Historical epidemiology of hepatitis C virus (HCV) in select countries - volume 2.

Chronic hepatitis C virus (HCV) infection is a leading cause of liver related morbidity and mortality. In many countries, there is a lack of comprehensive epidemiological data that are crucial in implementing disease control measures as new treatment options become available. Published literature, unpublished data and expert consensus were used to determine key parameters, including prevalence, viremia, genotype and the number of patients diagnosed and treated. In this study of 15 countries, viremic prevalence ranged from 0.13% in the Netherlands to 2.91% in Russia. The largest viremic populations were in India (8 666 000 cases) and Russia (4 162 000 cases). In most countries, males had a higher rate of infections, likely due to higher rates of injection drug use (IDU). Estimates characterizing the infected population are critical to focus screening and treatment efforts as new therapeutic options become available.

Strategies to manage hepatitis C virus (HCV) infection disease burden - volume 2.

The hepatitis C virus (HCV) epidemic was forecasted through 2030 for 15 countries, and the relative impact of two scenarios was considered: (i) increased treatment efficacy while holding the treated population constant and (ii) increased treatment efficacy and increased annual treated population. Increasing levels of diagnosis and treatment, in combination with improved treatment efficacy, were critical for achieving substantial reductions in disease burden. In most countries, the annual treated population had to increase several fold to achieve the largest reductions in HCV-related morbidity and mortality. This suggests that increased capacity for screening and treatment will be critical in many countries. Birth cohort screening is a helpful tool for maximizing resources. In most of the studied countries, the majority of patients were born between 1945 and 1985.

The present and future disease burden of hepatitis C virus (HCV) infections with today's treatment paradigm - volume 2.

Morbidity and mortality attributable to chronic hepatitis C virus (HCV) infection are increasing in many countries as the infected population ages. Models were developed for 15 countries to quantify and characterize the viremic population, as well as estimate the number of new infections and HCV related deaths from 2013 to 2030. Expert consensus was used to determine current treatment levels and outcomes in each country. In most countries, viremic prevalence has already peaked. In every country studied, prevalence begins to decline before 2030, when current treatment levels were held constant. In contrast, cases of advanced liver disease and liver related deaths will continue to increase through 2030 in most countries. The current treatment paradigm is inadequate if large reductions in HCV related morbidity and mortality are to be achieved.

Distribution of genetic polymorphisms associated with hepatitis C virus (HCV) antiviral response in a multiethnic and admixed population.

The prevalence of genetic polymorphisms identified as predictors of therapeutic-induced hepatitis C virus (HCV) clearance differs among ethnic groups. However, there is a paucity of information about their prevalence in South American populations, whose genetic background is highly admixed. Hence, single-nucleotide polymorphisms rs12979860, rs1127354 and rs7270101 were characterized in 1350 healthy individuals, and ethnicity was assessed in 259 randomly selected samples. The frequency of rs12979860CC, associated to HCV treatment response, and rs1127354nonCC, related to protection against hemolytic anemia, were significantly higher among individuals with maternal and paternal Non-native American haplogroups (64.5% and 24.2%), intermediate among admixed samples (44.1% and 20.4%) and the lowest for individuals with Native American ancestry (30.4% and 6.5%). This is the first systematic study focused on analyzing HCV predictors of antiviral response and ethnicity in South American populations. The characterization of these variants is critical to evaluate the risk-benefit of antiviral treatment according to the patient ancestry in admixed populations.

Relapse rates in chronic hepatitis B naïve patients after discontinuation of antiviral therapy with entecavir.

