Impact of hepatitis C oral therapy in portal hypertension

World J Gastroenterol. Jul 14, 2017; 23(26): 4669-4674
Published online Jul 14, 2017. doi: 10.3748/wjg.v23.i26.4669

Impact of hepatitis C oral therapy in portal hypertension
Diogo Libânio, Rui Tato Marinho

Abstract
Chronic hepatitis C is a leading cause of morbidity and mortality, mainly related to fibrosis/cirrhosis and portal hypertension. Direct antiviral agents are highly effective and safe and can now cure > 90% of the patients. Sustained viral response (SVR) after interferon-based regimens has been associated with improvement in liver function, fibrosis and portal hypertension in a significant proportion of patients, although a point of no return seems to exist from which viral elimination is no longer capable of preventing portal hypertension progression and liver decompensation. Indeed, although SVR is associated with improvement of hepatic venous pressure gradients and therefore a decreased risk of de novo esophageal varices, several studies show that viral clearance does not eliminate the risk of variceal progression, liver decompensation and death in patients with pre-established portal hypertension. Although evidence about the effects of direct antiviral agents (DAAs) on clinically significant outcomes is still scarce and with short follow-up, DAAs can decrease the burden of the disease if patients are timely treated before significant fibrosis and portal hypertension develops. Studies with longer follow-up are waited to establish the real magnitude of hepatitis C treatment on portal hypertension. Future studies should also focus on predictors of portal hypertension resolution since it can influence management and avoid unnecessary monitoring

Core tip: Hepatitis C is associated with significant morbidity and mortality, mainly through portal hypertension complications. Hepatitis C treatment is associated with improvement of liver function and fibrosis, better quality of life and reduced mortality. The knowledge of the impact of viral clearance on portal hypertension is also relevant because it greatly influences clinical outcomes and can influence management after treatment. Several studies show that the benefits on portal hypertension are higher if treatment is delivered before clinically significant portal hypertension is developed, encouraging timely and early treatment with the highly efficacious and safe direct antiviral agents.

INTRODUCTION

Chronic hepatitis C is a leading cause of morbidity and mortality worldwide mainly due to complications of cirrhosis, portal hypertension and hepatocellular carcinoma. Hypertensive bleeding is the most significant complication of portal hypertension, being associated with a high early mortality (20% at 6 wk)[1]. Mortality attributed to viral hepatitis has been increasing in the last decades and viral hepatitis was the seventh leading cause of death worldwide in 2013[2].

Direct antiviral agents (DAAs) are highly effective and safe and are changing the prognosis and burden of the disease. Sustained virologic response (SVR) is now achieved in > 90% of the patients and is associated with improvements in liver function, fibrosis and overall survival. Portal hypertension is also expected to improve with virological response, paralleling the improvements in liver inflammation and liver fibrosis. Liver transplantation due to viral hepatitis C can also decrease in the next years[3]. The knowledge of the effects of hepatitis C virus (HCV) elimination on clinically significant outcomes like portal hypertension and its complications is thus of unremarkable importance since it can influence management after SVR and is the focus of this report.

IMPACT OF SVR IN PORTAL HYPERTENSION BEFORE DAAs

Prior to DAAs development HCV treatment was mainly recommended in patients with advanced fibrosis or cirrhosis, in order to balance treatment benefits with the risk of liver complications and treatment adverse events. SVR was achieved in 40%-60% of cases with interferon (INF) based therapies and was associated with improvements in liver fibrosis, portal hypertension, liver-related adverse events, liver-related mortality, overall mortality and decreased HCC incidence[4-7]. HCV therapy was also associated with quality of life improvement, namely reducing decompensation and hospitalization rates[8,9].

Liver fibrosis, a major determinant of portal hypertension, was shown to improve in several studies using paired liver biopsies[10-13] and non-invasive biomarkers[12,14]. However, a “point of no return” seems to exist for both liver fibrosis, liver function and portal hypertension. Indeed, in a large cohort of INF-treated patients, 740/1094 (68%) of the patients who achieved SVR maintained fibrosis stage 20 mo after treatment and fibrosis improved in only 277/1094 (25%)[10].

Concerning portal hypertension, SVR was associated with a statistically significant yet modest decrease in hepatic venous pressure gradient (HVPG) 6 mo after INF-based therapy[15]. In a small study including 8 patients who achieved SVR with antiviral triple therapy there was a significant decrease in both HVPG and liver stiffness 24 wk after therapy (10.3 mmHg vs 6.1 mmHg and 21.3 kPa vs 6.4 kPa, P < 0.001), with 5 patients (62.5%) achieving an HVPG < 6 mmHg[16]. Indirect markers of portal hypertension such as platelet count[17-19] and spleen size[17] were also shown to improve after HCV eradication in INF-treated cirrhotic patients.

Concerning clinical endpoints after HCV eradication, a prospective study with 12 years follow-up showed a lower incidence of esophageal varices in Child A cirrhotic patients with SVR (0% vs 32%-39% in the untreated/non-SVR group)[20]. A lower incidence of de novo esophageal varices was also reported in cirrhotic patients who achieved SVR, although the progression of variceal size was not statistically different in patients with and without SVR[21], supporting the concept of the point of no return. Another prospective study by Di Marco et al[22] also showed that SVR was associated with a lower incidence of de novo esophageal varices in cirrhotic patients treated with PEG-INF and ribavirin (HR = 0.23, 95%CI: 0.11-0.48), although it was not associated with a decrease in variceal progression or liver decompensation in those with pre-existing varices[22].

Petta et al[23] also reported a reduced incidence of de novo esophageal varices in patients with SVR (3.4% vs 37.4%) On the other hand, although SVR was associated with a decrease in liver decompensation and mortality at 10 years, patients with esophageal varices at baseline had an increased risk of decompensation and death. Further supporting these findings, Lens et al[24] recently reported that cirrhotic patients with clinically significant portal hypertension at baseline remain at risk for liver decompensation after 5 years, regardless of SVR. In these study, although SVR was associated with a non-statistically significant decrease in HVPG, a higher baseline HVPG was found as the only predictor of liver decompensation at multivariate analysis.

Besides the absence of improvement in HVPG, other factors may also influence the development of complications of portal hypertension after SVR. Indeed, Nagaoki et al[25] reported that portosystemic collateral shunts at baseline (assessed by CT) were associated with exacerbation of esophageal varices and hepatic encephalopathy after SVR. Cofactors for liver disease such as obesity, alcohol consumption and hepatitis B may also contribute to minor improvement in portal hypertension after HCV eradication.

IMPACT OF SVR IN PORTAL HYPERTENSION WITH DAAs

In order to accomplish the goal of HCV elimination as an important health public threat by 2030[26], HCV treatment is nowadays recommended in almost all infected patients, even those without significant fibrosis[27]. This, together with the high SVR rates and the safety profile of DAAs, can change the history of HCV infection and improve clinical outcomes namely avoiding the development of portal hypertension and its improvement in patients with patients with established portal hypertension.

Liver fibrosis has also been shown to improve after INF-free DAA treatments, based on serum fibrosis biomarkers[28,29] and transient elastography[29,30]. SVR, liver function and fibrosis are undoubtedly important endpoints to assess the efficacy of HCV treatment, although portal hypertension and its complications (i.e., liver decompensation and liver-related mortality) may be more adequate to assess treatment effectiveness. In fact, the knowledge of the impact of DAA treatments in portal hypertension and cirrhosis complications may influence patient management after achieving SVR. Due to the novelty of DAA INF-free therapies (and thus short follow up times) there are only few studies assessing the effects of HCV novel treatments on portal hypertension and clinical decompensation.

