Prognostic factors in patients with advanced hepatocellular carcinoma treated with sorafenib

Background Sorafenib is the new reference standard for patients with advanced hepatocellular carcinoma (HCC). Aim To identify prognostic factors in sorafenib‐treated HCC patients and to evaluate outcomes with respect to liver function. Methods In this retrospective study, 148 HCC patients received sorafenib 400 mg b.d. across 11 Austrian institutions. Seventy‐eight HCC patients who received best supportive care (BSC) in the pre‐sorafenib era served as a control. Results In sorafenib‐treated patients, low baseline α‐fetoprotein, low Child–Pugh (CP) score, compensated cirrhosis, and low baseline aspartate aminotransferase (AST) were associated with significantly longer overall survival (OS) on univariate analysis. CP score and baseline AST remained independent prognostic factors on multivariate analysis. In patients with Barcelona Clinic liver Cancer (BCLC) stage B or C HCC (sorafenib: n = 139; BSC: n = 39), CP‐A patients had a median OS of 11.3 (sorafenib [n = 76]) vs. 6.4 (BSC [n = 17]) months (P = 0.010), and CP‐B patients had a median OS of 5.5 (sorafenib [n = 55]) vs. 1.9 (BSC [n = 22]) months (P = 0.021). In the sorafenib group, median OS according to baseline AST was 11.8 (<100 U/L [n = 58]) vs. 3.9 (≥100 U/L [n = 15]) months for CP‐A patients (P = 0.127), and 6.5 (<100 U/L [n = 33]) vs. 2.1 (≥100 U/L [n = 21]) months for CP‐B patients (P = 0.011). There was no survival difference between sorafenib and BSC in patients with BCLC stage D HCC (1.5 vs. 1.4 months; P = 0.116). Conclusions Sorafenib was associated with improved survival in both CP‐A and CP‐B patients. In CP‐B patients, baseline AST may be helpful in determining which patients are most likely to benefit from sorafenib.     

Intra‐arterial therapy with cisplatin suspension in lipiodol and 5‐fluorouracil for hepatocellular carcinoma with portal vein tumour thrombosis

Aliment Pharmacol Ther 2010; 32: 543–550

Summary

Background Portal vein tumour thrombosis is a negative prognostic factor for hepatocellular carcinoma (HCC). Aim To assess the efficacy of cisplatin in lipiodol emulsion combined with 5‐fluorouracil (5‐FU) for patients with HCC and portal vein tumour thrombosis. Methods The study subjects were 51 patients with the above‐specified criteria who received injection of cisplatin suspension in lipiodol emulsion followed by intra‐arterial infusion of 5‐FU. The primary objective was to determine tumour response to the treatment, while the secondary objectives were safety and tolerability. Independent factors for survival were also assessed. Results Ten patients had complete response and 34 patients had partial response (response rate, 86.3%). The median survival for all 51 patients was 33 months, while that for 10 complete response patients and 21 patients who showed disappearance of HCC following additional therapies was 39 months. The single factor that significantly influenced survival was therapeutic effect. Treatment was well tolerated and severe toxicity was infrequent, with only grade 3 toxicity (thrombocytopenia) in one patient. Conclusions The present study demonstrated the efficacy of hepatic arterial infusion chemotherapy using cisplatin‐lipiodol emulsion and 5‐FU without serious adverse effects in patients with unresectable HCC and portal vein tumour thrombosis.     

