No detectable resistance to tenofovir disoproxil fumarate in HBeAg+ and HBeAg- patients with chronic hepatitis B after 8 years of treatment.

A major hurdle in the long-term treatment of chronic hepatitis B (CHB) patients is to maintain viral suppression in the absence of drug resistance. To date, no evidence of resistance to tenofovir disoproxil fumarate (TDF) has been observed. A cumulative evaluation of CHB patients who qualified for resistance surveillance over 8 years of TDF treatment was conducted. Patients in studies GS-US-174-0102 (HBeAg-) and GS-US-174-0103 (HBeAg+) were randomized 2:1 to receive TDF or adefovir dipivoxil (ADV) for 48 weeks followed by open-label TDF through year 8. Population sequencing of HBV pol/RT was attempted for all TDF-treated patients at baseline and, annually if viremic, at discontinuation, or with addition of emtricitabine. Overall, 88/641 (13.7%) patients qualified for sequence analysis at one or more time points. The percentage of patients qualifying for sequence analysis declined over time, from 9 to 11% in years 1-2 to <4% over years 3-8. Forty-one episodes of virologic breakthrough (VB) occurred throughout the study, with most (n=29, 70%) associated with nonadherence to study medication. Fifty-nine per cent of VB patients with an opportunity to resuppress HBV achieved HBV DNA resuppression. A minority of patients who qualified for sequencing had polymorphic (41/165, 24.8%) or conserved (17/165, 10.3%) site changes in pol/RT, with six patients developing lamivudine and/or ADV resistance-associated mutations. No accumulation of conserved site changes was detected. The long-term treatment of CHB with TDF monotherapy maintains effective suppression of HBV DNA through 8 years, with no evidence of TDF resistance or accumulation of conserved site changes.

Once daily ledipasvir/sofosbuvir fixed-dose combination with ribavirin in patients with inherited bleeding disorders and hepatitis C genotype 1 infection.

AIM: People with inherited bleeding disorders have been disproportionally affected by HCV. We assessed the fixed-dose combination of the NS5A inhibitor ledipasvir (LDV) with the NS5B polymerase inhibitor sofosbuvir (SOF) with ribavirin (RBV) in patients with genotype 1 HCV and inherited bleeding disorders. METHODS: To be eligible, patients had to be over 18 years of age and have an inherited bleeding disorder. HCV treatment-naïve and -experienced patients could enrol. All patients received LDV 90 mg per SOF 400 mg once daily and weight-based RBV in a divided dose for 12 weeks. The primary efficacy endpoint was sustained virologic response (SVR), defined as HCV RNA below the limit of detection (15 IU mL-1 ) 12 weeks after the end of treatment (SVR12). RESULTS: Of the 14 patients enrolled, 8 (57%) had haemophilia A, 3 (21%) had haemophilia B and 2 (14%) had von Willebrand disease, and 1 (7%) had factor XIII deficiency. All 14 patients (100%, 95% CI: 77-100%) achieved SVR12. Treatment was well tolerated: all patients completed therapy, with mostly mild adverse events. No specific safety concerns associated with the patient's underlying bleeding disorders were noted. CONCLUSION: These results appear to suggest that people with HCV and inherited bleeding disorders can be safely and effectively treated with 12 weeks of LDV/SOF plus RBV.

Evolution of the HCV viral population from a patient with S282T detected at relapse after sofosbuvir monotherapy.

Clinical phase II/III studies of the nucleotide analogue HCV NS5B inhibitor sofosbuvir (SOF) have demonstrated high efficacy in HCV-infected patients in combination therapy. To date, resistance to SOF (S282T in NS5B) has rarely been detected in patients. In this study, we investigated the evolution of S282T viral variants detected in one HCV genotype 2b-infected patient who relapsed following 12 weeks of SOF monotherapy. Deep sequencing of the NS5B gene was performed on longitudinal plasma samples at baseline, days 2 and 3 on SOF, and longitudinal samples post-SOF treatment through week 48. Intrapatient HCV evolution was analysed by maximum-likelihood phylogenetic analysis. Deep sequencing analysis revealed a low level pre-existence of S282T at 0.05% of viral sequences (4/7755 reads) at baseline and 0.03% (6/23 415 reads) at day 2 on SOF. Viral relapse was detected at week 4 post-treatment where 99.8% of the viral population harboured S282T. Follow-up analysis determined that S282T levels diminished post-treatment reaching undetectable levels 24-48 weeks post-SOF. Phylogenetic analysis together with the persistence of unique post-treatment mutations in all post-SOF samples suggested that growth of wild type resulted from reversion of the S282T mutant to a wild type and not outgrowth of the baseline wild-type population. Our data suggest that a very low level of pre-existing S282T at baseline in this patient was enriched and transiently detected following SOF monotherapy. Despite relapse with drug resistance to SOF, this patient was successfully retreated with SOF plus ribavirin for 12 weeks and is now cured from HCV infection.