In patients successfully treated with DAAs, fibrosis and MELD score were shown to improve[31-33]. The decrease in necroinflammation along with fibrosis improvement can decrease intrahepatic resistance and thus portal pressure. In particular, improvement of liver inflammation, aminotransferases and liver function early during treatment can explain the rapid decreases in HVPG and liver stiffness that were found in some studies.

A well designed retrospective study conducted by the Austrian group evaluated the changes in HVPG and liver stiffness in 60 cirrhotic patients (84% Child A) treated with various combinations of DAAs[34]. SVR led to a reduction in HVPG in 80% of the patients (mean HVPG change -2.63 ± 0.38 mmHg, P < 0.001). Importantly, in the subgroup of patients with clinically significant portal hypertension (≥ 12 mmHg) at baseline, 63% achieved a HVPG decrease ≥ 10% and a decrease > 20% or to < 12 mmHg was found in 51%, at a median of 114 d after treatment. This beneficial effect was found in all strata of HVPG, although portal hypertension was less likely to improve in Child B patients. Liver stiffness and platelet counts improvements were also associated with SVR.

In another study including 33 cirrhotic patients treated with 48 wk sofosbuvir + ribavirin with clinically significant portal hypertension at baseline, 24% achieved a ≥ 20% decrease in HVPG at the end of treatment, although the median HVPG change in the entire cohort was modest (-0.5 mmHg)[35]. Interestingly, higher baseline MELD score was associated with a higher HVPG response (P = 0.04). Longer follow-up results of this trial are waited since the full effects of SVR on architectural changes and fibrosis improvement may have their effects later on time. Indeed, a more pronounced liver stiffness improvement was found between baseline and end of treatment than between end of treatment and 6 mo after, suggesting an important role of necroinflammation on the early improvements in liver stiffness[36]. Deterding et al[37] suggested a two-phasic decline of portal hypertension consisting of a first rapid phase during treatment (associated with improved inflammation) followed by a slower second phase after 6-12 mo (associated with fibrosis regression). This hypothesis will surely be tested and hopefully confirmed when longer follow-up results become available.

The results of the few studies evaluating the changes in portal hypertension shortly after DAA treatment thus suggest that portal hypertension improves quickly during and after HCV eradication, which can lead to improvements in clinically significant outcomes such as variceal bleeding, ascites and encephalopathy. This theoretical concept can favor the treatment of patients with decompensated cirrhosis in whom INF-treatments were previously contraindicated. However, treatment in this setting is still a matter of debate. Indeed, although HCV eradication can decrease Child-Pugh and MELD scores in a subset of patients (decreasing the need of liver transplantation), it does not necessarily improve liver function and portal hypertension sufficiently to the point of a compensated patient with a functional live and the need for liver transplantation may persist but be delayed due to the MELD decrease (MELD purgatory).

CONCLUSION

The available evidence shows that HCV eradication with both INF-based and DAA INF-free therapies can improve liver fibrosis and portal hypertension. The evidence of portal hypertension improvement with DAAs is still scarce but consistent with a rapid and significant improvement, which can also improve clinically significant outcomes such as variceal bleeding. However, data suggest that a point of no return exist, encouraging early treatment before the development of significant fibrosis and portal hypertension. DAA therapy, with its extremely high efficacy and safety profile, have an undoubtedly important role since it allows the cure of almost all infected patients, preventing fibrosis and portal hypertension and improving clinical outcomes.

As we have seen, patients with established portal hypertension can improve although for now there are no data about the long term effects of DAAs. The available evidence is mainly based on retrospective studies with heterogeneous populations and endpoints definitions. As randomized controlled trials with active treatment and control groups are not ethically acceptable at this time point, the best studies to answer these unsolved questions are prospective studies with well-defined inclusion and exclusion criteria, well-defined clinically significant endpoints and with long follow-up. We suggest that further studies include patients along the spectrum of HCV infection (from asymptomatic with minimal liver damage to cirrhotic patients) with stratification according to the stage of liver disease (ideally evaluated by non-invasive methods validated in HCV infection such as elastography and non-invasive markers of fibrosis). Additionally, the assessed endpoints should be clinically significant and well defined (e.g., variceal enlargement from small to large varices, de novo ascites, encephalopathy and hypersplenism) and follow-up should be longer than 5 years to evaluate the true impact of HCV treatment according to the stage of liver damage. Data collection should include an adequate characterization of disease stage at the beginning and at the end of follow-up (including aminotransferases, platelet count, ultrasound findings, liver stiffness, presence of ascites, varices and encephalopathy). These studies should then assess the treatment effects according to the stage of liver disease and should compare patients who achieve SVR with patients in whom these endpoint is not achieved.

Future studies should also focus on predictors of portal hypertension resolution since it can influence management and avoid unnecessary monitoring in the subset of patients with a very low probability of having clinically significant portal hypertension after treatment. Evaluation of molecular markers of extracellular matrix and hepatic stellate cell remodeling such as hyaluronic acid or alpha-2 macroglobulin may also have an investigational interest to assess if they can be a surrogate marker of the point of no return. The role of pre-existing significant porto-systemic shunts should also be evaluated.

Until the answers to these questions are available, screening for varices is still recommended in cirrhotic patients although recent Baveno VI consensus suggest that patients with Fibroscan^® < 20 kPa and platelet count above 150000/μL can avoid screening endoscopy[38]. In patients who undergo screening endoscopy and no varices are found, a follow-up screening after 3 years is still recommended if SVR was achieved and there are no cofactors (a 2 year interval is advised if there is ongoing liver injury).

Concerning patients with established portal hypertension and varices before treatment, the effects of SVR on variceal progression and on bleeding rates are also still unknown and should be evaluated in future studies. For now, those with small varices who achieved SVR and without cofactors should undergo follow-up endoscopy in 2 years, while patients with large varices should undergo primary prophylaxis and adequate management[38]. It should be also noticed that HCC surveillance should be continued in patients with F3 fibrosis or greater[27].

In conclusion, the development of portal hypertension can be prevented and it can be improved in a significant proportion of patients as long as the treatment is delivered in a timely manner, before the point of no return. The long-term effects of DAAs on portal hypertension are not completely established and studies with longer follow-up are needed, but there is evidence from studies of the pre-DAA era that show significant benefits of SVR on portal hypertension, encouraging early treatment before significant fibrosis (F3/F4) and portal hypertension are established.

References

Source

https://www.wjgnet.com/1007-9327/full/v23/i26/4669.htm

Patient Friendly Video On Managing Medications With Liver Disease & Cirrhosis

Cirrhosis - Managing Medications with Liver Disease



Published on Jun 27, 2017
Source - American Liver Foundation Great Lakes Division

A quick overview on the safety and use of medications commonly used to treat various complications of cirrhosis.

