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The natural history of compensated HCV-related cirrhosis: A prospective long-term study - pdf attached
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Journal of Hepatology March 2013
Eduardo Vilar Gomez1,, Yoan Sanchez Rodriguez2, Luis Calzadilla Bertot2, Ana Torres Gonzalez2,
Yadina Martinez Perez2, Enrique Arus Soler1, Ali Yasells Garcia3, Luis Perez Blanco2
1Department of Researches, National Institute of Gastroenterology, Havana, Cuba; 2Department of Hepatology,
National Institute of Gastroenterology, Havana, Cuba; 3Department of Gastroenterology, National Institute of Gastroenterology, Havana, Cuba
"This is the first report validating the concept of clinical stages [13] in a single and large group of Hispanic or Latin-American patients with compensated HCV-related cirrhosis. Our patient cohort was prospectively followed during a sufficient period to detect a necessary number of outcomes with very few patients lost during follow-up. The current study had four outcome events per predictor variable [35]. Primary and secondary clinical outcomes were adequately selected and standardized according to the current recommendations for the evaluation of prognosis in cirrhotic patients"
Background & Aims
The natural history of HCV-related compensated cirrhosis has been poorly investigated in Latin-American countries. Our study evaluated mortality and clinical outcomes in compensated cirrhotic patients followed for 6years.
Methods
Four hundred and two patients with compensated HCV-related cirrhosis were prospectively recruited in a tertiary care academic center. At the time of admission, patients were stratified as compensated (absence [stage 1] or presence [stage 2] of esophageal varices) as defined by D'Amico et al. Subjects were followed to identify overall mortality or liver transplantation and clinical complication rates.
Results
Among 402 subjects, 294 were categorized as stage 1 and 108 as stage 2. Over a median of 176weeks, 42 deaths occurred (10%), of which 30 were considered liver-related (7%) and 12 non-liver-related (3%); eight individuals (2%) underwent liver transplantation; 30 patients (7%) developed HCC, 67 individuals in stage 1 (22%) developed varices and any event of clinical decompensation occurred in 80 patients (20%). The 6-year cumulative overall mortality or liver transplantation was 15% and 45%, for stages 1 and 2, respectively (p<0.001). The cumulative 6-year HCC incidence was significantly higher among patients with varices (29%) than those without varices (9%), p<0.001. Similarly, the cumulative 6-year incidence of any clinical liver-related complication was higher in patients with stage 2 (66%) as compared to 26% in those with stage 1, respectively (p<0.001).
Conclusions
Our results indicate significant morbidity and mortality and clinical outcome rates in compensated cirrhotic patients with varices (stage 2).
Introduction
Chronic hepatitis C virus (HCV) infection is a leading cause of end-stage liver disease and hepatocellular carcinoma (HCC) worldwide [1], and the most common indication for orthotopic liver transplantation (OLT) in the Western world [2]. Once HCV-related cirrhosis has developed, the annual risk of clinical decompensation, death or transplantation, and hepatocellular carcinoma have been estimated to be ~6% (range, 4-8%), ~3% (range, 2-6%), and ~3% (range, 2-6%) per year, respectively [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. Although the course of compensated cirrhosis secondary to hepatitis C has been considered relatively slow, the risk of HCC, decompensation, and mortality appears to be higher in patients with esophageal varices. A recent study has estimated that the 5-year cumulative incidences of mortality, hepatic decompensation, and HCC were significantly higher (9%, 31%, and 17%, respectively) in HCV-related compensated cirrhotic patients with esophageal varices than those without esophageal varices (2%, 7%, and 9%, respectively) [10].
The natural history of compensated cirrhosis due to hepatitis C virus has been extensively studied in American, European or Japanese cirrhotic populations, however, there is currently no available information on Latin-American cohorts. Furthermore, the usefulness of a prognostic classification based on the presence or absence of varices has not been evaluated and validated in a large prospective cohort of Hispanic or Latin-American patients. Thus, our prospective study was designed to identify the 6-year cumulative incidence of overall mortality or liver transplantation, HCC and major clinical outcomes of hepatic decompensation in a large Cuban cohort of HCV-related cirrhotic patients according to two different clinical stages of compensated disease suggested by D'Amico et al. [13]: compensated cirrhosis with absence (stage 1) or presence of varices (stage 2). We also evaluated baseline characteristics and their association to clinical outcomes.
