J.A. Carrión

Transient elastography for diagnosis of advanced fibrosis and portal hypertension in patients with hepatitis C recurrence after liver transplantation

Recurrence of hepatitis C after liver transplantation (LT) is the main cause of graft loss and retransplantation. Frequent liver biopsies are essential to follow‐up hepatitis C virus (HCV)–induced liver damage. However, liver biopsy is an invasive and expensive procedure. We evaluated prospectively the diagnostic accuracy of noninvasive measurement of liver stiffness (by transient elastography) to assess the severity of hepatitis C recurrence after LT. For this purpose, we included 124 HCV‐infected liver transplant recipients who underwent 169 liver biopsies and 129 hepatic hemodynamic studies with determination of hepatic venous pressure gradient (HVPG). Simultaneously, patients underwent measurement of liver stiffness. Liver fibrosis was mild (F0‐F1) in 96 cases (57%) and significant (F2‐F4) in 73 (43%). HVPG was normal (<6 mm Hg) in 69 cases (54%) and elevated (≥6 mm Hg) in 60 (46%). Using a liver stiffness cutoff value of 8.5 kilopascals, the sensitivity, specificity, negative predictive value, and positive predictive value for diagnosis of fibrosis ≥F2 were 90%, 81%, 79%, and 92%, respectively. The area under the curve (AUC) for diagnosis of fibrosis ≥F2, ≥F3 and F4 were 0.90, 0.93, and 0.98, respectively. There was a close direct correlation between liver stiffness and HVPG (Pearson coefficient, 0.84; P < 0.001) and the AUC for diagnosis of portal hypertension (HVPG ≥6 mm Hg) was 0.93. Importantly, none of the individuals with liver stiffness below the cutoff value had either bridging fibrosis (F3) or cirrhosis (F4) or significant portal hypertension (HVPG ≥10 mm Hg). In conclusion, determination of liver stiffness is an extremely valuable tool to assess the severity of HCV recurrence after LT and in reducing the need of follow‐up liver biopsies. Liver Transpl 12:1791‐1798, 2006.

Hepatic venous pressure gradient identifies patients at risk of severe hepatitis C recurrence after liver transplantation

Liver biopsy is essential in the follow‐up of HCV‐infected liver transplant recipients. The aim of this study was to prospectively compare percutaneous (PLB) versus transjugular liver biopsy (TLB) in the assessment of liver damage. We also explored the diagnostic value of hepatic venous pressure gradient (HVPG) to identify patients at risk of severe HCV disease recurrence after liver transplantation (LT). One hundred sixteen paired PLB and TLB (with HVPG measurement) were performed 3 or 12 months after LT in 80 patients. Concordance for necroinflammation and fibrosis was fair or good, particularly 1 year after LT (kappa ≥ 0.6). At this point, a significant positive association was seen between the median HVPG and the fibrosis stage (2.5 mm Hg for F0; 5 mm Hg for F1, 6 mm Hg for F2, and 11.5 mm Hg for F3; Kruscal‐Wallis < 0.001). Despite this strong association, portal hypertension (HVPG ≥ 6 mm Hg) was detected in 1 (5%) of 22, 4 (16%) of 25, and 6 (60%) of 10 patients with fibrosis stages 0, 1, and 2, respectively. After a median follow‐up of 38 months, clinical decompensation occurred in 15 (19%) of 80 patients. Although the presence of significant fibrosis (F2‐F3) 1 year after transplantation was good to predict clinical decompensation (AUC: 0.80), an HVPG of 6 mm Hg or greater was extremely accurate at identifying patients at risk of disease progression (AUC: 0.96). In conclusion, HVPG determination is a valuable tool for follow‐up in patients with HCV recurrence after LT. (HEPATOLOGY 2006;43:492–499.)

Antiviral therapy increases the risk of bacterial infections in HCV-infected cirrhotic patients awaiting liver transplantation: A retrospective study

BACKGROUND/AIMS Recurrence of hepatitis C after liver transplantation (LT) is universal and may cause premature graft loss. We evaluated the efficacy and safety of antiviral therapy in HCV-infected patients with decompensated cirrhosis awaiting LT. METHODS Fifty-one patients underwent treatment with peginterferon-alfa-2a and ribavirin. A control group of 51 untreated individuals awaiting LT were matched by age, Child-Pugh and MELD scores and time on the waiting list. RESULTS Case and control patients were comparable for all relevant variables. Fifteen treated patients (29%) had undetectable HCV-RNA at the time of transplantation and 10 (20%) achieved SVR. Early virological response and non-1 genotype were the strongest predictors of viral clearance. There was a higher incidence of bacterial infections in treated patients vs controls, particularly in Child-Pugh B-C individuals (17 vs 3 episodes) (log-rank=0.0016). Importantly, the incidence of spontaneous bacterial peritonitis (SBP) in patients who were not receiving norfloxacin prophylaxis (n=83) was significantly higher in the treated group than in controls (log-rank=0.01). CONCLUSIONS Our data demonstrate that antiviral treatment prevents hepatitis C recurrence in 20% of HCV-infected patients. However, treatment should be recommended with caution in individuals with poor liver function who do not receive norfloxacin prophylaxis for SBP, since it increases the risk of bacterial infections.

