Systematic review: interferon-free regimens for patients with HCV-related Child C cirrhosis.

BACKGROUND: It is unclear whether the efficacy and long-term outcome of treating patients with hepatitis C virus (HCV)-positive cirrhosis with the new protease inhibitors will extend to those with Child C cirrhosis. AIM: To assess the effectiveness of the interferon-free regimens in Child C cirrhotic patients with HCV infection. METHODS: A systematic Medline search was conducted to retrieve studies describing the treatment of Child C patients with direct-acting agents. Citations from identified studies were cross-referenced and abstracts from European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Disease (AASLD) meetings were checked. Extracted data were evaluated using a meta-analysis to calculate a weighted response rate. RESULTS: Seven full-text records and two conference abstracts were retained for analysis from the 649 records identified. Data from an Italian real-life trial were also interrogated. Information on treatment outcome was available for 228 of the 240 Child C patients evaluated in the 10 trials. Overall, the weighted mean sustained virological response (SVR12) was 74.9% (95% CI: 65.6-82.4%). Neither duration of treatment (24 or 12 weeks), nor addition of ribavirin influenced these rates. The weighted SVR12 was 65.4% (95% CI: 46.8-80.2) after sofosbuvir/simeprevir, 76.0% (95% CI: 54.4-89.3%) after sofosbuvir/daclatasvir and 83.0% (95% CI: 73.4-89.6) after sofosbuvir/ledipasvir. Some studies did not provide information on the rate of post-treatment relapse or functional improvement. However, in those studies that did provide such data, a relapse was documented in 12.1% of patients and an improvement of ≥2 points on the model for end-stage liver disease (MELD) score in 61.1% of patients. CONCLUSION: The improvement in MELD scores strongly suggests HCV-positive patients with Child C cirrhosis should be treated with these agents.

HBsAg kinetics in chronic hepatitis D during interferon therapy: on-treatment prediction of response.

BACKGROUND: Therapy of chronic hepatitis D with Interferon is successful when testing for HDV-RNA turns negative. This end-point is disputed. AIM: To assess the role of serum hepatitis B surface antigen (HBsAg) in the clearance of HDV-RNA in pegylated interferon (Peg-IFN)-treated chronic hepatitis D (CHD). METHODS: Sixty-two patients with CHD, treated with Peg-IFN, were considered. The patients belonged to three groups: 14 patients cleared the HBsAg and HDV-RNA (responders, R), 12 cleared the HDV-RNA remaining positive for HBsAg (partial responders, PR) and 36 cleared neither the HBsAg nor the HDV-RNA (nonresponders, NR). RESULTS: In responders, at baseline the median value (mv) of HBsAg and HDV-RNA was 1187 and 188 663 IU/mL. By month 6 of therapy, HBsAg declined to less than 1000 IU/mL and HDV-RNA was undetectable in 12 patients. In NR, the pre-therapy median value of HBsAg and HDV viremia was 6577 and 676 319 IU/mL. There was no significant reduction of antigen at month 6; after a decline, HDV-RNA rebounded to baseline levels. In PR, the median value of baseline HBsAg was 7031 IU/mL; it declined at month 6 in the majority. HDV-RNA progressively declined from an initial median value of 171 405 IU/mL. HBsAg <1000 IU/mL at month 6 discriminated responders and PR from NR (P < 0.001). By ROC curve, the threshold of 0.105 log reduction of HBsAg associated with 1.610 log reduction of HDV-RNA from baseline to month 6 predicted the clearance of this marker. CONCLUSIONS: A reduction of serum HBsAg is mandatory for the definitive clearance of the HDV-RNA. Quantitative HBsAg may predict the long-term response to Peg-IFN therapy and provide a guide to prolong or stop treatment.

[Treatment of persistent postmastectomy pain with 5% Lidocaine medicated plaster]. / Trattamento del "persistent postmastectomy pain" con Lidocaina cerotto 5%.

