M. García-Retortillo

Antiviral therapy of patients with decompensated cirrhosis to prevent recurrence of hepatitis C after liver transplantation

BACKGROUND/AIMS After liver transplantation (LT) infection of the graft with the hepatitis C virus (HCV) is almost universal and chronic hepatitis and cirrhosis develop in a significant proportion of patients. One of the possible strategies to prevent HCV infection recurrence is to eradicate HCV before LT. METHODS We evaluated the efficacy and safety of antiviral therapy to prevent HCV recurrence in 30 HCV-cirrhotic patients awaiting LT. At the time of inclusion 15 patients were Child-Pugh A and 15 Child-Pugh B/C. The infecting genotype was 1b in 25 patients. Treatment with interferon alpha-2b 3 MU/day and ribavirin 800 mg/day was initiated when the expected time for LT was less than 4 months and continued until LT. The median duration of treatment was 12 weeks. RESULTS Nine patients (30%) achieved a virological response and 21 did not respond to therapy. In nine (43%) of the 21 non-responders viral load decreased > or =2 log10 during treatment. A viral load decrease > or = 2 log10 at week 4 of treatment was the strongest predictor of virological response. All nine virological responders have already undergone LT; six patients remain free of infection after a median follow-up of 46 weeks and HCV infection recurred in three patients after LT. In one of these patients HCV-RNA was still detectable in the explanted liver. Side effects were frequent and dose reduction was necessary in 19 (63%) of the 30 patients; no patient died while on therapy. CONCLUSIONS Our data support the utilization of antiviral therapy in HCV-infected patients awaiting LT as one of the strategies to prevent hepatitis C recurrence after transplantation.

Hepatitis C recurrence is more severe after living donor compared to cadaveric liver transplantation

Preliminary reports suggested that hepatitis C virus (HCV) infection has a more aggressive course following living donor liver transplantation (LDLT) compared to cadaveric liver transplantation (CLT). The aim of this prospective study was to establish if HCV disease recurrence differs between LDLT and CLT. A cohort of 116 consecutive HCV‐infected patients undergoing 117 LTs in a single center from March 2000 to August 2003 were followed‐up, including systematic liver biopsies. Severe recurrence (SR) was defined as biopsy‐proven cirrhosis and/or the occurrence of clinical decompensation. After a median follow‐up of 22 months (2.6–44 months), 26 (22%) patients developed SR (decompensation in 12), involving 17 (18%) of 95 patients undergoing CLT and 9 (41%) of 22 undergoing LDLT. The 2‐year probability of presenting SR was significantly higher in LDLT compared to CLT (45% vs. 22%, P = .019). By univariate analysis LDLT (P = .019) and an ALT higher than 80 IU/L 3 months after LT (P = .022) were predictors of SR. In 93 patients from whom a liver biopsy was available 3 months after LT, a lobular necroinflammatory score >1 (P < .01), LDLT (P < .01), and biliary complications (P = .046) were associated with SR. However, the only variables independently associated with SR were LDLT (odds ratio [OR], = 2.8; 95% CI,1.19‐6.6; P = .024) and a lobular necroinflammatory score >1 (OR, 3.1; 95% CI, 1.2‐8; P = .013). In conclusion, HCV recurrence is more severe in LDLT compared to CLT. Although our results were based on a single‐center experience, they should be considered in the decision‐making process of transplant programs, since severe HCV recurrence may ultimately compromise graft and patient survival. (HEPATOLOGY 2004; 40:699–707.)

Nosocomial transmission of HCV in the liver unit of a tertiary care center.