Registration studies show entecavir (ETV) to be effective and safe in NUC-naïve patients with chronic hepatitis B, but relapse rates after treatment discontinuation have not been well established. Relapse rates and predictors of relapse were evaluated in naïve HBeAg-positive and HBeAg-negative patients treated with ETV. Treatment duration was defined according to international guidelines. Virological relapse was defined as reappearance in serum of hepatitis B virus (HBV) DNA to >2000 IU/mL after discontinuation of treatment. A hundred and sixty-nine consecutive patients were treated for a median 181 weeks. 61% were HBeAg positive, 23% had cirrhosis, and mean HBV DNA level was 6.88 ± 1.74 log10 IU/mL. Ninety-two per cent became HBV DNA negative; 71% of HBeAg+ve patients became HBeAg negative and 68% anti-HBe positive; 14% became HBsAg negative and 13% anti-HBs positive. At the end of the study, 36 patients discontinued treatment: one due to breakthrough associated with resistant variants and 35 (20%) due to sustained virological response; 33 of these patients developed HBeAg seroconversion and 18 HBsAg seroconversion. Median off-treatment time was 69 weeks. Nine patients (26%), all HBeAg positive at baseline, developed virological relapse after a median 48 weeks off-treatment, 3 of them showed HBeAg reversion and 4 lost anti-HBe. No patient with HBsAg seroconversion relapsed. HBeAg clearance after week 48 of treatment was associated with an increase risk of relapse. After ETV discontinuation, HBsAg seroconversion was maintained in 100% of the patients, HBeAg seroconversion maintained in 90%, and virological relapse rate was 24%.

Fibrosis assessment in patients with nonalcoholic fatty liver disease: Adherence to proposed algorithms and barriers to complying with them.

INTRODUCTION AND AIMS: Fibrosis staging in patients with nonalcoholic fatty liver disease (NAFLD) is carried out through the application of stepwise algorithms but there is little real-world data on their use. Our aim was to calculate the number of patients with NAFLD and indeterminate or high risk for fibrosis, assessed through noninvasive scores, that consequently underwent further staging evaluation. MATERIALS AND METHODS: A cross-sectional multicenter cohort study was conducted on patients with NAFLD evaluated by hepatologists within the time frame of June 1 and July 31, 2018. The FIB-4 and NAFLD fibrosis scores were calculated in all the patients, and if at least one of the scores suggested indeterminate or high risk for fibrosis, we believed the patient should have undergone additional fibrosis staging assessment. RESULTS: The study included 238 patients. The median time interval from NAFLD diagnosis and inclusion in the analysis was 12.2 months (IQR 3.0-36.5). A total of 128 (54%) patients had at least one noninvasive score that suggested indeterminate or high risk for fibrosis but studies to confirm the fibrosis grade (elastography, biopsy, etc.) were performed on only 72 (56%). The main barriers encountered by the physicians for applying the staging algorithms were related to health insurance coverage and imaging study costs. CONCLUSIONS: A high percentage of patients with NAFLD were at indeterminate or high risk for fibrosis, according to noninvasive scores, but additional studies were carried out on only half of them, showing low adherence to current recommendations.

Fibrosis assessment in patients with nonalcoholic fatty liver disease: Adherence to proposed algorithms and barriers to complying with them. / Evaluación de fibrosis en pacientes con enfermedad por hígado graso no alcohólico: adherencia a los algoritmos propuestos y barreras para cumplir con ellos.

INTRODUCTION AND AIMS: Fibrosis staging in patients with nonalcoholic fatty liver disease (NAFLD) is carried out through the application of stepwise algorithms but there is little real-world data on their use. Our aim was to calculate the number of patients with NAFLD and indeterminate or high risk for fibrosis, assessed through noninvasive scores, that consequently underwent further staging evaluation. MATERIALS AND METHODS: A cross-sectional multicenter cohort study was conducted on patients with NAFLD evaluated by hepatologists within the time frame of June 1 and July 31, 2018. The FIB-4 and NAFLD fibrosis scores were calculated in all the patients, and if at least one of the scores suggested indeterminate or high risk for fibrosis, we believed the patient should have undergone additional fibrosis staging assessment. RESULTS: The study included 238 patients. The median time interval from NAFLD diagnosis and inclusion in the analysis was 12.2months (IQR 3.0-36.5). A total of 128 (54%) patients had at least one noninvasive score that suggested indeterminate or high risk for fibrosis but studies to confirm the fibrosis grade (elastography, biopsy, etc.) were performed on only 72 (56%). The main barriers encountered by the physicians for applying the staging algorithms were related to health insurance coverage and imaging study costs. CONCLUSIONS: A high percentage of patients with NAFLD were at indeterminate or high risk for fibrosis, according to noninvasive scores, but additional studies were carried out on only half of them, showing low adherence to current recommendations.