Study design, participants and setting
We conducted a prospective longitudinal "inception cohort" study to evaluate the mortality and incidence of major clinical complications in patients with cirrhosis secondary to HCV infection. At baseline, patients were classified according to two clinical stages of compensated cirrhosis and were included at different inception points, which correspond to the first diagnosis of each single stage. To do so, 440 patients with newly diagnosed HCV liver-related cirrhosis were consecutively evaluated at a tertiary care academic center (National Institute of Gastroenterology, Havana, Cuba) between January 2004 and June 2007, and those who fulfilled the following inclusion criteria irrespective of any previous antiviral treatment status (either naïve or non responders or sustained viral responders) were enrolled: male and female patients >18years of age, clinical (based on clinical, laboratory and imaging findings) or histological diagnosis of cirrhosis, without current or previous history of hepatic decompensation, absence of active alcoholism, and ability to provide informed consent. Patients were excluded if they had, at baseline, presence of other causes of liver disease, positive screening for viral hepatitis A (anti-HAV IgM) and B (HBsAg) and HIV, pregnancy or lactation, concomitant disease with reduced life expectancy, severe psychiatric conditions, drug dependence, and evidence of liver cancer on the basis of ultrasonography, α-fetoprotein (AFP) levels higher than 200ng/L, and computed tomography, magnetic resonance or selective hepatic angiography when indicated. A history of alcohol intake (more than 80g/day for males and more than 60g/day for females) for more than 10years was recorded, and alcohol abstinence was monitored at each clinic visit in the course of the patient interview, and confirmed by relatives.
Clinical and laboratory assessment
All patients were closely monitored for clinical, biochemical, and hematological status at baseline, monthly for the first 16weeks; thereafter, they were evaluated every 8weeks until the end of the study. Liver ultrasonography and serum α-fetoprotein determinations were carried out at baseline and every 24weeks during the study to screen for hepatocellular carcinoma. Patients with elevated AFP levels and/or new lesions suspected or detected during ultrasound examination were further evaluated with either computed tomography, magnetic resonance, hepatic angiography and/or echo-guided needle liver biopsy. An upper digestive endoscopy was performed before admission and then repeated annually during the course of the study to identify de novo varices.
Ascites was clinically identified and confirmed by abdominal ultrasound. Upper gastrointestinal bleeding secondary to portal hypertension was confirmed by endoscopic examination in the presence of esophageal/gastric varices or hypertensive gastropathy, and assessed according to established guidelines. [14] Hepatic encephalopathy was diagnosed in accordance with West Haven criteria for grading from 0 (subclinical) to 4 (coma) and spontaneous bacterial peritonitis (SBP) was diagnosed when ascites polymorphonuclear leukocyte count was >250/mm3, with or without positive ascites bacterial culture. Treatment of clinical complications was implemented according to the recommended standard of care. HCC treatment was implemented following the recommended guidelines, commensurate with available resources in our country. During the follow-up, all patients were eligible to receive interferon or peginterferon plus ribavirin treatment and those achieving a sustained virological response (SVR) or not were followed-up until data analysis, because the benefit of SVR on major clinical outcomes has not yet been proven in well-designed randomized controlled trials [15].
During the study period, patients with medium-large varices received prophylactic non-selective beta-blockers based on the recommended guidelines. [16] Essential hypertension was the second most common indication of ß-blockers.
The HCV RNA level was quantified by PCR assay (Amplicor Monitor HCV v.2.0; Roche Molecular System; lower limit of detection, 600IU/ml). HCV genotyping was performed by reverse hybridization (Inno-LiPA HCV; Innogenetics, Ghent, Belgium).
Definition of outcomes
For outcome analyses, compensated cirrhosis was classified according to the absence of esophageal varices and ascites (stage 1) and presence of esophageal varices in the absence of ascites and bleeding (stage 2) [13].
Overall clinical outcomes were measured from the study start date until the date of clinical outcome. Patients lost to follow-up were censored at the last date they were known to be alive. Some deaths were notified by family members interacting with physicians via telephone.
The primary outcome of the study was overall mortality or liver transplantation. Moreover, death, either related or unrelated to liver disease was also analyzed.
