Alejandro Soza

Predictors of nonalcoholic steatohepatitis (NASH) in obese patients undergoing gastric bypass.

Background: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are conditions gaining increasing recognition in hepatology as a potential cause of cirrhosis and end-stage liver disease. Obesity is one of the main risk factors. The aims of this study were to determine the frequency of NAFLD in obese patients and to identify variables that predict NASH. Methods: A prospective study was conducted of obese patients undergoing gastric bypass over a 20-month period. Assessment included liver function tests and evaluation of insulin resistance with the homeostatic model assessment (HOMA-IR). Liver biopsy was performed in all patients at the time of surgery. Clinical and biochemical variables were analyzed using a multivariate analysis to identify independent predictors of NASH. Results: 127 consecutive patients were included (62% female, 38% male, mean age 40±11 years, mean body mass index 42±6 kg/m2). Arterial hypertension was present in 52 patients (41%) and type 2 diabetes in 18 (14%). NAFLD was confirmed in 80 patients (63%), 47 (37%) had simple steatosis, and 33 (26%) had NASH. Cirrhosis was found in 2 patients corresponding to 1.6% of the total population. On multivariate analysis, AST >31 (IU/L) (OR 3.38, CI 1.17-9.8) and HOMA-IR >5.8 (OR 4.18, CI 1.39-12.49) independently predicted NASH. Conclusions: NAFLD is highly prevalent in morbidly obese patients. A high proportion of these patients exhibit NASH on histological examination. Insulin resistance represents the main predictor of NASH.

Non‐alcoholic fatty liver disease and its association with obesity, insulin resistance and increased serum levels of C‐reactive protein in Hispanics

Background: Non‐alcoholic fatty liver disease (NAFLD) is a metabolic disorder of the liver, which may progress to fibrosis or cirrhosis. Recent studies have shown a significant impact of ethnicity on susceptibility to steatosis‐related liver disease.

Analysis of natural variants of the hepatitis C virus internal ribosome entry site reveals that primary sequence plays a key role in cap-independent translation

The HCV internal ribosome entry site (IRES) spans a region of ∼340 nt that encompasses most of the 5′ untranslated region (5′UTR) of the viral mRNA and the first 24–40 nt of the core-coding region. To investigate the implication of altering the primary sequence of the 5′UTR on IRES activity, naturally occurring variants of the 5′UTR were isolated from clinical samples and analyzed. The impact of the identified mutations on translation was evaluated in the context of RLuc/FLuc bicistronic RNAs. Results show that depending on their location within the RNA structure, these naturally occurring mutations cause a range of effects on IRES activity. However, mutations within subdomain IIId hinder HCV IRES-mediated translation. In an attempt to explain these data, the dynamic behavior of the subdomain IIId was analyzed by means of molecular dynamics (MD) simulations. Despite the loss of function, MD simulations predicted that mutant G266A/G268U possesses a structure similar to the wt-RNA. This prediction was validated by analyzing the secondary structure of the isolated IIId RNAs by circular dichroism spectroscopy in the presence or absence of Mg2+ ions. These data strongly suggest that the primary sequence of subdomain IIId plays a key role in HCV IRES-mediated translation.

Increased orocecal transit time in patients with nonalcoholic fatty liver disease.

Intestinal bacterial overgrowth (IBO) has been suggested to play a pathogenic role in patients with nonalcoholic fatty liver disease (NAFLD). Delayed intestinal transit may contribute to IBO development. Ten nondiabetic patients with NAFLD and abnormal liver enzymes were recruited. Ten healthy individuals, matched by sex, age, and body mass index, were used as controls. Orocecal transit time (OCTT) was measured by the lactulose breath test. Anti-endotoxin core antibodies (EndoCAb) were determined. The effect of oral norfloxacin (400 mg BID during 2 weeks) on liver enzymes, lactulose breath test, and EndoCAb was also studied. NAFLD patients had higher basal breathed H2 and prolonged OCTT compared to controls (127 ± 61 vs. 57 ± 23 min, respectively; P = 0.0037). EndoCAb titers were similar in NAFLD patients and controls. Norfloxacin administration had no effect on ALT levels, lactulose breath test, or EndoCAb titers in patients with NAFLD. The present data show evidence of deranged intestinal motility in nondiabetic patients with NAFLD and support the hypothesis that NAFLD could be linked to endotoxin-induced liver damage of intestinal origin.