Despite its medical and legal implications, there are no prospective studies analyzing the incidence and mechanisms involved in the nosocomial transmission of hepatitis C virus (HCV) in liver units. This study prospectively investigates the nosocomial transmission of HCV in the liver unit of a tertiary care center from August 2000 to October 2002. The median prevalence of HCV infection among hospitalized patients was 50%. Anti‐HCV–negative patients admitted to the liver unit during the study period were prospectively followed, and serum markers of HCV infection were repeated 6 months after discharge. All known risk factors for HCV transmission (including the physical allocation of HCV‐infected and noninfected patients during hospitalization) were recorded. Complete follow‐up data were available in 1,301 (84.5%) of 1,540 patients. Six patients (0.46%) acquired HCV infection (annual incidence: 0.27/100 admissions). Phylogenetic analyses of recovered HCV sequences identified the source of infection as an HCV‐infected roommate (3 cases) and a patient receiving care by the same nurse team (1 case). The most relevant risk factors associated with HCV acquisition were duration of hospitalization (>10 days; OR, 35; 95% CI, 1.96‐622) and hospitalization with an HCV‐infected roommate (>5 days; OR, 12; 95% CI, 1.39‐103). In fact, HCV infection occurred in 1.7% of the 357 patients hospitalized longer than 10 days. In conclusion, HCV nosocomial infection appears to occur via patient‐to‐patient transmission in liver units, particularly in individuals who require long hospitalizations. Continuous reinforcement of universal prevention measures and, when possible, isolation of patients at higher risk might further reduce nosocomial HCV transmission. (HEPATOLOGY 2005;41:115–122.)

Association Between Severe Portal Hypertension and Risk of Liver Decompensation in Patients With Hepatitis C, Regardless of Response to Antiviral Therapy

BACKGROUND & AIMS Hepatic venous pressure gradient (HVPG) is associated with a risk of liver events in patients with chronic hepatitis C. Antiviral therapies that lead to a sustained virologic response (SVR) reduce portal pressure and prevent liver disease progression. However, it is not clear to what extent the progression of hepatitis C is modified once patients develop cirrhosis with severe portal hypertension (CSPH) (HVPG ≥ 10 mm Hg). We assessed the effects of HVPG and SVR on the risk of liver decompensation, hepatocellular carcinoma, and/or death in patients with hepatitis C-related cirrhosis. METHODS We collected data from 100 patients with hepatitis C and compensated cirrhosis who underwent HVPG measurement 3 months or less before (baseline) and 24 weeks after therapy with pegylated interferon alfa-2a and ribavirin at 4 hospitals in Spain, from 2001 through 2009. SVR was defined as undetectable serum HCV RNA level 24 weeks after treatment ended. Clinical data were collected until death, liver transplantation, or December 2012 (median, 5 y; interquartile range, 1.4-7 y). RESULTS Seventy-four patients had CSPH at baseline and 35% of patients achieved an SVR. During the follow-up period, 19 patients developed liver decompensation (ascites, variceal bleeding, or encephalopathy). The actuarial probability values for liver decompensation at 1, 5, and 7 years were 3%, 19% and 22%, respectively. The baseline level of HVPG, but not SVR, was associated independently with the risk of liver decompensation. CONCLUSIONS Patients with CSPH, regardless of an SVR to therapy for hepatitis C, remain at risk for liver decompensation within the first 5 years after treatment; they should be monitored closely.

A multidisciplinary support programme increases the efficiency of pegylated interferon alfa-2a and ribavirin in hepatitis C

BACKGROUND & AIMS Adherence to antiviral treatment is important to achieve sustained virological response (SVR) in chronic hepatitis C (CHC). We evaluated the efficiency of a multidisciplinary support programme (MSP), based on published HIV treatment experience, to increase patient adherence and the efficacy of pegylated interferon alfa-2a and ribavirin in CHC. METHODS 447 patients receiving antiviral treatment were distributed into 3 groups: control group (2003-2004, n=147), MSP group (2005-2006, n=131), and MSP-validation group (2007-2009, n=169). The MSP group included two hepatologists, two nurses, one pharmacist, one psychologist, one administrative assistant, and one psychiatrist. Cost-effectiveness analysis was performed using a Markov model. RESULTS Adherence and SVR rates were higher in the MSP (94.6% and 77.1%) and MSP-validation (91.7% and 74.6%) groups compared to controls (78.9% and 61.9%) (p<0.05 in all cases). SVR was higher in genotypes 1 or 4 followed by the MSP group vs. controls (67.7% vs. 48.9%, p=0.02) compared with genotypes 2 or 3 (87.7% vs. 81.4%, p=n.s.). The MSP was the main predictive factor of SVR in patients with genotype 1. The rate of adherence in patients with psychiatric disorders was higher in the MSP groups (n=95, 90.5%) compared to controls (n=28, 75.7%) (p=0.02). The cost per patient was € 13,319 in the MSP group and € 16,184 in the control group. The MSP group achieved more quality-adjusted life years (QALYs) (16.317 QALYs) than controls (15.814 QALYs) and was dominant in all genotypes. CONCLUSIONS MSP improves patient compliance and increases the efficiency of antiviral treatment in CHC, being cost-effective.

