ePTFE-TIPS vs repetitive LVP plus albumin for the treatment of refractory ascites in patients with cirrhosis.

BACKGROUND & AIMS: Reduction in portal pressure by self-expandable polytetrafluoroethylene (ePTFE)-covered transjugular intrahepatic portosystemic shunts (TIPS) is a treatment option for refractory ascites. Data on clinical outcomes after ePTFE-TIPS vs repetitive large-volume paracentesis (LVP) plus albumin (A) administration for the treatment of patients with refractory ascites are limited. METHODS: Retrospective comparison of ePTFE-TIPS vs LVP+A in terms of (i) control of ascites, (ii) occurrence of overt hepatic encephalopathy (HE) and (iii) transplant-free survival in cirrhotic patients with refractory ascites. RESULTS: Among n = 221 patients with cirrhosis and refractory ascites, n = 140 received ePTFE-TIPS and were compared to n = 71 patients undergoing repetitive LVP+A. After ePTFE-TIPS, ascites was controlled without any further need for paracentesis in n = 76 (54%; n = 7 without and n = 69 with diuretics). The need for frequent large-volume paracentesis was significantly higher in the LVP+A group than with ePTFE-TIPS (median 0.67 (IQR: 0.23-2.63) months vs 49.5 (IQR: 5.07-102.60) months until paracentesis, log-rank P < .001). De-novo incidence of HE was similar in ePTFE-TIPS and LVP+A patients (log-rank P = .361). Implantation of ePTFE-TIPS was associated with improved 1-year survival as compared to LVP+A (65.6% vs 48.4%, log-rank P = .033). Age (odds ratio (OR):1.05; 95% confidence interval (95% CI):1.03-1.07; P < .001), serum albumin (OR: 0.95; 95% CI: 0.92-0.99; P = .013) and hepatocellular carcinoma (OR: 1.66; 95% CI: 1.06-2.58; P = .026) emerged as independent predictors of survival. CONCLUSIONS: ePTFE-TIPS results in superior control of ascites without increasing the risk for overt HE as compared to LVP+A. Although ePTFE-TIPS improved 1-year survival in cirrhotic patients with refractory ascites, its use was not independently associated with transplant-free survival.

Response-guided boceprevir-based triple therapy in HIV/HCV-coinfected patients: the HIVCOBOC-RGT study.

BACKGROUND: The HIVCOBOC-RGT study (NCT01925183) was the first study to evaluate response-guided shortening of the duration of boceprevir (BOC)-based triple therapy in human immunodeficiency virus (HIV)/hepatitis C virus genotype 1-coinfected patients (HIV/HCV-GT1). METHODS: After 4 weeks of pegylated interferon-α-2a/ribavirin (PEGIFN/RBV) lead-in, patients with target-not-detectable HCV-RNA at week 8 (rapid virologic response; LI4W-W8UTND) received 24 weeks of BOC/PEGIFN/RBV (total: 28 weeks [W28]). Patients with target-detectable HCV-RNA at week 8 received 44 weeks of BOC/PEGIFN/RBV (total: 48 weeks [W48]). RESULTS: Fourteen patients (67%) had LI4W-W8UTND and were eligible for the shortened W28 arm, while 7 (33%) patients were allocated to the W48 arm. No breakthrough or relapse occurred in the W28 arm, resulting in a sustained virologic response (SVR12TND) rate of 100% (12/12). In the W48 arm, the SVR12TND was 50% (3/6), with 3 patients meeting the futility rule at treatment week 12. The preliminary overall SVR12TND rate was 83% (15/18). Serious adverse events were observed in 5 (24%) patients, with 2 (10%) patients requiring surgical treatment of abscesses. CONCLUSIONS: The majority of HIV/HCV-GT1 were eligible for response-guided shortening of treatment duration to W28 and all of these patients had a SVR12TND. If second-generation direct-acting antivirals are not available, W28 of BOC-based triple therapy may be recommended.

Health-related quality of life and severity of fatigue in HIV/HCV co-infected patients before, during, and after antiviral therapy with pegylated interferon plus ribavirin.

