Economic evaluation of sorafenib in the treatment of hepatocellular carcinoma in Canada

ABSTRACT

Background: A randomized phase III trial of sorafenib vs. placebo in hepatocellular carcinoma (HCC) demonstrated that sorafenib significantly prolonged overall survival (OS) compared to placebo.

Research design and methods: A Markov model was developed to evaluate the cost-effectiveness of sorafenib vs. best supportive care (BSC) in HCC from the perspective of the Canadian provincial Ministry of Health. The model followed survival and time to progression (TTP) in monthly cycles based on the extrapolation of patient level trial data. Health effects were expressed as life-years gained (LYG). Resource use included drugs, physician visits, laboratory tests, scans, and hospitalizations. Unit costs were gathered from public sources and were expressed in 2007 Canadian Dollars. Costs and effects were evaluated over a lifetime and discounted at 5%. Results were presented as mean ± standard deviation. Deterministic and probabilistic sensitivity analyses were conducted.

Results: LYG was longer for sorafenib (1.52 ± 0.16 vs. 1.03 ± 0.09 LYG/patient for sorafenib and BSC, respectively). The lifetime total costs were $47 511 ± 3 656 for sorafenib and $10 376 ± 1 649 for BSC, resulting in an incremental cost–effectiveness ratio (ICER) of $75 821/LYG, and deterministic ICER of $75 759/LYG. The results were most sensitive to OS, TTP and BSC costs after progression. Sensitivity analyses results showed that the model was robust.

Conclusions: The economic evaluation indicates that sorafenib is cost-effective as compared to BSC in HCC. Limitations include multiple data sources, use of expert opinion for resource use, and the lack of utility data.     

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.     

Safety and efficacy of sorafenib in hepatocellular carcinoma: the impact of the Child-Pugh score

Aliment Pharmacol Ther 2011; 34: 1193–1201

Summary

Background Sorafenib increases median survival and time to radiological progression in patients with advanced hepatocellular carcinoma, but its benefit for Child‐Pugh B patients remains uncertain. Aim To evaluate the safety and efficacy of sorafenib in real‐life clinical practice conditions and to assess the influence of Child‐Pugh class B on safety and efficacy. Methods All patients treated with sorafenib for advanced hepatocellular carcinoma in our institution were included prospectively. Adverse events, overall survival and time to progression were recorded. A case control study was performed to compare outcome of patients with comparable stages of hepatocellular carcinoma, but a different Child‐Pugh class. Results From March 2007 to May 2009, 120 patients were included. Overall survival was 11.1 months, Child‐Pugh A patients (n = 100) had significantly higher median survival than Child‐Pugh B patients (n = 20) (13 vs. 4.5 months, P = 0.0008). In multivariate analysis, Child‐Pugh class B, α‐fetoprotein level and total size of lesions were independent predictive factors of death. Patients with radiological progression in the first 3 months had shorter median survival (5.4 vs. 17.4 months). In a case control study, time to symptomatic progression (2.5 vs. 3.6 months), frequency of adverse events and discontinuation of sorafenib were not correlated with Child‐Pugh class. Conclusions Patients with advanced hepatocellular carcinoma treated with sorafenib had a median survival of 11 months. Sorafenib therapy must be considered with caution in Child‐Pugh B patients due to their poor survival. Radiological assessment of tumour progression at an early stage may be advantageous when tailoring sorafenib therapy.     

调强放疗联合索拉非尼治疗肝细胞癌合并门脉癌栓的疗效及预后因素分析#br#

摘要：目的　探讨调强放疗（IMRT）联合索拉非尼治疗肝细胞癌（HCC）合并门脉癌栓（PVTT）的疗效、安全性及预后影响因素。方法　纳入76例HCC合并PVTT的患者,根据治疗是否同步索拉非尼分为IMRT+索拉非尼组（30例）和单纯IMRT组（46例）。比较2组临床一般资料、生存结局、不良反应。Kaplan-Meier法测定2年累积生存（OS）率、无进展生存（PFS）率、无远处转移生存（DMFS）率并行Log-rank检验,单因素及多因素Cox模型分析预后影响因素。结果　IMRT+索拉非尼组与单纯IMRT组客观缓解率（ORR）分别为53.3%、43.5%（P＞0.05）。IMRT+索拉非尼组中位生存时间长于单纯IMRT组（12.0个月vs. 9.0个月）。IMRT+索拉非尼组与单纯IMRT组2年OS分别为23.8%和3.5%（Log-rank χ2=6.271,P=0.012）,2年PFS分别为7.5%和0（Log-rank χ2=6.205,P=0.013）,2年DMFS分别为9.5%和0（Log-rank χ2=4.346,P=0.037）。多因素分析显示,未同步索拉非尼、AST/ALT>1.26、肿瘤无反应均为影响HCC合并PVTT患者生存质量的独立危险因素（均P＜0.05）。2组不良反应发生率差异无统计学意义（P＞0.05）。结论　与单纯IMRT相比,IMRT同步索拉非尼改善了HCC合并PVTT患者的远期疗效,而未增加不良反应。AST/ALT<1.26、肿瘤有反应、IMRT同步索拉非尼的患者预后较好。     