Secondary outcomes included diagnosis of HCC, variceal hemorrhage, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, jaundice and development of varices in patients without diagnosis of varices at baseline (stage 1). De novo varices were defined as newly recognized esophageal or gastric varices during follow-up. In addition to individual clinical outcomes, we included clinical decompensation. Clinical decompensation was defined as the first occurrence of at least one of the following clinical conditions: ascites, hepatic encephalopathy, spontaneous bacterial peritonitis (SBP), variceal hemorrhage, or jaundice.
The diagnosis of hepatocellular carcinoma was established according to recommended guidelines. [17] Any clinical event of hepatic decompensation detected at the same time or after the diagnosis of HCC was considered for outcome analysis.
The MELD score was implemented to prioritize the organ allocation in liver transplantation candidates.
All clinical outcomes were verified and confirmed by three expert hepatologists when they occurred.
The study was conducted in compliance with the Declaration of Helsinki and approved by the ethics committee and the institutional review board of the National Institute of Gastroenterology. All patients provided written informed consent for participation.
Results
A total of 440 patients were examined for eligibility, and 402 were included in the study. Thirty-eight patients were excluded during the screening period because they met one or more of the exclusion criteria at baseline: seven patients with inexact date of diagnosis of cirrhosis or varices at baseline, 30 subjects with history of hepatic decompensation and one individual who withdrew their consent. The median follow-up period was 176weeks (IQR, 104-260weeks), being 200weeks (IQR, 104-284) for patients with stage 1 and 138weeks (IQR, 84-208) for subjects with stage 2. The flow of participants through the trial is presented in Fig. 1.
The patients' median age was 59 (IQR, 50-65) years and 61% were females, however, males were predominant in patients with compensated cirrhosis and stage 2 (54%). The distribution of Child-Pugh classes was similar in both groups. Forty-four (15%) of 294 patients without varices and 20 (19%) of 108 subjects with varices were in Child-Pugh class B. The MELD score medians were similar in patients with stages 1 and 2. Cirrhosis was diagnosed by liver biopsy or clinical criteria in 305 (76%) and 97 (24%) of 402 patients, respectively. A history of daily alcohol intake was more significant in patients with varices (24%) than in those without varices (10%). During the follow-up, overall alcohol users became abstainers.
Clinical outcomes
Mortality
During follow-up, 42 patients (10%) died, of which 30 deaths were liver-related and 12 non-liver-related. The 52-, 104-, 156-, 208-, 260-, and 312-week mortality rates were 1%, 6%, 9%, 11%, 16%, and 17%, respectively. The overall causes of deaths are summarized in Fig. 1. The majority of liver-related deaths were attributable directly to complications of end-stage liver disease and HCC, with variceal bleeding being the most common cause overall. In compensated cirrhotic patients, eight patients died due to myocardial infarction, which was the most frequent cause of non-liver-related death.
Ten patients in each group died after developing clinical decompensation (Fig. 1). Variceal hemorrhage was the most important cause of death in patients with stage 2. Among patients with stage 1, ten subjects died due to non-liver-related deaths without developing varices or any hepatic decompensation event, and four died secondary to hepatocellular carcinoma-related symptoms, vascular invasion or extrahepatic spread. Ten liver-related deaths (two bleeding, two ascites, two encephalopathy and four hepatorenal syndrome) and four liver transplants were documented in patients with stage 1.
Among patients with stage 2, two non-liver-related deaths (myocardial infarction) occurred with no hepatic decompensation, 10 patients died secondary to variceal hemorrhage and four subjects underwent liver transplantation. Overall, patients with stage 2, including HCCs, died with previous episodes of decompensation.
The cumulative overall mortality or transplantation at 312weeks (equivalent to 6years) was significantly higher in patients with stage 2 (45% with a 95% CI, 28-66%) as compared to those patients with stage 1 (15% with a 95% CI, 10-21%), which is equivalent to annual rates (per 100 persons-years) of 2.6 and 7 in stages 1 and 2, respectively (Table 2). The estimated hazard risk for overall mortality or transplantation increased 2.9-fold for patients with compensated disease with presence of varices compared to those with absence of varices (Fig. 2A).