Topic Highlights
Lactulose
Rifaximin
Water Pills - Diuretics
Antibiotics
Over The Counter Drugs (OTC) - Drugs with hidden acetaminophen (Tylenol)
Herbal Products
Prescription drugs that can cause confusion
Hepatitis C Medications
Transplant Medications

Conatus Announces emricasan Phase 2 study reduces liver portal hypertension predominantly due to NASH or HCV

Press Release

Conatus Announces Top-line Results From Multicenter Phase 2 Portal Hypertension Clinical Trial in Patients With Liver Cirrhosis

September 23, 2015 16:01 ET | Source: Conatus Pharmaceuticals

- Emricasan Significantly Lowered Portal Pressure in Patients With Severe Portal Hypertension -

- Conference Call and Webcast Presentation at 8:30 a.m. ET on Thursday, September 24 -

SAN DIEGO, Sept. 23, 2015 (GLOBE NEWSWIRE) -- Conatus Pharmaceuticals Inc. (NASDAQ:CNAT) today announced that the company's exploratory Phase 2 Portal Hypertension (PH) clinical trial of emricasan, a first-in-class, orally active pan-caspase inhibitor, met the following primary endpoints: a) a clinically meaningful and statistically significant change from baseline in hepatic venous pressure gradient (HVPG), a measurement of pressure in the portal vein, in patients with liver cirrhosis and severe portal hypertension (HVPG ≥12 mmHg); and b) a statistically significant change from baseline in cleaved Cytokeratin 18 (cCK18), a mechanism-specific biomarker of excessive cell death that contributes to chronic inflammation, in the total evaluable liver cirrhosis patient population.

The open-label PH trial was conducted at nine U.S. sites and enrolled 23 patients (22 evaluable) with portal hypertension and compensated liver cirrhosis that was predominantly due to nonalcoholic steatohepatitis (NASH) or hepatitis C virus (HCV), including patients with active HCV infection and patients who had a sustained viral response (SVR) to antiviral therapy. Portal hypertension, or elevated blood pressure in the major vein feeding into the liver, was confirmed by HVPG measurement >5 mmHg at baseline and measured again after treatment with 25 mg of emricasan orally twice daily for 28 days. Patients were divided according to the HVPG therapeutic threshold of 12 mmHg, which indicates more severe portal hypertension. Reducing the HVPG to below 12 mmHg or reducing HVPG by ≥10% or ≥20% has been strongly associated with clinical benefit in this patient population.

The HVPG endpoint was analyzed in: a) patients with baseline HVPG values ≥12 mmHg (N=12); b) patients with baseline HVPG values <12 mmHg (N=10); and c) all evaluable patients (N=22). HVPG measurement was standardized, and tracings were evaluated by a single expert reader not otherwise involved in the PH trial. HVPG decreased by a mean of 3.7 mmHg from the mean baseline of 20.6 mmHg in the higher baseline HVPG group (p<0.003), with 8 of 12 achieving a ≥10% decrease, 4 of 12 achieving a ≥20% decrease, and 2 of 12 achieving reductions below 12 mmHg. The changes from baseline HVPG were not statistically significant in the lower baseline HVPG group (+1.9 mmHg mean increase from mean baseline of 8.1 mmHg; p=0.12) or the total evaluable patient population (–1.1 mmHg from mean baseline of 15.2 mmHg; p=0.26). The cCK18 endpoint, analyzed in the total evaluable patient population, showed a statistically significant reduction (p<0.03) from baseline. Consistent with results from prior trials, emricasan was safe and well tolerated in the PH trial, with no dose-limiting toxicities and no drug-related serious adverse events. Detailed results are expected to be presented in a future scientific forum.

As liver cirrhosis progresses, portal pressure increases and hepatic function is eventually lost. Importantly, portal hypertension is largely responsible for events of hepatic decompensation including variceal bleeding, ascites, and encephalopathy, which contribute substantially to morbidity and mortality in these patients. By lowering elevated portal pressures, emricasan has the potential to decrease the risk of hepatic decompensation in liver cirrhosis patients over the short term, and may improve both liver function and structure over the long term through anti-inflammatory and anti-fibrotic effects.

David T. Hagerty, M.D., Executive Vice President of Clinical Development at Conatus, said, "We were excited to demonstrate that a drug candidate with the potential to achieve long-term resolution of fibrosis and cirrhosis also has the ability to induce a rapid and clinically meaningful reduction of severe portal hypertension. The reduction of portal pressure over a relatively short time frame in the patients with therapeutically relevant portal hypertension may reflect the initial impact of emricasan on the hyperdynamic circulation that is the predominant contributor to portal hypertension as cirrhosis progresses and/or a direct effect upon intrahepatic vasculature resistance. Future studies will be needed to assess the relative contribution of these mechanisms to the observed clinical effect. Decreasing HVPG has been identified by the FDA (U.S. Food and Drug Administration) as a validated, objective measure that may be acceptable as a surrogate endpoint for clinical trials of patients with liver cirrhosis. These results set the stage for future Phase 2b clinical trials in patients with cirrhosis and therapeutically relevant portal hypertension."

"These results demonstrate that emricasan can cause a clinically meaningful improvement in portal hypertension in the liver cirrhosis patients who need it most," said Conatus co-founder, President and Chief Executive Officer Steven J. Mento, Ph.D. "Specifically, patients with therapeutically relevant baseline portal hypertension showed meaningful decreases in HVPG. We believe the results from this trial establish the near-term effects of emricasan on portal hypertension. We are evaluating emricasan's potential longer-term effects on liver function and liver structure in our other two ongoing clinical trials: the Phase 2 Liver Cirrhosis (LC) trial and the Phase 2b post-transplant trial."

"Even though the number of patients in this trial was small," added Dr. Hagerty, "Conatus was encouraged by the consistency of responses in patients with portal hypertension and cirrhosis due primarily to NASH or HCV. These results further support our view that apoptosis and inflammation are important common mechanisms for progressive liver disease across multiple etiologies, and that treatment with emricasan is likely to provide both short- and long-term clinical benefits."

Conference Call/Webcast/Presentation

Conatus will host a conference call and webcast at 8:30 a.m. Eastern Time on Thursday, September 24, to discuss the top-line results and provide a mechanism-focused overview of liver cirrhosis and portal hypertension. To access the conference call, please dial 877-312-5857 (domestic) or 970-315-0455 (international) at least five minutes prior to the start time and refer to conference ID 45793794. An associated presentation and live and archived audio webcast of the call will be available in the Investor Center of the company's website at http://ir.conatuspharma.com/events.cfm.

About Emricasan Clinical Development

To date, emricasan has been studied in over 600 subjects in fifteen clinical trials across a broad range of liver disease etiologies and stages of progression. In multiple clinical trials, emricasan has demonstrated statistically significant, rapid and sustained reductions in elevated levels of key biomarkers of inflammation and apoptosis that are implicated in the severity and progression of liver disease. Importantly, these key biomarkers are known to be elevated and to have prognostic value in multiple hepatic indications that Conatus is currently pursuing. The company's ongoing Phase 2 LC trial is evaluating emricasan's potential medium-term effect on liver function using two other potential surrogate clinical endpoints – Model for End-Stage Liver Disease (MELD) score and Child-Pugh-Turcotte (CPT) status. The company also is evaluating emricasan's potential longer-term effects on liver structure in its ongoing Phase 2b clinical trial in post-orthotopic liver transplant (POLT) recipients who have reestablished liver fibrosis or cirrhosis post-transplant as a result of recurrent HCV infection and have successfully achieved a SVR following HCV antiviral therapy (POLT-HCV-SVR). The company currently is developing a strategy for initial registration of emricasan as a potential treatment for patients with liver cirrhosis.