Benefit of downsizing hepatocellular carcinoma in a liver transplant population

Aliment Pharmacol Ther 31 , 415–423

Summary

Background Long‐term results after downstaging hepatocellular carcinoma (HCC) prior to liver transplantation (LT) remain unknown. Aims To investigate dropouts and post‐transplant outcome among patients with downstaged HCC by transarterial chemo‐lipiodolization (TACL). Methods Between 2000 and 2007, 386 patients with HCC initially exceeding Milan criteria underwent TACL for tumour downstaging and were consecutively enrolled. Results Overall, 160 (41.5%) patients achieved successful downstaging of HCC to within Milan criteria. During the follow‐up, 82 eventually dropped off the waiting list for LT, with estimated dropout rates at 1, 2 and 5 years of 46.7%, 70.2%, and 87.2%, respectively. The overall post‐transplant survival rates at 1, 2 and 5 years were 89.2%, 70.3% and 54.6% and the corresponding rates for recurrence‐free survival were 74.7%, 71.8% and 66.3% respectively. Multivariate analysis indentified alpha‐fetoprotein (AFP) levels ≥100 ng/mL at LT (P = 0.003), maximum tumour size ≥7 cm (P = 0.002) and the lack of complete necrosis by TACL (P = 0.048) as independent predictors of HCC recurrence after LT. Patients with none of these risk factors had an excellent post‐transplant outcome, with an 87.5% probability of recurrence‐free survival up to 6 years. Conclusions These long‐term results may contribute to the database for optimizing management of LT candidates with downstaged HCC. Based on our data, patients with a maximum tumour size <7 cm who achieve complete necrosis together with AFP levels <100 ng/mL at LT may be the best candidates for LT following downstaging using TACL.     

Meta‐analysis: interferon improves outcomes following ablation or resection of hepatocellular carcinoma

Aliment Pharmacol Ther 2010; 32: 851–858

Summary

Background Hepatocellular carcinoma (HCC) is third most common cause of tumour‐related death in the US with hepatitis C virus (HCV) the most common aetiology. Surgical resection and tumour ablation are curative in patients who cannot be transplanted. With native liver having cirrhosis, HCC recurrence is a potential problem. Aim To perform a systematic review and meta‐analysis of studies evaluating efficacy of IFN to prevent HCC recurrence after its curative treatment in HCV‐related cirrhosis. Methods Ten studies (n = 645, 301 treated with IFN) on the use of IFN after resection or ablation of HCV‐associated HCC were analysed. Results Pooled data showed benefit of IFN for HCC prevention with OR (95% CI) of 0.26 (0.15–0.45); P < 0.00001. The proportion of patients surviving at 5 years (n = 505 in 6 studies) was in favour of IFN with OR of 0.31 [(95% CI 0.21–0.46); P < 0.00001]. Data were homogeneous for HCC recurrence (χ² 12.05, P = 0.21) and survival (χ² 6.93, P = 0.44). The benefit of IFN was stronger with sustained virological response compared with nonresponders for HCC recurrence [0.19 (0.06–0.60); P = 0.005] and survival [0.31 (0.11–0.90); P = 0.03]. Conclusion Interferon treatment after curative resection or ablation of HCC in HCV‐related cirrhotics prevents HCC recurrence and improves survival.     

Meta-analysis: the efficacy of anti-viral therapy in prevention of recurrence after curative treatment of chronic hepatitis B-related hepatocellular carcinoma

Aliment Pharmacol Ther 2011; 33: 1104–1112

Summary

Background The role of anti‐viral therapy in prevention of hepatocellular carcinoma (HCC) recurrence is to be defined. Aim To investigate the role of anti‐viral therapy in prevention of tumour recurrence after curative treatment of hepatitis B virus (HBV)‐related HCC. Methods A systematic electronic search on keywords including HCC and different anti‐viral therapies was performed through eight electronic databases, including Medline, EMBASE and Cochrane Databases. The primary outcome was HCC recurrence after curative treatment of HBV‐related HCC. The secondary outcomes were mortality related to HCC, mortality related to liver failure and the overall mortality. Results Nine cohort studies were included with a total number of 551 patients: 204 patients with anti‐viral treatment group and 347 patients without anti‐viral treatment (control group). There was significant difference in the incidence of HCC recurrence in favour of the anti‐viral treatment group (55% vs. 58%; odds risk (OR) = 0.59, 95% CI 0.35–0.97, P = 0.04). The risk of HCC was reduced by 41% in the anti‐viral treatment group. There were also significant differences in favour of anti‐viral treatment group in terms of liver‐related mortality (0% vs. 8%; OR = 0.13, 95% CI 0.02–0.69, P = 0.02) and overall mortality (38% vs. 42%; OR = 0.27, 95% CI 0.14–0.50, P < 0.001). Conclusions Anti‐viral therapy has potential beneficial effects after the curative treatment of HBV‐related hepatocellular carcinoma in terms of tumour recurrence, liver‐related mortality and overall survival. Anti‐viral therapy should be considered after curative treatment of hepatocellular carcinoma.     