*Compensated cirrhosis is characterized by the combination of stage 1 (absence of esophageal varices and ascites) and stage 2 (presence of esophageal varices in the absence of ascites and bleeding).
Fig. 2. Cumulative probability or incidence of overall outcomes according to the absence (stage 1) or presence (stage 2) of varices. (A) Cumulative probability of overall mortality or liver transplantation. (B) Cumulative incidence of liver-related mortality or transplantation. (C) Cumulative incidence of hepatocellular carcinoma. (D)*Cumulative incidence of development of varices. *Development of varices is only for stage 1.
Similarly, the cumulative liver-related mortality or transplantation at 312weeks was considerably higher in patients with varices (38% with a 95% CI, 22-58%), compared to patients without varices (10% with a 95% CI, 6-15%), corresponding to annual death rates (per 100 persons-years) of 6.3 and 1.6 for stages 2 and 1, respectively (Table 2). Likewise, the risk of death was increased 4.4-fold in cirrhotic patients with varices compared to those without varices (Fig. 2B).
Hepatocellular carcinoma
A total of 30 HCCs were identified during the study, the majority after the first year of follow-up; however, 3 (10%) were detected within the first 52weeks. Eighteen patients had advanced stage of HCC at the time of diagnosis, 10 died due to HCC, 16 were still alive, two were eligible for liver transplantation and two underwent transarterial chemoembolization.
The overall cumulative incidence of developing HCC was 13% (95% CI, 9-19%) at 312weeks of follow-up. Within each stratum, the cumulative incidence of HCC was significantly increased in compensated cirrhotic patients with varices (29% with a 95% CI, 16-47%) compared to compensated cirrhotic patients without varices (9% with a 95% CI, 6-15%), which is equivalent to annual HCC rates (per 100 persons-years) of 4.5 and 1.5 in the compensated stages 2 and 1 (Table 2). In compensated patients, the risk of developing HCC was estimated to increase to 3.6 times for stage 2, compared to those with stage 1 (Fig. 2C).
Development of varices
All patients were screened for varices before admission. Esophageal varices were present in 105 patients and gastric varices only in three patients. None of the patients refused to undergo a follow-up endoscopy during the study. During follow-up, 67 of the 294 patients (23%) without baseline varices developed gastroesophageal varices. The cumulative incidence of gastroesophageal varices at 312weeks was 46%, which corresponds to an annual rate (per 100 persons-years) of 7.3 (Fig. 2D and Table 2).
Clinical decompensation
The most common clinical cause of decompensation was ascites, which occurred in 62 patients (15%). Other decompensation events included variceal bleeding in 22 patients (5%), hepatic encephalopathy in 20 individuals (5%) and SBP in eight subjects (2%). In the overall group, 40 of 294 patients without varices (14%) and 40 of 108 with varices (37%) developed a new episode of hepatic decompensation, and the estimated annual rates of new-onset clinical decompensation were 3.8 and 14.7 per 100 person-years, respectively (Table 2). The 6-year cumulative incidence of a new occurrence of liver-related clinical complication was 26% (95% CI, 18-37%) for patients without varices and 66% (95% CI, 46-85%) for those with varices (Fig. 3A). In compensated cirrhotic patients, the risk of developing hepatic decompensation was increased 3-fold when esophageal varices were present.
Among 67 patients who developed varices during the study period, 26 (39%) presented at least one event of clinical decompensation, with ascites (24 [36%]), jaundice (16 [24%]), encephalopathy (8 [12%]), SBP (6 [9%]), and bleeding (2 [3%]) being the most common events experienced by patients.
The 6-year cumulative incidence of ascites was higher in patients with varices (45%), compared to 21% in patients without varices (HR=2.6) (Fig. 3B), corresponding to annual rates of 8.4 and 3.6 per 100 person-years, respectively. The cumulative incidence of developing new-onset variceal bleeding was significantly elevated in patients with compensated disease and varices (33%), with an annual incidence rate per 100 person-years of 6 (Fig. 3C). Furthermore, the cumulative incidence of a first episode of hepatic encephalopathy was 7% for patients in stage 1 and 14% for subjects in stage 2, corresponding to an annual incidence rate of 1.4 and 2.6, respectively. Once varices were present, the risk of developing encephalopathy increased 2.5-fold compared to patients without varices (Fig. 3D). The cumulative incidence of patients with de novo occurrence of SBP was significantly lower and similar in each group of compensated cirrhosis (Fig. 3E).