UNLABELLED: The aim of this study was to prospectively assess health-related quality of life (HRQL) and severity of fatigue before, during and after antiviral therapy in HIV/HCV co-infected patients. DESIGN: 59 HIV/HCV co-infected patients receiving pegylated interferon plus ribavirin (PEGIFN+RBV) in the HIVCOPEG study were included in this substudy evaluating the secondary endpoints HRQL and severity of fatigue. METHODS: HRQL and severity of fatigue were assessed using SF36 and FSS, respectively. Advanced liver fibrosis was defined as METAVIR F3/F4 or liver stiffness >9.5 kPa. RESULTS: At baseline, advanced liver fibrosis was associated with worse physical health. Mental health was impaired in female patients and in patients with a history of intravenous drug abuse, while a history of depression was associated with higher severity of fatigue. Female gender was associated with a more pronounced relative decrease in mental health during therapy. At follow-up, 24 weeks after the end of therapy, both physical health and fatigue symptoms had improved. Virological response was associated with better physical and mental health, as well as with reduced severity of fatigue. A correlation between anemia grade and the relative impairments in physical health, mental health and fatigue was observed. CONCLUSIONS: Antiviral therapy with PEGIFN+RBV impairs physical and mental health and increases severity of fatigue, while virological response is associated with improvements in physical health and fatigue symptoms. The optimization of anemia management is essential for reducing the burden of impaired HRQL and fatigue in HIV/HCV co-infected patients receiving antiviral therapy with PEGIFN+RBV.

IL28B and interferon-gamma inducible protein 10 for prediction of rapid virologic response and sustained virologic response in HIV-HCV-coinfected patients.

BACKGROUND: A polymorphism near the IL28B gene has been shown to be associated with virologic response to antiviral treatment in HCV-infected patients. The predictive value of interferon-gamma inducible protein 10 (IP10) on treatment outcome has been described in HCV patients. Data on combining these predictors in HIV-HCV-coinfected patients are not available. METHODS: Virologic parameters, IL28B single nucleotide polymorphisms (SNP) and pretreatment serum IP10 were determined in HIV-HCV-coinfected patients having completed antiviral therapy with pegylated interferon/ribavirin. RESULTS: A total of 72 HIV-HCV-coinfected patients were included in the study; 68% had HCV genotype (GT)-1/4 and 32% had HCV GT-2/3 infections. Rapid virologic response (63% vs. 28%; P = 0·023) and sustained virologic response (SVR: 81% vs. 51%; P = 0·008) rates were significantly higher in C/C vs. non-C/C patients. Patients with low pretreatment IP10 levels (< 400 pg/mL) achieved significantly higher SVR rates than patients with high (> 400 pg/mL) IP10 levels (78% vs. 13%; P < 0·0001). C/C SNP and low IP10 levels were associated with higher SVR rates in both patients with GT-1/4 and GT-2/3. The C/C patients with low IP10 achieved SVR rates of 97% compared with SVR rates of 9% in non-C/C patients with high IP10. CONCLUSION: The IL28B SNP influences rapid viral response, relapse rates and SVR. The combination of IL28B and IP10 represents a predictive model of SVR in HIV-HCV coinfection.

Low-dose peginterferon alfa-2a is safe and produces a sustained virologic response in patients with chronic hepatitis C and end-stage renal disease.

BACKGROUND & AIMS: Chronic hepatitis C increases mortality of patients with end-stage renal disease (ESRD). Ribavirin is not recommended for patients with renal dysfunction; peginterferon monotherapy is the most appropriate treatment for chronic hepatitis C in such patients. We evaluated the efficacy and safety of 2 dosages of peginterferon alfa-2a (40 kDa) in patients with chronic hepatitis C and ESRD on hemodialysis. METHODS: We performed a randomized, multicenter, open-label clinical study of 85 patients with chronic hepatitis C and ESRD who were receiving hemodialysis at specialist outpatient hepatology clinics. Patients were treated with subcutaneous peginterferon alfa-2a (40 kDa) at dosages of 135 or 90 µg/wk for 48 weeks. RESULTS: The incidences of overall sustained virologic responses (SVRs) (undetectable hepatitis C virus [HCV] RNA [<50 IU/mL] after 24 weeks of untreated follow-up) were 39.5% (15/38) in the 135 µg/wk group and 34.9% (15/43) in the 90 µg/wk group (odds ratio, 1.22; 95% confidence interval, 0.49-3.06; P = .67). Among patients with undetectable HCV RNA at week 12, 60.9% (14/23) of those in the 135 µg/wk group and 87.5% (14/16) of those in the 90 µg/wk group achieved an SVR. Therapy was well-tolerated with no new safety concerns. The most common adverse events (>10% of patients in at least 1 treatment group) included conditions associated with ESRD (anemia and hypertension) and with interferon treatment. CONCLUSIONS: Forty-eight weeks of treatment with low-dose peginterferon alfa-2a (40 kDa) is safe and produces an SVR in 35%-40% of patients with chronic hepatitis C and ESRD on hemodialysis.