About Conatus Pharmaceuticals

Conatus is a biotechnology company focused on the development and commercialization of novel medicines to treat liver disease. Conatus is developing its lead compound, emricasan, for the treatment of patients with chronic liver disease. Emricasan is a first-in-class, orally active pan-caspase inhibitor designed to reduce the activity of enzymes that mediate inflammation and apoptosis. Conatus believes that by reducing the activity of these enzymes, emricasan has the potential to interrupt the disease progression across the spectrum of liver disease. For additional information, please visit www.conatuspharma.com.

Forward-Looking Statements
This press release contains forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended. All statements other than statements of historical facts contained in this press release are forward looking statements, including statements regarding: presenting detailed results of the PH trial in a future scientific forum; emricasan's potential to decrease risk of hepatic decompensation; emricasan's potential to improve both liver function and structure through anti-inflammatory and anti-fibrotic effects; emricasan's potential to achieve long-term resolution of fibrosis and cirrhosis; emricasan's potential impact on hyperdynamic circulation and/or intrahepatic vasculature resistance; the acceptability of HVPG as a surrogate endpoint for clinical trials of patients with liver cirrhosis; whether the results from the PH trial establish the near-term effects of emricasan on portal hypertension or allow for future Phase 2b clinical trials in patients with cirrhosis and therapeutically relevant portal hypertension; emricasan's longer-term effects on liver function and liver structure; the importance of apoptosis as a common mechanism for progressive liver disease and that inhibiting apoptosis with emricasan is likely to be of both short- and long-term clinical benefit; the utility of MELD and CPT as potential surrogate clinical endpoints; the potential for emricasan to be a treatment for liver cirrhosis patients; and emricasan's potential to interrupt the disease progression across the spectrum of liver disease. In some cases, you can identify forward-looking statements by terms such as "may," "will," "should," "expect," "plan," "anticipate," "could," "intend," "target," "project," "contemplates," "believes," "estimates," "predicts," "potential" or "continue" or the negative of these terms or other similar expressions. These forward-looking statements speak only as of the date of this press release and are subject to a number of risks, uncertainties and assumptions, including: Conatus' ability to initiate and successfully complete current and future clinical trials; Conatus' ability to evaluate emricasan's potential medium-term and longer-term effects on liver function and liver structure in its other two ongoing clinical trials; Conatus' ability to develop a registration strategy and pathway for emricasan; Conatus' dependence on its ability to obtain regulatory approval for, and then successfully commercialize emricasan, which is Conatus' only drug candidate; Conatus' reliance on third parties to conduct its clinical trials, enroll subjects, manufacture its preclinical and clinical drug supplies and manufacture commercial supplies of emricasan, if approved; the potential that earlier clinical trials may not be predictive of future results; potential adverse side effects or other safety risks associated with emricasan that could delay or preclude its approval; results of future clinical trials of emricasan; the potential for competing products to limit the clinical trial enrollment opportunities for emricasan in certain indications; the uncertainty of the FDA's and other regulatory agencies' approval processes and other regulatory requirements; Conatus' ability to fully comply with numerous federal, state and local laws and regulatory requirements applicable to it; Conatus' limited operating history and its ability to operate successfully as a public company; Conatus' ability to obtain additional financing in order to complete the development and commercialization of emricasan; and those risks described in Conatus' prior press releases and in the periodic reports it files with the Securities and Exchange Commission. The events and circumstances reflected in Conatus' forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking statements. Except as required by applicable law, Conatus does not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise.MEDIA: David Schull Russo Partners, LLC (858) 717-2310 INVESTORS: Alan Engbring Conatus Pharmaceuticals Inc. (858) 376-2637

Can we Reduce Muscle Cramps in Patients with Cirrhosis?

Can we Reduce Muscle Cramps in Patients with Cirrhosis?

Kristine Novak

L-carnitine appears to be safe and effective for reducing muscle cramps in patients with cirrhosis, researchers report in the August issue of Clinical Gastroenterology and Hepatology.

Many patients with cirrhosis develop frequent muscle cramps, which reduce their quality of life. L-carnitine (L-beta-hydroxy-gamma-N-trimethyl aminobutyric acid) is an amino acid that transports long-chain fatty acids across the mitochondrial membrane, and has been proposed to provide energy for skeletal muscle. Hiroyuki Nakanishi et al evaluated its effects on muscle cramps in a prospective study.

Consecutive patients with cirrhosis and muscle cramps were given L-carnitine (300 mg) 3 times/day (900 mg/day total, n = 19) or 4 times/day (1200 mg/day total, n = 23) for 8 weeks. The frequency of muscle cramps was assessed by questionnaires, and the degree of muscle cramping was assessed by the visual analogue scale (VAS).

The VAS is a horizontal, 100 mm line with word descriptors at each end (left, totally without pain and right, unbearable pain). Patients mark points on the line the point that best indicates their current state. The VAS score is then determined by measuring millimeters from the left end of the line to the marked points.

At the end of the 8 week study period, muscle cramps decreased in 88.1% of all subjects; 28.6% of patients had no cramps at al.

Overall VAS scores decreased significantly, from a mean value of 69.9±22.5 at baseline to 26.2±29.1 after 8 weeks.

Muscle cramps were reduced in 43.5% of patients in the 1200 mg/day group and 10.5% in the 900 mg/day group. At the end of the 8-week study period, mean VAS scores were 9.9±13.5 in the 1200 mg/day group and 39.6±31.9 in the 900 mg/day group (see figure).

Nakanishi et al did not observe any adverse events.

VAS scores before and after 8 weeks of L-carnitine. Black lines indicate the 1200 mg group, gray the 900 mg group. (A) Overall, the mean VAS score was reduced significantly from 69.9 ± 22.5 to 26.2 ± 29.1 after 8 weeks of therapy. (B) VAS scores after 8 weeks were significantly lower in 1200 mg group than in 900 mg group

Why do patients with cirrhosis develop cramps, and why might L-carnitine reduce them? An analysis of skeletal muscle biopsies from patients with cirrhosis and found reductions in ATP, phosphocreatine, and total adenine nucleotides. Deficiencies in ATP result in insufficient dissociation of myosin from actin, and thereby prolonged muscle contraction and cramping.

Carnitine transports long-chain acyl groups from fatty acids into the mitochondrial matrix, so they can be broken down through β-oxidation to acetyl CoA to obtain usable energy via the citric acid cycle.

This process provides ATP for heart and skeletal muscles. Nakanishi et al propose that some patients with cirrhosis could have carnitine deficiency. Larger, randomized, controlled studies are necessary to further evaluate the efficacy of L-carnitine in reducing muscle cramps in patients with cirrhosis and other disorders.

http://journalsblog.gastro.org/can-we-reduce-muscle-cramps-in-patients-with-cirrhosis/

View All Articles:  AGA Journals Blog

Cirrhosis and decompensation are common among people with chronic hepatitis C

Cirrhosis and decompensation are common among people with chronic hepatitis C
Liz Highleyman
Produced in collaboration with hivandhepatitis.com

More than one-quarter of people with chronic hepatitis C at Kaiser-Permanente developed liver cirrhosis over 12 years and 40% of these experienced decompensation – higher rates than expected, according to a presentation at the recent Digestive Disease Week 2015 meeting in Washington, DC. The study also found that cirrhosis and decompensation were associated with comorbid conditions, supporting the idea of hepatitis C as a systemic disease.

