The need to improve fertility awareness.

Women and men globally are delaying the birth of their first child. In the UK, the average age of first conception in women is 29 years. Women experience age-related fertility decline so it is important that men and women are well-informed about this, and other aspects of fertility. A group of UK stakeholders have established the Fertility Education Initiative to develop tools and information for children, adults, teachers, parents and healthcare professionals dedicated to improving knowledge of fertility and reproductive health.

A 24-week dietary and physical activity lifestyle intervention reduces hepatic insulin resistance in the obese with chronic hepatitis C.

BACKGROUND/AIMS: Obesity- and virus-mediated insulin resistance (IR) are associated with adverse hepatic and metabolic outcomes in chronic hepatitis C (CHC). This study evaluates the tolerability and effects of a dietary and physical activity (PA) intervention in obese patients with insulin-resistant CHC. METHODS: Obese patients (body mass index, BMI ≥30 kg/m(2) ) with CHC were recruited prospectively. Non-diabetic patients with IR (homeostasis model assessment of IR, HOMA-IR >2.0) proceeded to a 24-week lifestyle intervention comprising pedometer monitored increase in PA (≥10 000 steps/day) and an individualised dietary plan. RESULTS: Ten non-cirrhotic and six cirrhotic patients [age 52 ± 8.5 years, BMI 35.9 (31.46-38.21)kg/m(2) ] were recruited, of whom all 16 (100%) completed the 24-week protocol. Increase in PA from 6853 (2440-9533) to 10 697 (7959-13566) steps/day (P = 0.001) and reduction in caloric intake from 2263 (1805.4-2697.0) to 1281 (1099.5-1856.3) kcal/day (equivalent to reduction of median 33% (25.3-49.8%), P < 0.001) were achieved. These behaviour changes led to a BMI reduction to 31.21 (28.72-36.10) (P < 0.001) and the HOMA-IR fell from 3.62 (2.75-4.87) to 2.08 (1.82-3.59) (P = 0.002). The hepatic insulin sensitivity index (ISI) improved significantly, but the skeletal muscle ISI did not. At week 24, 8/16 (50%) patients were no longer insulin-resistant (P = 0.008). CONCLUSIONS: This 24-week intervention reduced BMI and reversed IR in significant proportion of patients. Such adjunctive therapy may improve hepatic and metabolic status in obese insulin-resistant CHC.

The impact of hepatitis B knowledge and stigma on screening in Canadian Chinese persons.

BACKGROUND: Chronic hepatitis B (CHB) infection is endemic in East Asia, and those who emigrate to North America have higher rates of CHB infection when compared with the general population. To date, Chinese persons residing in Canada have not been mandated to be screened for CHB infection. OBJECTIVE: To understand factors that influence hepatitis B screening behaviour among the Chinese community in Toronto, Ontario, and to determine whether stigma acts as a barrier to screening. METHODS: Self-identified Chinese individuals at a family physician's office and at English as a second language (ESL) classes in Toronto completed a questionnaire with demographic questions, a hepatitis B virus (HBV) stigma scale and an HBV knowledge scale. Pearson product moment correlation and multiple regression techniques were used to analyze the data. RESULTS: The study group included 343 individuals. Their mean (± SD) age was 48.76 ± 17.49 years and the majority were born in China (n=229 [68%]). The mean score on the HBV knowledge scale was 10.13 ± 1.76 (range 0 to 15), with higher scores indicating greater HBV knowledge. The mean score on the stigma scale was 54.60 ± 14.18 (range 20 to 100), with higher scores indicating more stigma. Being an immigrant, having a family physician and having greater knowledge of HBV were associated with increased rates of screening for this infection. In contrast, greater levels of HBV stigma were associated with decreased likelihood of screening for HBV infection. CONCLUSIONS: HBV stigma is associated with reduced rates of screening for this infection.

Health state utilities and quality of life in patients with hepatitis B.