Portal pressure predicts outcome and safety of antiviral therapy in cirrhotic patients with hepatitis C virus infection.

BACKGROUND & AIMS: There are limited data on the efficacy and safety of antiviral therapy in patients with hepatitis C virus (HCV)-related cirrhosis, particularly on the impact of portal hypertension. METHODS: We assessed hepatovenous pressure gradient (HVPG), liver stiffness (transient elastography), and interleukin (IL)-28B polymorphisms (rs12979860) in 90 cirrhotic patients with HCV infection (82% genotype 1 or 4) before antiviral therapy with pegylated interferon and ribavirin. Efficacy and safety were evaluated. RESULTS: Rates of sustained virologic response were significantly lower among patients with clinically significant portal hypertension (CSPH; HVPG ≥ 10 mm Hg; n = 50) than among patients without CSPH (HVPG <10 mm Hg; n = 40): 14% vs 51% (P = .0007). Seventy-nine percent and 83% of patients with CSPH and without CSPH, respectively, received more than 80% of planned dose (P = .647). The predictive value of HVPG (area under the curve [AUC], 0.743) was greater than that of liver stiffness (AUC, 0.647) or of baseline HCV RNA levels (AUC, 0.620). The IL-28B polymorphism was not associated significantly with a sustained virologic response. Multivariate analysis revealed that HVPG (odds ratio [OR], 14.3; P = .009), baseline HCV RNA levels (OR, 5.3; P = .019), and HCV genotype (OR, 6.5; P = .046) were independent risk factors for treatment failure. A trend toward higher incidence of anemia and neutropenia was observed for patients with CSPH. The incidence and grade of thrombocytopenia were significantly higher among patients with than without CSPH (94% vs 75%; P = .006). CONCLUSIONS: HVPG is an independent predictor of response to antiviral therapy, with better predictive value than liver stiffness, baseline HCV RNA levels, HCV genotype, or IL-28B polymorphism. The incidence and grade of thrombocytopenia during antiviral therapy are higher among patients with CSPH. In evaluating cirrhotic HCV patients for antiviral treatment, measurement of HVPG should be considered.

Mitochondrial toxicity is associated with virological response in patients with HIV and hepatitis C virus coinfection treated with ribavirin and highly active antiretroviral therapy.

The combination of highly active antiretroviral therapy (HAART) plus ribavirin (RBV) in patients with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection has been reported to cause mitochondrial toxicity (MT). Sixty-four patients with HIV-HCV coinfection who were receiving antiviral therapy were evaluated for MT. Patients with concomitant HAART showed greater increases in lactate levels than did patients without HAART, and this difference was more pronounced in patients who received higher dosages of RBV. The incidence of pancreatic enzyme elevations and symptomatic pancreatitis was higher among patients who received HAART and high-dose RBV. Hepatic steatosis increased in patients who received HAART and high-dose RBV. Patients who showed signs of MT achieved higher rates of sustained virologic response than did patients without MT (73% vs 44%).

IP-10 correlates with hepatitis C viral load, hepatic inflammation and fibrosis and predicts hepatitis C virus relapse or non-response in HIV-HCV coinfection.