Pilot study: rapamycin in advanced hepatocellular carcinoma

Background The PI3K/Akt/mTOR signal pathway is involved in hepatocarcinogenesis. Rapamycin (=sirolimus), a specific mTOR inhibitor, leads to G(1) arrest of many malignant cell lines and currently, analogues of rapamycin are being investigated as a cancer chemotherapeutic adjuvant. Aim To study the toxicity and tolerability of rapamycin therapy in patients with advanced hepatocellular carcinoma (HCC). Methods Between June 2005 and February 2007, patients with advanced HCC, not eligible for any established therapy, were included in the study. Results Eighteen patients (F/M: 5/13) with compensated liver cirrhosis (Child A n = 11, Child B n = 5, Child C n = 2) and histologically proven HCC were included in this study. According to the BCLC staging system, most of the patients enrolled had an advanced HCC: BCLC stage B: n = 2, Barcelona Clinic Liver‐Cancer (BCLC) stage C: n = 14, BCLC stage D: n = 2. Overall, therapy with rapamycin was well tolerated. Most common toxicities were thrombocytopaenia and anaemia. We did not observe any partial or complete tumour response. At 3 months, two patients had stable disease and at 6 months, all patients had progressed. The median overall survival was 5.27 months, median time to progression was 3 months. Conclusion Rapamycin is well tolerated in patients with advanced HCC, but only minimally effective.     

Survival after treatment with curative intent for hepatocellular carcinoma among patients with vs without non‐alcoholic fatty liver disease

Background

Non‐alcoholic fatty liver disease (NAFLD) is expected to become a leading aetiology of hepatocellular carcinoma (HCC)‐related mortality in the United States. HCC treatments with curative intent (OLT, orthotopic liver transplantation; resection; RFA, radiofrequency ablation) can improve survival in carefully selected patients.

Aim

To compare survival after receipt of curative treatment for NAFLD and non‐NAFLD‐HCC aetiologies (HCV, chronic hepatitis C; HBV, chronic hepatitis B; ALD, alcoholic liver disease) and by treatment was performed.

Methods

A cohort of 17 664 patients was assembled using linked Surveillance, Epidemiology, and End Results and Medicare data from 1991 to 2011 with confirmed diagnosis of HCC.

Results

The cohort was mostly male, aged 70 (21‐106) years, without cardiovascular disease, and had liver cirrhosis without decompensation, metastatic HCC or large tumour size (>5 cm). The NAFLD‐HCC group was mostly female and older with more cardiovascular disease, metastatic HCC, and large tumour size and less cirrhosis and decompensated liver disease than the non‐NAFLD‐HCC groups. The NAFLD group was 47% less likely to receive any curative treatment as compared with non‐NAFLD aetiologies (OR 0.53, P < .001). NAFLD‐HCC had worse median survival after OLT (3.2, 0‐12.9 years, P = .01) but had improved survival after resection (2.4, 0‐12.0 years, P < .001) as compared with non‐NAFLD‐HCC. No significant survival differences existed for RFA by HCC aetiology. NAFLD was not an independent predictor of mortality after OLT, resection or RFA.