Liver stiffness identifies two different patterns of fibrosis progression in patients with hepatitis C virus recurrence after liver transplantation.

Significant liver fibrosis (F ≥ 2) and portal hypertension (hepatic venous pressure gradient [HVPG] ≥ 6 mmHg) at 1 year after liver transplantation (LT) identify patients with severe hepatitis C recurrence. We evaluated whether repeated liver stiffness measurements (LSM) following LT can discriminate between slow and rapid “fibrosers” (fibrosis stage F2‐F4 at 1 year after LT). Eighty‐four patients who had undergone LT and who were infected with hepatitis C virus (HCV) and 19 LT controls who were not infected with HCV underwent LSM at 3, 6, 9, and 12 months after LT. All HCV‐infected patients underwent liver biopsy 12 months after LT (paired HVPG measurements in 74); 31 (37%) were rapid fibrosers. Median LSM (in kilopascal) at months 6, 9, and 12 were significantly higher in rapid fibrosers (9.9, 9.5, 12.1) than in slow fibrosers (6.9, 7.5, 6.6) (P < 0.01 all time points). The slope of liver stiffness progression (kPa × month) in rapid fibrosers (0.42) was significantly greater than in slow fibrosers (0.05) (P < 0.001), suggesting two different speeds of liver fibrosis progression. Figures were almost identical for patients with HVPG ≥ 6 mmHg or HVPG < 6 mmHg at 1 year after LT. Multivariate analysis identified donor age, bilirubin level, and LSM as independent predictors of fibrosis progression and portal hypertension in the estimation group (n = 50) and were validated in a second group of 34 patients. The areas under the receiver operating characteristic curve that could identify rapid fibrosers and patients with portal hypertension as early as 6 months after LT were 0.83 and 0.87, respectively, in the estimation group and 0.75 and 0.80, respectively, in the validation group. Conclusion: Early and repeated LSM following hepatitis C recurrence in combination with clinical variables discriminates between rapid and slow fibrosers after LT. (HEPATOLOGY 2009.)

Donor and Recipient IL28B Polymorphisms in HCV-Infected Patients Undergoing Antiviral Therapy before and after Liver Transplantation

IL28B gene polymorphisms are associated with the response to antiviral therapy in hepatitis C patients. We investigated the influence of IL28B polymorphisms on the response to therapy before and after liver transplantation (LT). Genotyping of SNPs rs8099917 and rs12979860 was performed in 128 HCV‐infected liver transplant recipients and in their donors; all patients underwent antiviral treatment after LT. The prevalence of genotypes rs12979860CC and rs8099917TT was higher in donors than in recipients (50% vs.19%, p < 0.001 and 67% vs. 38%, p < 0.001, respectively). Response to antiviral therapy was significantly higher for recipient genotype rs12979860CC as compared to rs12979860CT/TT both before (100% vs. 48% p = 0.013) and after LT (59% vs. 25% p = 0.002). The figures were almost identical for SNP rs8099917. Sustained virological response after LT was particularly high in patients with favorable recipient and donor genotypes (p < 0.01 for both SNPs). In a subgroup of 34 patients treated while awaiting LT, a favorable donor IL28B genotype was associated with an improved virological response after LT. Our results support a major role of recipient IL28B genotype in the response to antiviral treatment for hepatitis C recurrence. Interestingly, donor genotype also seems to influence the response pattern, especially in recipients who have a favorable IL28B genotype.

Serum fibrosis markers identify patients with mild and progressive hepatitis C recurrence after liver transplantation.

BACKGROUND & AIMS Significant fibrosis (fibrosis stage [F] >or= 2) and portal hypertension (hepatic venous pressure gradient [HVPG] >or= 6 mm Hg) in patients 1 year after liver transplantation indicate progressive hepatitis C recurrence. This study evaluated whether serum fibrosis markers can predict hepatitis C recurrence during the first year after liver transplantation. METHODS Hyaluronic acid, amino-terminal propeptide of type-III-procollagen, tissue inhibitor of matrix metalloproteinase type-1 concentrations were measured in serum samples from 133 patients infected with hepatitis C virus (HCV) at 3, 6, and 12 months after liver transplantation; routine laboratory tests were also performed. Liver biopsy samples (n = 133) and HVPGs (n = 94) were analyzed 1 year after transplantation. Sixteen patients who were not infected with HCV served as controls. RESULTS An algorithm, including the 3 markers (3-M-ALG) and 3 published scores (aspartate aminotransferase [AST]-to-alanine aminotransferase ratio, AST-to-platelet ratio index, and Benlloch) were analyzed. One year after liver transplantation, 50 patients (38%) had significant fibrosis (F >or= 2) and 31 (32%) had an HVPG >or= 6 mm Hg. The area under the receiver operator characteristic curve of the 3-M-ALG used to identify F >or= 2 at 3, 6, and 12 months after transplantation (0.67, 0.77, and 0.78) and of those with HVPG >or= 6 at the same time points (0.75, 0.87, and 0.90) were significantly higher than values obtained with the 3 published scores. At 12 months, a 3-M-ALG >or= 2 identified most patients at risk of decompensation/death. CONCLUSIONS Serum markers can accurately discriminate between patients with mild and progressive hepatitis C recurrence after liver transplantation.