BACKGROUND: Interferon (IFN)-gamma inducible protein 10 (IP-10) is increased in hepatitis C virus (HCV) monoinfection, correlates with hepatic inflammation and predicts non-response (NR) to antiviral therapy. We aimed to clarify the role of IP-10 in HIV-HCV coinfection. METHODS: Serum IP-10 levels of 30 HIV-HCV-coinfected patients treated with pegylated (PEG)-IFN-alpha2a (180 microg/week) and ribavirin (800-1,200 mg/day) were measured at baseline and 24 h after first IFN dose. The predictive value of IP-10 was compared with established markers of treatment outcome by applying a multivariate logistic regression model. RESULTS: Patients with NR (476 +/- 156 pg/ml) or virological relapse (508 +/- 298 pg/ml) had significantly higher baseline IP-10 levels compared with patients who had a sustained virological response (SVR; 293 +/- 97 pg/ml, P = 0.001). The IFN-induced increase of IP-10 was significantly stronger in patients with an SVR (P = 0.017). IP-10 levels were associated with HCV viral load, alanine aminotransferase (ALT) levels, hepatic inflammatory activity and fibrosis stage. Advanced fibrosis, high HCV viral load, hepatovenous pressure gradient and pretreatment IP-10 > 400 pg/ml predicted NR to antiviral therapy. In the multivariate analysis, IP-10 was identified as the strongest baseline predictor of SVR with a specificity and sensitivity of 83.4% and 92.9%, respectively. CONCLUSIONS: Pretreatment IP-10 levels correlated with HCV viral load, ALT levels, hepatic inflammation and fibrosis. An IP-10 cutoff level of 400 pg/ml might serve as a useful predictive marker for anti-HCV therapy in HIV-HCV-coinfected patients because it could discriminate patients with expected NR or HCV relapse after therapy from patients with an SVR before starting antiviral treatment.

Antiviral therapy decreases GpIIb/IIIa activation of platelets in patients with chronic hepatitis C.

Interferon alpha (IFN-alpha) is used to treat haematological and solid malignancies and is the gold standard therapy for chronic hepatitis C infection in combination with ribavirin. It has a well known platelet lowering effect and was recently shown to impair platelet aggregation in the presence of various agonists and has been accused to increase patients' bleeding risk during IFN-alpha therapy. Thus, we hypothesised that antiviral treatment decreases GpIIb/IIIa activation and affects global platelet function. In a prospective clinical trial, we examined the effects of combination therapy with pegylated IFN-alpha 2a (PegIFN-alpha 2a) and ribavirin on platelet GpIIb/IIIa activation and platelet secretion in 20 patients with chronic hepatitis C at week 2, 4, 8 and 12 after the beginning of therapy. In addition, we determined global platelet function (CEPI-CT) with the PFA-100 and vWF-Ag levels. Antiviral therapy significantly decreased GpIIb/IIIa activation in a time dependent manner, whereas markers of platelet secretion (P-selectin, beta-thromboglobulin) remained unchanged. Despite a marked elevation of vWF-Ag levels, CEPI-CT did not change compared to baseline levels. Antiviral therapy significantly decreases GpIIb/IIIa activation in patients with chronic hepatitis C, while vWG-Antigen levels are markedly increased and alpha-granule secretion is not affected. This does not result in an alteration of global platelet function as assessed by the PFA-100, because elevated vWF-Antigen levels might compensate for the acquired defect.

Treatment intensification with boceprevir in HIV-positive patients with acute HCV-genotype 1 infection at high risk for treatment failure.

BACKGROUND: According to current guidelines, the universal use of direct-acting antiviral agents in HIV-positive patients with acute hepatitis C (AHC) is not recommended. We aimed to evaluate the concept of treatment intensification with boceprevir (BOC) in HIV-positive patients with HCV-genotype 1 AHC (HIV/AHC-GT1) at high risk for failure to pegylated interferon/ribavirin therapy (PEGIFN/RBV). METHODS: Nineteen consecutive HIV-positive patients with HIV/AHC-GT1 who underwent antiviral therapy were studied retrospectively. Patients were treated with PEGIFN/RBV for 24 or 48 weeks, depending on rapid virologic response (RVR; undetectable HCV-RNA at treatment week [W] 4). Patients without complete early virologic response (cEVR; undetectable HCV-RNA at W 12) were offered treatment intensification with BOC at W 12, resulting in 36 weeks of BOC/PEGIFN/RBV triple therapy (total treatment duration: 48 weeks). RESULTS: Thirty-seven percent (7/19) of patients had an RVR and 74 % (14/19) of patients had a cEVR. BOC was used in four out of five patients who did not achieve cEVR and one patient elected to proceed with PEGIFN/RBV. Sustained virologic response (SVR; undetectable HCV-RNA 24 weeks after the end of treatment) rates were 100 % (14/14) among patients with cEVR treated with PEGIFN/RBV and 75 % (3/4) among patients without cEVR receiving BOC add-on. The patient without cEVR who preferred to continue with PEGIFN/RBV did not achieve SVR. Thus, the overall SVR rate was 89 % (17/19) in intention to treat analysis. CONCLUSIONS: BOC add-on in selected HIV/AHC-GT1 resulted in a high overall SVR rate. If 2nd generation direct-acting antiviral agents (DAAs) are not available, treatment intensification with BOC can be considered in HIV/AHC-GT1 at high risk for failure to PEGIFN/RBV.

