Patient survival, graft survival, rate of HCV recurrence, severity of HCV recurrence, graft loss from HCV, and interval for recurrence in CLTx and LLTx were similar.     

Entecavir therapy for adefovir-resistant hepatitis B virus infection in kidney and liver allograft recipients

The aim of our study was to assess the efficacy and safety of entecavir in kidney- and liver-transplant recipients with chronic hepatitis B virus (HBV) infection. Ten male transplant patients with chronic HBV infection (eight kidney- and two liver-transplant patients), who have become adefovir (n=9) or lamivudine-resistant (n=1) were given entecavir at 0.5 to 1 mg/d. All patients were HBs Ag positive: six were HBe Ag(-)/HBe Ab(+), and four were HBe Ag(+)/HBe Ab(-). After a median follow-up of 16.5 months, entecavir therapy was associated with a significant decrease in HBV DNA viral load, that is, 3.86 (2.71-6.46) log10 copies/mL at baseline down to 2.94 (2.15-4) log10 copies/mL at last follow-up (P=0.004). Rate of HBV DNA clearance was 50% in both HBeAg(+) and HBeAg(-) patients. There were no significant changes in renal function or hematological parameters. This study demonstrates that entecavir therapy is safe and efficient in HBV(+) organ-transplant patients.     

Hepatitis B liver disease in cyclosporine-treated renal allograft recipients

To establish the impact of cyclosporine on the development of chronic hepatitis in hepatitis B surface antigen (HBsAg)-positive renal allograft recipients, the incidence and outcome of chronic hepatitis in 20 cyclosporine-treated patients (CsA group) were compared with 13 azathioprine-treated patients (AZA group). All 33 patients had a functioning graft for 2 years or longer. Twenty-nine of the 33 patients were HBsAg-positive prior to the initiation of hemodialysis. The difference in the incidence of chronic hepatitis between these 2 groups was not statistically significant (78.6% in the AZA group vs. 52.4% in the CsA group, P = 0.12). In the CsA group, 3 patients (15%) developed liver cirrhosis, and there was a 5% mortality. The AZA group had a 7.7% mortality, and 4 patients (30.8%) developed liver cirrhosis. Serial serum samples obtained from these 33 HBsAg-positive renal allograft recipients were analyzed for antibody to hepatitis D virus (anti-HD). Anti-HD was found in 3 patients. Two of them developed anti-HD seroconversion after renal transplantation during a mean follow-up of 4 years. All 3 patients developed chronic hepatitis and 2 of them have subsequently developed liver cirrhosis. There was a mortality of 6.1% in 33 HBsAg-positive patients compared with a 5.3% mortality in 57 HBsAg-negative renal allograft recipients. The difference was not statistically significant. We conclude from this study that (1) CsA-treated HBsAg-positive renal allograft recipients have a tendency to develop chronic hepatitis like AZA-treated patients; (2) HBsAg-positive patients have an increased risk of HDV superinfection after renal transplantation, and this may result in rapid progression to liver cirrhosis; (3) HBsAg-positive patients who acquire HBsAg prior to renal transplantation have a low overall mortality, including death due to liver disease, for a mean follow-up of 4 years.     

Use of hepatitis B core antibody-positive liver allograft in hepatitis C virus-positive and -negative recipients with use of short course of hepatitis B immunoglobulin and Lamivudine

