Human immunodeficiency virus-infected liver transplant recipients with incidental hepatocellular carcinoma: A prospective multicenter nationwide cohort study.

There is a lack of data on incidental hepatocellular carcinoma (iHCC) in the setting of liver transplantation (LT) in human immunodeficiency virus (HIV)-infected patients. This study aims to describe the frequency, histopathological characteristics, and outcomes of HIV+ LT recipients with iHCC from a Spanish multicenter cohort in comparison with a matched cohort of LT patients without HIV infection. A total of 15 (6%) out of 271 patients with HIV infection who received LT in Spain from 2002 to 2012 and 38 (5%) out of the 811 HIV- counterparts presented iHCC in liver explants (P = 0.58). Patients with iHCC constitute the present study population. All patients also had hepatitis C virus (HCV)-related cirrhosis. There were no significant differences in histopathological features of iHCC between the 2 groups. Most patients showed a small number and size of tumoral nodules, and few patients had satellite nodules, microvascular invasion, or poorly differentiated tumors. After a median follow-up of 49 months, no patient developed hepatocellular carcinoma (HCC) recurrence after LT. HIV+ LT recipients tended to have lower survival than their HIV- counterparts at 1 (73% versus 92%), 3 (67% versus 84%), and 5 years (50% versus 80%; P = 0.06). There was also a trend to a higher frequency of HCV recurrence as a cause of death in the former (33% versus 10%; P = 0.097). In conclusion, among LT recipients for HCV-related cirrhosis, the incidence and histopathological features of iHCC in HIV+ and HIV- patients were similar. However, post-LT survival was lower in HIV+ patients probably because of a more aggressive HCV recurrence. Liver Transplantation 23 645-651 2017 AASLD.

Human immunodeficiency virus infection does not worsen prognosis of liver transplantation for hepatocellular carcinoma.

UNLABELLED: The impact of human immunodeficiency virus (HIV) infection on patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) is uncertain. This study aimed to assess the outcome of a prospective Spanish nationwide cohort of HIV-infected patients undergoing LT for HCC (2002-2014). These patients were matched (age, gender, year of LT, center, and hepatitis C virus (HCV) or hepatitis B virus infection) with non-HIV-infected controls (1:3 ratio). Patients with incidental HCC were excluded. Seventy-four HIV-infected patients and 222 non-HIV-infected patients were included. All patients had cirrhosis, mostly due to HCV infection (92%). HIV-infected patients were younger (47 versus 51 years) and had undetectable HCV RNA at LT (19% versus 9%) more frequently than non-HIV-infected patients. No significant differences were detected between HIV-infected and non-HIV-infected recipients in the radiological characteristics of HCC at enlisting or in the histopathological findings for HCC in the explanted liver. Survival at 1, 3, and 5 years for HIV-infected versus non-HIV-infected patients was 88% versus 90%, 78% versus 78%, and 67% versus 73% (P = 0.779), respectively. HCV infection (hazard ratio = 7.90, 95% confidence interval 1.07-56.82) and maximum nodule diameter >3 cm in the explanted liver (hazard ratio = 1.72, 95% confidence interval 1.02-2.89) were independently associated with mortality in the whole series. HCC recurred in 12 HIV-infected patients (16%) and 32 non-HIV-infected patients (14%), with a probability of 4% versus 5% at 1 year, 18% versus 12% at 3 years, and 20% versus 19% at 5 years (P = 0.904). Microscopic vascular invasion (hazard ratio = 3.40, 95% confidence interval 1.34-8.64) was the only factor independently associated with HCC recurrence. CONCLUSIONS: HIV infection had no impact on recurrence of HCC or survival after LT. Our results support the indication of LT in HIV-infected patients with HCC.

Pegylated interferon plus ribavirin in HIV-infected patients with recurrent hepatitis C after liver transplantation: a prospective cohort study.