Conclusion

Patients with NAFLD‐HCC had worse survival after OLT but favourable survival after resection, particularly in the absence of cirrhosis, as compared with non‐NAFLD‐HCC aetiologies.

     

Impact of evidence‐based medicine on the treatment of patients with unresectable hepatocellular carcinoma

Aliment Pharmacol Ther 31 , 493–501

Summary

Background A randomized controlled trial performed by the Barcelona Clinic Liver Cancer (BCLC) published in 2002 demonstrated that transcatheter arterial chemoembolisation (TACE) is an effective treatment for well‐selected patients with unresectable hepatocellular carcinoma (HCC). Aim To access whether this information has modified the use of TACE in clinical practice. Methods From 2042 HCC patients included in the Italian Liver Cancer database, we selected 336 cases diagnosed over two 4‐year periods (1999–2002, n = 161 and 2003–2006, n = 175), fulfilling the inclusion criteria of the BCLC study. These groups were compared for TACE application rate, patient characteristics and survival. Results Patients undergoing TACE increased in the 2003–2006 period (from 62% to 73%, P = 0.035), with an increase in of Child‐Pugh class A (from 64% to 77%, P = 0.048) and advanced HCC patients (from 54% to 69%, P = 0.041). In the 1999–2002 period, there was no significant difference in survival between TACE‐treated and untreated patients, while in the 2003–2006 period, TACE‐treated patients survived longer (P < 0.0001). Conclusions Following the publication of studies providing evidence of a survival benefit of TACE in selected patients with unresectable HCC, significantly more patients with well‐compensated cirrhosis underwent TACE within this very homogenous population, leading to an increased survival despite a more advanced tumour stage.     

Predicting survival in patients with hepatocellular carcinoma treated by transarterial chemoembolisation

Aliment Pharmacol Ther 2011; 34: 196–204

Summary

Background Transarterial chemoembolisation (TACE) is first‐line treatment in unresectable hepatocellular carcinoma (HCC) and rescue treatment after failure of radical treatments in early stage HCC. Prognostic tools for HCC using time‐fixed Cox models may be unreliable in patients treated with TACE because time‐varying predictors interact. Aim To explore time‐dependent variables as survival predictors in patients with HCC receiving TACE as first‐line or second‐line treatment. Methods Eighty four consecutive patients with HCC (mean age 68; male gender 62%; Child‐Pugh class: A n = 73, B n = 11; Barcelona Clinic Liver Cancer class: A n = 44, B n = 24, C n = 16) treated with TACE were enrolled. Clinical, laboratory and radiological follow‐up data were collected from the time of first treatment. Time‐fixed and time‐dependent Cox analyses were done. Results Overall survival rates were 89.6% (95% CI 82.5–97.2) at 12 months, 58.8% (95% CI 46.2–74.9) at 24, 35.4% (95% CI 22.3–56.1) at 36 and 17.2% (95% CI 7.0–41.7) at 48 months. Performance status (P < 0.001), number of nodules (P < 0.016) and prior therapy (P = 0.017) were the only variables strongly linked to survival by time‐fixed Cox model. Performance status (P < 0.001), prior therapy (P = 0.005), number of treatments (P = 0.013), complete response after TACE (P = 0.005) and bilirubin level (P < 0.001) were associated with survival using a time‐dependent Cox model. Conclusions Survival after TACE is influenced most by performance status, complete response and bilirubin. Compared with the time‐fixed models, a time‐dependent Cox model has the potential to estimate a more precise prognosis in HCC patients treated with TACE.     