Epidemiology, disease burden and outcomes of cirrhosis in a large secondary care hospital in South Auckland, New Zealand.

BACKGROUND: Liver cirrhosis is an important cause of morbidity and mortality; however, little is known about its impact in New Zealand. AIMS: We aim to determine the disease burden, epidemiology and outcomes of cirrhotic patients. METHODS: This is a retrospective study of cirrhosis patients under secondary public hospital care in a geographically defined region, between the years 2000 and 2011. Cirrhosis complications and mortality was recorded. Poisson log-linear regression analysis was performed for incidence rate ratio (IRR) and Cox regression analysis was used to analyse time-related events. RESULTS: Seven hundred and forty-six cirrhotic patients were analysed; most were European/Other (39.9%), Pacific islanders (21.6%), Southeast Asian/Chinese (17.8%) and Maori (12.3%). 68.4% were male. The common primary aetiologies for cirrhosis were chronic hepatitis B (CHB) cirrhosis (37.3%), alcoholic liver disease (ALD) cirrhosis (24.1%), chronic hepatitis C (CHC) cirrhosis (22.3%) and non-alcoholic fatty liver disease (NAFLD) cirrhosis (16.4%). The hepatocellular carcinoma (HCC) mortality rates were highest in NAFLD and CHB cirrhosis groups (3.0 and 3.1 per 100 patient-year respectively), compared with ALD and CHC groups (2.2 and 1.4 per 100 patient-year, all P < 0.05 respectively). Patients with ALD and NAFLD cirrhosis had the highest all-cause and non-HCC mortality rate compared with viral hepatitis cirrhosis groups. The IRR for HCC incidence, liver-related mortality and HCC mortality were 1.087, 1.098 and 1.114, respectively (all P < 0.001), suggesting increasing incidence and disease burden over the study period. CONCLUSION: The number of cirrhotic patients in secondary care is increasing steadily. Cirrhosis complications and mortality rates are also rising, particularly the incidence and mortality of HCC.

Directly acting antivirals (DAAs) for the treatment of chronic hepatitis C virus infection in liver transplant patients: "a flood of opportunity".

Chronic hepatitis C virus (HCV) is the leading cause of liver transplantation (LT) in adults. However, infection of the allograft is universal and associated with reduced graft and patient survival. Although successful eradication improves posttransplant outcome, current antiviral therapies have poor efficacy and tolerability. Direct acting antiviral agents (DAAs) provide new opportunities for treatment of HCV recurrence. The addition of a first-generation NS3/4A protease inhibitor (PI) has increased the efficacy of pegylated interferon and ribavirin in patients with chronic HCV genotype 1 infection. Preliminary efficacy results from open-labeled studies of PI-based triple therapy in LT recipients are encouraging. However, the tolerability of triple therapy is reduced following LT, because of increased anemia and drug-drug interactions. The use of PI-based triple therapy in LT recipients seems best suited to larger centers, experienced with management of PI toxicity. Fortunately, other classes of DAAs targeting different steps of HCV replication are in clinical trials, including nucleotide polymerase (NUC-NS5B) inhibitors, nonnucleotide polymerase (non-NUC-NS5B) inhibitors and NS5A inhibitors. Several dual and triple DAA regimens are in clinical development. Phase II studies conducted in patients before and after LT suggest that these regimens will dramatically reduce the impact of recurrent HCV. There is a tide in the affairs of men. Which, taken at the flood, leads on to fortune (Shakespeare: J Caesar Act 4, scene 3).