BACKGROUND: The effect of chronic hepatitis B (CHB) infection on health-related quality of life (HRQoL) and health state utilities has not been well characterized. OBJECTIVE: To measure utility scores and HRQoL across disease states associated with CHB infection. METHODS: Patients attending four tertiary care clinics for CHB were approached between July 2007 and March 2009. Respondents completed version 2 of the Short-Form 36 Health Survey, the EQ5D, a visual analogue scale, the Health Utilities Index Mark 3, standard gamble, and demographics and risk factor surveys in English, Cantonese or Mandarin. Charts were reviewed to determine disease stage and comorbidities. RESULTS: A total of 433 patients were studied: 294 had no cirrhosis; 79 had compensated cirrhosis; seven had decompensated cirrhosis; 23 had hepatocellular carcinoma; and 30 had received a liver transplant. The mean standard gamble utilities for these disease states were 0.89, 0.87, 0.82, 0.84 and 0.86, respectively. HRQoL scores in noncirrhotic patients were similar to those of the general population. Scores of patients with compensated cirrhosis were not significantly lower; however, patients with decompensated cirrhosis and hepatocellular carcinoma had significantly lower HRQoL scores compared with noncirrhotic patients (P<0.05). Similar scores were observed among patients on and off oral antiviral treatment. Post-liver transplant patients had a higher HRQoL than patients with decompensated cirrhosis. Age, number of comorbidities and relationship status were significantly associated with HRQoL scores. CONCLUSIONS: HRQoL in CHB patients is only impaired in the later stages of liver disease. Neither CHB infection nor antiviral treatment is associated with a lower quality of life.

Metabolomic profiling of 17 bile acids in serum from patients with primary biliary cirrhosis and primary sclerosing cholangitis: a pilot study.

BACKGROUND: Primary biliary cirrhosis and primary sclerosing cholangitis are two cholestatic diseases characterised by hepatic accumulation of bile acids. AIMS: This study compares serum bile acid levels in patients with primary biliary cirrhosis and primary sclerosing cholangitis and from age and sex-matched non cholestatic donors. METHODS: Seventeen bile acids were quantified using liquid chromatography coupled to tandem mass spectrometry. Serum samples from cholestatic patients were compared with those of non-cholestatic donors. RESULTS: The concentration of total bile acids, taurine and glycine conjugates of primary bile acids was elevated in both patients with primary biliary cirrhosis and primary sclerosing cholangitis when compared to non-cholestatic donors. Samples from primary sclerosing cholangitis patients displayed reduced levels of secondary acids, when compared to non cholestatic and primary biliary cirrhosis sera. The ratio of total glycine versus total taurine conjugates was reduced in patients with primary biliary cirrhosis, but not in primary sclerosing cholangitis. CONCLUSION: The present study suggests that circulating bile acids are altered differentially in primary biliary cirrhosis and primary sclerosing cholangitis patients.

Biliary atresia and survival into adulthood without transplantation: a collaborative multicentre clinic review.

BACKGROUND: Biliary atresia is a progressive biliary injury which occurs only in infants. AIMS: To review the experience of patients surviving into adulthood without the need for liver transplantation in childhood. METHODS: A multicentre review of patients with biliary atresia treated surgically who survived into adulthood without the need for transplantation. RESULTS: Twenty-two patients were identified across four centres. Median age at the last follow-up was 25 years (range: 18-46), and 21 patients had clinical features of portal hypertension. At last follow-up values of liver enzymes varied from normal to 15 × the upper limit of normal (ULN) for ALT (median 2.11 × ULN) and 9 × the ULN for ALP (median 2.02 × ULN). Six patients had a serum bilirubin > 50 µmol/l. Pruritus and jaundice were noted in 8 of 20 patients (40%) and 11 of 22 patients (50%) respectively. Thirteen patients (59.1%) were shown to have imaging features of sclerosing cholangitis, with strictures of intrahepatic bile duct(s) (IHBD), dilatation of IHBD (n = 8), or stone(s) within the IHBD (n = 5). A history of presumed bacterial cholangitis was present in 11 patients (50%). Successful pregnancies were recorded in three of fourteen female patients. Four patients underwent transplant between the ages of 20-27 years. Twenty-one patients (95.5%) were alive, including 18 (81.8%) with their native liver at the time of last follow-up. CONCLUSIONS: Some patients treated for biliary atresia will survive into adulthood with their native liver, but commonly with secondary biliary disease including cholangitis and portal hypertension.