INTRODUCTION: With the shortage of donor organs, increasing number of hepatitis B core antibody (HBcAb)-positive [HBcAb(+)] liver allografts are being used for liver transplantation (LTx) in patients who are HBcab-negative [HBsAb(-)]. This study was aimed at assessing outcomes for hepatitis C virus (HCV)-positive [HCV(+)] and HCV-negative [HCV(-)] patients who received HBcAb(+) liver grafts from deceased donors and also received a short course of hepatitis B immunoglobulin (HBIg) with long-term lamivudine therapy after LTx. MATERIALS AND METHODS: From February 1995 through February 2003, 28 patients (mean age 53.8 +/- 10.2 years, 19 men and nine women, 16 HCV[-]; 12 HCV[+]) received HbcAb(+) liver allografts. All recipients received a short course of HBIg prophylaxis (10,000 units/day for 4 days) and long-term lamivudine 100 mg/d after LTx in addition to a tacrolimus-based immunosuppressive regimen. RESULTS: Seven (25%) of the 28 recipients died during follow-up and three recipients required retransplantation. Three recipients (10.7%) developed HBV infection during follow-up, one of whom died 36 months after LTx and the other two had YMDD mutant HBV. The overall 6-year actuarial patient survival after transplantation was 74.4% and those for HCV(-) and HCV(+) recipients were 81.3% and 66.6%, respectively (P = .46). The overall 6-year actuarial graft survival was 63.9% and those for HCV(+) and HCV(-) recipients were 68.8% and 57.1%, respectively (P = .6). CONCLUSION: We conclude that HBcAb(+) liver grafts can be used for both HCV(+) patients and HCV(-) patients who are critically ill, have early hepatocellular carcinoma, or have been exposed to HBV in the past. A short course of HBIg-lamivudine combination therapy provides effective prophylaxis against HBV infection in 89% of recipients of HBcAb(+) grafts.     

Nutritional markers in liver allograft recipients

BACKGROUND: Malnutrition is common in patients with end-stage liver disease considered for transplantation, but it is unclear whether this affects the outcome after transplantation. AIM.: To determine whether the severity of malnutrition in liver transplant candidates affects outcome after transplantation. METHODS: We did a prospective study of 61 patients with chronic liver disease accepted for transplantation. FINDINGS: The Child-Pugh and Model for End-Stage Liver Disease (MELD) score correlated significantly but weakly with the mid-arm circumference (MAC) (rho=-0.34 and -0.31, P=0.015 and 0.025, respectively) but not with hand-grip strength, triceps skin-fold thickness (TSFT), or mid-arm muscle circumference. The Child-Pugh score but not the MELD was significantly associated with intensive therapy unit stay but not eventual outcome; there was a weak but statistically significant correlation between death and MAC (rho=+0.29, P=0.04) and TSFT (rho=+0.25, P=0.02). CONCLUSIONS: These findings suggest that nutritional parameters and markers of disease severity do not correlate well with outcomes after transplantation.     

Lamivudine therapy in kidney allograft recipients who are seropositive for hepatitis B surface antigen

BACKGROUND: There are numerous recent reports on the use of lamivudine for hepatitis B virus (HBV) infection after renal transplantation. However, the optimal strategy (prophylactic, preemptive, or salvage approach) for starting lamivudine treatment in this patient group has not been determined. The aim of this study was to assess how the timing of lamivudine therapy affected the HBV serological status and the transaminase levels in renal allograft recipients with chronic HBV infection. METHODS: We investigated outcomes for patients who were seropositive for hepatitis B surface antigen (HBsAg) and underwent transplantation before or after October 2004 (the date our institution implemented a prophylactic lamivudine treatment strategy against HBV). The data included serum liver enzyme levels and polymerase chain reaction (PCR) screening results for HBV-DNA in serum. RESULTS: Fifteen patients (11 before October 2004, four after October 2004) were included in the study. Preoperatively all patients had normal transaminases levels and 2 of 15 patients had detectable HBV-DNA on PCR. Eight of the 15 total HBsAg-positive patients in our series were not placed on lamivudine at the time of renal transplantation. Half of those who were not treated initially showed transaminase elevations in the first year of follow-up requiring lamivudine therapy at that time. In contrast, all seven individuals who received lamivudine at the time of transplantation were negative for HBV-DNA throughout the follow-up. CONCLUSION: To prevent viral replication in HBsAg-positive patients who are scheduled for renal transplantation, it is best to initiate lamivudine therapy before or immediately after transplantation.     