Loss of HBsAg antigen during treatment with entecavir or lamivudine in nucleoside-naïve HBeAg-positive patients with chronic hepatitis B.

This retrospective analysis was conducted to describe the characteristics of nucleoside-naïve hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B, who achieved hepatitis B surface antigen (HBsAg) loss during entecavir or lamivudine therapy. HBeAg-positive adults with chronic hepatitis B, elevated serum alanine aminotransferase, and compensated liver disease were randomized to double-blind treatment for up to 96 weeks with entecavir 0.5 mg/day or lamivudine 100 mg/day. HBsAg and hepatitis B virus (HBV) DNA were measured at regular intervals during and off-treatment follow-up. Through a maximum duration of 96 weeks on-treatment and 24 weeks off-treatment, HBsAg loss was confirmed in 18/354 (5.1%) patients treated with entecavir and 10/355 (2.8%) patients treated with lamivudine. Among the 28 patients with confirmed HBsAg loss, 27 (96%) achieved HBV DNA <300 copies/mL, and 27 (96%) achieved confirmed HBeAg loss. All entecavir recipients with HBsAg loss had HBV DNA <300 copies/mL. Caucasian patients, and those infected with HBV genotype A or D, were significantly more likely to lose HBsAg. This retrospective analysis of data from a randomized, global phase three trial shows that confirmed loss of HBsAg occurred in 5% of nucleoside-naïve HBeAg-positive patients treated with entecavir, and that HBsAg loss is associated with sustained off-treatment suppression of HBV DNA.

Model for end-stage liver disease-based allocation system for liver transplantation in Argentina: does it work outside the United States?

BACKGROUND: In July 2005, Argentina was the first country after the United States to adopt the MELD system. The purpose of the present study was to analyse the impact of this new system on the adult liver waiting list (WL). METHODS: Between 2005 and 2009, 1773 adult patients were listed for liver transplantation: 150 emergencies and 1623 electives. Elective patients were categorized using the MELD system. A prospective database was used to analyse mortality and probability to be transplanted (PTBT) on the WL. RESULTS: The waiting time increased inversely with the MELD score and PTBT positively correlated with MELD score. With scores >/= 18 the PTBT remained over 50%. However, the largest MELD subgroup with <10 points (n = 433) had the lower PTBT (3%). In contrast, patients with T(2) hepatocellular carcinoma benefited excessively with the highest PTBT (84.2%) and the lowest mortality rate (5.4%). The WL mortality increased after MELD adoption (10% vs. 14.8% vs. P < 0.01). Patients with <10 MELD points had >fourfold probability of dying on the WL than PTBT (14.3% vs. 3%; P < 0.0001). CONCLUSIONS: After MELD implementation, WL mortality increased and most patients who died had a low MELD score. A comprehensive revision of the MELD system must be performed to include cultural and socio-economical variables that could affect each country individually.

Characteristics of Liver Transplantation in Argentina: A Multicenter Study.

INTRODUCTION: There is a lack of information regarding outcomes after liver transplant in Latin America. OBJECTIVES: This study sought to describe outcomes after liver transplant in adult patients from Argentina. METHODS: We performed an ambispective cohort study of adult patients transplanted between June 2010 and October 2012 in 6 centers from Argentina. Only patients who survived after the first 48 hours postransplantation were included. Pretransplantation and posttransplantation data were collected. RESULTS: A total of 200 patients were included in the study. Median age at time of transplant was 50 (interquartile range [IQR] 26 to 54) years. In total, 173 (86%) patients had cirrhosis, and the most frequent etiology in these patients was hepatitis C (32%). A total of 35 (17%) patients were transplanted with hepatocellular carcinoma. In patients with cirrhosis, the median Model for End-Stage Liver Disease (MELD) score at time of liver transplant was 25 (IQR 19 to 30). Median time on the waiting list for elective patients was 101 (IQR 27 to 295) days, and 3 (IQR 2 to 4) days for urgent patients. Almost 40% of the patients were readmitted during the first 6 months after liver transplant. Acute rejection occurred in 27% of the patients. Biliary and vascular complications were reported in 39 (19%) and 19 (9%) patients, respectively. Renal failure, diabetes, and dyslipidemia were present in 40 (26%), 87 (57%), and 77 (50%) at 2 years, respectively. CONCLUSIONS: We believe the information contained in this article might be of value for reviewing current practices and developing local policies.