Over years or decades, chronic hepatitis C virus (HCV) infection can lead to serious liver disease including advanced fibrosis, cirrhosis, liver cancer, decompensated liver failure and the need for a liver transplant. People with decompensation – which occurs when the liver can no longer carry out its vital functions – may develop ascites (abdominal fluid accumulation), bleeding varices (enlarged veins) in the oesophagus or stomach and hepatic encephalopathy (brain impairment).

Continue reading...

Video Weekend: Hepatitis C - Understanding The Liver, and Cirrhosis

Video Weekend: Understanding The Liver, and Cirrhosis

Good afternoon folks, welcome to our first edition of video weekend. Today's innovative videos offer a better understanding of HCV, how the liver works, possible disease complications, and a quick look at treatment, brought to you by Armando Hasudungan and Joe Galati, M.D.  

Knowledge Is Power

The phrase “knowledge is power” is a profound one to be sure, especially when applied to hepatitis C. Acquiring knowledge about hepatitis C can lead to an early diagnosis, a cure, and important management strategies to treat complications of this sometimes life-threatening virus. For most people, this can be an enormous undertaking, one that is made easier through self-education, advocacy and loving support.  

Hepatitis C is a serious disease, affecting almost 3 percent of the population worldwide, and up to 60-80 percent of those infected will go on to develop a chronic infection. In addition, more than 350,000 people die yearly from hepatitis C related diseases.

Disease Progression
The natural history of hepatitis C still remains controversial, research indicates that liver damage such as fibrosis or cirrhosis can take decades to develop. In an interesting article, found here, researchers named alcohol intake, co-infection with HBV or HIV, smoking, diabetes, obesity, age at time of infection, and duration of HCV infection, as several host factors relevant in determining the progression of hepatitis C. The latter two proved to be key factors associated with higher mortality risk.

Links
To learn more about the basics of HCV click here, newly diagnosed click here, and finally for treatment information, click here.

Videos
Please take a few moments to view these engaging artful, and informative videos. Hopefully they will help you better understand the liver and various aspects of hepatitis C.

Liver Anatomy and Blood Supply

Uploaded By Armando Hasudungan
Find Armando Hasudungan on Facebook

**Mr. Hasudungan's commentary will slow down after his introduction



Microbiology - Hepatitis C Virus

Uploaded By Armando Hasudungan

Liver Cirrhosis - Complications and Symptoms 

Uploaded By Armando Hasudungan

What Is Hepatic Encephalopathy? Information For Patients
View All Joe Galati, M.D.,Videos 
Website



Approved New Hepatitis C Treatment: Solvadi/Sofosbuvir
Joe Galati, M.D.

Stay well and enjoy the rest of your weekend.
Always Tina

Liver cancer screening highly beneficial for people with cirrhosis

Liver cancer screening highly beneficial for people with cirrhosis

Dr. Amit Singal, Assistant Professor of Internal Medicine and Clinical Sciences, and Medical Director of the Liver Tumor Clinic in the Harold C. Simmons Cancer Center

DALLAS – May 5, 2014 – Liver cancer survival rates could be improved if more people with cirrhosis are screened for tumors using inexpensive ultrasound scans and blood tests, according to a review by doctors at UT Southwestern Medical Center.

The meta-analysis of 47 studies involving more than 15,000 patients found that the three-year survival rate was much higher among patients who received liver cancer screening – 51 percent for patients who were screened compared to 28 percent of unscreened patients. The review also found that cirrhosis patients who were screened for liver cancer were more likely to receive curative treatment rather than palliative, or end-of-life, care.

“Curative therapies, such as surgery or a liver transplant, are only available if patients are found to have liver cancer at an early stage. Unfortunately, right now, only a minority of patients’ cancers are found at an early stage,” said Dr. Amit Singal, Assistant Professor of Internal Medicine and Clinical Sciences, and Medical Director of the Liver Tumor Clinic in the Harold C. Simmons Cancer Center, the only National Cancer Institute-designated cancer center in North Texas and one of just 66 NCI-designated cancer centers in the nation.

Rick Curiel, 60, of Forney, Texas, said liver cancer screening saved his life. Mr. Curiel, one of Dr. Singal’s patients, had cirrhosis and a 2012 screening found tumors on his liver. The cancer was surgically treated at the Simmons Cancer Center, paving the way for him to have a life-saving liver transplant at UT Southwestern in 2013.

“Without the screening, they wouldn’t have discovered it,” said Mr. Curiel who was eventually able to return to work installing hardwood floors. “I am living proof that this works.”

Liver cancer is the third leading cause of cancer-related deaths worldwide. People with cirrhosis are at a higher risk for liver cancer, with 3 to 5 percent of those with cirrhosis developing liver cancer every year. The rate at which the incidence of liver cancer is increasing is one of the fastest among all solid tumors in the U.S.

Dr. Singal’s findings, published in the Public Library of Science Medical Journal, are particularly significant for Texas because the state has high rates of fatty liver disease and Hepatitis C, both of which are correlated with cirrhosis. Texas also has the second highest incidence of hepatocellular carcinoma, or HCC, the most common type of liver cancer in the U.S. Many cases of HCC can be caught early with screening.

“We have a simple test, an abdominal ultrasound which is painless and easy, but we found that less than 20 percent of at-risk people have the test done, largely due to providers failing to order it,” Dr. Singal said.

He said he hopes his study will encourage both patients and doctors to request the test.

Dr. Singal pointed out that liver cancer screening is not yet recommended by the United States Preventative Services Task Force, in part because a randomized study has not yet been done, which points to a conundrum in the field. When a randomized study was attempted in 2005, many patients opted out when they heard evidence that liver cancer screening could be so beneficial. None of the patients wanted to be the ones randomly chosen to not get the tests.

Dr. Singal hopes his findings will convince more cirrhosis patients and their doctors that screening is worthwhile.

“Just because we don’t have a randomized trial doesn’t mean there isn’t a benefit. We’re stuck in the middle ground where we’ve gone halfway. People are starting to believe liver cancer screening is helpful, but there’s not enough evidence to prove a definite benefit,” Dr. Singal said. “Part of our goal is providing evidence to both patients and physicians that liver cancer screening is beneficial.”

UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center includes 13 major cancer care programs with a focus on treating the whole patient with innovative treatments, while fostering groundbreaking basic research that has the potential to improve patient care and prevention of cancer worldwide. In addition, the Center’s education and training programs support and develop the next generation of cancer researchers and clinicians.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. Numbering more than 2,700, the faculty is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in 40 specialties to nearly 90,000 hospitalized patients and oversee more than 1.9 million outpatient visits a year.

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Media Contact: Patrick McGee
214-648-3404
patrick.mcgee@utsouthwestern.edu

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Update Hepatitis C Online Course: Management of Cirrhosis-Related Complications

Update - Hepatitis C Online Course

When an educational program is released pertaining to HCV this blog points the reader to the new learning activity.

This year a "Hepatitis C Online Course" was launched by the CDC and brought to you by a collaboration between the University of Washington and the International Antiviral Society-USA (IAS-USA).

The "Hepatitis C Online Course" has been recently updated to include Module 3; Management of Cirrhosis-Related Complications.

The interactive course is offered in a text, video and slide presentation format.


A few topics in Module 3 include; Calculating and Interpreting MELD Score , Hepatic Encephalopathy , Diagnosis and Management of Ascites , and Referral for Liver Transplantation.