BACKGROUND & AIMS: The aim of this study was to evaluate the results of treatment with pegylated interferon and ribavirin for the recurrence of hepatitis C after liver transplantation in HCV/HIV-coinfected patients. METHODS: This was a prospective, multicentre cohort study, including 78 HCV/HIV-coinfected liver transplant patients who received treatment for recurrent hepatitis C. For comparison, we included 176 matched HCV-monoinfected patients who underwent liver transplantation during the same period of time at the same centres and were treated for recurrent hepatitis C. RESULTS: Antiviral therapy was discontinued prematurely in 56% and 39% (p = 0.016), mainly because of toxicity (22% and 11%, respectively; p=0.034). Sustained virological response (SVR) was achieved in 21% of the coinfected patients and in 36% of monoinfected patients (p = 0.013). For genotype 1, SVR rates were 10% and 33% (p = 0.002), respectively; no significant differences were observed for the other genotypes. A multivariate analysis based on the whole series identified HIV-coinfection as an independent predictor of lack of SVR (OR, 0.17; 95% CI, 0.06-0.42). Other predictors of SVR were donor age, pretreatment HCV viral load, HCV genotype, and early virological response. SVR was associated with a significant improvement in survival: 5-year survival after antiviral treatment was 79% for HCV/HIV-coinfected patients with SVR vs. 43% for those without (p = 0.02) and 92% vs. 60% in HCV-monoinfected patients (p < 0.001), respectively. CONCLUSIONS: The response to pegylated interferon and ribavirin was poorer in HCV/HIV-coinfected liver recipients, particularly those with genotype 1. However, when SVR was achieved, survival of coinfected patients increased significantly.

Safety and efficacy of triple therapy with peginterferon, ribavirin and boceprevir within an early access programme in Spanish patients with hepatitis C genotype 1 with severe fibrosis: SVRw12 analysis.

BACKGROUND & AIMS: The addition of protease inhibitors (PIs) changed the hepatitis C virus (HCV) treatment standards and improved sustained viral response (SVR) rates in patients with genotype 1 HCV infection. METHODS: Prospective, multicentre, national registry that includes naïve and treatment-experienced patients with HCV genotype 1 infection, who had bridging fibrosis or cirrhosis and were treated with triple therapy (peginterferon alfa-2a or alfa-2b, ribavirin and boceprevir) as compassionate use, and in accordance with the Summary of Product Characteristics. RESULTS: Most of the patients (68.2%) were male, with a mean age of 53 years, 75% (n = 128) had HCV 1b genotype and baseline viral load of 6.2 log. According to prior treatment, 20% of patients were treatment-naïve and 80% had received prior treatment. Approximately 36.5% of patients (n = 62) reported at least one serious adverse events (SAEs) (total SAEs = 103). The most common SAEs were neutropenia (57.6%), anaemia (47.6%) and grade 3 thrombopenia (25.9%). Patients with albumin <3.5 g/dl and bilirubin >2 mg/dl had an increased relative risk (greater than one-fold) for SAEs, including infections and hepatic decompensation. In the intent-to-treat analysis (n = 170), the overall percentage of patients with SVRw12 was 46.5%. In patients with 1 log decrease at week 4 (lead-in phase), the overall SVRw12 rate was 67.0%. In the patients initiating triple therapy with boceprevir (n = 139), the global response rate was 56.4%. In a multivariate analysis, an increased probability of achieving SVR was associated with response to prior treatment (relapsers), >1 log decrease in viral load in the lead-in phase and baseline albumin >3.5 g/dl. CONCLUSIONS: Triple therapy in patients with severe fibrosis/cirrhosis is associated with a higher rate of SAE and a lower rate in comparison with patients with mild disease. However, for patients with intact liver function, it could be considered as a treatment option, when other alternatives would not be available.

[Lead-in period and week 8 as predictive tools for response to boceprevir therapy: a retrospective study of Spanish real clinical practice]. / Período de lead-in y semana 8 como herramientas de predicción de la respuesta en el tratamiento con boceprevir: estudio retrospectivo de la práctica clínica real en España.