Does hepatic vein transit time performed with contrast-enhanced ultrasound predict the severity of hepatic fibrosis?

Previously published data suggest a hepatic vein transit time (HVTT) threshold of more than 24 s can distinguish mild to moderate from advanced fibrosis. In this study, we attempted to validate HVTT as a noninvasive index of hepatic fibrosis. Patients were scanned using real-time, pulse-inversion mode following bolus injections of the contrast agent Definity. HVTT was correlated with the degree of fibrosis obtained from contemporaneous liver biopsy. The study population included 40 patients with chronic liver disease and five healthy volunteers. Mean HVTT correlated with histologic grade as follows: absence/minimal fibrosis (n = 18), 25.6 ± 11.8 s; moderate fibrosis (n = 17), 21.5 ± 5.9 s; and severe fibrosis (n = 8), 20.9 ± 5.5 s, (p = .615). Poor sensitivity (57%) and specificity (43%) prevent validation of the previously published HVTT threshold as a surrogate marker of hepatic fibrosis. Further work investigating the different interaction of Definity, SonoVue and Levovist with the reticulo-endothelial system may help explain the discrepant results reported here.

No resistance to tenofovir disoproxil fumarate detected after up to 144 weeks of therapy in patients monoinfected with chronic hepatitis B virus.

UNLABELLED: Tenofovir disoproxil fumarate (TDF) is a nucleotide analogue with potent activity against human immunodeficiency virus type 1 and hepatitis B virus (HBV). To date, no reports of HBV clinical resistance to TDF have been confirmed. In two phase 3 studies (GS-US-174-0102 and GS-US-174-0103), 375 hepatitis B e antigen-negative (HBeAg(-) ) patients and 266 HBeAg(+) patients with chronic hepatitis B (some nucleoside-naive and some lamivudine-experienced) were randomized 2:1 to receive TDF (n = 426) or adefovir dipivoxil (ADV; n = 215) for 48 weeks. After week 48, eligible patients received open-label TDF with no interruption. The studies are being continued through week 384/year 8; week 144 data are presented here. Per protocol, viremic patients (HBV DNA level ≥ 400 copies/mL or 69 IU/mL) had the option of adding emtricitabine (FTC) at or after week 72. Resistance analyses of HBV polymerase/reverse transcriptase (pol/RT) were based on population dideoxy sequencing. Phenotypic analyses were conducted in HepG2 cells with recombinant HBV derived from patient serum. Most patients maintained TDF monotherapy treatment across both studies (607/641, 95%). A resistance analysis of HBV pol/RT was performed at the baseline for all patients, for viremic patients at week 144 or at the last time when they were on TDF monotherapy (34 on TDF and 19 on ADV-TDF), and for patients who remained viremic after the addition of FTC (7/20 on TDF and 5/14 on ADV-TDF). No patient developed amino acid substitutions associated with resistance to TDF. Virological breakthrough on TDF monotherapy was infrequent over 144 weeks (13/426, 3%) and was attributed to documented nonadherence in most cases (11/13, 85%). Persistent viremia (≥400 copies/mL) through week 144 was rare (5/641, 0.8%) and was not associated with virological resistance to TDF by population or clonal analyses. CONCLUSION: No nucleoside-naive or nucleoside-experienced patient developed HBV pol/RT mutations associated with TDF resistance after up to 144 weeks of exposure to TDF monotherapy.

The natural history of hepatitis C infection acquired through injection drug use: meta-analysis and meta-regression.