Sensitivity to antiviral therapy may change after liver transplantation in patients with chronic hepatitis C virus infection

Summary.  In hepatitis C virus (HCV)‐infected patients, it is generally assumed that the pattern of response to antiviral therapy remains unaltered after liver transplantation (LT). However, changes in the circulating HCV quasispecies and in the gene expression profiles of the graft might influence response to treatment after LT. We evaluated 22 HCV‐infected patients who received antiviral treatment while awaiting LT and in whom HCV infection recurred. Eleven of these patients underwent a new antiviral treatment course. Our study analyses the early virological response to both treatment courses to assess the influence of the changes in HCV on the response to therapy. Patients were considered early virological responders (EVR) if viral load declined ≥2log10 during the first 12 weeks of therapy. The remaining individuals were considered nonresponders (NR). HCV sequences from hypervariable region 1 and nonstructural 5A (NS5A) region before both treatment regimens were compared. Of 11 patients, 8 (73%) showed identical early response to both courses of therapy (group A: five EVR‐EVR, three NR‐NR). Interestingly, the response changed in three patients (27%) (group B): two NR became EVR after transplantation, whereas one EVR became NR. Fixation of mutations within the NS5A occurred preferentially in group B (100%) compared with group A (37%)(P = 0.12). However, the number of fixed mutations was not significantly different between groups, suggesting that the changes in sensitivity to therapy after LT are not exclusively dependent on variations in HCV strains. In conclusion, in HCV‐infected patients undergoing LT, the pattern of response to antiviral treatment may change after transplantation, and this possibility needs to be incorporated in clinical practice.

Applicability and accuracy improvement of transient elastography using the M and XL probes by experienced operators

Transient elastography (TE) is the reference method to obtain liver stiffness measurements (LSM), but no results are obtained in 3.1% and unreliable in 15.8%. We assessed the applicability and diagnostic accuracy of TE re‐evaluation using M and XL probes. From March 2011 to April 2012 868 LSM were performed with the M probe by trained operators (50–500 studies) (LSM1). Measurements were categorized as inadequate (no values or ratio <60% and/or IQR/LSM >30%) or adequate. Inadequate LSM1 were re‐evaluated by experienced operators (>500 explorations) (LSM2) and inadequate LSM2 using XL probe (LSMXL). Inadequate LSM1 were obtained in 187 (21.5%) patients, IQR/LSM >30% in 97 (51%), ratio <60% in 24 (13%) and TE failed to obtain a measurement in 67 (36%). LSM2 achieved adequate registers in 123 (70%) of 175 registers previously considered as inadequate. Independent variables (OR, 95%CI) related to inadequate LSM1 were body mass index (1.11, 1.04–1.18), abdominal circumference (1.03, 1.01–1.06) and age (1.03, 1.01–1.04) and to inadequate LSM2 were skin‐capsule distance (1.21, 1.09–1.34) and abdominal circumference (1.05, 1.01–1.10). The diagnostic accuracy (AUROC) to identify significant fibrosis improved from 0.89 (LSM1) to 0.91 (LSM2) (P = 0.046) in 334 patients with liver biopsy or clinically significant portal hypertension. A third evaluation (LSMXL) obtained adequate registers in 41 (93%) of 44 patients with inadequate LSM2. Operator experience increases the applicability and diagnostic accuracy of TE. The XL probe may be recommended for patients with inadequate values obtained by experienced operators using the M probe. http://clinicaltrials.gov (NCT01900808).