INTRODUCTION: Most discontinuations due to lack of virological response occur during the first few weeks of hepatitis C virus (HCV) triple therapy. Improved knowledge of baseline factors and their correlation with boceprevir decision points may predict treatment success. METHODS: An observational, retrospective study was conducted to describe the lead-in period as a clinical decision tool in HCV genotype 1 patients treated with boceprevir. Data were collected from the medical records of 186 consecutive patients distributed across 20 Spanish general hospitals. RESULTS: This study included 171 patients. A total of 80% had fibrosis F3/F4, 74% were previously treated, and 26% were treatment-naïve. After the lead-in period, 54.5% of the patients had a reduction of ≥1 log10; this reduction occurred in 52.5% of those with advanced fibrosis. Boceprevir therapy was started in 94% of the patients. Discontinuations at week 4 were limited to null responders with cirrhosis. The baseline factors associated with virological response at week 4 were IL28B, previous response, and fibrosis score. At week 8, HCV-RNA was undetectable in 48.8% of the patients. The correlation between responses at weeks 8 and 12 was 88%. CONCLUSION: In the Spanish clinical setting, lead-in was mainly used as a clinical decision point for non-responders with cirrhosis. The good correlation between stopping rules at weeks 8 and 12 could be used to anticipate discontinuation, thus saving adverse events and costs.

Use of artificial intelligence as an innovative donor-recipient matching model for liver transplantation: results from a multicenter Spanish study.

BACKGROUND & AIMS: There is an increasing discrepancy between the number of potential liver graft recipients and the number of organs available. Organ allocation should follow the concept of benefit of survival, avoiding human-innate subjectivity. The aim of this study is to use artificial-neural-networks (ANNs) for donor-recipient (D-R) matching in liver transplantation (LT) and to compare its accuracy with validated scores (MELD, D-MELD, DRI, P-SOFT, SOFT, and BAR) of graft survival. METHODS: 64 donor and recipient variables from a set of 1003 LTs from a multicenter study including 11 Spanish centres were included. For each D-R pair, common statistics (simple and multiple regression models) and ANN formulae for two non-complementary probability-models of 3-month graft-survival and -loss were calculated: a positive-survival (NN-CCR) and a negative-loss (NN-MS) model. The NN models were obtained by using the Neural Net Evolutionary Programming (NNEP) algorithm. Additionally, receiver-operating-curves (ROC) were performed to validate ANNs against other scores. RESULTS: Optimal results for NN-CCR and NN-MS models were obtained, with the best performance in predicting the probability of graft-survival (90.79%) and -loss (71.42%) for each D-R pair, significantly improving results from multiple regressions. ROC curves for 3-months graft-survival and -loss predictions were significantly more accurate for ANN than for other scores in both NN-CCR (AUROC-ANN=0.80 vs. -MELD=0.50; -D-MELD=0.54; -P-SOFT=0.54; -SOFT=0.55; -BAR=0.67 and -DRI=0.42) and NN-MS (AUROC-ANN=0.82 vs. -MELD=0.41; -D-MELD=0.47; -P-SOFT=0.43; -SOFT=0.57, -BAR=0.61 and -DRI=0.48). CONCLUSIONS: ANNs may be considered a powerful decision-making technology for this dataset, optimizing the principles of justice, efficiency and equity. This may be a useful tool for predicting the 3-month outcome and a potential research area for future D-R matching models.

[Hepatitis B infection transmission by anti-HBc-positive grafts]. / Transmisión de la infección B por injertos anti-HBc positivos.

In Spain, the rate of anti-HBc positive, HBsAg-negative carriers is approximately 10% of adults between the ages of 26 and 65 years. It is therefore impossible to exclude these donors without increasing the mortality of recipients on waiting lists. The incidence of de novo hepatitis B infection in HBsAg-negative recipients of anti-HBc-positive donors is high without prophylaxis and is related to the serological state of the recipient against HBV. Anti-HBc and anti-HBs-positive recipients have low risk, with or without prophylaxis. This patient group therefore does not require prophylaxis but rather periodic posttransplantation checkups. For the other recipient groups (naïve, anti-Hbc and anti-HBs isolates), prophylaxis with IgG HB, lamivudine or combined therapy decreases the incidence of infection. These patients should be treated with prophylaxis immediately after transplantation. Depending on the risk, cost and benefit, patients should currently be treated with lamivudine 100mg/d indefinitely or for longer periods (>10 years). Periodic checkups of HBsAg should be conducted, and if there is graft dysfunction then HBV DNA should be checked. IF HBV DNA is discovered in the donor and found to be positive in serum or in the biopsy, the prophylaxis should be an analogue with a high barrier to resistance from the start. Grafts from anti-HBc-positive donors are not considered at-risk grafts and are used according to donor severity, without being determined by the recipient's serological profile.