Efficacy and safety of continuous 4-year telbivudine treatment in patients with chronic hepatitis B.

In the phase-III GLOBE/015 studies, telbivudine demonstrated superior efficacy vs lamivudine during 2-year treatment in HBeAg-positive and HBeAg-negative chronic hepatitis B (CHB). After completion, 847 patients had an option to continue telbivudine treatment for further 2 years. A total of 596 (70%) of telbivudine-treated patients, who were serum HBV DNA positive or negative and without genotypic resistance to telbivudine at the end of the GLOBE/015 trials, were enrolled into a further 2-year extension study. A group of 502 patients completed 4 years of continuous telbivudine treatment and were included in the telbivudine per-protocol population. Amongst 293 HBeAg-positive patients, 76.2% had undetectable serum HBV DNA and 86.0% had normal serum ALT at the end of 4 years. Notably, the cumulative rate of HBeAg seroconversion was 53.2%. Amongst 209 HBeAg-negative patients, 86.4% had undetectable HBV DNA and 89.6% had normal serum ALT. In patients who had discontinued telbivudine treatment due to HBeAg seroconversion, the HBeAg response was durable in 82% of patients (median 111 weeks of off-treatment follow-up). The cumulative 4-year resistance rate was 10.6% for HBeAg-positive and 10.0% for HBeAg-negative patients. Most adverse events were mild or moderate in severity and transient. Renal function measured by estimated glomerular filtration rate (eGFR) increased by 14.9 mL/min/1.73 m(2) (16.6%) from baseline to 4 years (P < 0.0001). In conclusion, in HBeAg-positive and HBeAg-negative CHB patients without resistance after 2 years, two additional years of telbivudine treatment continued to provide effective viral suppression with a favourable safety profile. Moreover, telbivudine achieved 53% of HBeAg seroconversion in HBeAg-positive patients.

Diabetes mellitus following liver transplantation in patients with hepatitis C virus: risks and consequences.

Recurrent hepatitis C virus (HCV) infection of the allograft occurs universally following liver transplantation. Longitudinal natural history studies have identified several pre- and posttransplant factors associated with more rapid fibrosis progression, including baseline host and viral factors, donor factors and posttransplant immunosuppression effects, such as metabolic syndrome. Evidence accumulated over the past two decades indicates that HCV has metabolic associations, in particular insulin resistance and diabetes mellitus. Approximately half of HCV-positive liver transplant recipients develop posttransplant diabetes mellitus (PTDM), which is associated with accelerated fibrosis progression and poorer graft and patient survival outcomes. This review summarizes the risks and consequences of insulin resistance and PTDM in HCV-positive liver transplant recipients. Risk for developing PTDM is one factor that should be considered when choosing the primary immunosuppressive regimen following liver transplantation. Comparative studies suggest that cyclosporine A-based immunosuppression may provide improved responses to antiviral therapy and reduced incidence of PTDM compared with tacrolimus-based immunosuppression. Addressing insulin resistance and PTDM in HCV-positive liver transplant recipients may have the potential to slow HCV complications and improve survival outcomes.

Sirolimus conversion regimen versus continued calcineurin inhibitors in liver allograft recipients: a randomized trial.

A large prospective, open-label, randomized trial evaluated conversion from calcineurin inhibitor (CNI)- to sirolimus (SRL)-based immunosuppression for preservation of renal function in liver transplantation patients. Eligible patients received liver allografts 6-144 months previously and maintenance immunosuppression with CNI (cyclosporine or tacrolimus) since early posttransplantation. In total, 607 patients were randomized (2:1) to abrupt conversion (<24 h) from CNI to SRL (n = 393) or CNI continuation for up to 6 years (n = 214). Between-group changes in baseline-adjusted mean Cockcroft-Gault GFR at month 12 (primary efficacy end point) were not significant. The primary safety end point, noninferiority of cumulative rate of graft loss or death at 12 months, was not met (6.6% vs. 5.6% in the SRL and CNI groups, respectively). Rates of death at 12 months were not significantly different, and no true graft losses (e.g. liver transplantation) were observed during the 12-month period. At 52 weeks, SRL conversion was associated with higher rates of biopsy-confirmed acute rejection (p = 0.02) and discontinuations (p < 0.001), primarily for adverse events. Adverse events were consistent with known safety profiles. In conclusion, liver transplantation patients showed no demonstrable benefit 1 year after conversion from CNI- to SRL-based immunosuppression.