Efficacy and safety of ombitasvir/paritaprevir/r and dasabuvir compared to IFN-containing regimens in genotype 1 HCV patients: The MALACHITE-I/II trials

BACKGROUND & AIMSnTelaprevir plus pegylated interferon/ribavirin (TPV+PegIFN/RBV) remains a therapeutic option for chronic hepatitis C virus (HCV) genotype (GT) 1 infection in many regions. We conducted two open-label, phase IIIb trials comparing safety and efficacy of all-oral ombitasvir/paritaprevir/ritonavir and dasabuvir±ribavirin (OBV/PTV/r+DSV±RBV) and TPV+PegIFN/RBV.nnnMETHODSnTreatment-naïve (MALACHITE-I) or PegIFN/RBV-experienced (MALACHITE-II) non-cirrhotic, chronic HCV GT1-infected patients were randomized to OBV/PTV/r+DSV+weight-based RBV, OBV/PTV/r+DSV (treatment-naïve, GT1b-infected patients only), or 12weeks of TPV+PegIFN+weight-based RBV and 12-36 additional weeks of PegIFN/RBV. The primary endpoint was sustained virologic response 12weeks post-treatment (SVR12). Patient-reported outcome questionnaires evaluated mental and physical health during the studies.nnnRESULTSnThree hundred eleven treatment-naïve and 148 treatment-experienced patients were randomized and dosed. Among treatment-naïve patients, SVR12 rates were 97% (67/69) and 82% (28/34), respectively, in OBV/PTV/r+DSV+RBV and TPV+PegIFN/RBV-treated GT1a-infected patients; SVR12 rates were 99% (83/84), 98% (81/83), and 78% (32/41) in OBV/PTV/r+DSV+RBV, OBV/PTV/r+DSV, and TPV+PegIFN/RBV-treated GT1b-infected patients. Among treatment-experienced patients, SVR12 rates were 99% (100/101) and 66% (31/47) with OBV/PTV/r+DSV+RBV and TPV+PegIFN/RBV. Mental and physical health were generally better with OBV/PTV/r+DSV±RBV than TPV+PegIFN/RBV. Rates of discontinuation due to adverse events (0-1% and 8-11%, respectively, p<0.05) and rates of hemoglobin decline to <10g/dl (0-4% and 34-47%, respectively, p<0.05) were lower for OBV/PTV/r+DSV±RBV than TPV+PegIFN/RBV.nnnCONCLUSIONSnAmong non-cirrhotic, HCV GT1-infected patients, SVR12 rates were 97-99% with 12week, multi-targeted OBV/PTV/r+DSV±RBV regimens and 66-82% with 24-48 total weeks of TPV+PegIFN/RBV. OBV/PTV/r+DSV±RBV was associated with a generally better mental and physical health, more favorable tolerability, and lower rates of treatment discontinuation due to adverse events.

Histological Resolution of Steatohepatitis After Iron Depletion

After its description in the early eighties (1), nonalcoholic steatohepatitis (NASH) has become a well-defined clinical entity with potentially dangerous consequences including progression to cirrhosis (2). The pathogenesis of NASH considers the occurrence of fat accumulation in the liver cell followed by a sequential series of events including an inflammatory response leading to hepatocellular injury which may lead to a fibrogenic response (3). While fat accumulation has been mainly related to insulin resistance, factors that trigger inflammation and fibrosis progression are less clear. Iron overload has been regarded as an important factor related to both insulin resistance and oxidative stress (4, 5). In fact, it has been reported that patients with hepatic steatosis have increased ferritin and transferrin saturation reflecting iron overload (6) and that iron depletion may have an insulin-sparing effect (7), which suggests a significant role of iron in the pathogenesis of fatty liver and NASH. Albeit it has been suggested that phlebotomy might be a useful treatment for NASH with concomitant iron overload, published data on the effects of iron depletion on both biochemical and histological alterations in these patients are limited.In the present communication we report a patient showing complete histological resolution of NASH after iron depletion therapy, highlighting the importance of iron overload in the occurrence of both liver fat accumulation and inflammatory changes seen in NASH.