BACKGROUND & AIMS: Our aim was to estimate the rate of progression to cirrhosis for those infected with hepatitis C virus (HCV) through injection drug use. METHODS: We searched the published literature for articles assessing cirrhosis in this population and abstracted data on cirrhosis prevalence, mean duration of infection, mean age, mean alanine aminotransferase (ALT) enzyme levels, proportion of males, proportion HIV co-infected, proportion consuming excessive alcohol, and study setting. Summary progression rates were estimated using weighted averages and random effects Poisson meta-regression. The impact of co-variates was assessed by estimating the posterior probability that the relative risk (RR) of progression exceeded 1.0. RESULTS: A total of 47 published articles were identified. After adjusting for covariates in 44 studies representing 6457 patients, the estimated rate of progression to cirrhosis, was 8.1 per 1000 person-years (95% credible region (CR), 3.9-14.7). This corresponds to a 20-year cirrhosis prevalence of 14.8% (95% CR, 7.5-25.5). A 5% increase in the proportion of male participants and a 5% increase in the proportion consuming excessive alcohol were associated with faster progression (probability RR>1=0.97 and 0.92, respectively). A 5% increase in the proportion of HIV co-infected, an increase in ALT of 5 IU/L and studies in settings with a high risk of referral bias were not associated with faster progression (probability RR>1=0.42, 0.65, and 0.43, respectively). CONCLUSIONS: Analysis of aggregate level data suggests that for patients who contracted HCV through injection drug use prognosis is poor in populations with many male patients and high levels of alcohol consumption.

Cell-type specific gene expression signature in liver underlies response to interferon therapy in chronic hepatitis C infection.

BACKGROUND & AIMS: Chronic hepatitis C virus (CHC) infection is treated with interferon/ribavirin, but only a subset of patients respond. Treatment nonresponders have marked pretreatment up-regulation of a subset of interferon stimulated genes (ISGs) in their livers, including ISG15. We here study how the nonresponder gene expression phenotype is influenced by clinical factors and uncover the cellular basis of the phenotype through ISG15 protein expression. METHODS: Seventy-eight CHC patients undergoing treatment were classified by clinical (gender, viral genotype, viral load, treatment outcome) and histologic (inflammation, fibrosis) factors and subjected to gene expression profiling on their pretreatment liver biopsies. An analysis of variance model was used to study the influence of individual factors on gene expression. ISG15 immunohistochemistry was performed on a subset of 31 liver biopsy specimens. RESULTS: One hundred twenty-three genes were differentially expressed in the 78 CHC livers when compared with 20 normal livers (P < .001; fold change, > or =1.5-fold). Of genes influenced by a single factor, genotype (1 vs 2/3) influenced more genes (17) than any other variable; when treatment outcome was included in the analysis, this became the predominant influence (24 genes), and the effect of genotype was diminished. Treatment response was linked to cell-specific activation patterns: ISG15 protein up-regulation was more pronounced in hepatocytes in treatment nonresponders but in Kuppfer cells in responders. CONCLUSIONS: Genotype is a surrogate marker for the nonresponder phenotype. This phenotype manifests as differential gene expression and is driven by activation of different cell types: hepatocytes in treatment nonresponders and macrophages in treatment responders.

ISG15, a ubiquitin-like interferon-stimulated gene, promotes hepatitis C virus production in vitro: implications for chronic infection and response to treatment.

Upregulation of interferon (IFN)-stimulated genes (ISGs), including IFN-stimulated gene 15 (ISG15) and other members of the ISG15 pathway, in pre-treatment liver tissue of patients chronically infected with hepatitis C virus (HCV) is associated with subsequent treatment failure (pegylated IFN-alpha/ribavirin). This study assessed the effect of ISG15 on HCV production in vitro. The levels of ISG15 and of its conjugation to target proteins (ISGylation) were increased by plasmid transfection, but ISGylation was inhibited by small interfering RNA directed against the E1 activating enzyme, Ube1L, in Huh7.5 cells. Cells were infected with HCV FL-J6/JFH virus, and HCV RNA and viral titres were determined. Levels of both HCV RNA and virus increased when levels of ISG15 and ISGylation were increased, and decreased when ISGylation was inhibited. The effects of ISGylation on HCV were independent of upstream IFN signalling: IFN-alpha-induced ISG expression was not altered by Ube1L knockdown. Thus, although ISG15 has antiviral activity against most viruses, ISG15 promotes HCV production. HCV might exploit ISG15 as a host immune evasion mechanism, and this may in part explain how increased expression of ISGs, especially ISG15, correlates with subsequent IFN-based treatment failure.

Hepatitis C and diabetes: one treatment for two diseases?