Successful hepatitis B vaccination in liver transplant recipients with donor-specific hyporesponsiveness

Currently, patients are prescribed lifelong treatment with hepatitis B immunoglobulin (HBIg) after liver transplantation (LT) for hepatitis B virus (HBV)-related diseases in order to prevent reinfection with HBV. Active immunization with an HBV vaccine would be a preferable alternative; however, the immunosuppressive environment in LT recipients is believed to elicit a poor response to vaccination. Minimizing the exposure of the HBV-infected LT recipients to immunosuppressants would be beneficial in inducing adaptive immunity against HBV by vaccination. In this study, in addition to efforts to minimize immunosuppression, prophylaxis with HBV vaccination combined with continuous HBIg administration was performed in 17 LT recipients who had undergone transplantation attributable to HBV-related diseases. During the observation period, the overall response rate to HBV vaccination was 64.7%. The immune status of the recipients was evaluated by a mixed lymphocyte reaction assay in response to allostimulation. Patients showing a donor-specific hyporesponse with a well-maintained response to the third-party stimulus always achieved a sustained immune response to the vaccine, whereas patients showing a hyporesponse to both the donor and the third-party stimulus were unable to do so. Thus, inducing an anti-donor-specific immunosuppressive status by minimizing immunosuppression should enable post-transplant HBV vaccination to be a promising prophylactic strategy.     

Failure of reactivation of hepatitis B after liver transplantation in hepatitis B surface antigen-negative, core antibody-positive recipients

BACKGROUND: Hepatitis B virus (HBV) infection after liver transplantation may occur in patients previously not exposed to the virus, but who receive an organ from a surface antigen (HBsAg)-negative, core antibody (HBcAb)-positive donor. The risk of HBV reactivation after liver transplantation in recipients that are HBsAg negative and HBcAb positive requires definition, because reactivation in kidney and bone marrow transplant patients has occurred. PATIENTS AND METHODS: A total of 409 HBsAg-negative patients underwent transplantation between April 1994 and June 1999. Pretransplantation sera were tested subsequently for HBcAb and HBsAb and posttransplantation sera for HBsAg. RESULTS: Of the 55 recipients who were positive for HBcAb, 48, who were immunosuppressed predominantly using tacrolimus, showed no evidence of HBV reactivation as shown by the absence of HBsAg (mean follow up 21.3+/-13.5 months). The remaining seven died within 6 months. CONCLUSIONS: In our experience, HBV reactivation did not occur in HBsAg-negative, HBcAb-positive recipients after liver transplantation, most of whom were immunosuppressed with tacrolimus. We would not, therefore, currently recommend HBV prophylaxis in these patients.     

Role of cytokine gene polymorphism in hepatitis C recurrence and allograft rejection among liver transplant recipients

BACKGROUND: Cytokines play a key role in the regulation of immune responses. The maximal capacity of cytokine production varies between individuals and was shown to correlate with polymorphism in cytokine gene promoters. The objective of this study was to analyze the role of cytokine allelic variations in susceptibility to early graft rejection episodes and recurrence of hepatitis C infection in liver transplant (LTx) recipients. METHODS: The genetic profile of five cytokines was studied in 68 LTx recipients and 49 controls using polymerase chain reaction sequence specific primers. All individuals were genotyped as high or low producers of TNF-alpha and IL-6 and high, intermediate, or low producers of transforming growth factor beta (TGF-beta), interferon gamma (IFN-gamma), and interleukin 10 (IL-10) based on single nucleotide substitutions. RESULTS: No statistically significant differences were observed between patients with or without early rejection episodes. A significant proportion of patients more prone to rejection were genotyped as having a low production profile of IL-10 compared with the control population (P=0.04). These data are in accordance with reports regarding other solid-organ transplant recipients. Patients with no recurrence of hepatitis C had the inherent ability to produce higher TGF-beta levels than did patients with recurrent disease (P=0.042). Among nonrecurrent patients, the percentage of genetically low IL-10 producers was higher than among recurrent patients (P=0.07). Furthermore, a genetic tendency to produce higher levels of IFN-gamma was noted among LTx recipients with nonrecurrent hepatitis C than among those with recurrent hepatitis C. CONCLUSIONS: While no significant correlation was detected between particular cytokine profile and early rejection episodes, our data strongly suggest an association between cytokine gene polymorphism of TGF-beta, IL-10, and INF-gamma and recurrence of hepatitis C in LTx recipients.     