Persistent postmastectomy pain (PPMP) syndrome is characterized by neuropathic pain that develops following surgery in breast cancer patients. The reported incidence of PPMP ranges between 30% and 50% and is estimated to increase as the number of women surviving cancer continues to rise. Though effective, today's drug treatments are poorly tolerated, limiting their use and reducing adherence to therapy. Since neuropathic pain is localized, international guidelines suggest that topical treatment with 5% Lidocaine medicated plaster either alone or combined with systemic drugs can be considered for pain management. In this retrospective study we reviewed the medical records of 11 patients treated with 5% lidocaine medicated plaster for moderate-to-severe PPMP at our institute between November 2013 and October 2014. Analysis showed that treatment with 5% Lidocaine medicated plaster, either alone or in combination with systemic drugs, achieved significant pain control already after the first week of therapy. The effectiveness and tolerability of 5% Lidocaine medicated plaster we observed suggests that it is a viable option in the management of PPMP.

Long-term outcome of hepatitis B virus-related Chronic Hepatitis under protracted nucleos(t)ide analogues.

Long-term outcome of patients with chronic hepatitis B virus (HBV) infection under continuous nucleos(t)ide analogues (NUCs) has been poorly elucidated. We enrolled 121 anti-HBe-positive patients into a prospective surveillance programme while on (>36 months) NUCs therapy. HBV-DNA clearance, add-on therapy and safety were evaluated. Development of cirrhosis, events of liver decompensation and hepatocellular carcinoma (HCC) during the follow-up were the main endpoints, as the complication-free survival. At baseline, 74 patients (61%) had chronic hepatitis, the remainders a cirrhotic liver. HBV-DNA levels >38 000 IU/mL were discovered in 103 patients. At enrolment, 79 patients were naïve to NUCs treatment. Lamivudine monotherapy (n = 70) or a different NUC (n = 51) was administered. At month 6 of therapy, HBV-DNA clearance was documented in 88 patients (73%). Treatment schedule was modified in 52 patients due to breakthrough or suboptimal response. During a mean follow-up of 6 ± 3 years, viral clearance was achieved in the majority of patients. Ten of 74 patients (13.5%) with chronic hepatitis progressed to cirrhosis, 1 patient developed a HCC. In the 47 patients with cirrhosis at presentation, HCC occurred in 14 (30%) and liver decompensation in 5 (11%). The 5 and 10-year event-free survivals were, respectively, 89.3% (95% CI, 81.7 -96.9) and 75.6% (95% CI, 61.5 -89.7) for patients with chronic hepatitis, and 70.2% (95% CI, 56.3 -84.1) and 40.4% (95% CI, 16.9 -63.9) for those with cirrhosis. Protracted, effective treatment with oral NUCs affects the natural history of chronic HBV infection by reducing the incidence of cirrhosis and risk of complications, but does not guarantee against the development of HCC in cirrhosis at presentation.

Estimates of HCV-1 patients attaining RVR following dual therapy with peg-interferon and ribavirin.

BACKGROUND: Given the significant side-effects and healthcare costs associated with telaprevir- or boceprevir-combination therapy, identifying patients likely to respond to dual therapy peg-interferon (Peg-IFN)/ribavirin is highly desirable. Since the perception of how large the pool of patients who may achieve rapid virologic response (RVR) is vaguely ascertained, we searched the literature for this information. METHODS: Studies on patients treated with Peg-IFN/ribavirin were identified by searching MEDLINE and analyzed by meta-analysis. The primary end point was weighted estimates of RVR. The influence on race/ethnicity, baseline viremia, type of Peg-IFN, ribavirin dosage, and significant hepatic fibrosis on the results was evaluated. RESULTS: Across 38 studies on 13,219 patients, the fraction of RVR patients was 19.6 %. The only baseline factor influencing RVR was race/ethnicity, with higher rates in Asian (26.7 %) and Caucasian patients (22.5 %). Of the 1,735 RVR patients, 85.1 % attained sustained virologic response (SVR). In these, SVR was influenced by ribavirin dose (86.8 vs. 72.8 % for high or low), type of Peg-IFN (91.8 % for alpha-2b vs. 82.9 % for alpha-2a), and treatment duration (91.7 % for 48 weeks vs. 79.4 % for 24 weeks). CONCLUSIONS: One fifth to one fourth of hepatitis C virus genotype 1 (HCV-1) patients can be safely treated with dual therapy of Peg-IFN/ribavirin, and may be spared from cost and inconvenience of regimens considering the addition of HCV protease inhibitors.

Unawareness of HBV infection among inpatients in a Southern Italian hospital.