Hepatitis C virus quasispecies in plasma and peripheral blood mononuclear cells of treatment naïve chronically infected patients.

Summary.u2002 Peripheral blood mononuclear cells (PBMCs) from 45 treatment naïve, HIV‐negative, chronically hepatitis C virus (HCV)‐infected patients were analyzed for the presence of HCV RNA. Viral RNA was detected in 73% of the studied patients. Single‐strand conformation polymorphism assays and sequence analysis of the HCV 5′untranslated regions amplified from RNA recovered from both Plasma and PBMCs suggested virus compartmentalization in 57.6% of patients studied. In summary, our study presents evidence that HCV RNA can be found in PBMCs of treatment naïve chronically infected patients that are not immunocompromised or co‐infected with the human immunodeficiency virus.

Liver transplantation for hepatocellular carcinoma: evaluation of the alpha-fetoprotein model in a multicenter cohort from Latin America.

The French alpha‐fetoprotein (AFP) model has recently shown superior results compared to Milan criteria (MC) for prediction of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) in European populations. The aim of this study was to explore the predictive capacity of the AFP model for HCC recurrence in a Latin‐American cohort.

Genetic variations in host IL28B links to the detection of peripheral blood mononuclear cells–associated hepatitis C virus RNA in chronically infected patients

Hepatitis C virus (HCV) is mainly hepatotropic; however, several reports document the presence of genomic viral RNA in extrahepatic sites including peripheral blood mononuclear cells (PBMCs). In this study, the presence of HCV RNA was initially evaluated in the plasma and peripheral blood mononuclear cells (PBMCs) of 53 HCV‐infected patients who were treated per protocol. PBMC‐associated HCV RNA was detectable in 79% of patients. Early virological response to combined pegylated interferon‐α (PegIFN) and ribavirin (RBV) therapy in patients with undetectable levels of PBMCs‐associated HCV RNA was 100%, while it was 60% (P = 0.003) in those who had detectable levels of PBMC‐associated HCV RNA. A sustained virological response was observed in 35% of patients with detectable PBMC‐associated HCV RNA, but was 70% in patients with undetectable levels of PBMC‐associated HCV RNA (P = 0.07). In a multivariate analysis incorporating parameters such as HCV genotype, viral load, presence of cirrhosis and absence of PBMC‐associated HCV RNA, a significant relationship was observed between the detection of PBMC‐associated HCV RNA and the sustained virological response (OR 19.4, 95% CI: 2.1–486.2, P = 0.0061). The association between single nucleotide polymorphism (SNP) in IL28B, known predictor of antiviral therapy outcome, and the occurrence of HCV RNA in PBMC in 84 chronically infected patients was then evaluated. Results suggest that the presence of a G allele in rs8099917, known to associate to a poor response to PegIFN/RBV therapy, also predicts an increased association of HCV RNA with PBMC (OR: 3.564; 95% CI: 1.114–11.40, P = 0.0437).

Cost Effectiveness of Daclatasvir/Asunaprevir Versus Peginterferon/Ribavirin and Protease Inhibitors for the Treatment of Hepatitis c Genotype 1b Naïve Patients in Chile

Introduction Daclatasvir and Asunaprevir (DCV/ASV) have recently been approved for the treatment of chronic hepatitis C virus infection. In association, they are more effective and safer than previous available treatments, but more expensive. It is unclear if paying for the additional costs is an efficient strategy considering limited resources. Methods A Markov model was built to estimate the expected costs in Chilean pesos (CL