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.     

Sorafenib versus cytotoxic chemotherapy for patients with advanced hepatocellular carcinoma: a retrospective,single-institution study

Background Prior to the 2008 advent of sorafenib, traditional cytotoxic agents were the therapeutic mainstay for patients with advanced hepatocellular carcinoma (HCC). We thus undertook a clinical study of sorafinib and conventional cytotoxic therapy for HCC, comparing efficacy and safety. Methods From January, 2002 to December, 2009, 173 patients with unresectable HCC were reviewed retrospectively. Among them, 44 (25.4%) had been treated with sorafenib, and the remainder had received cytotoxic therapy (CTX). We evaluated objective response rate (ORR), progression free survival (PFS), overall survival (OS), and toxicity profiles. Results Median OS of sorafinib was 23.0 weeks (95% CI, 8.1–37.9) vs 43.6 weeks (95% CI, 34.0–53.2) for CTX. Likewise, median PFS was 11.1 weeks (95% CI, 6.5–15.8) vs 12.4 weeks (95% CI, 8.1–16.7) for sorafenib and CTX, respectively. Neither parameter differed significantly (OS, p = 0.105; PFS, p = 0.496). ORR and disease control rate for sorafenib were 2.3% and 52.3% vs 6.2% and 43.4% for CTX. CTX-treated patients experienced more Grade 3/4 neutropenia (19.7% vs 0% for sorafenib), while sorafenib therapy was more often linked to dermatologic toxicities (all grades), such as hand-foot skin reaction, rash, and pruritus. Conclusion Although sorafenib has become the treatment of choice for advanced HCC, there are still unsettled issues regarding the optimal use of sorafenib. Our analysis indicates that conventional CTX can be another option of treatment for advanced HCC. To improve clinical outcomes, further prospective investigations which define the role of CTX are needed.     

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.     

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.     

A randomized phase II of gemcitabine and sorafenib versus sorafenib alone in patients with metastatic pancreatic cancer

Purpose Patients with metastatic pancreatic cancer have limited therapeutic options. The role of the Ras-Raf-MAPK pathway and of vascular endothelial growth factor in pancreatic carcinogenesis provided the rational to evaluate the efficacy of sorafenib with or without gemcitabine in a randomized phase II study. Methods Patients with metastatic pancreatic cancer were randomized to sorafenib alone (arm A) or sorafenib with gemcitabine (arm B). Results Arm A was closed to accrual at interim analysis due to the lack of objective response. Median PFS and OS were 2.3 and 4.3 months respectively. There was one partial response among the 37 patients in arm B. Median PFS and OS were 2.9 and 6.5 months respectively. There were more grade 3 and 4 toxicities in arm B with the most common being neutropenia (17%), thrombocytopenia (8%), alkaline phosphatase elevation (14%), venous thromboembolism (8%), diarrhea, hypokalemia and ALT elevation (5%) each. Several associations were noted between single nucleotide polymorphisms in ribonucleotide reductase, Cox-2, vascular endothelial growth factor and survival in patients treated with gemcitabine and sorafenib. Conclusions Neither sorafenib alone or sorafenib in combination with gemcitabine manifested promising activity in metastatic pancreatic cancer.     