Randomized prospective study evaluating tenofovir disoproxil fumarate prophylaxis against hepatitis B virus reactivation in anti-HBc-positive patients with rituximab-based regimens to treat hematologic malignancies: The Preblin study

Background Hepatitis B virus (HBV) reactivation in patients with resolved HBV infection (HBsAg negative, antiHBc positive) is uncommon, but potentially fatal. The role of HBV prophylaxis in this setting is uncertain. The aim of this study was to compare the efficacy of tenofovir disoproxil fumarate (TDF) prophylaxis versus close monitoring in antiHBc-positive, HBsAg-negative patients under treatment with rituximab (RTX)-based regimens for hematologic malignancy. Methods PREBLIN is a phase IV, randomized, prospective, open-label, multicenter, parallel-group trial conducted in 17 hospitals throughout Spain. Anti-HBc-positive, HBsAg-negative patients with undetectable HBV DNA were randomized to receive TDF 300 mg once daily (Group I) or observation (Group II). The primary endpoint was the percentage of patients showing HBV reactivation during 18 months following initiation of RTX treatment. Patients with detectable HBV DNA (Group III) received the same dose of TDF and were analyzed together with Group I to investigate TDF safety. Results Sixty-one patients were enrolled in the study, 33 in the TDF treatment group and 28 in the observation group. By ITT analysis, HBV reactivation was 0% (0/33) in the study group and 10.7% (3/28) in the observation group (p = 0.091). None of the patients in either group showed significant differences in liver function parameters between baseline and the last follow-up sample. TDF was generally well tolerated and there were no severe treatment-related adverse events. Conclusion In patients with hematological malignancy and resolved hepatitis B infection receiving RTX-based regimens, HBV reactivation did not occur in patients given TDF prophylaxis.

Reactivación del virus de la hepatitis B en un paciente con artritis reumatoide tras el tratamiento con rituximab

The reactivation of hepatitis B virus (HBV) infection is defined as an increase in HBV replication in a patient with an inactive or resolved hepatitis (usually accompanied by increased serum transaminase levels). Most reported cases have occurred in patients with hematologic malignancies after chemotherapy.1–3 Recently, there have been reports of HBV reactivation in patients with rheumatoid arthritis after treatment with biological therapies such as rituximab (RTX)4,5 (Table 1). Although most cases of HBV reactivation have occurred in patients with serology indicating chronic HBV infection, patients with resolved HBV infection can develop this complication.5 We report the case of a 77 year old patient with a history of seropositive and erosive rheumatoid arthritis of 12 years of evolution, receiving the first cycle of RTX in February 2008. Serology for HBV in 2001 was HBsAg negative and anti-HBc positive, compatible with resolved hepatitis B. The patient received methotrexate from 2002 to 2004 and the treatment was stopped by the appearance of oral ulcers. In 2005, treatment was started with infliximab 3 mg/kg every 8 weeks with good response; after one year of treatment, the patient presented a lack of response in March 2006 and it was suspended due to multiple episodes of lung infections and switched to etanercept 50 mg weekly. From 2005 to 2008, serum levels of ALT transaminase (GPT) ansd AST (GOT), remained stable, but new virus serology was not requested. Due to poor control of symptoms (disease activity score [DAS] 28 joints 6.43) the patient

Impact of Anthropometric Features on the Applicability and Accuracy of FibroScan® (M and XL) in Overweight/Obese Patients.

Transient elastography is the reference method for liver stiffness measurement (LSM) in the general population, having lower applicability in obese patients. We evaluated the applicability and diagnostic accuracy of the M and XL probes in overweight/obese patients to establish the most appropriate approach.