Strategies for assignment of HIV-HCV genotype-1-coinfected patients to either dual-therapy or direct-acting antiviral agent-based triple-therapy.

BACKGROUND: The aim of this study was to evaluate strategies for assignment of HIV-HCV genotype-1-coinfected patients (HIV-HCV-GT1) to either dual-therapy or direct-acting antiviral agent (DAA)-based triple-therapy. METHODS: A total of 148 treatment-naive HIV-HCV-GT1 who received antiviral therapy with pegylated interferon/ribavirin were included in this multinational, retrospective analysis. Patients with rapid virological response (RVR) were treated for 48 weeks, while patients without RVR received either 48 or 72 weeks of treatment. IL28B rs12979860 (IL28B) non-C/C, advanced liver fibrosis and high HCV RNA were considered as established risk factors for treatment failure. RESULTS: A trend toward higher sustained virological response (SVR) rates in patients with IL28B C/C (65% [37/57] versus 51% [40/79]; P=0.097) was observed. Higher SVR rates were observed in patients without advanced liver fibrosis (61% [47/77] versus 42% [22/52]); P=0.036) and without high HCV RNA (73% [35/48] versus 49% [49/100]; P=0.006), as well as in patients with RVR (90% [35/39] versus 45% [49/109]; P<0.001). SVR rates varied statistically significantly between the risk factors for treatment failure subgroups (86% [6/7] versus 69% [34/49] versus 48% [21/44] versus 20% [4/20] for zero, one, two and three risk factors, respectively; P<0.001). In patients without RVR, higher rates of SVR were observed in those treated for 72 weeks (62% [23/37]), when compared to patients treated for 48 weeks (36% [26/72]; P=0.01). CONCLUSIONS: RVR had an excellent positive predictive value for the response to dual-therapy in HIV-HCV-GT1, emphasizing the utility of a lead-in phase for assigning these patients to dual-therapy or DAA-based triple-therapy. The use of an IL28B-guided approach was suboptimal, while a combination of established baseline predictors may provide guidance for individual treatment decisions prior to the initiation of antiviral therapy. However, the extension of treatment duration to 72 weeks in HIV-HCV-GT1 without RVR should be strongly considered if triple-therapy is not available.

Variation in both IL28B and KIR2DS3 genes influence pegylated interferon and ribavirin hepatitis C treatment outcome in HIV-1 co-infection.

Pegylated-IFN and ribavirin remains the current treatment for chronic HCV infection in patients co-infected with HIV-1, but this regimen has low efficacy rates, particularly for HCV genotype 1/4 infection, has severe side effects and is extremely costly. Therefore, accurate prediction of treatment response is urgently required. We have recently shown that the NK cell gene, KIR2DS3 and a SNP associated with the IL28B gene synergise to increase the risk of chronic infection in primary HCV mono-infected patients. Identification of SNPs associated with the IL28B gene has also proven very powerful for predicting patient response to treatment. Patients co-infected with HIV-1 are of particular concern given they respond less well to HCV treatment, have more side effects and suffer a more rapid liver disease progression. In this study, we examined both IL28B and KIR2DS3 for their ability to predict treatment response in a cohort of HIV-1/HCV co-infected patients attending two treatment centres in Europe. We found that variation in both host genetic risk factors, IL28B and KIR2DS3, was strongly associated with sustained virological response (SVR) to treatment in our co-infected cohort (n = 149). The majority of patients who achieved a rapid virological response (RVR) achieved a SVR. However, it is currently impossible to predict treatment outcome in patients who fail to achieve an RVR. In our cohort, the presence of host genetic risk factors, IL28B-T and KIR2DS3 alleles, resulted in increased odds of treatment failure in these RVR negative patients (n = 88). Our data suggests that testing for host genetic factors will improve predicting treatment responsiveness in the clinical management of co-infected patients, and provides further evidence of the importance of the innate immune system in the immune response to HCV.