Randomized clinical trial comparing high versus standard dose of ribavirin plus peginterferon alfa-2a in hepatitis C genotype 3 and high viral load. Dargen-3 study.

INTRODUCTION: Less than half of patients with chronic hepatitis C genotype 3 (G3) and high viral load (HVL) without a rapid virological response (RVR) achieve a sustained virological response (SVR) when treated with peginterferon plus ribavirin (RBV). OBJECTIVES: To assess the impact of high doses of RBV on SVR in patients with G3 and HVL. METHODS: Ninety-seven patients were randomized to receive peginterferon α-2a+RBV 800 mg/day (A; n=42) or peginterferon α-2a+RBV 1600 mg/day+epoetin ß 400 IU/kg/week SC (B; n=55). Patients allocated to group B who achieved RVR continued on RBV (800mg/day) for a further 20 weeks (B1; n=42) while non-RVR patients received a higher dose of RBV (1600 mg/day)+epoetin ß (B2; n=13). RESULTS: RVR was observed in 64.3% of patients in A and in 76.4% in B (p=0.259). Intention-to-treat (ITT) analysis showed SVR rates of 64.3% (A) and 61.8% (B), with a reduction of -2.5% (-21.8% to 16.9%) (p=0.835). The SVR rate was 61.9% in arm B1 and 61.5% in arm B2. No serious adverse events were reported, and the rate of moderate adverse events was < 5%. CONCLUSIONS: G3 patients with high viral load without RVR did not obtain a benefit from a higher dose of RBV. Higher doses of RBV plus epoetin ß were safe and well tolerated (Clin Trials Gov NCT00830609).

Safety and anti-HCV effect of prolonged intravenous silibinin in HCV genotype 1 subjects in the immediate liver transplant period.

BACKGROUND & AIMS: Reinfection of the graft is the rule in patients with HCV cirrhosis undergoing liver transplantation, and HCV-RNA reaches pre-transplantation levels within the first month. Short-term intravenous silibinin monotherapy is safe and shows a potent in vivo anti-HCV effect. We aimed at evaluating the safety and antiviral effect of prolonged intravenous silibinin, started immediately before liver transplantation. METHODS: Single centre, prospective, pilot study, to assess the safety and effect on HCV-RNA kinetics during at least 21 days of intravenous silibinin monotherapy (20 mg/kg/day) in 9 consecutive HCV genotype 1 subjects, in comparison to a control, non-treated group of 7 consecutive prior transplanted subjects under the same immunosuppressive regimen (basiliximab, steroids, delayed tacrolimus, micophenolate). RESULTS: Intravenous silibinin led to significant, maintained and progressive HCV-RNA decreases (mean HCV-RNA drop at week 3, -4.1 ± 1.3 log(10)IU/ml), and lack of viral breakthrough during administration. Four patients (44%) reached negative HCV-RNA, maintained during silibinin treatment, vs. none in the control group, but HCV-RNA relapsed in all of them after a median of 21 days (16-28), following silibinin withdrawal. Partial responders to silibinin showed marked decreases in HCV-RNA when compared to controls, but lower than complete responders. There were no clinical adverse effects, and silibinin led to asymptomatic transient hyperbilirubinemia (week 2, 4.2 ± 2.2 vs. 2.5 ± 3.6 mg/dl; p=0.02). CONCLUSIONS: Prolonged intravenous silibinin monotherapy was safe in the immediate liver transplantation period, leading to a potent and time dependent antiviral effect and lack of HCV-RNA breakthrough during administration. However, HCV-RNA rebounded after withdrawal, and silibinin monotherapy did not avoid reinfection of the graft.

Acute hepatitis C in Spain: a retrospective study of 131 cases.

