11. A Randomized Study to Assess the Safety and Efficacy of Adefovir Dipivoxil Substitution for Hepatitis B Immune Globulin in Liver Transplantation Patients Receiving Long-term Low-dose IM HBIg and Lamivudine Prophylaxis

P. W. Angus; S. I. Strasser; S. Patterson; G. W. McCaughan; E. Gane


Combination hepatitis B (HBV) immune globulin (HBIg) and lamivudine (LAM) provides effective prophylaxis against graft re-infection following liver transplant (OLTx) but HBIg is expensive and inconvenient, necessitating long-term monthly clinic follow-up. The aims of this study were to determine the safety, efficacy and economics of substituting adefovir dipivoxil (ADV) for HBIg, whilst continuing LAM, in patients transplanted for HBV related liver disease.



This was a randomized, prospective, multi-centre, open label study of adults at least 12 months post-OLTx for HBV disease who were receiving HBIg and LAM prophylaxis without recurrence of HBV infection in the graft. No OLTx grafts had been obtained from executed prisoners or other institutionalized persons. Patients were randomized (1:1) to receive ADV 10mg daily or to continue HBIg. LAM therapy was continued in both groups. Lactating or pregnant females as well as patients with HIV or a creatinine >180 µmol/L were excluded. All direct costs of antiviral prophylaxis were recorded (LAM, ADV, HBIg, clinic visits). Patients were reviewed at least 3 monthly until study completion.


Thirty-four patients were randomized: 16 to ADV/LAM (one withdrew consent after 2 months and is not included in the analysis) and 18 to continue HBIg/LAM. Patient groups at baseline did not differ significantly in time since OLTx, ALT, renal function, HBsAb titre, HBeAg status, Hepatitis C or D status, duration of prior antiviral therapy, or HBV DNA load at OLTx. One patient on ADV became HBsAg positive after 5 months but is persistently HBV PCR undetectable with a further 20 months of follow-up. All remaining patients are HBsAg and HBV DNA undetectable at a median of 17.2 months (range 7-31) from randomization. One patient on ADV had deterioration in renal function (creatinine 198 µmol/L from baseline 136 µmol/L in setting of diabetic nephropathy) requiring dose adjustment and ultimately ADV cessation after 15 months (peak creatinine 211 µmol//L). No other patient required dose adjustment (mean change in creatinine for other ADV patients +6 µmol/L). There were no further adverse events related to study therapy. Cost effectiveness analysis (using costs from the largest centre) is in favor of combination ADV/LAM therapy: $US 7,277 vs. $US 12,505 per treatment-year for LAM/HBIg (not including other societal costs).



In adults more than one-year post-OLTx for HBV disease who are without evidence of graft reinfection, switching from HBIg/LAM to ADV/LAM provides safe, effective and convenient protection against recurrent HBV. This strategy significantly reduces costs of long-term antiviral prophylaxis.


12. Decline in the Need for Liver Transplantation for End Stage Liver Disease secondary to Hepatitis B in the United States

W. Kim; J. T. Benson; A. Hindman; C. Brosgart; C. Fortner-Burton



Liver transplant (LTx) physicians have anecdotally noticed that fewer patients seem to come to LTx for hepatitis B (HBV)-related end stage liver disease, coincident with widespread application of effective antiviral agents. We analyzed nationwide data on patients who were waitlisted for HBV-related liver disease in the US.



All LTx candidates registered to the Organ Procurement and Transplantation Network for LTx between 1994 and 2006 were identified. All patients whose primary diagnosis included hepatitis B and/or hepatitis C (HCV) were included in the analysis. The outcome of waiting on the list was categorized into LTx, death and improvement.



The figure compares the number of registrants with HBV and HCV between 1994 and 2006. There was a rapid increase in the number of registrants with HBV and HCV in the 1990s. However, the number of registrants for HBV peaked in 2000 (n=586), which was followed by a 30% reduction in the ensuing 6 years (n=409 for 2006). This was in contrast to the number of registrants with HCV, which dipped in 2002 following implementation of MELD then regained its previous level. Among HBV patients, the proportion of registrants of Asian race increased from 12% to 35% and African race from 5% to 15% between 1994 and 2006. The proportion of HBV patients with HCC at the time of LTx increased from 8% to 12% over time.



The number of patients registered for LTx in the US for decompensated liver disease secondary to HBV decreased substantially since 2000, a trend not mirrored in HCV. Many other epidemiologic explanations for this trend are feasible, but widespread application of antiviral agents may have contributed to the decreased incidence of decompensated liver disease.



28. Survival and Risk of Hepatitis B Virus (HBV) Recurrence in HIV-HBV Coinfected Liver Transplant Recipients: Preliminary Findings from the HIV-TR Study

C. S. Coffin; C. L. Berg; L. M. Dove; F. Poordad; M. P. Curry; F. G. Regenstein; K. E. Sherman; M. E. Roland; P. G. Stock; N. Terrault



Liver transplantation (LT) is the treatment of choice for HBV-infected patients with end stage liver disease, but the outcome of LT in HIV+ patients may be complicated by HIV disease progression and/or recurrent liver disease post-LT. Aims: To evaluate the safety and efficacy of LT for HBV-HIV coinfected patients.



Multicenter prospective cohort study of HIV-HBV coinfected patients in the “Solid Organ Transplantation in HIV Study” (HIV-TR) undergoing LT from 2003-2007. HIV-specific criteria included undetectable HIV viral load if on antiretrovirals (ARV) or prediction of full suppression post-LT if unable to tolerate ARV and CD4 cells >100/mm3, or >200/mm3 if there was a history of opportunistic infections or neoplasms. Standardized post-LT HBV prophylaxis included hepatitis B immunoglobulin (HBIG) & antivirals: tenofovir with lamivudine (LAM) or emtricitabine. Sera were collected pre-transplant, 12, 26, 52 wks & 2 yr post-LT. We assessed patient and graft survival and HBV recurrence (defined by positive HBV DNA and hepatitis B surface antigen, HBsAg, in serum). Ultra-sensitive real-time PCR was used to detect HBV genomes using S-gene specific primers and fluorescent-labeled Taq-man based DNA probes (range 20 – 2 x 107 IU/ml). A contemporary cohort of 60 HBV monoinfected LT recipients with median follow-up of 21.2 mo (0 - 42.0) served as controls for survival analysis.



16 coinfected patients [all Caucasian males, median age 46 yrs, pre-LT CD4 count median 362/mm3 (range 128-1070), 1 with HCC, 2 with HCV coinfection] were followed for median 8.5 mo (range 0.46-36) after LT. At the time of LT, 68% were on anti-HBV drugs with efficacy against LAM-resistant HBV and 50% had HBV DNA >20 IU/ml; range 80-3.5x106 IU/ml in those detectable. All patients remained HBsAg negative post-LT on combination prophylaxis but low-level HBV viremia (range 9 – 79 IU/ml, mean 26 IU/ml) was detected in 44% (31% of these patients had detectable HBV DNA pre-LT). Cumulative 1-year survival was 86% (95% CI: 59-97%) in coinfected patients and 93% (95% CI: 83-98%) in monoinfected patients (p=0.58, log-rank test). No patient died from recurrent HBV infection in either group.



Short-term outcomes in this cohort of HBV-HIV coinfected patients undergoing LT are comparable to HBV monoinfected patients. Combination HBIG and antivirals effectively prevents serologically evident HBV infection in all patients, however, low-level viremia is intermittently detected in up to 44%. The clinical significance of low-level viremia in the absence of HBsAg is unknown but suggests long-term combination prophylaxis will be essential to prevent recurrence.