Antiepidermal growth factor receptor monoclonal antibody improves survival outcomes in the treatment of patients with metastatic colorectal cancer

The aim of this study was to determine whether or not the addition of anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody (mAb) to standard chemotherapy or best supportive care (BSC), compared with chemotherapy or BSC alone, can improve overall survival (OS) and progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC), and evaluate the influence of KRAS mutant status on the efficacy of anti-EGFR mAb. Medline, Embase, the Cochrane controlled trials register, and the Science Citation Index were searched. Nine trials were identified, covering a total of 7941 patients. The treatment of mCRC with a combination of anti-EGFR mAb and chemotherapy or BSC, as compared with chemotherapy or BSC alone, improved the OS [hazard ratio (HR), 0.90 (0.84-0.96); P=0.002]. The benefit of anti-EGFR mAb in patients with KRAS wild-type tumors was apparent in relation to a marginal trend toward improved OS [HR, 0.84 (0.70-1.01); P=0.06], and significantly improved PFS [HR, 0.64 (0.51-0.81); P<0.001]. No benefit for the addition of anti-EGFR mAb was detected for any efficacy end-point in patients with KRAS mutant tumors. The summary HRs (anti-EGFR mAb vs control) were 0.98 (0.88-1.08) (P=0.71) for OS and 1.08 (0.94-1.25) (P=0.27) for PFS, respectively. In conclusion, this analysis provides confirmation that, compared with chemotherapy or BSC alone, anti-EGFR mAb with chemotherapy or BSC reduces the risk of progression and death of mCRC and that this benefit is seen only in patients with wild-type KRAS tumors.     

Comparative efficacy of brigatinib versus ceritinib and alectinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small cell lung cancer

Objective: Brigatinib, ceritinib, and alectinib are approved to treat crizotinib-refractory anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC), but no trial has compared them head-to-head. A matching-adjusted indirect comparison (MAIC) was conducted to estimate the relative efficacy of these agents in the crizotinib-refractory setting.

Methods: MAIC is a propensity score-type method that adjusts for differences in baseline characteristics between trials to estimate relative efficacy. Analyses were based on patient-level data from the ALTA trial for brigatinib and published summary-level trial data from ASCEND-1 and ASCEND-2 for ceritinib and NP28761 and NP28673 for alectinib. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared.

Results: After matching, all key baseline characteristics were balanced between trials. Compared with ceritinib, brigatinib was associated with longer PFS (ASCEND-1: median 15.7 vs 6.9 months, hazard ratio (HR) [95% confidence interval]?=?0.38 [0.26–0.57]; ASCEND-2: median?=?18.3 vs 7.2 months, HR?=?0.33 [0.20–0.56]) and OS (ASCEND-1: not available; ASCEND-2: median 27.6 vs 14.9 months, HR?=?0.33 [0.17–0.63]). Versus alectinib, brigatinib was associated with longer PFS (NP28761: median?=?17.6 vs 8.2 months, HR?=?0.56 [0.36–0.86]; NP28673: median?=?17.6 vs 8.9 months, HR?=?0.61 [0.40–0.93]); results for OS were inconclusive (NP28761: median?=?27.6 vs 22.7 months, HR?=?0.70 [0.42–1.16]; NP28673: median?=?27.6 vs 26.0 months, HR?=?0.66 [0.39–1.09]). ORR was similar.

Conclusion: In crizotinib-refractory ALK?+?NSCLC patients, relative efficacy estimates suggest brigatinib may have prolonged PFS and OS vs ceritinib and prolonged PFS vs alectinib.     

Race affects healing of erosive oesophagitis in patients treated with proton pump inhibitors

Aliment Pharmacol Ther 2011; 34: 487–493

Summary

Background Erosive oesophagitis appears to be more common in white vs. nonwhite patients with gastro‐oesophageal reflux disease (GERD). Aim To evaluate the association between race and erosive oesophagitis healing in patients with GERD treated with once‐daily proton pump inhibitors (PPIs). Methods Data from five double‐blind trials of once‐daily treatment with esomeprazole 40 mg vs. omeprazole 20 mg or lansoprazole 30 mg for erosive oesophagitis healing (evaluated at weeks 4 and 8 by endoscopy) were pooled and stratified by baseline race and Los Angeles (LA) severity grade. Multiple logistic regression models were fit with erosive oesophagitis healing (dependent variable) and race (independent variable), with adjustments for treatment, study, baseline LA grade, age, gender, BMI, Helicobacter pylori status, hiatal hernia and interactions of these factors with race. Results Of 11 027 patients, 91% were white. Nonwhite (n = 978) and black (n = 613) patients were less likely to have severe baseline erosive oesophagitis (LA grade C or D) than white patients [adjusted OR: 0.69 (95% CI, 0.61–0.79) and 0.67 (0.57–0.78), respectively; P < 0.0001]. At week 8, nonwhite and black patients had lower healing rates than white patients [OR: 0.75 (0.63–0.89) and 0.67 (0.54–0.83), respectively; P ≤ 0.001]. Greater odds of healing were associated with less severe baseline LA grade, increasing age, hiatal hernia, esomeprazole treatment (vs. lansoprazole or omeprazole) and lansoprazole treatment (vs. omeprazole) (all P ≤ 0.0009); no factor interacted significantly with race. Conclusions Nonwhite patients with GERD had less severe baseline erosive oesophagitis, but were less likely than white patients to have erosive oesophagitis healing after 8‐week PPI therapy.     