Links
Hepatitis C Online Course
Module 3 Update: Management of Cirrhosis-Related Complications

Hepatitis C Online Course
Hepatitis C patients taking part in the online course are given an opportunity to learn more about the progression of HCV, the evaluation and prognosis of patients with cirrhosis and noninvasive tests for diagnosing and assessing liver fibrosis. Other topics in the online course include a video presentation explaining "Extrahepatic Conditions Related to Hepatitis C Virus (HCV)" which may affect small vessels, skin, kidneys, salivary gland, eyes, thyroid, and immunologic system.

Begin here.......

Hepatitis C Virus (HCV) Infection: Looking Beyond the Interferon Alfa Era

Hepatitis C Virus (HCV) Infection: Looking Beyond the Interferon Alfa Era

New York, NY - June 25, 2013

Sorry folks, I am a bit late bringing this to you.

In June over at the IAS–USA website an interactive and highly enjoyable question and answer course was launched. The easy to follow activity is offered in both an audio and webcast format.

Hepatitis C patients taking part in the CME are given an opportunity to learn more about the virus, disease progression, treatment regimens and side effects - to name a few. For instance in this presentation by Kenneth E. Sherman, MD, PhD: HCV is a LIVER Disease, the in-depth "question and answer" lecture discusses non-invasive methods for the assessment of liver fibrosis, biopsy,  liver fibrosis, and cirrhosis with an emphasis on HCV as a liver disease.

Listen to the audio below, and Watch the Webcast here. After clicking on the webcast, scroll to the bottom of the page, click on “I have read these instructions and understand them,” to begin activity. All course topics are provided below, view all webcasts at the IAS–USA website.

The good news - no registration required!



Overview of the Basics of HCV Infection Management: Optional Precourse Workshop for Practitioners Who are New to HCV Care
Robert T. Schooley, MD

Welcome to the Annual IAS-USA New York HCV Course
Robert T. Schooley, MD; David L. Thomas, MD, MPH

HCV Treatment Now? When and How to Manage HCV in Treatment-Naive and Treatment-Experienced Patients
Mark Sulkowski, MD

HCV is a LIVER Disease
Kenneth E. Sherman, MD, PhD

Practical Management of Adverse Effects in Patients with Chronic HCV Infection
Jennifer J. Kiser, PharmD

Strategies for Treating HCV in HIV/HCV Coinfected Patients: A Case-Based Panel Discussion
Arthur Y. Kim, MD

The "Grab Bag": Selected Hot Topics in Viral Hepatitis Management
Kenneth E. Sherman, MD, PhD

Cure Without Interferon Alfa: Scientific Basis and Clinical Evidence
David L. Thomas, MD, MPH

The Fragile Relationship Between HCV and Its Human Host
Robert T. Schooley, MD

 

View all webcasts available online at the IAS–USA website.

Of Interest
Hepatitis C Online Course

Don't miss this recent "Hepatitis C Online Course" funded by the CDC and brought to you by a collaboration between the University of Washington and the International Antiviral Society-USA (IAS-USA)

Click here to begin........ 

Baseline MELD Score Predicts Hepatic Decompensation during Therapy in Patients with Chronic Hepatitis C and Advanced Cirrhosis

Research Article

Baseline MELD Score Predicts Hepatic Decompensation during Antiviral Therapy in Patients with Chronic Hepatitis C and Advanced Cirrhosis 

Citation: Dultz G, Seelhof M, Herrmann E, Welker M-W, Friedrich-Rust M, et al. (2013)
Baseline MELD Score Predicts Hepatic Decompensation during Antiviral Therapy in Patients with Chronic Hepatitis C and Advanced Cirrhosis.
PLoS ONE 8(8): e71262. doi:10.1371/journal.pone.0071262

Editor: James Fung, The University of Hong Kong, Hong Kong

Received: February 28, 2013; Accepted: June 27, 2013; Published: August 1, 2013

Copyright: © 2013 Dultz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The authors have no support or funding to report.

Competing interests: The authors have declared that no competing interests exist.

Introduction Only

Full Text Available @ PLOS ONE....

Chronic hepatitis C virus (HCV) infection is a major health burden with more than 170 million infected individuals worldwide. Progression to liver cirrhosis is observed in 2–35% of the patients after 20–25 years of chronic infection and once liver cirrhosis is established, the cumulative 5-year risk to develop hepatocellular carcinoma (HCC) is estimated to be 17% [1], [2].

For more than one decade, available antiviral treatment consisted of a dual therapy with pegylated interferon alfa-2a or -2b (peginterferon) in combination with the guanosine analog ribavirin leading to sustained virologic response (SVR) rates in approximately half of the patients [3], [4]. Licensing of the new HCV protease inhibitors boceprevir and telaprevir, as part of a triple therapy for untreated HCV genotype 1 patients and those who failed previous treatment, represents a milestone in HCV treatment. Untreated patients undergoing triple therapy achieve significantly higher SVR rates (66–75%) as compared to those receiving the dual therapy alone (37–44%) [5], [6], [7]. Patients with a previous virologic relapse, partial response, or non-response to peginterferon and ribavirin also benefit when retreated with boceprevir or telaprevir-containing triple therapies [8], [9].

It is well established, that the presence of advanced fibrosis or compensated liver cirrhosis negatively influence a patient’s individual chance for achieving an SVR [10]. In turn, patients with advanced disease may benefit most from antiviral therapy since it was demonstrated in several long-term follow up cohort studies that SVR can prevent hepatic decompensation, development of hepatocellular carcinoma, and is associated with reduced overall mortality [11], [12], [13], [14]. Albeit still unsatisfactory, subanalyses of the pivotal boceprevir and telaprevir trials have shown that SVR rates for patients with advanced fibrosis and liver cirrhosis receiving triple therapy are higher as compared to those receiving peginterferon and ribavirin alone (52–62% vs. 33–38%) [5], [6].

In patients with more severe disease, e.g. patients with advanced cirrhosis and those on the waiting list for liver transplantation, successful antiviral therapy in selected cases may halt the progression of liver disease, can prevent HCV re-infection of the transplanted liver and subsequently leads to a decrease of post-transplant morbidity and mortality [15], [16], [17], [18], [19], [20]. However, SVR rates in those patients have been shown to be poorer (approximately 25%) and peginterferon and ribavirin in those patients is associated with potentially life-threatening side effects and discontinuation rates ranged from 20–100%.

Recently, preliminary data from the French early access program for telaprevir and boceprevir (CUPIC study) reporting antiviral efficacies and the occurrence of adverse events in more than 400 cirrhotic patients receiving antiviral triple therapy were presented [21]. About 38–48% of the cirrhotic patients experienced serious adverse events during the first 16 weeks of antiviral triple therapy and 8 patients died.

Thus, decision making for antiviral therapy in patients with (advanced) liver cirrhosis remains a clinical challenge facing the dilemma of increased SVR rates on the one hand and therapeutic schedules that are associated with increased complications and fatal outcomes on the other hand [22]. Moreover, predictive factors in cirrhotic patients that are associated with serious adverse events and/or hepatic decompensation during antiviral therapy are poorly defined.

The aim of this retrospective cohort study was to define baseline characteristics that can help to predict the risk for hepatic decompensation in HCV patients with advanced liver cirrhosis during antiviral therapy with peginterferon and ribavirin. Clinical events indicating hepatic decompensation (ascites, hepatic encephalopathy, upper gastrointestinal bleeding, hospitalization) as well as laboratory data were recorded at baseline and during a follow up period of 72 weeks.