BACKGROUND AND AIMS: The management of acute hepatitis C (AHC) is controversial. We have conducted a retrospective study to determine the epidemiological and biochemical aspects, the genotypes, the spontaneous clearance of HCV (SVC), and the treatment responses in patients with AHC. METHODS: We have retrospectively collected data from 131 patients with AHC from 18 Spanish hospitals. RESULTS: The mean age was 43 ± 16 years (17-83), 69% were symptomatic. The causes of infection were nosocomial in 40% and intravenous drug users in 20%. Eighty two percent had genotype 1. The delay from symptoms-onset to HCV-RNA confirmation was 50 ± 68 days (range, 11-350 days) and to treatment (in 59%) 14±1 3 weeks (range, 2-58 days). In the treated group, 80% achieved sustained virological response (SVR) versus 57% SVC in untreated patients (p = 0.004). Up to 96% of those treated within the first 12 weeks had SVR versus 86% of those treated later (p = 0.04). Patients with HCV-RNA(-) at week 4 resolved with or without treatment more frequently than those HCV-RNA(+) (98% versus 69%, p = 0.005). The treatment was not beneficial if HCV-RNA was undetectable at week 12. No differences in SVR were found in genotype 1 patients treated for 24 or 48 weeks. Patients with low baseline viral load achieved higher SVC and SVR. The SVC in patients with bilirubin > 5 mg/dL was 78 versus 40% in those with lower values (p = 0.004). CONCLUSIONS: The most common transmission route was nosocomial. SVR was higher in patients treated than SVC in non-treated.Early treatment (before week 12) achieved the highest response rate. SVC and SVR were more common in patients with a low baseline viral load. Undetectable HCV-RNA at week 4 was associated with high SVR and SVC rates. Jaundice was related with SVC.

Severe rhabdomyolysis due to rosuvastatin in a liver transplant subject with human immunodeficiency virus and immunosuppressive therapy-related dyslipidemia.

Statins are relatively safe first-line agents to use in the setting of dyslipidemia associated with immunosuppressive therapy in subjects undergoing liver transplantation, and also in HIV-infected patients with dyslipidemia due to antiretroviral drugs, especially ritonavir-boosted protease inhibitors. Rosuvastatin, a new statin, has demonstrated higher potency than previously released statins and is not extensively metabolized by the liver P450 system; therefore, the probability of deleterious pharmacokinetic interactions with commonly used immunosuppressants and antiretroviral drugs is reduced. We present the first case of severe rhabdomyolysis in a liver transplant patient receiving rosuvastatin for the treatment of immunosuppressive therapy-related grade IV dyslipidemia, an HIV-infected subject on protease inhibitor-sparing HAART, that resolved after rosuvastatin withdrawal, probably related to interactions between calcineurin inhibitors and hepatic rosuvastatin uptake transporters such as organic anion transporting polypeptides (OATPs).

Peginterferon plus ribavirin and sustained virological response in HCV-related cirrhosis: outcomes and factors predicting response.

OBJECTIVES: Patients with hepatitis C virus (HCV) cirrhosis are difficult to treat and have a high risk of liver decompensation or hepatocellular carcinoma. We sought to identify factors that could predict treatment response. METHODS: Collaborating centers (n=26) provided data for patients (n=568) with HCV cirrhosis undergoing treatment with peginterferon-α plus ribavirin (RBV). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes. RESULTS: Sustained viral response (SVR) in naive patients was 30.7%, with no significant differences between centers. Median follow-up was 35 months (range: 1-81). Factors predicting SVR were: non-genotype 1 (odds ratio (OR)=4.183; 95% confidence interval (CI): 2.353-7.438) overall dose and ≥80% of the scheduled time of treatment (OR=3.177; 95% CI: 1.752-5.760); serum γ-glutamyl transpeptidase (GGT) <76 IU per ml (OR=4.092; 95% CI: 2.418-6.927); baseline viral load <6 × 10(5) (OR=2.597; 95% CI: 1.583-4.262); absence of ultrasound signs of portal hypertension (OR=2.067; 95% CI: 1.26-3.39). No patient with a HCV-RNA decline <1 log(10) at week 4 achieved SVR. Event-free survival at 5 years was 91% in patients with SVR vs. 59% in non-responders (P<0.001). Overall survival in patients with SVR was 98% vs. 86% in non-responders (P=0.005). Independent factors predicting events were absence of SVR (hazard ratio (HR)=2.66; 95% CI: 1.32-5.54), baseline serum albumin <3.9 g per 100 ml (HR=3.06; 95% CI: 1.81-5.15), presence of esophageal varices on endoscopy (HR=2.489; 95% CI: 1.546-4). Improved outcome was more evident in responders with less advanced disease at baseline. CONCLUSIONS: SVR can be achieved in approximately one-third of patients with HCV-related cirrhosis. SVR independently reduces the likelihood of clinical decompensation and improves survival.