Hepatitis B virus (HBV) infection may run undetected. Unawareness of an ongoing infection delays the diagnosis of HBV-related liver disease and favours the spread of the virus. We have evaluated among hepatitis B surface antigen-positive (HBsAg) inpatients admitted to a Southern Italian hospital the proportion of those aware of their carrier status and correlated the status to signs of liver disease. All patients admitted to the San Giovanni Rotondo Hospital from March 2008 to July 2009 were tested for HBV and hepatitis C virus (HCV) markers, and those positive for HBsAg were interviewed and underwent examinations for liver function and abdominal ultrasound. Overall, of 25,000 patients admitted during the observation period 311 (1.2%) were positive for HBsAg, most of them (98%) being anti-HBe positive. HCV and HDV co-infections were ascertained in 2.9% and 0.6% of cases, respectively. Two hundred and fifty-three subjects (81%) agreed to undergo further investigation, 132 of them (52%) were HBV-DNA positive. One hundred and two patients (40.3%) were unaware of their infection; this was encountered among 29% of HBV-DNA-positive and 52% of HBV-DNA-negative subjects (P < 0.01). Subjects already aware of their infection were more likely to present with abnormal alanine aminotransferase (ALT) levels (27%vs 15%), serological presence of HBV-DNA (63.6% vs. 36%) and liver cirrhosis (30%vs. 13%). A high proportion of HBsAg-positive patients (40.3%) were unaware of their infection, which had evolved to the stage of liver cirrhosis in a consistent percentage of them.

Sustained virological responses following standard anti-viral therapy in decompensated HCV-infected cirrhotic patients.

BACKGROUND: Little data is available about predictors of sustained virological response (SVR) during anti-viral therapy of patients with decompensated HCV cirrhosis. AIMS: To determine whether rapid and early virological responses (RVR and EVR) could predict SVR and help optimize treatment in these patients. METHODS: A total of 94 cirrhotics underwent treatment with peg-interferon alfa-2b (1.5 microg/kg weekly) and ribavirin (800/1200 mg daily) for 48 or 24 weeks for genotypes 1/4 or genotypes 2/3, respectively. RESULTS: Overall, SVR was achieved in 33 patients (35.1%), 16% with genotype 1/4 and 56.8% with genotype 2/3 (P < 0.01). At treatment week 4, 34 patients had undetectable HCV-RNA, 10 with genotype 1/4 and 24 with genotype 2/3. Of RVR patients, 24 achieved SVR (70.5%), 6 and 18 with genotypes 1 and non-1. At the multivariate analysis, only EVR, genotypes 2 and 3, and adherence to full course and dosage of therapy retained their independent predictive power, with corresponding ORs of 25.5 (95% CI 3.0-217.3), 4.2 (95% CI 1.2-15.3) and 9.1 (95% CI 2.2-38.0), respectively. CONCLUSION: In decompensated cirrhotic patients, anti-viral therapy with current regimens is feasible and associated with an overall SVR rate of 35.1%. Treatment ought to be pursued among patients who attain an EVR, and maintain a full course and dosage of therapy.

Early discontinuation of ribavirin in HCV-2 and HCV-3 patients responding to Peg-interferon alpha-2a and ribavirin.

Guidelines for the treatment of patients infected with hepatitis C virus of genotypes 2 and 3 (HCV-2 and HCV-3, respectively) recommend a 24-week course of Peg-interferon (Peg-IFN) alpha-2a combined with ribavirin, despite 50% of patients in registration trials attaining a sustained virologic response (SVR) following Peg-IFN alpha-2a monotherapy. The aim of this study was to delineate patient characteristics that might help to identify individuals likely to benefit from ribavirin discontinuation. One hundred and forty-four HCV-2- and HCV-3-infected patients initiated Peg-IFN alpha-2a (180 microg/week) and ribavirin (1000 or 1200 mg/day); those with viral clearance at week 4 were randomized to either Peg-IFN alpha-2a monotherapy (n = 59) or continuing combination therapy (n = 61) until week 12. Overall, all but one patient with a rapid virologic response (RVR) responded by the end of therapy and the overall SVR rates were lower after discontinuation of ribavirin (54%vs 82%; P < 0.001). In RVR patients who discontinued ribavirin, low baseline viraemia helped predict SVR (odds ratio 11.2, 95% CI 2.7-47.1). SVR rates were similar in patients receiving mono- or combination therapy with low (< or =300,000 IU/mL) and intermediate viraemia (86%vs 81% and 70%vs 71%, 86% refers to low viraemic patients receiving monotherapy and 81% to those receiving combination therapy. Similarly, 70% refers to patients with intermediate viraemic levels receiving monotherapy and 71% to those receiving combination therapy), but different in those with high (>700,000 IU/mL) viraemia (37%vs 88%; P = 0.004). Thus in HCV-2- and HCV-3-infected patients, withdrawal of ribavirin and continuation of Peg-IFN alpha-2a monotherapy may be appropriate to attain an SVR, providing viraemia is cleared early during therapy and associated with low baseline viral load. These results warrant future investigations, as discontinuing ribavirin could lead to considerable savings in cost and quality of life related to over-treatment.