Access to direct-acting antivirals for the treatment of hepatitis C in a country with limited resources. / Evaluación del acceso a antivirales para el tratamiento de la hepatitis C en un país con recursos limitados.

AIMS: To estimate the number of patients that have access to treatment of hepatitis C with direct-acting antivirals in Argentina and evaluate the factors associated with the lack of access. MATERIALS AND METHODS: A cross-sectional cohort study was conducted that included all the consecutive prescriptions of direct-acting antivirals issued at health centers that participated in the ECHOTM telemedicine project directed by the Hospital Italiano de Buenos Aires, within the time frame of January 2016 and February 2017. RESULTS: A total of 143 treatment prescriptions were included and overall access was 70% (95% CI 62-77%). The only independent factor associated with a lack of treatment access was coverage by a public healthcare system (OR 4.98 [95% CI 2.05- 12.09]). CONCLUSION: Patients with hepatitis C that were covered by a public healthcare system had a 4 times higher chance of not having access to treatment with direct-acting antivirals than patients covered by other healthcare systems (private insurance or the social welfare system).

Argentine folk medicine: genotoxic effects of Chenopodiaceae family.

Chenopodium ambrosioides L. and Chenopodium multifidum L. (Chenopodiaceae), common name: Paico, are medicinal plants. They are aromatic shrubs growing in South America. For centuries, they have been used due to its medicinal properties. However, there are few reports in literature about the genotoxic effects of these plants. There for, the aim of these work is the evaluation of genetic damage induced by decoction and infusion of this plants which were assayed in different concentrations (1, 10, 100, 1,000 microL extract/mL culture), by addition of the extract to human lymphocyte cell cultures, negative controls were included. The endpoints evaluated were chromosomal aberrations (CA), sister chromatid exchanges (SCE), cell proliferation kinetics (CPK) and mitotic index (MI). The repeated measure analysis of variance was used for statistic evaluation of the results. The results showed: (a) statistical increase in the percentage of cells with CA and in the frequency of SCE when cultures were exposed to both aromatic plants, (b) a decrease in MI of both Paicos assayed, although no modification in the CPK values was observed, (c) no effect was noticed in the analysis of Chenopodium album L., which was used as negative control of the essential oil. These results suggest a cyto and genotoxic effect of Chenopodium ambrosioides and Chenopodium multifidum aqueous extracts related to the essential oil of the plant (as Chenopodium album did not perform).

Studies of portal hemodynamics and hepatic oxygen consumption during acute liver allograft rejection.

Hemodynamics and oxygen variables, plasma cytokines, and histological features of a liver tissue sample obtained by transvenous biopsy were evaluated during 65 episodes of acute rejection. The hepatic venous pressure gradient was significantly higher in patients with acute rejection than in those without (5.1+/-0.3 vs. 3.1+/-0.2 mmHg, P<0.01). The increase in pressure gradient was related to the severity of rejection lesions. Hepatic blood flow was significantly lower in patients with than in those without acute graft rejection (1.28+/-0.11 vs. 1.75+/-0.13 L/min, P<0.05). Plasma interleukin-6 levels were significantly increased in patients with acute rejection and positively correlated with pressure gradient values. In patients with acute rejection, a significant decrease in hepatic venous oxygen content (-16%) was associated with a significant increase in hepatic oxygen consumption (+24%), whereas hepatic oxygen transport did not change significantly. In treated patients with a favorable response, the pressure gradient decreased significantly by 46%, but it remained elevated in patients who later developed chronic graft rejection. In conclusion, this study confirms that acute graft rejection may induce an increase in portal pressure, which is related to the severity of rejection lesions. It also shows that acute rejection decreases hepatic blood flow and increases hepatic oxygen consumption. In addition, it suggests that the hepatic venous pressure gradient might be useful to determine the outcome of rejection.

