Mylène Sebagh

Survival and recurrence of hepatitis C after liver transplantation in patients coinfected with human immunodeficiency virus and hepatitis C virus

Liver transplantation in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is a recent indication. In a single center, we have compared the survival and severity of recurrent HCV infection after liver transplantation in HIV‐HCV–coinfected and HCV‐monoinfected patients. Seventy‐nine patients receiving a first liver graft for HCV‐related liver disease between 1999 and 2005 were included. Among them, 35 had highly active antiretroviral therapy–controlled HIV infection. All patients were monitored for HCV viral load and liver histology during the posttransplantation course. Coinfected patients were younger (43 ± 6 versus 55 ± 8 years, P < 0.0001) and had a higher Model for End‐Stage Liver Disease (MELD) score (18.8 ± 7.4 versus 14.8 ± 4.7; P = 0.008). The 2‐year and 5‐year survival rates were 73% and 51% and 91% and 81% in coinfected patients and monoinfected patients, respectively (log‐rank P = 0.004). Under multivariate Cox analysis, survival was related only to the MELD score (P = 0.03; risk ratio, 1.08; 95% confidence interval, 1.01, 1.15). Using the Kaplan‐Meier method, the progression to fibrosis ≥ F2 was significantly higher in the coinfected group (P < 0.0001). Conclusion: The results of liver transplantation in HIV‐HCV–coinfected patients were satisfactory in terms of survival benefit. Earlier referral of these patients to a liver transplant unit, the use of new drugs effective against HCV, and an avoidance of drug toxicity are mandatory if we are to improve the results of this challenging indication for liver transplantation. (HEPATOLOGY 2007.)

Hepatitis C virus therapy in liver transplant recipients: Response predictors, effect on fibrosis progression, and importance of the initial stage of fibrosis

Antiviral therapy after liver transplantation (LT) using interferon (IFN) and ribavirin (RBV) can achieve a sustained virological response (SVR) rate ranging from 20% to 45%. The aims of our study were to assess efficacy and tolerability of therapy, effect on fibrosis progression and the importance of the initial fibrosis stage to outcome. A total of 113 hepatitis C virus (HCV)‐infected LT patients received 133 courses of IFN (standard, n = 29, pegylated IFN [pegIFN], n = 104) and RBV (75% genotype 1). Early virological response (EVR), end‐of‐treatment (EOT), and SVR were obtained in 74%, 55%, and 38%, respectively. EVR, completion of treatment, viral load before therapy, genotype non‐1, and use of pegIFN were predictive of SVR, but only EVR remained in the multivariate analysis. SVR was obtained in 45% patients who received a second course of therapy. Paired biopsies at baseline, at EOT and at long‐term were available in 42 patients. The mean fibrosis stage remained stable in patients with SVR and increased in patients without response. Rejection episodes were observed in 6% of patients. Tolerability of therapy decrease in patients with fibrosis stage ≥3 on baseline liver biopsy. A total of 20% of them died or were retransplanted due to liver failure as opposed to 1% of patients who had fibrosis stage <3. In conclusion, IFN and RBV achieved SVR in 38% of patients. EVR is independently associated with SVR. Fibrosis stage remained stable in patients with SVR and increased in nonresponders. Fibrosis stage ≥3 was associated with a high rate of liver failure, arguing for an early introduction of antiviral therapy. Liver Transpl 14:1766–1777, 2008.

Hepatocellular Carcinoma Is Associated With an Increased Risk of Hepatitis B Virus Recurrence After Liver Transplantation