Meta-analysis: the outcome of anti-viral therapy in HCV genotype 2 and genotype 3 infected patients with chronic hepatitis.

BACKGROUND: Anti-viral therapy seems more successful in HCV genotype 2 than genotype 3-infected patients. AIM: To report sustained virological response (SVR) rates for HCV-2 and HCV-3 infection. METHODS: Meta-analyses were carried out on SVR data on 2275 patients treated for 24 weeks in eight individual trials and on 968 patients with rapid virological response (RVR) treated for 12-16 weeks or 24 weeks in four studies. RESULTS: After 24 weeks of therapy, SVR rates were 74% and 68%, respectively, for HCV-2 and HCV-3 genotype patients. Among high viraemics, SVR rate in HCV-2 infection (75%) differed from the 58% value in HCV-3 infection. Among low viraemic patients, respective rates were 79% and 75%. In RVR patients treated for 12-16 or 24 weeks, SVR rates in HCV-2 infection were 83% and 84%, respectively, and in HCV-3 infection 84% and 86%. In patients without RVR treated for 24 weeks, SVR was higher in HCV-2, with a 17.8% weighted difference. CONCLUSIONS: Twenty-four weeks of therapy should remain standard duration for HCV-2 and low viraemic HCV-3 patients. In RVR patients, HCV-3 patients respond to short-treatment as well as HCV-2 patients, irrespective of basal viraemia. Patients without RVR may need longer treatment than the recommended 24 weeks.

Sequential treatment with lamivudine and alpha-interferon in anti-HBe-positive chronic hepatitis B patients: a pilot study.

BACKGROUND: In chronic hepatitis B, long-term use of alpha interferon is hampered by side effects, and long-term treatment with nucleos(t)ide analogues is burdened by drug-resistant mutants. We hypothesized that alternate rounds of lamivudine and alpha interferon might circumvent previous shortcomings. AIM: To evaluate efficacy of sequential lamivudine or IFN-alpha2b monotherapies in preventing occurrence of tyrosine-methionine-aspartate-aspartate (YMDD) mutants and achieving virological and biochemical response. METHODS: Fifteen patients with hepatitis B surface antigen, anti-HBe-positive chronic hepatitis received four consecutive rounds of monotherapy with lamivudine (100 mg/day), IFN-alpha2b (5MU/tiw), lamivudine, IFN-alpha2b. Serum HBV-DNA levels were evaluated during and off treatment, HBV polymerase and pre-core/core regions sequenced. RESULTS: End-of-treatment response was achieved in 10 patients (67%). One patient did not respond, a second developed genotypic resistance at week 24. A rebound in viremia occurred in three patients at week 48. Six patients (40%) remained sustained responders. Triple promoter mutations at nucleotides 1762-1764-1896 prevailed in non-responders (60%) as compared to responders (20%). L180M/M204V mutations were identified during virological breakthrough. CONCLUSION: Sequential approach of alternate rounds of lamivudine or interferon may help patients to tolerate a prolonged schedule of therapy and protect them from emergence of viral strains.

Ultrasonographic and biochemical parameters in the non-invasive evaluation of liver fibrosis in hepatitis C virus chronic hepatitis.