Evolution of prognostic factors in hepatocellular carcinoma in Japan

Aliment Pharmacol Ther 31 , 407–414

Summary

Background The surveillance of hepatocellular carcinoma (HCC) has become prevalent, and the modalities for its treatment have improved. Aim To understand the changes that occur in the characteristics and prognostic factors of HCC with time. Methods Newly diagnosed HCC patients were divided into two groups; patients treated before 31 December 2000 (n = 504), and after 1 January 2001 (n = 746), and their clinical backgrounds and prognostic factors were analysed. Results The number of patients negative for both Hepatitis B surface antigen (HBsAg) and Hepatitis C virus antibody (HCVAb) increased with time (NBNC‐HCC). The size of HCC decreased in patients who were positive for HBsAg (B‐HCC) or HCVAb (C‐HCC), whereas no difference was observed in NBNC‐HCC. The patient survival of C‐HCC improved; however, no difference was detected for NBNC‐HCC. In multivariate analysis, low albumin, high aspartate aminotransferase (AST), ascites, large tumour size, multiple tumour number and high alpha‐fetoprotein were risk factors for survival before 2000, whereas the presence of HBsAg was additionally selected as a good prognostic factor and AST was excluded after 2001. Conclusions The prognostic factors as well as clinical background of HCC changed with time, and the presence of HBsAg was found to be an additional good prognostic factor after 2001.     

Effects of metformin on clinical outcome in diabetic patients with advanced HCC receiving sorafenib

Background and objective: Several studies have reported an association between type 2 diabetes mellitus and hepatocellular carcinoma (HCC). Data from several retrospective studies and meta-analyses have highlighted a reduction of about 50% in the risk of developing HCC in cirrhotic patients treated with metformin for diabetes. The aim of this study was to evaluate the different outcomes of patients who received or did not receive metformin during treatment with sorafenib.

Methods: We analyzed 93 patients consecutively treated with sorafenib. Forty-two (45.2%) patients were diabetic, of whom 31 were on metformin. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and compared with the log-rank test.

Results: The concomitant use of sorafenib and metformin was associated with a median PFS of 2.6 months (95% CI 1.9–3.3) compared to 5.0 months (95% CI 2.5–8.2) for patients receiving sorafenib alone (p = 0.029). The median OS of patients treated with the combination was 10.4 months (95% CI 3.9–14.4) compared to 15.1 months (95% CI 11.7–17.8) for those who were not given metformin (p = 0.014).

Conclusions: Our findings could be the result of increased tumor aggressiveness and resistance to sorafenib in metformin-treated patients.     

Severe infusion reactions to infliximab: aetiology, immunogenicity and risk factors in patients with inflammatory bowel disease