Low vitamin D levels are associated with impaired virologic response to PEGIFN + RBV therapy in HIV-hepatitis C virus coinfected patients.

BACKGROUND: Low 25-hydroxyvitamin D [25(OH)D] levels are commonly found in HIV-hepatitis C virus (HCV) coinfected patients and are associated with liver fibrosis. No association between 25(OH)D levels and response to pegylated interferon α-2a/2b plus ribavirin (PEGIFN + RBV) has yet been reported for HIV-HCV coinfected patients. DESIGN: Epidemiological characteristics, HIV and HCV infection parameters, liver biopsies, as well as data on virologic response was available in 65 patients who received chronic hepatitis C (CHC) therapy with PEGIFN + RBV within a prospective trial. 25(OH)D levels were retrospectively assessed using stored screening serum samples obtained within 35 days prior to CHC treatment. METHODS: According to their 25(OH)D levels, patients were assigned to the normal (>30 ng/ml; D-NORM), the insufficiency (10-30 ng/ml; D-INSUFF), or the deficiency (<10 ng/ml; D-DEF) group. HCV-GT 1/4, high HCV-RNA load (>6 × 10 IU/ml), advanced liver fibrosis (METAVIR F3/F4), and IL28B rs12979860non-C/C were considered as established risk factors for treatment failure in HIV-HCV coinfected patients. RESULTS: Thirty-seven (57%) and 15 (23%) patients presented with D-INSUFF and D-DEF, respectively, whereas only 13 (20%) patients had normal 25(OH)D levels. Substantial differences in cEVR (D-NORM 92% vs. D-INSUFF 68% vs. D-DEF 47%; P = 0.008) and SVR (D-NORM 85% vs. D-INSUFF 60% vs. D-DEF 40%; P = 0.029) rates were observed between 25(OH)D subgroups. Especially in difficult-to-treat patients with multiple (three to four) established risk factors, low 25(OH)D levels were clearly associated with lower rates of SVR [patients without 25(OH)D deficiency 52% vs. D-DEF 0%; P = 0.012]. CONCLUSION: Low 25(OH)D levels may impair virologic response to PEGIFN + RBV therapy, especially in difficult-to-treat patients. Vitamin D supplementation should be considered and evaluated prospectively in HIV-HCV coinfected patients receiving CHC treatment.

A prospective evaluation of pulmonary, systemic and hepatic haemodynamics in HIV-HCV-coinfected patients before and after antiviral therapy with pegylated interferon and ribavirin.

BACKGROUND: Patients coinfected with HIV and HCV are at risk for developing portal hypertension (PHT), hyperdynamic circulation and pulmonary arterial hypertension (PAH). Data on the influence of antiviral therapy with pegylated interferon-α (PEG-IFN-α) and ribavirin (RBV) are limited. METHODS: Haemodynamic parameters, including hepatic venous pressure gradient (HVPG), pulmonary arterial pressure (PAP(mean)), cardiac output (CO) and systemic vascular resistance (SysVR), were prospectively evaluated before and after PEG-IFN-α+RBV therapy in 80 HIV-HCV-coinfected patients. RESULTS: Baseline evaluation showed a mean HVPG of 4.7 mmHg, CO of 6.15 l/min and PAP(mean) of 14.8 mmHg. PHT was present in 26% of patients, hyperdynamic circulation in 5% and PAH in 4%. Patients with advanced fibrosis (METAVIR stage F3/F4; n=32) had significantly higher CO (P=0.008), lower SysVR (P=0.035), higher PAP(mean) (P=0.018) and higher pulmonary vascular resistance (P=0.022) than patients with stage F0-F2 fibrosis (n=48). Both hyperdynamic circulation and PAH were significantly associated with liver stiffness, fibrosis stage and portal pressure; a non-significant trend was found for CD4(+) T-cell counts and HIV RNA levels. No significant changes in PAP(mean), CO and SysVR were observed after PEG-IFN-α+RBV treatment, although a significant decrease in HVPG was noted in patients with HCV eradication (P=0.013). CONCLUSIONS: The overall prevalence of hyperdynamic circulation and PAH in HIV-HCV coinfection is low. Advanced fibrosis, increased liver stiffness, elevated portal pressure and probably CD4(+) T-cell count and HIV viraemia represent risk factors for hyperdynamic circulation and PAH. PHT is present in 26% of HIV-HCV-coinfected patients evaluated for antiviral therapy. Successful HCV eradication significantly decreases HVPG.