Partial splenic embolization and peg-IFN plus RBV in liver transplanted patients with hepatitis C recurrence: safety, efficacy and long-term outcome.

BACKGROUND: There is limited information on the long-term outcome in liver transplant (LT) subjects undergoing partial splenic embolization (PSE) prior to full dose pegylated interferon/ribavirin (peg-IFN/RBV). METHODS: Retrospective review of eight LT subjects after PSE and antiviral therapy. RESULTS: Baseline platelets and neutrophils were <50 000 cells/mL and <1000 cells/mL in 75% and 50%. Mean splenic infarction volume was 85 +/- 13%. PSE produced major complications in three (37.5%): recurrent sterile netrophilic ascites and renal insufficiency (n = 2), and splenic abscess (n = 1). Full-dose peg-IFN/RBV was started in seven (87.5%), with two early withdrawals (28.6%) despite early virological response (toxicity and infection); both subjects died. Anemia led to RBV dose-adjustment in six (86%), with human recombinant erythropoietin (EPO) use in four (57%). No peg-IFN adjustments or granulocyte-colonies stimulating factor were needed. Two patients reached sustained virological response (SVR) (28.6%). Two non-responders maintained prolonged therapy with biochemical/histological improvement. After a median follow-up of 151 wk, we observed significant improvements in hematological parameters, aspartate aminotransferase, alanine aminotransferase, international normalized ratio, and prothrombin activity. CONCLUSIONS: Extensive PSE after LT produced significant morbidity (37.5%). Peg-IFN/RBV was completed in five out of seven (71%), with SVR in two (28.6%). RBV adjustement due to anemia was high despite EPO use. Only patients able to complete or maintain antiviral therapy survived, with long-term significant benefits in hematological parameters and liver function tests.

Pharmacokinetics, efficacy, and safety of mycophenolate mofetil in combination with standard-dose or reduced-dose tacrolimus in liver transplant recipients.

The pharmacokinetics of mycophenolate mofetil (MMF) in liver transplant recipients may change because of pharmacokinetic interactions with coadministered immunosuppressants or because changes in the enterohepatic anatomy may affect biotransformation of MMF to mycophenolic acid (MPA) and enterohepatic recirculation of MPA through the hydrolysis of mycophenolate acid glucuronide to MPA in the gut. In the latter case, the choice of formulation (oral versus intravenous) could have important clinical implications. We randomized liver transplant patients (n = 60) to standard (10-15 ng/mL) or reduced (5-8 ng/mL) trough levels of tacrolimus plus intravenous MMF followed by oral MMF (1 g twice daily) with corticosteroids. Pharmacokinetic sampling was performed after the last intravenous MMF dose, after the first oral MMF dose, and at selected times over 52 weeks. The efficacy and safety of the 2 regimens were also assessed. Twenty-eight and 27 patients in the tacrolimus standard-dose and reduced-dose groups, respectively, were evaluated. No significant differences between the tacrolimus standard-dose and reduced-dose groups were seen in dose-normalized MPA values of the time to the maximum plasma concentration (1.25 versus 1.28 hours), the maximum plasma concentration (15.5 +/- 7.93 versus 13.6 +/- 7.03 microg/mL), or the area under the concentration-time curve from 0 to 12 hours (AUC(0-12); 53.0 +/- 20.6 versus 43.8 +/- 15.5 microg h/mL) at week 26 or at any other time point. No relationship was observed between the tacrolimus trough or AUC(0-12) and MPA AUC(0-12). Exposure to MPA after oral and intravenous administration was similar. Safety and efficacy were similar in the two treatment groups. In conclusion, exposure to MPA is not a function of exposure to tacrolimus. The similar safety and efficacy seen with MMF plus standard or reduced doses of tacrolimus suggest that MMF could be combined with reduced doses of tacrolimus.