Abstract Epidemiological data clearly indicate a link between chronic hepatitis C (CHC) and disturbed glucose homeostasis. The prevalences of both type 2 diabetes mellitus (T2DM) and insulin resistance (IR) are higher among those chronically infected with hepatitis C when compared with the general population and those with other causes of chronic liver disease. Both IR and diabetes are associated with adverse outcomes across all stages of CHC including the liver transplant population. The adverse effects that directly influence patient outcome are reduced responsiveness to antiviral therapy, more rapid progression of fibrosis to cirrhosis and a higher incidence of hepatocellular carcinoma. Although both viral and host factors are known to contribute to IR (and therefore the risk of T2DM), there is a paucity of evidence to support interventions targeting IR with pharmacotherapy or lifestyle intervention. The purpose of this review is to examine the impact of abnormalities of glucose homeostasis in CHC, and in so doing, to raise a number of questions. How do we identify those at risk of diabetes in CHC? Can we reduce the incidence of hepatoma and reduce transplant-related morbidity and mortality by preventing or treating diabetes? Can we improve the response to antiviral therapy by pretreating IR and T2DM in treatment candidates? Ultimately, can we cure two diseases, diabetes and CHC, with one treatment?

The cyclophilin inhibitor Debio 025 combined with PEG IFNalpha2a significantly reduces viral load in treatment-naïve hepatitis C patients.

UNLABELLED: The anti-hepatitis C virus (HCV) effect and safety of three different oral doses of the cyclophilin inhibitor Debio 025 in combination with pegylated interferon-alpha2a (PEG IFN-alpha2a) were investigated in a multicenter, randomized, double-blind, placebo-controlled escalating dose-ranging phase II study in treatment-naïve patients with chronic hepatitis C. Doses of 200, 600, and 1,000 mg/day Debio 025 in combination with PEG IFN-alpha2a 180 microg/week for 4 weeks were compared with monotherapy with either 1,000 mg/day Debio 025 or 180 microg/week PEG IFN-alpha2a. In patients with genotypes 1 and 4, the 600- and 1,000-mg combination treatments induced a continuous decay in viral load that reached -4.61 +/- 1.88 and -4.75 +/- 2.19 log(10) IU/mL at week 4, respectively. In patients with genotypes 2 and 3, HCV RNA levels at week 4 were reduced by -5.91 +/- 1.11 and -5.89 +/- 0.43 log(10) IU/mL, respectively, with the same treatment regimens. Adverse events were comparable between treatment groups apart from a higher incidence of neutropenia associated with PEG IFN-alpha2a and an increased incidence of isolated hyperbilirubinemia at the highest dose of Debio 025 (1,000 mg/day). CONCLUSION: These results confirm that Debio 025 has a potent activity and an additive effect on HCV RNA reduction in genotype 1 and 4 patients at 600 and 1,000 mg/day when combined with PEG IFN-alpha2a.

Retreatment of chronic hepatitis C: who and how?

All but about 10% of patients with chronic hepatitis C (CHC) (predominantly those infected with genotype 1) can respond to some degree to 'combination' therapy with interferon (IFN) and ribavirin. The slower the virological response to treatment, the less likely sustained viral clearance will take place. Many factors influence response to antiviral therapy; most cannot be reversed (e.g. sex, age, cirrhosis, genotype and viral load). A sustained viral clearance is considerably facilitated by compliance with full-dose therapy for the prescribed time. The potential cause(s) for non-response need(s) to be ascertained before attempting retreatment. The 10% of patients who are true 'null' responders may respond to the new specifically targeted antiviral therapies but whether the response can be sustained off-therapy is unclear. Adjunctive therapies may facilitate response to retreatment if intolerance to treatment leading to diminished or absent doses was problematic in the past. Retreatment with a long-acting IFN and an adequate ribavirin dose (15 mg/kg), but given for 72 weeks in prior relapsers following 48 weeks of treatment, will enhance sustained virological response (SVR) rates. No benefit is gained from changing one pegylated IFNalpha (PEG IFNalpha) to another unless the treatment duration is extended. Only alpha-interferons are effective. For those individuals who still fail to achieve SVR, recruitment to trials of new treatments should be encouraged particularly for those with advanced liver disease. Lifestyle modification may be appropriate in attempt to reduce the chance of complications of liver disease, namely hepatocellular carcinoma, by smoking cessation, eliminating obesity and increasing coffee consumption.