Aliment Pharmacol Ther 2011; 34: 51–58

Summary

Background Infliximab (IFX) elicits acute severe infusion reactions in about 5% of patients with inflammatory bowel disease (IBD). Aim To investigate the role of anti‐IFX antibodies (Ab) and other risk factors. Methods The study included all IBD patients treated with IFX at a Danish university hospital until 2010 either continuously (IFX every 4–12 weeks) or episodically (reinitiation after >12 weeks). Anti‐IFX Ab were measured using radioimmunoassay. Results Twenty‐five (8%) of 315 patients experienced acute severe infusion reactions. Univariate analysis showed that patients who reacted were younger at the time of diagnosis (19 vs. 26 years, P = 0.013) and at first IFX infusion (28 vs. 35 years, P = 0.012). Furthermore, they more often received episodic therapy (72% vs. 31%, P < 0.001) and logistic regression revealed this as the only significant predictor of reactions (OR 5 [2–13]; P < 0.001). IFX reinitiation after 6 months intermission further increased the risk (OR 8 [3–20], P < 0.001). Most reactions (n = 14, 88%) occurred at 2nd infusion in the 2nd treatment series (P = 0.006). Anti‐IFX IgG Ab were highly positive in 19 of 20 patients (95%) shortly after the reactions (median 84 U/mL). Anti‐IFX IgG Ab measured prior to the retreatment series were negative in 7 of 11 patients tested (64%). Anti‐IFX IgE Ab were negative in all patients with reactions. Conclusions Acute severe infusion reactions were strongly associated with development of anti‐IFX IgG Ab, but not with anti‐IFX IgE Ab. The risk was particularly high at the 2nd infusion in retreatment series. Negative anti‐IFX Ab before reinitiation did not rule out reactions.     

The effects of sorafenib on the portal hypertensive syndrome in patients with liver cirrhosis and hepatocellular carcinoma--a pilot study

Aliment Pharmacol Ther 2012; 35: 83–91

Summary

Background Increased intrahepatic vascular resistance and hyperperfusion in the splanchnic circulation are the principal mechanisms leading to portal hypertension in cirrhosis. Several preclinical studies have demonstrated a beneficial effect of the multikinase inhibitor sorafenib on the portal hypertensive syndrome. Aim To investigate the effect of sorafenib on hepatic venous pressure gradient (HVPG), systemic hemodynamics and intrahepatic mRNA expression of proangiogenic, profibrogenic and proinflammatory genes. Methods Patients with liver fibrosis/cirrhosis and hepatocellular carcinoma were treated with sorafenib 400 mg b.d. HVPG measurement and transjugular liver biopsy were performed at baseline and at week 2. Changes in HVPG and intrahepatic mRNA expression of vascular endothelial growth factor (VEGF), platelet‐derived growth factor (PDGF), RhoA, tumour necrosis factor‐alpha (TNF‐α) and placental growth factor (PlGF) were evaluated. Results Thirteen patients (m/f = 12/1; Child–Pugh class A/B = 10/3) were included. The most common aetiology of liver disease was alcohol consumption (n = 7). Eleven patients had an elevated portal pressure, including eight patients with clinically significant portal hypertension. A significant decrease of HVPG (≥ 20% from baseline) was observed in four subjects. In HVPG responders, we observed mRNA downregulation of VEGF, PDGF, PlGF, RhoA kinase and TNF‐α, while no substantial mRNA decrease was found in nonresponders in any of the five genes. In two of the four HVPG responders we observed a dramatic (43–85%) mRNA decrease of all five investigated genes. Conclusion Larger controlled clinical trials are needed to demonstrate any potential beneficial effect of sorafenib on portal hypertension in patients with cirrhosis.     

Randomised clinical trial: efficacy of peginterferon alfa-2a in HBeAg positive chronic hepatitis B patients with lamivudine resistance

Aliment Pharmacol Ther 2011; 34: 424–431

Summary

Background Previous studies suggested that a finite course of peginterferon alfa‐2a may offer an alternative rescue therapy for patients with lamivudine resistance. However, because of the limitation of study design and small sample size, it is difficult to make definitive conclusion. Aim To explore the role of peginterferon alfa‐2a, in the rescue treatment of HBeAg‐positive chronic hepatitis B patients with lamivudine resistance. Methods In this randomised study, chronic hepatitis B patients with lamivudine resistance were treated with peginterferon alfa‐2a for 48 weeks (n = 155) or adefovir for 72 weeks (n = 80). All enrolled patients were treated with lamivudine for the first 12 weeks. Results At 6 months posttreatment, 14.6% (18/123) of peginterferon alfa‐2a‐treated patients achieved HBeAg seroconversion, in contrast to 3.8% (3/80) of adefovir‐treated patients after 72 weeks continuous therapy (P = 0.01). For peginterferon alfa‐2a‐treated patients, the rate of HBeAg seroconversion at week 72 was significantly higher in patients who had HBsAg decline >0.5 Log₁₀ IU/mL from baseline at week 24, compared with patients with HBsAg decline ≤0.5 Log₁₀ IU/mL from baseline at week 24 (25.5% vs. 7.7%, P = 0.01). After 72 weeks continuous adefovir treatment, 22.5% of patients achieved HBV DNA <80 IU/mL, compared with 10.6% in peginterferon alfa‐2a‐treated patients at 6 months off‐treatment (P = 0.02). Conclusions Overall, the response to peginterferon alfa‐2a among patients with lamivudine resistance was suboptimal. HBeAg seroconversion rate at week 72 by 48 weeks peginterferon alfa‐2a treatment was higher than continuous adefovir therapy. Monitoring HBsAg levels can help to predict response to peginterferon alfa‐2a.     