Apoptosis induction and ERK/NF‐κB inactivation are associated with magnolol‐inhibited tumor progression in hepatocellular carcinoma in vivo

Although hepatitis B and/or hepatitis C virus were recognized as major risk factor for the development of hepatocellular carcinoma (HCC), certain occupational, environmental, and lifestyle factors also play key roles in HCC tumorigenesis. Moreover, in molecular signaling route, extracellular signal‐regulated kinase (ERK)/nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) signaling was found to be overexpressed and linked to poor prognosis in HCC. Thus, to identify possible nature compound that can suppress ERK/NF‐κB may be benefit to HCC patient. Magnolol, a natural compound derived from herbal plant Magnolia officinalis, has been recognized as a liver protection and antitumor reagent. However, whether magnolol‐inhibited HCC progression correlates with disruption of ERK/NF‐κB signaling is remained unclear. In this studies, we performed SK‐Hep1/luc2 HCC bearing animal model to investigate the anticancer efficacy and mechanism of magnolol on tumor progression. Tumor size and tumor growth rate were dramatically suppressed after treatment of magnolol. In addition, expression of phospho‐ERK (p‐ERK), NF‐κB p65 (Ser536), and tumor progression‐associated proteins, such as matrix metallopeptidase 9 (MMP‐9), vascular endothelial growth factor (VEGF), X‐linked inhibitor of apoptosis protein (XIAP), and CyclinD1 were all significantly decreased by magnolol. Most important, major extrinsic and intrinsic apoptosis signaling factors, including active caspase‐8 and caspase‐9 were both enhanced by magnolol. This study indicated that apoptosis induction through extrinsic/intrinsic pathways and blockage of ERK/NF‐κB activation were associated with magnolol‐inhibited tumor progression in HCC in vivo.     

Silymarin use and liver disease progression in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis trial

Aliment Pharmacol Ther 2011; 33: 127–137

Summary

Background Silymarin is the most commonly used herbal product for chronic liver disease; yet, whether silymarin protects against liver disease progression remains unclear. Aim To assess the effects of silymarin use on subsequent liver disease progression in 1049 patients of the Hepatitis C Antiviral Long‐Term Treatment against Cirrhosis (HALT‐C) trial who had advanced fibrosis or cirrhosis and had failed prior peginterferon plus ribavirin treatment. Methods Patients recorded their use of silymarin at baseline and were followed up for liver disease progression (two point increase in Ishak fibrosis score across baseline, year 1.5, and year 3.5 biopsies) and over 8.65 years for clinical outcomes. Results At baseline, 34% of patients had used silymarin, half of whom were current users. Use of silymarin was associated (P < 0.05) with male gender; oesophageal varices; higher ALT and albumin; and lower AST/ALT ratio, among other features. Baseline users had less hepatic collagen content on study biopsies and had less histological progression (HR: 0.57, 95% CI: 0.33–1.00; P‐trend for longer duration of use=0.026). No effect was seen for clinical outcomes. Conclusions Silymarin use among patients with advanced hepatitis C‐related liver disease is associated with reduced progression from fibrosis to cirrhosis, but has no impact on clinical outcomes (Clinicaltrials.gov #NCT00006164).     

A population‐based study elicits a reverse correlation between age and overall survival in elderly patients with rectal carcinoma receiving adjuvant chemotherapy

Colorectal cancer is the third most common cancer and the fourth most common cause of cancer‐related death globally. This population‐based study aimed to explore the predictive factors that affected the overall survival of rectal cancer patients receiving adjuvant chemotherapy plus radical surgery using a Cox proportional hazards modeling approach. A total of 619 patients with rectal cancer who underwent surgery were enrolled between October 2006 and May 2013. Clinical characteristics of the patients were compared among the groups and potential prognostic factors were analyzed using the spss program, version 19.0. Patients aged ≥ 70 years have distinctive characteristics such as lager tumour size (≥ 5 cm), damaged micturition and higher incidence of diabetes compared to younger and middle‐aged patients. Male gender, tumour size (≥ 5 cm), poor differentiation, later stage, adjuvant chemotherapy, damaged micturition, hypertension or diabetes are associated with a worse prognosis for rectal cancer patients (P < 0.05). However, smoking is a favourable factor to the patients (P = 0.018). Age of ≥ 70 years is an independent prognostic factor for patients with rectal cancer after surgery (P = 0.000) and elderly patients with Stage II and III disease receiving adjuvant chemotherapy show a favourable prognosis. The elderly patients who suffered from diabetes receiving adjuvant chemotherapy have a poor prognosis. Further prospective and large population studies are warranted to confirm the findings of this study.     