Randomized clinical trial: efficacy and safety of telbivudine and lamivudine in treatment-naïve patients with HBV-related decompensated cirrhosis.

Patients with decompensated cirrhosis owing to chronic hepatitis B viral (HBV) infection have a high morbidity/mortality rate, and the treatment remains a challenge. We studied the safety and efficacy of telbivudine and lamivudine in such patients. This noninferiority, double-blind trial randomized 232 treatment-naive patients with decompensated HBV (1:1) in 80 academic hospitals to receive once-daily telbivudine 600 mg or lamivudine 100 mg for 104 weeks. Primary composite endpoint was proportion of patients with HBV DNA <10 000 copies/mL, normal alanine aminotransferase (ALT) and Child-Turcotte-Pugh score improvement/stabilization at week 52. Response rates using a post hoc modified endpoint (HBV DNA <300 copies/mL [57 IU/mL] and ALT normalization) in intent-to-treat analysis (missing = failure) were 56.3%vs 38.0% after 76 weeks (P = 0.018) and 45.6%vs 32.9% after 104 weeks (P = 0.093) for telbivudine vs lamivudine. Telbivudine treatment was an independent predictive factor for HBV DNA <300 copies/mL and ALT normalization (P = 0.037). Response rates with protocol-defined composite endpoint in intent-to-treat analysis (M = F) were 56.2 vs 54.0% (noninferiority not achieved) and 39.1%vs 36.4% (noninferiority achieved) in telbivudine and lamivudine groups at 52 and 104 weeks. Telbivudine treatment was associated with a significant improvement in glomerular filtration rate compared to lamivudine treatment and was also associated with a trend for improvement in survival (87%vs 79%). No cases of lactic acidosis were reported. Telbivudine compared to lamivudine was associated with a higher rate of patients with both viral suppression and ALT normalization, a trend towards a higher rate of survival and significant improvement in glomerular filtration.

Sofosbuvir and velpatasvir with or without voxilaprevir in direct-acting antiviral-naïve chronic hepatitis C: patient-reported outcomes from POLARIS 2 and 3.

BACKGROUND: Chronic hepatitis C infection leads to impairment of patient-reported outcomes (PROs). Treatment with direct-acting antiviral regimens results in short- and long-term improvement of these outcomes. AIM: To assess PROs in patients treated with a newly developed direct-acting antiviral, a fixed-dose combination of sofosbuvir/velpatasvir (SOF/VEL) with/without voxilaprevir (VOX). METHODS: The PRO data were collected from participants of POLARIS-2 and POLARIS-3 clinical trials (DAA-naïve, all HCV genotypes). Participants self-administered SF-36v2, FACIT-F, CLDQ-HCV and WPAI:SHP instruments at baseline, during treatment, and in follow-up. RESULTS: Of 1160 patients, 611 received SOF/VEL/VOX and 549 received SOF/VEL (52.8 ± 11.0 years, 55.9% male, 75.4% treatment-naïve, 33.9% cirrhotic). The sustained viral response at 12 weeks (SVR12) rates were 95%-98%. During treatment, improvements in most PRO scores were significant (all but one P < .01) and ranged from, on average, +2.3 to +15.0 points (on a 0-100 scale) by the end of treatment. These improvements were similar between SOF/VEL/VOX and SOF/VEL arms (all P > .05). After treatment discontinuation, patients treated with both regimens achieved significant and clinically meaningful PRO gains (+2.7 to +16.7 by post-treatment week 12, +3.9 to +20.1 by post-treatment week 24; all but one P < .001). Multivariate analysis showed that depression, anxiety and cirrhosis were the most consistent independent predictors of PRO impairment while no association of PROs with the treatment regimen choice was found (all P > .05). CONCLUSIONS: The pan-genotypic regimens with SOF/VEL with or without VOX not only have excellent efficacy and safety, but also significantly positively impact patients' experience both during treatment and after achieving sustained virologic response in DAA-naïve patients with HCV.