The magnitude of week 4 HCV RNA decay on pegylated interferon/ribavirin accurately predicts virological failure in patients with genotype 1.

BACKGROUND: Current stopping rules during pegylated interferon (peg-IFN)/ribavirin (RBV) treatment rely on week 12 HCV RNA response, but earlier identification of non-responders offers clinical and economic advantages. AIMS AND METHODS: To evaluate, among 129 HCV-genotype-1-infected, treatment-naive patients receiving peg-IFN/RBV, the feasibility of predicting treatment failure using receiver operating characteristics (ROC) curves after measuring week 4 HCV RNA decreases, and to assess baseline predictors of not achieving sustained virological response (SVR). RESULTS: Peg-IFN-alpha2b was used in 84.5% of patients. Fifty-three (41%) reached SVR. The best cutoff value of HCV RNA decrease at week 4 to predict non-SVR corresponded to 1 log10 IU/ml: sensitivity and negative predictive value: 100%; specificity: 64%; positive predictive value: 66%; ROC curve area: 0.91 (95% confidence interval [CI]: 0.86-0.96). By applying this threshold, treatment could have been discontinued at week 4 in 64% of virological non-responders (49/76). By univariate analysis, baseline HCV RNA > 800,000 IU/ml (P = 0.029), older age (P = 0.011), and higher aspartate aminotransferase (AST) levels (P = 0.005) or AST/alanine aminotransferase ratio values (P = 0.04) were associated with failure. After multivariate analysis, only baseline HCV RNA >800,000 IU/ml (odds ratio [OR]: 2.12; 95% CI: 1.005-4.488; P = 0.048) and higher AST levels (OR: 1.01; 95% CI: 1.003-1.024; P = 0.011) remained statistically significant. CONCLUSIONS: The lack of > or = log10 IU/ml decrease in baseline HCV RNA at week 4 was 100% predictive of treatment failure, independently associated with HCV RNA > 800,000 IU/ml and higher AST levels.

Syncytial giant cell hepatitis in human immunodeficiency virus-infected patients with chronic hepatitis C: 2 cases and review of the literature.

Syncytial giant cell hepatitis (SGCH) among adult human immunodeficiency virus (HIV)-infected patients has been rarely described. Most cases have been reported in subjects coinfected with the hepatitis C virus (HCV), but its prevalence and outcome remain unknown. We performed a retrospective analysis of all cases of SGCH among 332 liver biopsies from HIV-infected patients seen at a tertiary center in Madrid, Spain, between 1984 and March 2004. Two hundred fifty specimens were obtained from HCV-coinfected patients. There were 2 cases of SGCH, leading to an observed overall prevalence of 0.6% (0.8% when considering only HCV-coinfected patients). In addition to histological changes secondary to chronic hepatitis C, the liver cords were replaced by syncytial giant cells with up to 30 nuclei. There was no histological evidence of measles (among paramyxoviruses) or herpes viruses group infections. In patient 1, there was a progressive clinical worsening after a 3-month course of prednisone, leading to liver failure and death. His postmortem liver biopsy showed more abundant giant hepatocytes accompanied with the development of a histologic pattern of severe fibrosing cholestatic hepatitis. The second patient received a prolonged course of pegylated interferon-alpha-2b and ribavirin with clearance of syncytial giant hepatocytes despite HCV-RNA persistence. SGCH is a rare histological finding among HIV-infected patients with chronic hepatitis C. Specific treatment with pegylated interferon and ribavirin can lead to histological resolution and biochemical improvement, even in the absence of HCV-RNA clearance.

Prevention of de novo HBV infection by the presence of anti-HBs in transplanted patients receiving core antibody-positive livers.