Clinical trial: the efficacy and safety of oral PF‐03491390, a pancaspase inhibitor – a randomized placebo‐controlled study in patients with chronic hepatitis C

Aliment Pharmacol Ther 31 , 969–978

Summary

Background Elevated serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) reflect hepatocellular injury in patients with chronic hepatitis C virus (HCV). Increased apoptosis and activated caspases are present in these patients. PF‐03491390 inhibits multiple caspases and lowers serum AST and ALT levels in patients with chronic liver diseases. Aim To determine if treatment with an oral pancaspase inhibitor could reduce serum AST and ALT in patients with HCV. Methods Double‐blind, randomized, placebo‐controlled, parallel‐dose study in 204 patients treated with placebo or PF‐03491390 (5, 25 or 50 mg) orally twice daily (b.d.) for up to 12 weeks. Serum AST and ALT were monitored weekly. Results Significant reductions in serum AST and ALT were observed within 1 week of initiating PF‐03491390 in all treatment groups (P < 0.0001). These reductions in AST and ALT were maintained throughout the 12 week treatment period and returned to baseline levels when PF‐03491390 was discontinued. Increasing the dose did not further lower AST or ALT. The most frequently reported adverse events were headache and fatigue. Conclusion PF‐03491390 significantly reduced serum AST and ALT levels in patients with chronic HCV, and was well tolerated over 12 weeks.     

A tumour‐promoting role of Th9 cells in hepatocellular carcinoma through CCL20 and STAT3 pathways

Hepatocellular carcinoma (HCC ) is a common and aggressive human malignancy. An imperative demand is present for a better understanding of the functions and regulations of the immune system and how they affect HCC pathogenesis. Recently, a group of interleukin 9 (IL ‐9)‐producing CD 4⁺ T cells, termed Th9 cells, has been described in mice and humans with both tumour‐inhibiting as well as tumour‐promoting effects. The specific roles of Th9 cells in human HCC are not entirely understood. Here, we examined the frequencies and functions of IL ‐9‐producing Th9 cells in HCC patients. We found that the frequencies of circulating IL ‐9‐producing Th9 cells were significantly higher in HCC patients compared to in healthy individuals. In HCC patients, the frequencies of IL ‐9‐producing Th9 cells were significantly higher in peritumour and tumour tissues than in unaffected liver tissues. Interestingly, HCC patients with higher tumour‐infiltrating Th9 frequency had significantly shorter disease‐free survival period after resection. Previously, high expression of CCL 20 was associated with poor prognosis in HCC . CCL 20 also induced epithelial‐mesenchymal transition‐like changes in HCC cells. We found that incubation of primary HCC cells with autologous Th9 significantly elevated the CCL 20 production from tumour cells, which could be partially inhibited by suppressing STAT 3. Together, this study suggested a tumour‐promoting role of Th9 cells in HCC .     

Age Cohort Differences in Illicit Drug Use and Hepatitis C Among African American Substance Users

Identifying prognostic indicators for undiagnosed Hepatitis C is crucial to attenuate the negative impact of this disease. This study explored the influence of recent and more distal injection drug use on biologically confirmed Hepatitis C infection among a sample (N = 260) of older and younger African Americans. Data from the baseline assessment of the NEURO-HIV epidemiologic study was analyzed using confounder adjusted regression techniques. Older adults were more likely to test positive for Hepatitis C (OR = 2.80, 95% CI = 1.53–5.11) due to lifetime injection drug use (AOR = 5.37, 95% CI = 3.10–9.28). Clinical implications are discussed.     