Comparison of a new quantitative cytomegalovirus DNA assay with other detection methods.

OBJECTIVE: We assessed a new cytomegalovirus (CMV) DNA hybridization assay. We also compared the assay with other currently used assays to determine its use in the early detection of active CMV infection. PATIENTS AND METHODS: Sequential whole blood samples collected from 109 patients who had undergone orthotopic liver transplantation were tested using the Murex hybrid capture system, cell culture, antigen detection, and serology. Liver biopsies performed during the study period for graft dysfunction in 84 patients were examined for histological features of CMV hepatitis. The biopsies were also immunostained for the presence of CMV antigens. RESULTS: Fifteen patients developed clinically significant CMV disease (CMV syndrome in six patients and CMV hepatitis in nine patients, including two patients with disseminated CMV disease). In all 15, CMV DNA was detected by the hybrid capture assay between 1 and 20 days before other CMV assays. Fourteen of the 15 patients had CMV DNA levels greater than 50 pg/ml; the other patient had a value of 48 pg/ml. Of the remaining 94 patients with no evidence of CMV disease, 86 were negative by the hybrid capture assay and 8 were positive; all but one patient had values less than 50 pg/ml. DNA levels fell rapidly in all patients during antiviral therapy. CONCLUSION: Unlike conventional CMV detection methods, this hybridization assay is an early predictor of clinically significant CMV infection after liver transplantation and also provides quantitation of viral load, allowing monitoring of antiviral therapy.

Antibodies to hepatitis C virus envelope proteins correlate with hepatitis C viraemia after liver transplantation.

BACKGROUND: Liver transplant recipients for hepatitis C virus (HCV)-related cirrhosis usually remain anti-HCV-seropositive after transplantation. The aim of this study was to characterize, longitudinally, the profile of HCV-specific antibodies and cryoglobulins in liver transplant recipients with recurrent HCV infection. METHODS: Serial serum samples were collected prospectively before, at 1 month after, and at 12 months after transplantation for HCV cirrhosis in 30 patients infected with genotype 1. The antibodies against HCV envelope proteins (E1 and E2) were quantitated by enzyme-linked immunosorbent assay and antibodies against core, E2/hypervariable region I (HVRI), NS3, NS4, and NS5A antigens by a line immunoassay. Sera were also tested for cryoglobulins. RESULTS: The titer of each anti-HCV antibody had fallen at 1 month after transplantation (P<0.05) with the exception of anti-E1 levels, which had risen in 16 patients with acute hepatitis C at that time (P=0.01). Anti-E1 and anti-E2 titers, but not antibodies against other HCV antigens, increased to pre-transplantation levels or higher at 12 months, which correlated with serum HCV RNA levels. Cryoglobulinemia was present in nine patients after transplantation (30%) and was associated with lower anti-E1 levels (P=0.04) and more severe graft damage. CONCLUSIONS: The early increase in antibodies to HCV envelope proteins in correlation with viremia suggests that the envelope-specific humoral immune response may be directly stimulated by HCV replication. Anti-E1 levels may be a useful marker in monitoring patients with recurrent HCV infection.

Colonoscopy in unexplained lower gastrointestinal bleeding.

Two hundred and forty patient with unexplained gastrointestinal blood loss underwent colonoscopy. Significant lesions which were thought to be likely causes of bleeding were identified in 98 patients, ie, 41% of total, which included active colitis in 9%, large polyps in 10% and colorectal cancer in 12% of patients. Of the cancers found at colonoscopy, 64% were Dukes A or B. This study confirms the role of colonoscopy in the investigation of unexplained chronic lower gastrointestinal bleeding.

Neurological disease in patients with human immunodeficiency virus infection.