Haemodynamic effects of octreotide in portal hypertensive rats receiving propranolol.

BACKGROUND: The aim of this study was to investigate short-term effects of propranolol (a non-selective beta-adrenergic antagonist), octreotide (a long-acting somatostatin analogue), or a combination of these substances on splanchnic and systemic haemodynamics and arterial blood gases in rats with portal vein stenosis. METHODS: Splanchnic and systemic haemodynamics were measured using the radioactive microspheres method. Eight rats first received an i.v. infusion of isotonic saline (10 microL/min for 15 min) and then an i.v. infusion of octreotide (8 micrograms.h/kg for 15 min). Eight other rats first received a bolus i.v. injection of propranolol (2 mg) and an i.v. infusion of octreotide 15 min later. RESULTS: Propranolol or octreotide alone significantly decreased portal pressure (both by 23%), portal tributary blood flow (35 and 10%, respectively) and cardiac index (36 and 26%, respectively). Octreotide administration in rats pretreated with propranolol significantly decreased cardiac index but did not change portal and arterial pressures or portal tributary blood flow. Propranolol significantly increased arterial oxygen tension. Octreotide alone or combined with propranolol significantly decreased oxyhaemoglobin saturation and pH and increased carbon dioxide tension. CONCLUSIONS: In rats with portal vein stenosis, the somatostatin analogue, octreotide, accentuates the short-term decrease in cardiac index due to propranolol. In addition, octreotide altered arterial blood gases and acid-base status. In contrast, octreotide does not further decrease portal pressure in animals receiving propranolol.

Acute and chronic haemodynamic effects of naftazone in portal hypertensive rats.

It has been demonstrated that hyperproduction of nitric oxide (NO) plays a major role in the vasodilatation of cirrhosis; thus, the vasodilatation might be reversed by an inhibition of NO production. Experimental studies in isolated aortic rings showed that naftazone inhibits the effects of NO production. The aim of this study was to evaluate the haemodynamic effects of acute and chronic administration of naftazone in rats with portal hypertension. Haemodynamic values were measured either before and 10 min after intravenous administration of 432 microg/kg of naftazone or after 4 days of oral administration of 10 mg/kg per day. Acute administration of naftazone significantly reduced portal pressure in portal vein-stenosed and cirrhotic rats. This reduction was related to a decrease in the resistance of the liver and collateral circulation and it was associated with an increased cardiac output. Oral administration of naftazone significantly decreased portal pressure in rats with portal vein stenosis; this decrease depended on a significant reduction of portal blood flow. In both groups, arterial pressure did not change significantly. These haemodynamic effects differed from those observed following prazosin or propranolol administration. However, these effects were similar but less marked than those observed following N-nitro-L-arginine administration in systemic and splanchnic arterial territories. In conclusion, acute and oral administration of naftazone significantly reduces portal pressure by two different mechanisms in portal hypertensive rats. The exact mechanism has, however, to be elucidated.

Evaluation of genetic damage induced by a nitroimidazole derivative in human lymphocytes: Tinidazole (TNZ).

One of the useful drugs in the treatment against infestations caused by Trichomonas vaginalis, Entamoeba histolytica and Giardia lamblia is Tinidazole (TNZ) 1-[2-(ethylsulfonyl) ethyl]-2-methyl-5-nitroimidazole) (Gilman R.H., Marquis G.S., Miranda E., Vestegui M., Martinez H., 1988. Rapid reinfection by Giardia lamblia after treatment in a hyperendemic third world community. Lancet i, 343-345). We decided to evaluate the potential genetic damage induced by TNZ using different biological biomarkers such as the mitotic index (MI), sister chromatid exchange (SCE) and cell proliferation kinetics (CPK). We observed a significant decrease (P<0.0005) in the MI as well as an increase (P<0.0005) in SCE frequency and no modifications in the replication index (RI). The results obtained suggest a potential genotoxic and cytotoxic effect of TNZ in human peripheral blood cultures in vitro.