The combination of sorafenib with transarterial chemoembolisation for hepatocellular carcinoma

Aliment Pharmacol Ther 2011; 34: 205–213

Summary

Background Standard of practice involves using transarterial therapy for multifocal hepatocellular carcinoma (HCC) alone and sorafenib only for more advanced HCC, but the sorafenib and transarterial therapy combination may provide greater efficacy. Aim To evaluate the safety and efficacy of concurrent sorafenib and transarterial therapy in HCC. Methods Consecutive cases of HCC were treated with sorafenib and transarterial therapy, receiving sorafenib 2 to 4 weeks before transarterial therapy. Baseline clinical parameters, adverse events (AEs) and survival were collected. Results A total of 47 patients received sorafenib and transarterial therapy. The majority of the patients were male (70%) with HCV (60%), median age of 60 years, good performance status (0–1), stable cirrhosis (Child: A 72%; B 28%), unresectable tumour (stage: B 81%; C 19%) and median AFP of 24 ng/mL. Median follow‐up was 12 months and median time on sorafenib was 6 months. LC Bead TACE was used with a median frequency of 3. The majority of the patients (89%) experienced AEs. The most common AEs were fatigue (51%), hand‐foot skin reaction (51%) and diarrhoea (43%). Grade 3 and 4 AEs included fatigue (13%) and hand‐foot skin reaction (26%). Most patients required a dose reduction (66%). The main AE related to transarterial therapy was post‐TACE syndrome (23%). The disease control rate was 68% at 6 months. Overall median survival rate was 18.5 months (95% CI 16.1–20.9 months). Conclusion Concurrent sorafenib and transarterial therapy is overall safe with no unexpected side effects and encouraging efficacy that warrants further study.     

Use of the AST to platelet ratio index in HCV/HIV co-infected patients

Aliment Pharmacol Ther 2011; 33: 566–577

Summary

Background The AST to platelet ratio index (APRI), a non‐invasive marker of liver fibrosis, has not been well studied in HCV/HIV (hepatitis C virus/human immunodeficiency virus) co‐infected patients with advanced HIV. Aim To compare the accuracy of APRI in HCV/HIV co‐infected patients to that in HCV mono‐infected patients and to determine the impact of CD4+ T‐cell counts on its performance. Methods We identified 106 consecutive HCV/HIV co‐infected patients and 105 matched HCV mono‐infected patients who underwent liver biopsy at Harborview Medical Center over a 5‐year period. Performance characteristics were calculated and receiver operating characteristic (ROC) analysis conducted. Results The area under the ROC curve (AUROC) of APRI for predicting significant fibrosis was similar when comparing those with and without HIV co‐infection (0.77 vs. 0.86, P = 0.18), but was lower in HIV co‐infected patients with CD4 counts <250 cells/mm³ (0.64 vs. 0.86, P = 0.05). In HIV co‐infected patients with CD4 counts ≥250, APRI had higher negative predictive value (93% vs. 88%, P = 0.57), positive predictive value (63% vs. 40%, P = 0.43) and specificity (95% vs. 88%, P = 0.05) than in those with lower CD4 counts. Conclusions The AST to platelet ratio index (APRI) performance characteristics appear to be suboptimal in HCV/HIV co‐infected patients with CD4 counts <250 and they require further study in this population at increased risk for advanced liver disease.     

Patterns of hepatocellular carcinoma development in hepatitis B virus and hepatitis C virus related cirrhosis.