Management of adverse effects of Peg-IFN and ribavirin therapy for hepatitis C.

HCV infects approximately 2-3% of the global population and is a leading cause of end-stage liver disease and hepatocellular carcinoma. Treatment of HCV infection with Peg-IFN in combination with ribavirin can eradicate HCV infection in 40-90% of patients; however, a major barrier to treatment uptake and delivery is the association of this therapy with frequent and, at times, serious adverse effects. Recognition and effective management of these adverse effects are critical components of the successful treatment of chronic HCV infection. In clinical trials, approximately 10-15% of patients discontinue Peg-IFN and ribavirin therapy due to adverse effects; however, in clinical practice, the rate of treatment discontinuation has been reported to be substantially higher. The off-target effect of Peg-IFN and ribavirin impacts most, if not all, organ systems; the most common adverse effects are hematologic, dermatologic, neurologic, immunologic, gastrointestinal, pulmonary, cardiovascular, and ocular. Regional and global variability exists in the nature of these adverse effects and the strategies employed to ameliorate their impact. This article provides a comprehensive literature review that systematically describes the adverse effects of Peg-IFN-α and ribavirin on various organ systems and, more importantly, recommends consensus approaches to managing those effects.

Erythropoietin treatment is associated with more severe thrombocytopenia in patients with chronic hepatitis C undergoing antiviral therapy.

BACKGROUND: Erythropoietin (EPO) not only stimulates erythropoiesis but also thrombopoiesis. As pegylated-interferon-alpha(PEG-IFN-alpha)-induced thrombocytopenia may become a limiting factor for continuation of therapy, the present study investigated if EPO can alleviate PEG-IFN-alpha induced thrombocytopenia. Further, we hypothesize that EPO increases platelet reactivity and protease activated receptor 1 (PAR-1) expression during combination antiviral therapy. METHODS: Forty patients with chronic hepatitis C received either 10,000 IU EPO 3 x/week or placebo in a randomized, placebo-controlled, double-blinded fashion for 4 wk and combination antiviral therapy with PEG-IFN-2a and ribavirin. RESULTS: EPO alleviated the decrease in hemoglobin during combination antiviral therapy with ribavirin (10%vs 20%, p < 0.0001). Platelet counts decreased stronger in EPO than in placebo group on day 28 (p= 0.007). EPO induced a 40% increase in PAR-1 (p < 0.0001), which was accompanied by 100% increase in platelet reactivity (p < 0.0001). PFA-100 platelet plug formation time and PEG-IFN-alpha-induced vWF-increase were not different between study groups. CONCLUSIONS: Treatment with EPO alleviated the decrease in hemoglobin but worsened PEG-IFN-alpha induced thrombocytopenia after the first 4 wk of combination therapy. EPO caused PAR-1 receptor upregulation on platelets, which promoted an increase in platelet reactivity without affecting PFA-100 platelet plug formation time. EPO is not a useful option for short-term support of platelet production during antiviral therapy.

Arterial embolization of unresectable hepatocellular carcinoma with use of microspheres, lipiodol, and cyanoacrylate.