Antihypertensive efficacy of indapamide SR in hypertensive patients uncontrolled with a background therapy: the NATIVE study*

ABSTRACT

Objectives: Antihypertensive monotherapy rarely achieves blood pressure (BP) control. NATIVE (NATrilix SR use in combInation antihypertensiVe thErapy) evaluated indapamide sustained release (SR) in hypertensive patients receiving background therapy.

Research design and methods: Patients remaining hypertensive (systolic BP [SBP], 145–180?mmHg; diastolic BP [DBP], 95–105?mmHg) while receiving an angiotensin-converting enzyme (ACE) inhibitor (n = 709), β-blocker (n = 629), calcium-channel blocker (CCB; n = 493), angiotensin II type 1 receptor blocker (ARB; n = 75), α-blocker (n = 29) or other therapy (n = 6) were enrolled, recruited by physicians from 228 centres in Pakistan. Indapamide SR 1.5?mg was administered daily for 3 months with background therapy. BP was assessed every 2 weeks, and blood glucose and total cholesterol were evaluated at baseline and study end in a patient subgroup. Adverse events were also recorded.

Main outcome measures and results: Of 2073 enrolled patients (49% males; mean age 51 years), 1941 received indapamide SR and background therapy. SBP and DBP decreased significantly (SBP, 166 ± 16?mmHg at baseline vs. 132 ± 12?mmHg at 3 months; DBP, 102 ± 8?mmHg vs. 83 ± 6?mmHg; both p < 0.0001 vs. baseline). Patients uncontrolled with an ACE inhibitor, β-blocker, CCB or ARB achieved an SBP/DBP decrease of 34 ± 15/19 ± 9, 33 ± 17/19 ± 10, 33 ± 15/18 ± 8 or 35 ± 16/20 ± 12?mmHg, respectively (all p < 0.0001). In all, 84% of patients achieved target SBP (≤?140?mmHg) and 61% achieved BP normalisation (SBP <?140, DBP <?90?mmHg). The absence of placebo control may lead to an overestimation of the extent of the BP reduction achieved. Glucose and cholesterol levels were unaffected by indapamide SR. Four percent of patients experienced side-effects, which were mild-to-moderate in severity.

Conclusions: In patients with hypertension despite antihypertensive therapy, indapamide SR significantly reduced BP with a good acceptability profile. Indapamide SR may represent an effective additional therapy for patients who do not achieve BP goals with other antihypertensive agents.     

Meta-analysis: Treatment of hepatitis B infection reduces risk of hepatocellular carcinoma

Background Chronic hepatitis B (CHB) infection leads to development of hepatocellular carcinoma (HCC), but the effects of treatment in preventing HCC are not clear. Aim To study the effects of interferon (IFN) or nucleoside/tide analogue (NA) on the risk of developing HCC in CHB patients. Methods Randomized trials, case–control and cohort studies were retrieved from five electronic databases and international conferences over the past 10 years. Relative risks (RRs) of HCC with or without treatment were studied. Results Twelve studies (n = 2742) enrolling patients treated by IFN vs. control showed that the risk of HCC after treatment was reduced by 34% (RR: 0.66, 95% CI: 0.48–0.89). Benefit is more significant among patients with early cirrhosis than among those without cirrhosis. Five studies (n = 2289) compared patients treated by NA with control. The risk of HCC after treatment was reduced by 78% (RR: 0.22, 95% CI: 0.10–0.50). HBeAg‐positive patients showed more significantly reduced HCC risk with treatment. Patients without cirrhosis benefited more from NA than those with cirrhosis. Resistance to NA has obviated the benefit of the treatment. Conclusions IFN or NA treatment significantly reduces risk of HCC. While IFN benefited patients with cirrhosis, NA benefited patients with no cirrhosis and HBeAg‐positive CHB infection.     

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.