To compare incidence, risk factors and morphologic pattern of hepatocellular carcinoma (HCC) development in hepatitis B virus (HBV) and hepatitis C virus (HCV) related cirrhosis, 401 patients were followed prospectively by periodic ultrasound examination for 14-189 months (mean: 84.8+/-36.7). During follow-up, 77 (19.2%) patients developed HCC, with 5 and 10 year cumulative incidence of 10 and 27.5%, respectively. The risk of HCC was significantly higher in HBV and HCV co-infected patients (P=0.014) compared to those with single HBsAg or anti-HCV (antibodies to hepatitis C virus) positivity. In anti-HCV positive cases the annual risk of HCC increased from 2% in the first 5 year period to 4% in the third 5 year period, while it decreased from 2 to 0% in the same time periods in the HBsAg positive group. By Cox's regression, age above 59 years (P=0.001), male sex (P=0.09), longer duration (P=0.04) and more advanced stage (P=0.01) of cirrhosis, lower platelets count (P=0.001) and higher ALT levels were significant risk factors for HCC in anti-HCV positive patients, while only high alpha-fetoprotein (AFP) levels during follow-up (P=0.04) was a significant risk factor for HCC in HBsAg positive cases. The pattern of HCC was nodular in 63 (81.8%) patients and infiltrating in 14 (18.2%), and the former type was associated with older age (P=0.0001), longer duration (P=0.002) and more advanced stage (P=0.0001) of cirrhosis but not with the viral etiology of disease. In contrast, development of infiltrating HCC was unrelated to age and disease duration and stage, and was associated with male sex (P=0.01), HBV infection (P=0.06) and HBV and HCV co-infection (P=0.0001). Our results indicate different incidence profile, risk factors and patterns of morphogenesis of HCC development in HBV and HCV associated cirrhosis, suggesting different mechanisms of carcinogenesis.     

Pre-operative transarterial chemoembolization for resectable hepatocellular carcinoma adversely affects post-operative patient outcome

Background  Long‐term outcomes after hepatic resection for hepatocellular carcinoma are not satisfactory because of high recurrence rates. Aim  To assess whether a single session of pre‐operative transarterial chemoembolization affects post‐operative outcome. Methods  We analysed outcomes retrospectively in 334 consecutive patients who underwent hepatic resection for hepatocellular carcinoma, initially judged resectable. Ninety‐seven of these patients had each undergone a single session of pre‐operative transarterial chemoembolization (transarterial chemoembolization + hepatic resection group), whereas 237 had not (hepatic resection group). Results  Most clinicopathological characteristics were similar in the two groups. The overall survival rate was significantly higher in the hepatic resection than in the transarterial chemoembolization + hepatic resection group (P = 0.011), whereas their disease‐free survival rates were comparable (P = 0.67). The overall and disease‐free survival rates of the transarterial chemoembolization + hepatic resection group with incomplete tumour necrosis were significantly lower than those of the hepatic resection group (P < 0.001 and P = 0.006, respectively). Multivariate analysis showed that pre‐operative transarterial chemoembolization, serum alpha‐fetoprotein elevation (>1000 ng/mL), tumour size (>5 cm) and vascular invasion were independent risk factors for poor overall survival after hepatic resection. Conclusions A single session of pre‐operative transarterial chemoembolization for initially resectable hepatocellular carcinoma worsens overall survival rate. It may also increase the risk of tumour recurrence in patients who achieve incomplete tumour necrosis.     

Giving rituximab in patients with occult or resolved hepatitis B virus infection: are the current guidelines good enough?

Introduction: Hepatitis B virus (HBV) reactivation after ‘resolved’ infection can occur in the setting of immunosuppression, including iatrogenically induced by anti-CD20 antibodies. The presence of antibodies against the HBV core antigen (anti-HBc) is a marker of risk for this phenomenon. The risk of this occurring in patients with circulating HBV surface antigen (HBsAg) is well characterized, but is less well characterized in patients who are HBsAg negative.

Areas covered: This article reviews the literature regarding HBV reactivation in the context of rituximab therapy. We have limited our review to HBsAg-negative patients, and clinical outcomes following HBV reactivation.

Expert opinion: We have recommended prophylactic anti-viral therapy for all HBsAg-negative/anti-HBc-positive patients undergoing rituximab therapy in combination with other immunosuppressive therapy.