Continue To Full Text Article

EASL 2013: Watch - NEW PATHS FOR CIRRHOSIS TREATMENT

Source - ILC Press

Also View - EASL: New Advances in The Management of Patients with Cirrhosis

EASL: New Advances in The Management of Patients with Cirrhosis

New Advances in The Management of Patients with Cirrhosis

Amsterdam, The Netherlands, Thursday 25 April 2013: New data from clinical studies presented for the first time at the International Liver Congress™ 2013 provide new rationale for an old and established treatment option for portal hypertension.[1] Additionally, spleen stiffness predicts the occurrence of clinical complications, which is of paramount importance in clinical practice.[2]

In patients with cirrhosis, increasing blood pressure in the abdominal circulatory system (known as portal hypertension) leads to potentially lethal complications which might be prevented with simple medical treatment. Patients with cirrhosis and portal hypertension have increased gastrointestinal permeability which allows the movement of bacteria or bacterial components through the lining of the gut into the blood stream in a process known as bacterial translocation. Bacterial components such as lipopolysaccharide can be involved in the genesis of complications of cirrhosis.

The first study evaluated the effects of a non-selective beta-blocker (NSBB) on gastrointestinal permeability and bacterial translocation in patients with cirrhosis with high levels of portal hypertension.1 Patients with severe portal hypertension (HVPG* ≥20mmHg) had increased markers of gastrointestinal permeability and bacterial translocation compared to patients with lower levels of portal hypertension (HVPG<20mmHg). Treatment with NSBB significantly reduced HVPG, improved gastrointestinal permeability and decreased bacterial translocation (LPS-binding protein (LBP) -16% p=0.018; IL-6 -41% p< 0.0001) levels.

Patients who were found to have the highest levels of gastrointestinal permeability were also found to be at most risk of bleeding from oesophageal varices; a complication of cirrhosis which carries a high risk of mortality.

These findings provide a new rationale for the use of non-selective beta-blockers in patients with cirrhosis. EASL’s Treasurer Prof. Mauro Bernardi commented on the data: “The movement of bacteria from the gut and into the bloodstream is extremely serious and potentially fatal in patients with cirrhosis often leading to complications or death. Beta-blockers have been successfully used in a number of conditions and as a standard treatment to control blood pressure in other disease areas. In cirrhosis, they have been used for decades for primary and secondary prophylaxis of bleeding from oesophageal varices. The results of this study show that besides improving portal hypertension, as it was thought up to now, their beneficial effects are also due to their ability to reduce bacterial translocation which may widen the indications for the use of these drugs in this setting.”

In the diagnostic landscape, promising data to support the validity of non-invasive techniques were also presented at the congress. HVPG, an invasive measurement technique currently considered as the best predictor to identify progression to severe scarring of the liver and disrupted essential body functions (clinical decompensation), was compared to techniques such as the evaluation of spleen stiffness (SS) combined with the MELD** score.2

The study showed that in compensated (early) patients with cirrhosis both the SS (p<0.0001) and the MELD (p=0.016) score provided an accurate prediction of clinical decompensation, and their combination in a new score had a predicting power even superior to that of HVPG.

Prof. Mauro Bernardi added, “HVPG is an invasive technique, which can often be discomforting for patients, is only performed in specialised centres and needs experienced operators to be fully reliable. While further studies will be required, if non-invasive techniques continue to present accurate predictions, they would be welcomed in the overall management of compensated patients with cirrhosis.”

Disclaimer: the data referenced in this release is based on the submitted abstract. More recent data may be presented at the International Liver Congress™ 2013.

http://virtualpressoffice.easl.eu/press-release---new-advances-in-the-management-of-patients-with-cirrhosis/

AASLD: Adult Patients with Ascites Due to Cirrhosis- New Update of Practice Guideline Released

The American Association for the Study of Liver Diseases (AASLD) has released an update of the practice guideline on the Management of Adult Patients with Ascites Due to Cirrhosis last published in 2009 in the journal HEPATOLOGY.

Cirrhosis is the eighth leading cause of death in the United States and ascites is the most common complication of cirrhosis.

The practice guideline is intended for physicians and allied health professionals and provides recommendations for the diagnosis and treatment of ascites. This update includes new sections on umbilical hernias, hepatic hydrothorax, and cellulitis. Click here to access the updated practice guideline.

AASLD News: April 11, 2013

Management of patients with complications of cirrhosis

Management of patients with complications of cirrhosis

Christopher Fowler PhD, MBA, RN, ACNP-BC

The Nurse Practitioner: The American Journal of Primary Health Care

April 2013 Volume 38 Number 4 Pages 14 - 22

Despite significant improvements in medical care, the management of patients with cirrhosis remains challenging with less than optimal results. Although liver transplantation is the most effective treatment for end-stage liver disease and survival after transplant has consistently improved over the years, a scarcity of donor organs and growing incidence of cirrhosis requires continued improvement in ways to manage this complex group of patients.

 

Clinicians caring for individuals with chronic liver disease must remain vigilant for subtle changes in patient condition. Patients and caregivers must be educated to encourage frequent follow-up, adherence to prescribed therapeutic regimens, and communication regarding adverse reactions

 

Full article can be found @ Nursing Center.com

Increased risk of cognitive impairment in cirrhotic patients with bacterial infections

Related @ Healio

Bacterial infection increased cognitive impairment among cirrhotic patients

Patients with cirrhosis who developed bacterial infection were at significantly increased risk for cognitive impairment, according to recent results...
Read more...

Journal of Hepatology

Increased risk of cognitive impairment in cirrhotic patients with bacterial infections

Received 27 November 2012; received in revised form 2 March 2013; accepted 6 March 2013. published online 25 March 2013.

Accepted Manuscript
Abstract
PDF

Abstract
Background & aims

A causal relationship between infection, systemic inflammation and hepatic encephalopathy (HE) has been suggested in cirrhosis. No study, however, has specifically examined, in cirrhotic patients with infection, the complete pattern of clinical and subclinical cognitive alterations and its reversibility after the resolution. Our investigation was aimed at describing the characteristics of cognitive impairment in hospitalized cirrhotic patients, in comparison with patients without liver disease, with and without infection.

Methods
One-hundred and fifty cirrhotic patients were prospectively enrolled. Eighty-one patients without liver disease constituted the control group. Bacterial infections and sepsis were actively searched in all patients independently of their clinical evidence at entry. Neurological and psychometric assessment was performed at admission and in case of nosocomial infection. The patients were re-evaluated after the resolution of the infection and 3 months later.

Results
Cognitive impairment (overt or subclinical) was recorded in 42% of cirrhotics without infection, in 79% with infection without SIRS and in 90% with sepsis. The impairment was only subclinical in controls and occurred only in patients with sepsis (42%). Multivariate analysis selected infection as the only independent predictor of cognitive impairment (OR 9.5; 95% CI 3.5-26.2; p=0.00001) in cirrhosis. The subclinical alterations detected by psychometric tests were also strongly related to the infectious episode and reversible after its resolution.

Conclusions
Infections are associated with a worse cognitive impairment in cirrhotics compared to patients without liver disease. The search and treatment of infections is crucial to ameliorate both clinical and subclinical cognitive impairment of cirrhotic patients.

Hemorrhagic ascites leads to worse outcomes in cirrhotic patients

Hemorrhagic ascites leads to worse outcomes in cirrhotic patients

Urrunaga NH. J Hepatol. 2013;doi:10.1016/j.jhep.2013.01.015.