BACKGROUND & AIMS Hepatitis B virus (HBV) recurrence after orthotopic liver transplantation (OLT) is significantly reduced by prophylaxis with hyperimmune antibody to hepatitis B surface antigen (anti-HBs) globulins (HBIG) and antiviral drugs. The role of hepatocellular carcinoma (HCC) in HBV recurrence remains unclear. We investigated the association between HCC pre-OLT and HBV recurrence post-OLT. METHODS We studied 99 hepatitis B surface antigen-positive patients who underwent OLT for cirrhosis. The median follow-up period was 43 months. All patients received HBIG, and 51 also received lamivudine and/or adefovir. Of these 99 patients, 31 had HCC before OLT. Total HBV DNA and covalently closed circular (ccc)-DNA were measured in tumor and nontumor tissues from the explanted livers of 16 of these 31 HCC patients and, also, in a context of tumor recurrence, in 3 patients who developed HBV/HCC recurrence. RESULTS Fourteen patients (14.1%) developed HBV recurrence within a median period of 15 months post-OLT. HCC at OLT, a pre-OLT HBV DNA viral load > or = 100,000 copies/mL, and HBIG monoprophylaxis were independently associated with HBV recurrence post-OLT. Eleven out of the 31 patients with HCC at OLT presented with HBV recurrence and 3 out of the 68 patients without HCC had HBV recurrence (P < .0001). HBV recurrence was more frequent in patients who developed HCC recurrence (7/8 patients, 87.5%) than in those who did not (4/23 patients, 17.4%) (P < .0001). In the 16 explanted livers, cccDNA was detectable in HCC cells in 11 and in nontumor cells in 12. cccDNA was detected in a context of HCC recurrence in 2 of the 3 patients tested who developed HBV/HCC recurrence. CONCLUSIONS The associations of HCC pre-OLT, and HCC recurrence with HBV recurrence post-OLT, and the detection of HBV DNA and cccDNA in HCC suggest that HBV replication in tumor cells may contribute to HBV recurrence post-OLT.

High incidence of antitissue antibodies in patients experiencing chronic liver allograft rejection

BACKGROUND The precise immunologic mechanisms responsible for chronic rejection of liver allografts are unknown. We have recently shown in a rodent model that recipients of liver allografts developed non-major histocompatibility complex antitissue antibodies. The aim of the present study was to test this hypothesis in the clinical setting. METHODS Posttransplant sera of 14 patients undergoing chronic rejection and of 48 control patients (12 liver transplant patients with chronic active hepatitis or liver cirrhosis related to hepatitis C virus [HCV] infection and without chronic rejection, 10 with sclerosing cholangitis, and 26 with normal liver function tests and liver biopsy) were tested for the presence of antitissue antibodies by indirect immunofluorescence. Pretransplant sera of all these patients lacked antitissue antibodies. RESULTS Antitissue antibodies were detected in 71% of patients who developed chronic rejection (before or at the time of chronic rejection). This incidence was significantly greater than that observed in patients not undergoing rejection (HCV-related chronic active hepatitis, 16%; sclerosing cholangitis, 0%; normal liver biopsy, 7%). All these autoantibodies were directed against the smooth muscle and/or the nucleus. In two patients, anti-smooth muscle antibodies had an antiactin or antivimentin specificity. CONCLUSIONS These results show a strong association between chronic allograft rejection and the development of antitissue antibodies and suggest that these antibodies could be used to identify patients at high risk of developing chronic rejection after liver transplantation.

Recurrence of autoimmune disease, primary sclerosing cholangitis, primary biliary cirrhosis, and autoimmune hepatitis after liver transplantation

Key Points

Plasma cell hepatitis in liver allografts: Variant of rejection or autoimmune hepatitis?

In this issue, Fiel et al. use the phrase “plasma cell hepatitis (de novo autoimmune hepatitis)” to describe what they eventually conclude to be a variant of acute rejection. This study was likely prompted by curiosity about the significance of plasma cell–rich infiltrates in liver allograft biopsies. Patients were first chosen for study with a free-text search of pathology reports for the key words “liver allograft,” “lymphoplasmacytic,” and “plasma cell(s).” These results were then cross-referenced with all patients undergoing liver transplantation for hepatitis C virus (HCV)–induced cirrhosis. “Hepatitis” was not included in the search. Twenty-eight (42%) initially selected patients were excluded because they had histological and/or clinical evidence of concomitant acute cellular rejection, chronic rejection, mechanical bile duct obstruction, hepatic artery thrombosis/stenosis, cytomegalovirus or other nonhepatotropic viral infection, or medicationinduced hepatotoxicity. Additional patients were excluded because their biopsies contained 30% plasma cells. The outcome of these highly selected patients was not good. Twenty-three of 38 (60%) died (n 10) or developed graft failure and portal hypertension. Neither detailed descriptions of the causes of death and allograft failures nor the treatment approaches before these endpoints were included. One might assume that portal hypertension developed because of plasma cell hepatitis (PCH)–induced classical cirrhosis, but silently developing veno-occlusive disease due to centrilobularbased rejection can lead to the same endpoint. Also, lowering immunosuppression after widespread perivenular inflammation is found on biopsy might lead to an adverse outcome. The authors concluded that PCH represents a form of acute rejection because this cohort (1) frequently developed PCH in association with suboptimal immunosuppression, (2) had a high incidence of acute rejection before the development of PCH that signaled a propensity toward rejection, and (3) had a better outcome when they were treated with increased immunosuppression. Fiel et al. address 3 distinct but related questions in this article: (1) how does one distinguish between rejection and recurrent HCV, (2) how does one distinguish between HCV and autoimmune hepatitis (AIH), and, most importantly, (3) how does one distinguish between rejection and AIH? The Mt. Sinai group is to be congratulated on tackling some of these very difficult issues. The authors appear to have distinguished recurrent HCV from acute rejection by examining the centrilobular areas for necroinflammatory activity involving a majority of perivenular regions. They stated the following:

Fibrosing cholestatic hepatitis in HIV/HCV co-infected transplant patients-usefulness of early markers after liver transplantation.