AIM: To analyze whether the presence of anti-HBs in liver transplant recipients is effective in preventing HBV infection. METHODS: Twenty-three patients receiving anti-HBc positive liver were studied. Nine recipients were anti-HBc positive as a result of previous HBV infection. Of them, one also received HBV vaccine during the pre-liver transplantation period. Fourteen recipients were anti-HBs positive due to HBV vaccine administered during the pre-transplant period. Liver biopsy was obtained in 10/14 anti-HBc negative/anti-HBs positive recipients and in 4/9 anti-HBc positive recipients. RESULTS: After a mean follow-up period of 46 months, 1 recipient with protective serum anti-HBs levels developed de novo HBV infection as a consequence of immune escape HBV mutants. Among the 14 vaccinated anti-HBc negative/anti-HBs positive recipients, 1/10 patients with available liver biopsy (10%) had liver HBV-DNA at 13 mo post-liver transplantation without serum viral markers and did not develop de novo HBV infection. The vaccinated anti-HBc positive recipient without HBV vaccine response was HBV-DNA positive in serum and liver, viral DNA was continuously negative in the following tests, so a spontaneous seroconversion was diagnosed. CONCLUSION: The presence of anti-HBs as a result of HBV vaccine or past HBV infection seems to be effective at protecting patients receiving livers from anti-HBc positive donors. However, the emergence of immune escape HBV mutants, which can evade the anti-HBs protection, should be considered as a risk of HBV infection.

[Acute hepatitis E in Madrid: description of 18 cases]. / Hepatitis aguda E en Madrid: descripción de 18 casos.

INTRODUCTION: Hepatitis E virus (HEV) is the main cause of non-A non-B enterically transmitted hepatitis in underdeveloped countries but is rare in industrialized areas. However, in the last few years, several sporadic autochthonous hepatitis E cases have been reported in Europe and no risk factors, such as visiting to endemic areas, could be found in these patients. OBJECTIVE AND PATIENTS: Twelve patients with sporadic autochthonous hepatitis E (no risk factors such as traveling to endemic areas) and six imported cases (travel to Nepal, Santo Domingo, China, Brazil and Ecuador) were studied between June 1999 and December 2005. RESULTS: HEV infection was diagnosed in patients with symptoms of acute hepatitis and the presence of IgG and IgM antibodies in serum with no other markers of hepatitis. HEV infection is probably overlooked in industrialized countries. CONCLUSIONS: This diagnosis should be suspected in patients with acute hepatitis and anti-HEV antibodies in serum without known risk factors such as traveling to endemic areas.

Safe use of pegylated interferon/ribavirin in hepatitis C virus cirrhotic patients with hypersplenism after partial splenic embolization.

BACKGROUND AND AIMS: Partial splenic embolization (PSE) is a non-surgical alternative for the treatment of hypersplenism. Thrombocytopenia precludes the use of pegylated interferon (peg-IFN) and ribavirin in cirrhotic patients with hepatitis C virus (HCV). We aimed to evaluate the role of PSE as a procedure allowing combined HCV therapy in this setting. METHODS: A retrospective analysis of the safety and rate of sustained virological response (SVR) after a full-dose course of peg-IFN plus ribavirin in eight HCV cirrhotic patients with severe hypersplenism undergoing PSE at a tertiary centre in Madrid, Spain, from May 2002 to August 2004. RESULTS: Six patients (75%) were in Child-Pugh class B (median score 7). PSE significantly improved the mean platelet (P = 0.012), leucocyte (P = 0.017) and haemoglobin (P = 0.035) levels, and prothrombin activity (P = 0.012). After a mean of 20 weeks after PSE all patients started weight-adjusted ribavirin plus peg-IFN-alpha2b (n = 6) or 180 microg/week of peg-IFN-alpha2a (n = 2). Six subjects (75%) completed therapy with no peg-IFN dose reductions; the dose of ribavirin was reduced in two patients reaching haemoglobin levels of less than 10 g/dl (one also received erythropoietin and granulocyte colony-stimulating factor because of neutrophil counts < 300 cells/microl). Three patients (38%) achieved SVR. Portal vein thrombosis was observed in 50% of patients, but did not preclude antiviral therapy. The pathogenic mechanism was multifactorial. It was successfully managed with anticoagulant therapy in two cases. CONCLUSIONS: PSE allowed the safe use of peg-IFN plus ribavirin in HCV cirrhotic patients with severe cytopenias who otherwise would never have been treated. The rate of SVR was 38%.