 February 6, 2013

The presence of hemorrhagic ascites is predictive of poor outcome in patients with cirrhosis, according to recent results.In a retrospective case-control study, researchers evaluated the records of 1,113 patients with cirrhosis and ascites who received paracentesis at a single hospital between 2003 and 2010. Hemorrhagic ascites (HA) was identified in 214 cases, and outcomes within this group were compared with those of 642 matched controls with cirrhosis and ascites.
 

HA was most frequently spontaneous, with hepatocellular carcinoma (HCC) and iatrogenic causes occurring next most commonly. Spontaneous HA was significantly more common among those with ascitic fluid red blood cell counts between 10,000 mcL and 50,000 mcL (72%) than those with 50,000 mcL or more (52%; P=.003 for difference). Patients with HA related to HCC had significantly poorer survival rates than those with HA from other causes (P=.001).

HA participants were more likely to experience acute kidney injury (P<.001), sepsis (P<.01) and spontaneous bacterial peritonitis (P<.001), and also required transfusion (P<.001), vasopressors (P<.001) and ICU-level care more frequently (P=.001) than controls. Median albumin (2.5 g/dL vs. 2.8 g/dL; P<.01) and hemoglobin levels (10.2 g/dL vs. 11.2 g/dL; P<.001) were significantly lower compared with controls, while median MELD score (18 vs. 16; P<.001), bilirubin (3.0 mg/dL vs. 2.5 mg/dL; P=.04) and creatinine (1.1 mg/dL vs. 1 mg/dL; P=.004) were higher.

Patients with HA had higher mortality rates at 1 month (87% compared with 72%), 1 year (72% vs. 50%) and 3 years (61% vs. 41%), and a shorter median survival time than controls (1 year vs. 5.6 years). Multivariate analysis indicated an independent association between mortality and HA (HR=1.34; 95% CI, 1.07-1.68), after adjusting for other predictors including MELD score, ICU-level care, hepatitis C infection and HCC.

Don C. Rockey

“Patients with hemorrhagic ascites have poorer outcomes than those without hemorrhagic ascites,” researcher Don C. Rockey, MD, Department of Internal Medicine, Medical University of South Carolina, told Healio.com. Rockey and colleagues suggested that HA and other well-defined clinical features should be included in an improved prognostic score for this patient population.

http://www.healio.com/hepatology/cirrhosis-liver-failure/news/online/%7B7BA83759-DB97-4702-B2CF-26D131C0809D%7D/Hemorrhagic-ascites-leads-to-worse-outcomes-in-cirrhotic-patients

FDA Grants Orphan-Drug Designation for Novel Terlipressin Formulation for the Treatment of Ascites

FDA Grants Orphan-Drug Designation for Novel Terlipressin Formulation for the Treatment of Ascites

 

BOTHELL, Wash. and CHICAGO, Jan. 4, 2013 -- PharmaIN Corporation and LAT Pharma LLC today announced that the US Food and Drug Administration (FDA) has granted their request for orphan-drug designation for terlipressin for the treatment of ascites due to all etiologies except for cancer. Ascites, or fluid accumulation in the abdomen, is a serious complication of liver cirrhosis. The companies' lead new drug candidate PHT101 (or PGC-C12E-Terlipressin) incorporates novel drug delivery technologies that may enable once-daily administration via subcutaneous injection dosing in chronic outpatient populations.

 

Chronic liver disease/cirrhosis is the 12th leading cause of death due to disease in the US, killing an estimated 27,000 people each year. Approximately 60% of cirrhosis patients eventually develop ascites. Ascites patients face a significantly increased risk of other life-threatening complications, such as spontaneous bacterial peritonitis (SBP) and hepatorenal syndrome (HRS), with a very poor prognosis of 50% survival two years after onset. Current treatments include salt-restricted diet, high doses of diuretics, and frequent paracentesis, the removal of large volumes of ascitic fluid with a needle through the abdominal wall. People with ascites are also often candidates for liver transplantation.

 

Elijah Bolotin , PhD, President of PharmaIN, said, "Orphan-drug designation by the FDA indicates the importance of this new drug candidate to a desperately ill group of patients. We are excited about the medical potential of PHT101, which synergistically incorporates two of our proprietary technologies designed to enable safer and more effective drug therapy: PGC-Hydrophobic Core nanocarrier-based delivery and unique fatylation that leads to a pro-drug."

 

"Orphan-drug designation represents a major milestone toward making PHT101 available to patients suffering from ascites due to liver cirrhosis," said John Thottathil , PhD, Chief Scientific Officer of LAT Pharma. "PHT101 would bring a novel, mechanistic approach to ascites therapy as opposed to the current standard of care involving symptom relief. Orphan status may accelerate our clinical development program. It also opens the door to special funding opportunities, such as the Orphan Product Grants Program, and provides important incentives to investors, including seven years of market exclusivity and certain tax credits."

 

Terlipressin reduces portal vein pressure and increases mean arterial pressure (MAP) in cirrhotic patients with splanchnic vasodilation. Increasing MAP in ascites patients could potentially down-regulate the excessive salt and water retention that leads to ascitic fluid buildup. For more than 20 years unmodified IV-bolus terlipressin has been used in Europe and Asia as rescue therapy for hepatorenal syndrome (HRS) and esophageal variceal bleeding (EVB). Scores of publications have demonstrated the safety and efficacy of IV terlipressin in hospitals, and many have suggested the medical potential of an outpatient version of the drug.

 

PHT101 is in preclinical testing and is protected by a US patent issued in 2011. International patent applications have been filed. The novel drug delivery technologies are covered by a separate patent estate.

 

About PharmaIN Corporation

Based in Bothell, WA, PharmaIN is focused on improving the efficacy, safety, and speed to market of injectable peptides/proteins (biologics) for the treatment of cirrhotic liver disease, congestive heart failure (CHF), cancer, inflammation, and other serious medical conditions. The Company has developed proprietary Protected Graft Copolymer (PGC) nanocarrier excipients (15 patent families) and other drug delivery and fatylation technologies. Unique benefits of these technologies include prolonging circulation time in the blood by protecting against enzymatic degradation while preserving drug activity; creating optimal pharmacokinetic/pharmacodynamic profiles to avoid peaks and troughs in drug concentrations; and enabling more effective targeting of cancer, inflammation, and infection sites because of the carrier's uniquely small size (10-20nm). PGC is a highly versatile nanocarrier platform as demonstrated by the improved performance of small peptides through very large proteins, both for subcutaneous and intravenous administration. For more about PharmaIN visit www.pharmain.com.

 

About LAT Pharma LLC

LAT Pharma was founded in 2006 with the express goal of inventing, developing, and commercializing a lifesaving new therapy for people afflicted with advanced liver disease and its deadly complications. Each member of the Chicago-based management team has decades of pharma/biotech industry experience primarily in the area of new drug development and commercialization. The company is supported by medical advisors who are worldwide leaders in chronic liver disease. LAT Pharma holds an exclusive global license to all unique terlipressin compounds arising from its collaboration with PharmaIN and is responsible for clinical development, marketing, and out-licensing of PHT101. For more about LAT Pharma visit www.lat-pharma.com .

 

SOURCE LAT Pharma LLC

 

http://www.prnewswire.com/news-releases/fda-grants-orphan-drug-designation-for-novel-terlipressin-formulation-for-the-treatment-of-ascites-185655002.html