We followed prospectively all patients with HIV infection admitted to the infectious diseases ward at Auckland Hospital over a seven month period. Neurological manifestations of HIV infection were the primary reason for admission in 18 of the 55 patients (33%). Diagnoses were usually presumptive, based on history, clinical findings, radiological appearances and response to empirical therapy. Eight patients had cerebral toxoplasmosis, three primary cerebral lymphoma, two cytomegalovirus retinitis, two HIV neuropathy, one cryptococcal meningitis, one HIV encephalopathy, and one HIV meningitis. Another patient with HIV infection was admitted to the neurology ward at Auckland Hospital with HIV myelopathy during the same seven month period. The median survival of the patients treated for presumptive toxoplasmosis was 7.5 months. Only two patients had not developed AIDS, one having HIV meningitis and the other HIV myelopathy, and in both, symptoms resolved spontaneously with no relapse at one year follow up. The spectrum of neurological manifestations of HIV infection is wide. Investigations to determine the most likely diagnosis are indicated and specific therapy may lead to both excellent palliation and prolonged survival.

Upper gastrointestinal endoscopy in patients with human immunodeficiency virus infection: is it worthwhile?

AIM: To determine the diagnostic accuracy of upper gastrointestinal endoscopy in a selected group of patients with HIV infection, who had severe symptoms unresponsive to empirical treatment. METHOD: We reviewed all patients with HIV infection, who had undergone upper gastrointestinal endoscopy at Auckland Hospital. Specific diagnoses were based on the endoscopic appearances and on the histological and microbiological examination of endoscopic biopsies taken from the oesophagus, stomach and duodenum. RESULTS: A definitive diagnosis was reached in 16 of the 21 patients endoscoped, of whom 13 had a good clinical response to treatment. The median survival was three months. The most common diagnosis was oesophageal candidiasis seen in six patients, all of whom responded to treatment with a median survival of six months. Invasive cytomegalovirus gastrointestinal disease was seen in three patients, none of whom had positive blood cultures for cytomegalovirus. All responded to intravenous ganciclovir. Three patients with severe diarrhoea had opportunistic infection of the small bowel. All three had advanced AIDS with a median survival of less than one month. CONCLUSION: Upper gastrointestinal endoscopy has a high diagnostic yield in patients with HIV infection with oesophageal symptoms which fail to respond to antifungal therapy, or with severe weight loss and diarrhoea and it should be considered in these patients because excellent palliation may be possible.

Low-cost, simultaneous, single-sequence genotyping of the HLA-A, HLA-B and HLA-C loci.

New automated DNA sequencing technology has enabled the development of an assay for genotyping the three major HLA class 1 loci from a single sequence of each gene containing exon 3, intron 2 and exon 2. The assay allows 31 subjects (with 3 negative controls) to be genotyped at all three loci simultaneously, using a 96-well plate format. Genotypes were assigned by comparing each sequence to a database of 307 HLA-A, 563 HLA-B and 166 HLA-C alleles. Unequivocal, 4-digit allele assignments were made for 40 of 130 HLA-A genes, 82 of 130 HLA-B genes and 97 of 130 HLA-C genes from 21 European, 20 Tongan and 24 Niuean subjects. Ambiguity in interpretation of the sequence contributed to 66 of the 170 equivocal allele assignments, and 105 equivocal assignments were due to polymorphisms outside exons 2 and 3. All known alternative interpretations of ambiguous genotypes were identified, and seven HLA-B and two HLA-C ambiguities were resolved by reading the out-of-phase exon 2 sequence that followed an indel in intron 2. The genotypes of a subgroup of 27 heterozygous subjects, whose genotypes contained all of the alleles identified in this study, were confirmed with commercial, generic PCR-SSP typing. In European subjects, the repertoire of HLA-B/HLA-C haplotypes was almost identical to previously published data. We identified five new HLA-B/HLA-C haplotypes in the Polynesian subjects, and the remaining haplotypes were of Asian origin. In summary, we are describing a low-cost, sequencing assay for the three major HLA class I loci that provides a level of resolution that is comparable with a commercial PCR-SSP assay.

Fulminant hepatic failure in a young mother.

We report the case of a mother who developed fulminant hepatic failure with hypoglycaemia, coagulopathy, Grade III hepatic encephalopathy, two days after the delivery of her fourth child. She had complained of pruritus for the final two weeks of pregnancy. She received supportive medical management within a critical care unit, and the hepatic failure resolved completely within 48 hours. Liver biopsy confirmed the diagnosis of acute fatty liver of pregnancy. This case is unusual in that this patient deteriorated markedly following delivery, at a time when spontaneous recovery is normally expected.