In vitro genotoxic evaluation of the medicinal plant Chenopodium ambrosioides L.

Chenopodium ambrosioides (Chenopodiaceae) is an anthelmintic herb used in Latin-America's folk medicine. The aim of this work is to evaluate genetic damage induced by decoction and infusion of this plant which were assayed in different concentrations (1, 10, 100, 1000 microg/ml), by addition of the extract to human lymphocyte cell cultures. The endpoints evaluated were chromosomal aberrations (CA), sister chromatid exchanges (SCE), cell proliferation kinetics (CPK) and mitotic indexes (MI). The repeated measure analysis of variance was used for statistic evaluation of the results. The results showed (a) a statistical increase in the percentage of cells with CA and in the frequency of SCE when cultures were exposed to both preparations of Paico, (b) a decrease in MI of both preparations assayed, although no modification in the CPK values either in the infusion or in the decoction was observed. These results suggest a possible genotoxic effect of both preparations, probably due to different active principles.

Polyacrylonitrile membrane interposition between a xenograft and a patient in fulminant liver failure: the concept of xenohemodiafiltration in clinical practice.

Fulminant hepatic failure is an important cause of morbidity and mortality in intensive care units. Conventional therapies are not sufficiently effective. Liver transplantation may be life saving, but a "bridge therapy" is needed until transplantation is performed. Hepatic extracorporeal xenohemodiafiltration (XHDF) is aimed at the transitory support of a patient with fulminant hepatic failure. The first clinical case of XHDF is presented. The system consisted of cross-circulation between a porcine liver and a patient with fulminant liver failure through a polyacrylonitrile membrane. The procedure lasted for 5 hours and produced hemodynamic, biochemical, and metabolic improvements. Intracranial pressure decreased from 34 to 5 cm H2O, serum ammonia fell from 673 to 370 ng/dl, lactic acid from 11 to 5.3 mmol/L, and bilirubin from 7.4 to 2.5 mg/dl. Hemodynamic values were maintained stable throughout the procedure. The patient was able to undergo transplantation and remains alive 11 months later. XHDF is a clinical experimental method that can constitute an alternative clinical therapy to support patients with fulminant hepatic failure until an organ is available for transplantation.

[Influence of anemia on hemodynamic changes in patients with cirrhosis]. / Influence de l'anémie sur les modifications hémodynamiques des malades atteints de cirrhose.

OBJECTIVE: The aim of this retrospective study was to evaluate the systemic and splanchnic hemodynamic changes induced by anemia in patients with cirrhosis. METHOD: 148 patients (Child-Pugh A: 46 patients, Child-Pugh B: 64 patients and Child-Pugh C: 38 patients) were included in the study. Anemia was defined by a blood hemoglobin level < 12 g/dL. A systemic and splanchnic hemodynamic study was performed in all patients. RESULTS: A significant elevation of the hepatic venous pressure gradient was observed in Child-Pugh A patients with anemia but not in Child-Pugh B and C patients. In the 2 latter groups, cardiac index was significantly increased and systemic vascular resistance decreased in patients with anemia. CONCLUSION: Anemia may worsen the hemodynamic changes associated with cirrhosis.

[Multifocal biliary papillomatosis: an indication for liver transplantation]. / Papillomatose multifocale des voies biliaires: une indication de transplantation hépatique.

Biliary papillomatosis is a uncommon disease. Because of the high rate of recurrence and the possibility of malignant transformation, liver resection or transplantation was recommended. A case of diffuse bilobar biliary papillomatosis, in a 60 years old patient, responsible for cholangitis, cholestasis and for high portal pressure (esophageal varices grade I and II and hypersplenisme) is reported. The patient had had an external biliary drainage leading to an great loss of hydroelectrolytic component important. Opacification and biopsies under endoscopic control assert the right diagnosis. He was treated by a orthotopic liver transplantation. Post operative course was simple. In the 9th month, it was asymptomatic with a completely satisfactory evolution. The other therapeutic modalities was discussed, as well as the review of the literature.