We performed a retrospective analysis of 46 patients with histologically confirmed hepatocellular carcinoma (HCC) who were treated with transarterial embolization (TAE) of the hepatic arteries. To induce permanent embolization, microspheres (Embosphere; 100 to 700 micron) and a mixture of ethiodized oil (Lipiodol Ultrafluide) with cyanoacrylate (Glubran) was injected. A total of 106 TAE procedures were performed. Cumulative survival rates were calculated. No patient died during embolization or within the first 24 hours. Severe procedure-related complications were observed in 2 patients. At the time of analysis, 38 of 46 patients were alive. The 180-, 360-, 520-, and 700-day cumulative survival rates for the total study population were 80.6%, 70.7%, 70.7%, and 47.1%, respectively, with a median survival of 666 days. TAE with the use of microspheres and Lipiodol and cyanoacrylate for unresectable HCC is a feasible treatment modality. Bland embolization with the use of microspheres can be used in patients for whom chemoembolization is not desired.

Survival in patients undergoing transjugular intrahepatic portosystemic shunt: ePTFE-covered stentgrafts versus bare stents.

In patients with liver cirrhosis, implantation of a transjugular intrahepatic shunt (TIPS) leads to reduction of portal pressure, but not of mortality compared with other therapies. The high stenosis rates of conventional bare stents causes high reintervention rates and costs and may be correlated with poor survival. ePTFE-covered stentgrafts provide much improved patency rates, but their impact on survival is unclear. All suitable patients receiving either bare TIPS (419/466) or undergoing implantation of ePTFE endoprostheses (89/100) in several centers in Austria up to 2002 were included in this retrospective analysis. Both patient groups were compared regarding survival with Kaplan-Meier and Cox regression analysis. Unmatched and 1:1-matched survival analyses were performed. Patients undergoing ePTFE stentgraft implantation had significantly higher survival rates in all analyses. The 3-month, 1-year, and 2-year survival rates were 93%, 88%, and 76% for the ePTFE-group and 83%, 73%, and 62% for conventional TIPS patients, respectively. The matched survival analyses validated these findings. The model of the stent, patient age, and Child-Pugh Class (CPC) were independent predictors of survival. In conclusion, patients undergoing ePTFE-endoprosthesis implantation had higher survival rates within 2 years after TIPS-implantation. This may be the result of improved patency rates after correct placement (up to the inferior caval vein [ICV]) of the ePTFE stentgraft. These data should be validated in a prospective series.

ePTFE-covered stent-grafts for revision of obstructed transjugular intrahepatic portosystemic shunt.

PURPOSE: To determine whether transjugular intrahepatic portosystemic shunt (TIPS) revisions with the Hemobahn stent-graft or the Viatorr endoprosthesis increase secondary patency rates. METHODS: Between 1998 and June 1999, Hemobahn endoprostheses (W.L. Gore, Flagstaff, AZ, USA) were used for the revision of obstructed TIPS in seven patients, 51-67 years of age (mean 59 years). From June 1999 to 2000, the Viatorr endoprosthesis (W.L. Gore, Flagstaff, AZ, USA) was used for revision of obstructed TIPS in nine patients, 33-64 years of age (mean 49 years). Follow-up included duplex ultrasound, clinical assessment and venous portography. RESULTS: The technical success rate of TIPS revision with the Hemobahn stent-graft was 100%. The pressure gradient decreased from a mean of 20 mmHg to 10 mmHg. The mean follow-up was 407 days (range 81-868 days). In two patients TIPS occlusion occurred at 62 and 529 days after stent-graft placement, respectively; in another two patients outflow tract stenosis occurred at 275 and 393 days, respectively. The technical success rate of TIPS revision with the Viatorr endoprosthesis was also 100%. The pressure gradient decreased from a mean of 27 mmHg to 11 mmHg. At a mean follow-up of 201 days (range 9-426 days), all Viatorr endoprostheses are still patent without in-graft stenosis, but angioplasty was required in two patients to treat a portosystemic pressure gradient > 15 mmHg. Four of the nine patients in the Viatorr group suffered from new encephalopathy after TIPS revision. CONCLUSION: The Viatorr endoprosthesis yielded optimal results with 100% in-graft patency rates at follow-up but had a high incidence of new encephalopathy, whereas the use of Hemobahn stent-graft for TIPS revision did not appear to improve the secondary patency rates in our series.