Long-term lamivudine monotherapy prevents development of hepatitis B virus infection in hepatitis B surface-antigen negative liver transplant recipients from hepatitis B core-antibody-positive donors

BACKGROUND: Liver transplantation from hepatitis B core-antibody (HBcAb)-positive donors to hepatitis B surface-antigen (HBsAg)-negative recipients has been associated with a risk of hepatitis B virus (HBV) infection in the absence of antiviral prophylaxis. The aim of this study is to assess the efficacy of long-term lamivudine monotherapy to prevent development of HBV infection in HBsAg-negative recipients of liver allografts from HBcAb-positive donors. METHODS: From 315 cadaveric adult liver transplantations performed at our unit between July 1999 and March 2005, 18 recipients (5.7%) received liver allografts from HBcAb-positive donors, 13 of whom were HBsAg-negative pre-transplantation. The recipients consisted of four females and 14 males, age range 28-65 yr (median 49.5 yr). Post-transplantation, HBsAg-negative recipients were administered lamivudine 100 mg daily long term. HBsAg-positive recipients were administered low-dose hepatitis B immunoglobulin (HBIg) and lamivudine according to our usual protocol. Standard post-transplantation immunosuppression was given. Recipients were followed up regularly (range 2-69 months, median 21 months) for development of de novo HBV infection. RESULTS: Ten HBsAg-negative recipients received long-term lamivudine. One patient (HBcAb and HBsAb positive pre-transplant) did not receive lamivudine and, in two patients, lamivudine was discontinued following urgent re-transplantation for primary graft non-function. All 13 of the HBsAg-negative recipients were still alive, with no evidence of HBV infection at the end of follow-up. CONCLUSION: Long-term lamivudine monotherapy was effective in preventing development of HBV infection in HBsAg-negative liver transplant recipients from HBcAb-positive donors.     

Safety of ultra-rapid intravenous infusion of hepatitis B immunoglobulin in liver transplant recipients

Purpose

To evaluate the safety of institutional protocol for ultra-rapid hepatitis B immunoglobulin (HBIG) infusion (10,000 IU in 30 minutes) for hepatitis B virus prophylaxis in adult liver transplant recipients.

Methods

In this case-controlled study, prospectively recruited liver transplant recipients received ultra-rapid infusions of HBIG (10,000 units in 30 minutes) for 6 months. The historical control group consisted of patients who had received 1-hour HBIG infusions (conventional rapid infusion) for the precedent 6 months.

Results

We found that 1472 patients had received 5744 ultra-rapid HBIG infusions, whereas 1343 patients had received 5200 conventional rapid HBIG infusions. Adverse side-effects were observed after 7 (0.13%) and 9 (0.16%) infusions, respectively (P = .763). The number of infusions per month increased significantly, from 878 ± 34 before the introduction of ultra-rapid infusion to 957 ± 29 afterwards (P < .001), an increase of 10.5%. The maximal capacity of HBIG infusions per day in the outpatient clinic increased from 53 for conventional rapid infusion to 65 for ultra-rapid infusion, without expansion of the outpatient facility or equipment.

Conclusions

Nearly all adult liver recipients able to tolerate 1-hour infusions of HBIG can also tolerate ultra-rapid infusions well. Thus, it seems to be reasonable to perform ultra-rapid infusion protocol widely for patient convenience.