Retransplantation in patients with hepatitis C recurrence after liver transplantation

Hepatitis C virus (HCV) infection recurs universally after liver transplantation (LT) and fibrosis progression is accelerated in the graft. Retransplantation (RT) is the only therapeutic option to achieve long-term survival in patients with decompensated cirrhosis after LT. Patient and graft survival rates after RT are inferior to those after primary LT. It is generally accepted that severe hepatitis C recurrence (cholestatic hepatitis) and forms with rapid fibrosis progression have a poor survival after RT. However, it is not clear whether rapid fibrosis progression in the first graft will be followed by the same rate of fibrosis progression in the second graft. The use of prognostic scores as screening tools has shown an improvement in survival in HCV-infected patients after RT, reaching similar survival rates as those obtained in non HCV-infected patients. Moreover, these scores can identify candidates with a high risk of mortality in whom the use of a new organ would be unreasonable. Prevention of severe hepatitis C recurrence could be the first step to avoid RT. Thus, antiviral treatment on the waiting list (if possible) and early identification and treatment of patients with severe hepatitis C recurrence may be a good strategy to avoid RT. In addition, active management of factors which can accelerate fibrosis progression (donor age, post-transplant diabetes, high dose of corticosteroids) might reduce the incidence of severe forms of hepatitis C recurrence.

Hepatitis C Virus Compartmentalization and Infection Recurrence after Liver Transplantation

Hepatitis C virus (HCV) compartmentalization may have important implications in the pathogenesis of HCV infection. The aim of this study was to investigate the presence and relevance of HCV compartmentalization in the setting of liver transplantation (LT). We collected samples of serum, peripheral blood mononuclear cells (PBMC), perihepatic lymph nodes (PLN) and liver explant at the time of LT, and serum and PBMC after transplantation from 57 HCV‐infected cirrhotic patients undergoing LT: 38 individuals received antiviral treatment before LT and 19 were untreated controls. HCV‐RNA levels were determined by real‐time PCR and the hypervariable region 1 (HVR‐1) was sequenced. HCV‐RNA was detected in all samples from control patients. In virological responders, recurrence after LT was associated with residual HCV‐RNA in the liver explant. Within the entire cohort, 47% of patients harbored differences in direct sequences from distinct compartments. Quasispecies analysis revealed that in most cases, HVR‐1 sequences recovered after infection recurrence were identical or closely related to those isolated from the liver explant and serum at the time of LT. Our study shows that a significant proportion of HCV‐infected cirrhotic patients exhibit compartmentalization. Viral variants originating within the liver appear to be the main cause of HCV recurrence after LT.

Hepatitis C virus superinfection of liver grafts: a detailed analysis of early exclusion of non-dominant virus strains

Liver transplantation (LT) of hepatitis C virus (HCV)-infected grafts into HCV-infected recipients leads to superinfection with two different virus strains. To characterize the virological outcomes of HCV superinfection immediately after LT, we performed phylogenetic analysis of a fragment of the NS5B gene in donor and recipient serum samples prospectively collected before and after LT, starting on day 1. In four of six cases, the donor strain finally prevailed, while in the remaining two cases, the native recipient strain overtook the donor quasispecies. Clonal sequence analysis showed that, in three cases, the expelled strain was undetectable 1 day after LT. Our study shows that superinfection with a different HCV strain can lead to the exclusion of one strain by the other as soon as the first day after LT. This would suggest that competition might not be limited to the replication level, but could also take place during virus entry.

Liver Stiffness 1 Year After Transplantation Predicts Clinical Outcomes in Patients With Recurrent Hepatitis C

The value of transient elastography (TE) to assess clinical outcomes in hepatitis C recurrence after liver transplantation (LT) has not been explored so far. We studied 144 hepatitis C–infected and 48 non–hepatitis C virus (HCV)‐infected LT recipients and evaluated the prognostic value of TE 1 year after transplantation to predict clinical decompensations and graft and patient survival. In HCV patients, cumulative probabilities of liver decompensation 5 years after LT were 8% for patients with liver stiffness measurement (LSM) <8.7 kilopascals (kPa) versus 47% for patients with LSM ≥ 8.7 kPa (p < 0.001). Five‐year graft and patient cumulative survival were 90% and 92% in patients with LSM < 8.7 kPa (p < 0.001) and 63% and 64% in patients with LSM ≥ 8.7 kPa, respectively (p < 0.001). Patients with low LSM 1 year after LT had excellent outcomes independently from receiving antiviral treatment or achieving sustained virological response (SVR). In contrast, graft survival significantly improved in patients with LSM ≥ 8.7 kPa who achieved SVR. No association between outcomes and LSM at 12 months was observed in non‐HCV patients. In conclusion, LSM 1 year after LT is a valuable tool to predict hepatitis C‐related outcomes in recurrent hepatitis C and can be used in clinical practice to identify the best candidates for antiviral therapy.