Combination low-dose hepatitis B immune globulin and lamivudine therapy provides effective prophylaxis against posttransplantation hepatitis B.

Although antiviral prophylaxis with lamivudine monotherapy appears to reduce post-liver transplantation recurrence of hepatitis B virus (HBV) infection, breakthrough infections occur in at least 20% of the patients because of the development of drug resistance. Combined lamivudine and intravenous hepatitis B immune globulin (HBIG) therapy (10,000-IU doses) may reduce this risk, but its use is limited by cost ( approximately US $45,000/yr) and availability. We report the experience at liver transplant centers in Australia and New Zealand in which lamivudine has been used in combination with much lower doses of HBIG than used in conventional HBIG prophylaxis. Lamivudine, 100 mg/d, was administered to hepatitis B surface antigen (HBsAg)-positive candidates on listing for transplantation and was continued posttransplantation. HBIG, 400 or 800 IU, was administered intramuscularly (IM) daily for 1 week from transplantation and monthly thereafter. Thirty-seven HBsAg-positive patients underwent transplantation using this protocol. Thirty-six of these patients were HBV DNA positive by polymerase chain reaction (PCR) or hybridization assay. Thirty-four patients had chronic HBV, 2 patients had hepatitis B and C, and 1 patient had hepatitis B, C, and D. Five patients died within 1 month of transplantation and are not included in the analysis. Mean follow-up in the remaining 32 patients was 18.4 months (range, 5 to 45 months). Treatment was well tolerated, with no significant adverse events. Thirty-one of 32 patients were HBsAg negative, and all 32 patients were HBV DNA negative by PCR at latest follow-up. The cost of treatment was US $967 for lamivudine and between $2,290 and $4,480/yr for IM HBIG. Lamivudine and low-dose HBIG treatment prevents posttransplantation recurrence of hepatitis B and is likely to be more cost-effective than high-dose HBIG regimens.

Ribavirin therapy for hepatitis C infection following liver transplantation.

Hepatitis C infection following orthotopic liver transplantation may lead to progressive chronic graft dysfunction. In this study, seven liver transplant recipients with chronic allograft dysfunction due to hepatitis C infection (one acquired and six recurrent infections) were treated with oral ribavirin for 6 months. Symptoms of lethargy, nausea and anorexia improved in all patients within 2 weeks of starting the drug, with a fall in serum AST of at least 40% by this time. Ribavirin-induced haemolysis was clinically significant in three patients, necessitating a reduction in the daily dose of ribavirin from 1.2 g to 0.2 g. Comparison of the pre- and post-treatment biopsy specimens in the four patients who tolerated the full dose of ribavirin and who had normal AST levels at the end of 6 months of treatment showed significant histological improvement with reduction in either lobular or periportal inflammation in all of the patients and a reduction in periportal fibrosis in one patient. HCV RNA remained detectable in serum in all of the patients at the end of the study.

A longitudinal analysis of hepatitis C virus replication following liver transplantation.

BACKGROUND & AIMS: The pathogenesis of graft injury in liver transplant recipients with recurrent hepatitis C virus (HCV) infection remains poorly understood. In this study, the relationship between HCV replication, genotype, and the evolution of graft damage was investigated. METHODS: HCV RNA was quantified in 184 protocol sera from 25 patients transplanted for HCV cirrhosis. HCV isolates were genotyped, and hepatic expression of core and NS4 antigens was sought in protocol allograft biopsy specimens. RESULTS: Acute lobular hepatitis was accompanied by a steep increase in HCV RNA levels and the appearance of core and NS4 antigens in the graft. Methylprednisolone treatment for acute rejection led to a 4-100-fold increase in serum HCV RNA. At the end of follow-up, HCV RNA levels were 3-112 times pretransplant levels and were higher in patients with more severe hepatitis. Progressive liver damage developed in 7 of 14 patients with HCV genotype 1b and in 1 of 11 patients infected with other genotypes (P = 0.03). CONCLUSIONS: Peak viremia levels and the initial detection of HCV antigens in hepatocytes suggests increased viral replication at the time of acute HCV hepatitis in the graft. Genotype 1b and higher viremia levels were associated with more severe chronic graft damage.