BACKGROUND: Prior studies suggest that platelet counts of <140 000/microL can discriminate patients with different stages of fibrosis. AIM: To determine the added value of abdominal ultrasound analysis of morphological liver features in increasing the diagnostic accuracy of platelet counts for the prediction of liver fibrosis at histology. METHODS: In a retrospective study, clinical records of 1143 chronic hepatitis C patients at their first presentation, naives to both liver biopsy and anti-viral treatment, were reviewed. Sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios of following indices were evaluated singularly or in combination: platelet counts <140 000/microL; nodular liver surface, spleen and portal vein size. RESULTS: All indices had specificity rate of > or =90% in excluding bridging fibrosis/cirrhosis, whereas sensitivity was acceptable (51%) for only platelet counts <140 000/microL. None of the ultrasonographic parameters singularly evaluated and reached an acceptable sensitivity rate. For ruling cirrhosis in or out, specificity rate was > or =82% for all tests, with the highest value reported by portal vein size. Low platelet counts plus nodular liver surface had the best sensitivity. CONCLUSIONS: No additional significant predictive value was given by adding ultrasonographic parameters to low platelet counts, whereas only a mild non-significant improvement in sensitivity was obtained combining platelet counts <140 000/microL with the presence of nodular liver surface. The platelet counts <140 000/microL showed the best predictive value for including both significant fibrosis and cirrhosis.

Treatment of patients with HCV infection with or without liver biopsy.

Expert consensus recommends liver biopsy before therapy for chronic hepatitis C. A cost effectiveness analysis suggested that the best strategy in the management of patients was to treat without biopsy. We compared therapy in patients who did, or did not undergo biopsy. Hepatitis C virus (HCV)-positive patients (78) who did not agree to (n = 57) or with contraindications to liver biopsy (n = 21) (group A) were matched for age, sex and genotype with those who consented (group B). Before therapy (interferon/ribavirin for 12 months), a clinical diagnosis of chronic hepatitis, on the basis of standard biochemical and ultrasonographic parameters. The two groups showed similar baseline characteristics. A noninvasive, diagnosis of chronic hepatitis was made in 75.6% of group A, and in 83.3% of group B (P = 0.26). Concordance between clinical and histological diagnosis in group B amounted to 91%. End-of-therapy virological response was 52.6% in group A, and 57.7% in group B (P = 0.63). Sustained virological response was 41.0% [95% confidence interval (CI) 30.1-51.9] and 43.6% (95% CI 32.6-54.6) in the two groups (P = 0.87). Predictors of sustained response were noninvasive diagnosis of chronic hepatitis (P = 0.006), lack of portal hypertension (P = 0.037), platelets >10(5)/mm3 (P = 0.007), prothrombin >70% (P = 0.02), and genotype 2 or 3 (P < 0.0001). At multivariate analysis, genotype (P < 0.0001) and platelets (P = 0.004) maintained their predictive power. In most patients with HCV infection, virological clearance after therapy can be achieved irrespective of whatever a liver biopsy might show.

Viral clearance in HCV viraemic patients with normal alanine aminotransferase after combination therapy: a controlled, open-labelled study.

BACKGROUND: In patients with chronic hepatitis C virus infection and persistently normal alanine aminotransferase levels, liver fibrosis has been reported in 0-22% of cases and advanced liver disease in 5-10% of cases. AIM: To determine whether patients with persistently normal alanine aminotransferase levels clear infection after anti-viral therapy at equal or different rates from infected patients with raised alanine aminotransferase levels. METHODS: Thirty-five hepatitis C virus RNA-positive patients with fibrosis at liver histology (Group 1) were matched for genotype, sex, age and histology with patients with raised alanine aminotransferase levels (Group 2). Both groups were treated with 3 MU interferon-alpha2b plus ribavirin (1000-1200 mg) for 12 months. RESULTS: End-of-therapy response was achieved in 71.4%[95% confidence interval (CI), 56.4-86.3] of patients in Group 1 and in 52.3% (95% CI, 42.8-61.9) of those in Group 2 (P = 0.04). At week 72, 22 patients (62.8%; 95% CI, 46.8-78.1) in Group 1 and 50 patients (47.5%; 95% CI, 38.0-57.1) in Group 2 showed a sustained virological response (P = 0.11). Non-1 genotype was the only independent predictor of sustained response (P = 0.002), with an odds ratio of 3.45 (95% CI, 1.58-7.50). At month 3 of therapy, the positive predictive values for non-response were 100% and 96% in Groups 1 and 2, respectively. CONCLUSIONS: Interferon and ribavirin induce comparable sustained virological response in patients with persistently normal or raised alanine aminotransferase levels. Stage 1 fibrosis, rather than alanine aminotransferase levels, may be the criterion on which to decide whether or not to treat patients with persistently normal alanine aminotransferase levels.