We characterized fibrosing cholestatic hepatitis (FCH) in a large cohort of HIV/HCV co‐infected patients. Between 1999 and 2008, 59 HIV infected patients were transplanted for end‐stage liver disease due to HCV. Eleven patients (19%) developed FCH within a mean period of 7 months [2–27] after liver transplantation (LT). At Week 1 post‐LT, the mean HCV viral load was higher in the FCH group: 6.13 log10 IU/mL ± 1.30 versus 4.9 log10 IU/mL ± 1.78 in the non‐FCH group, p = 0.05. At the onset of acute hepatitis after LT, activity was moderate to severe in 8/11 HIV+/HCV+ patients with FCH (73%) versus 13/28 (46%) HIV+/HCV+ non‐FCH (p = 0.007) patients. A complete virological response to anti‐HCV therapy was observed in 2/11 (18%) patients. Survival differed significantly between the two groups (at 3 years, 67% in non‐FCH patients versus 15% in FCH patients, p = 0.004). An early diagnosis of FCH may be suggested by the presence of marked disease activity when acute hepatitis is diagnosed and when a high viral load is present. The initiation of anti‐HCV therapy should be considered at this point.

Impact of bevacizumab on functional recovery and histology of the liver after resection of colorectal metastases

The impact of bevacizumab on functional recovery and histology of the liver was evaluated in patients undergoing hepatic resection for colorectal liver metastases (CLM) following bevacizumab treatment.

A new indication for liver transplantation: Nodular regenerative hyperplasia in human immunodeficiency virus–infected patients

Nodular regenerative hyperplasia is one of the causes of noncirrhotic portal hypertension and has recently been described in human immunodeficiency virus–infected patients, and the potential role of a prothrombotic state and hepatotoxic antiretroviral medication has been suggested. Moreover, it is now established that liver transplantation is feasible in HIV‐infected patients. We describe here our experience concerning 3 HIV‐infected patients with severe complications of nodular regenerative hyperplasia treated with liver transplantation. Liver Transpl 14:1194–1198, 2008.

Twenty-year protocol liver biopsies: Invasive but useful for the management of liver recipients

BACKGROUND & AIMS Most liver transplant centres have discontinued the practice of protocol liver biopsies (LB), mainly because of the perceived lack of therapeutic benefit. This study aimed to examine the usefulness of 20-year LBs. METHODS Ten, 15, and 20-year protocol LBs from 147 patients surviving for >20 years were reviewed. Twenty-year biopsy findings were correlated with clinical data. RESULTS Twenty-year-biopsy patients (N=91) and 20-year-non-biopsy patients (N=56) were similar in terms of transplant data, adverse events, and liver function tests (LFTs). Twenty-year LBs revealed a 90% prevalence of abnormalities, among which viral chronic hepatitis (VCH) was the most common (46%). Between 15 and 20 years, hepatic structural abnormalities were the only disorder to increase (p=0.008). An individual progression of abnormalities occurred in 56% of patients. At 20 years, the negative and positive predictive values (PV) of LFTs with respect to histological abnormalities were 95% and 18%, respectively; in VCH, Fibrotest and transient elastography displayed poor discriminative ability for fibrosis (80% and 81% discordance, respectively), but were satisfactory regarding significant fibrosis (negative PV of 77.7% and 80%, respectively). A decrease in immunosuppression was less frequent (14/91 vs. 20/56, p=0.008) while an increase was more common (15/91 vs. 2/56, p=0.017) in 20-year-biopsy patients than in non-biopsy patients. Antiviral therapy was administered in seven of the 20-year biopsy patients, but in none of the non-biopsy patients (p=0.04). CONCLUSIONS Twenty-year LBs provided important histological information on graft function that was available to a limited degree from LFTs and non-invasive markers. They exerted an impact on immunosuppressive and antiviral therapies.