IL-10 haplotypes as possible predictors of spontaneous clearance of HCV infection.

BACKGROUND: In hepatitis C virus infection an inappropriate ratio of pro-inflammatory and anti-inflammatory cytokines may either determine different outcomes of the infection or affect the benefit of antiviral treatment. Given that polymorphisms in regulatory regions of cytokine genes influence cytokine production, we determined frequency of polymorphisms of IL-10, IFNgamma, and TNFalpha genes in HCV-infected patients and healthy controls, and investigated their association with either ongoing or cleared HCV infection, or with response to treatment. METHODS: Genomic DNA from 270 patients and 145 controls sharing the same ethnic background was studied by polymerase chain reaction, restriction enzyme digestion, direct sequencing, and microsatellite analysis. RESULTS: The IL-10 ATA haplotype was more frequent in patients with spontaneous HCV RNA clearance (36.0%) than in patients with persistent infection (23%) (p=0.009, p corrected = 0.036). Neither TNF -308 and -238 polymorphisms nor IFNgamma alleles variability were associated with different HCV outcome. However, the combination of ATA homozygous state and IFNgamma 119 allele was more frequent in patients with spontaneous HCV clearance than in patients with ongoing disease (p=0.012; p corrected = 0.048). We could not confirm the reported effect of genetic influence on the response to treatment. CONCLUSIONS: Our findings indicate that heterogeneity in the promoter region of the IL-10 gene has a role in determining a spontaneous favourable outcome of HCV infection.

[The role of transdermal anesthesia with EMLA in urologic surgery]. / Ruolo dell'anestesia transdermica con EMLA in chirurgia urologica.

The review of 50 cases of urologic diseases has allowed us to show the utility of EMLA; even if it has been limited by some practical factors, it has permitted alone or as a first step in local and loco-regional anesthesia, to carry out surgical urologic procedures, with good surgical conditions, both for the surgeon and for the patient.

Crystallization and preliminary crystallographic data for the augmenter of liver regeneration.

A new cellular growth factor termed augmenter of liver regeneration (ALR) has been crystallized. ALR has been shown to have a proliferative effect on liver cells while at the same time producing an immunosuppressive effect on liver-resident natural killer cells and liver-resident mononuclear leukocytes. In addition, ALR appears to play an important role in the synthesis and stabilization of mitochondrial gene transcripts in actively regenerating cells. ALR crystals diffract to beyond 2 A resolution and belong to space group P2(1)2(1)2, with a = 125.1, b = 108.1 and c = 38.5 A. Based on four molecules per asymmetric unit, the Matthews coefficient is calculated to be 2.16 A(3) Da(-1) which corresponds to a solvent content of 43%.

The in vivo effect of hepatotrophic factors augmenter of liver regeneration, hepatocyte growth factor, and insulin-like growth factor-II on liver natural killer cell functions.

Fine balanced sequential changes of the levels of circulating hepatotrophic factors are essential for normal liver regeneration. Our recent studies have indicated that liver-resident natural killer (NK) cells are important regulators of liver regeneration and have raised the possibility that hepatotrophic factors might mediate their activities through NK cells. In the present study, we assessed the effects of in vivo administration of three hepatotrophic factors (augmenter of liver regeneration [ALR], insulin-like growth factor-II [IGF-II], and hepatocyte growth factor [HGF]) on NK cells in normal rats. Each of the three, given over a 1-day period in doses known to produce hepatotrophic activity, induced inhibition of NK cell cytotoxic activities in the population of mononuclear leukocytes (MNL) in the liver, but not in MNL from the spleen or peripheral blood. In contrast to these results obtained by the whole animal treatment, the three molecules had no effect on NK cell functions when added to cultures of MNL from the livers, spleens, or blood of untreated rats. These data support and extend our previously advanced hypothesis that ALR and other hepatotrophic factors play an important role in liver regeneration by regional regulation of NK cells through some as-yet-unknown intermediary mechanism.