There was no difference in the 6-year cumulative incidence of jaundice among patients with (14%) or without varices (19%), equivalent to an annual incidence rate of 2.4 and 3.6, respectively. The risk of developing jaundice did not increase when varices were present (Fig. 3F).
Effect of antiviral treatment on major clinical outcomes
Most patients were naïve to antiviral therapy during the study period. During the follow-up period, 182 patients were treated with SOC, 160 completed the antiviral treatment, and 31 achieved an SVR (10 of 48 subjects who completed treatment with Peg/Rib and 21 of 112 patients who completed treatment with IFN/Rib). The SVR rates were significantly lower in those receiving Peg/Rib. Most of the patients treated with Peg/Rib were previous non-responders to IFN/Rib when they were treated at pre-cirrhotic stages, thus, the SVR may be lower. No patient experienced hepatic decompensation during the antiviral treatment.
Among patients with SVR, only one liver-related death (p=0.18) and one HCC development (p=0.26) were recorded. Similarly, four patients with SVR developed hepatic decompensation as compared to 90 patients without SVR (p=0.07). Significant reductions of major clinical outcomes were reported in patients with SVR, however, they did not reach statistical signification.
Predictors of liver-related mortality or liver transplantation, hepatocellular carcinoma, clinical decompensation and development of varices
At multivariate analysis, presence of varices at baseline, Child-Pugh score7, high blood pressure, albumin≤35, serum sodium≤134, INR1.5, total bilirubin35, and cholesterol≤3.2 were independently associated with liver-related mortality or transplantation. In terms of impact on prognosis, serum sodium≤134 (sHR=34), CP score7 (sHR=6), total bilirubin35 (sHR=4.8), cholesterol≤3.2 (sHR=4.3), presence of varices (sHR=3.9), and a history of high-blood pressure (sHR=0.09) were the most important prognostic factors.
The presence of varices at baseline, age60, CP score7, MELD score15, INR1.5, creatinine110, sodium≤134, and platelets≤120 were independently associated with an increased risk of HCC development. In addition to the presence of varices at admission, CP score7, INR1.5, total bilirubin35, albumin≤35, serum sodium≤134, cholesterol≤3.2, platelets≤120, presence of HCC during follow-up and history of high-blood pressure as a protective factor were significantly associated with a new event of clinical decompensation. However, only a history of hypertension, platelets≤120, and HCC during the study period were retained as predictors of decompensation in analyses restricted to patients with stage 1. Otherwise, in patients with stage 2, predictors of decompensation were similar to overall subjects.
Finally, male gender, platelets≤120, sodium≤134, and cholesterol≤3.2 were significantly associated with the development of varices among patients with stage 1. Significant variables in the multivariable models are reported in Table 3, Table 4.
Discussion
The aim of our study was to describe the clinical course of compensated cirrhotic patients classified at diagnosis according to the absence (stage 1) or presence (stage 2) of varices. Therefore, our results show the probability of each event occurring, starting from each stage (stage 1 vs. stage 2) as they were defined at study inclusion, without accounting for transition across different stages.
The present study clearly demonstrates an accelerated clinical course of the disease in compensated HCV-related cirrhotic patients when varices are present (stage 2). Among patients with varices, the rate of liver-related death or liver transplantation was high (6-year cumulative rate 38%, annualized rate 6.3%).
The cumulative occurrence of HCC was higher in compensated patients with varices (29%) than in those without them (9%). Thus, the annual risk of developing HCC increased to 4.5 per annum, if varices were present. Additionally, patients with stage 2 developed higher cumulative incidence of a first episode of hepatic decompensation (66%), ascites (45%), variceal hemorrhage (33%), and hepatic encephalopathy (14%) in comparison to those with stage 1, however, no differences were found for a first episode of SBP and jaundice among these subjects. The annual risk for developing hepatic decompensation increases from 3.8% to 14.7% once varices are present. Finally, the cumulative incidence of varices development was 46% during the 6years of follow-up, which corresponds to annual rates of 7.3%.
In general, our observed annual rates of liver-related deaths were slightly lower than rates reported in American (HALT-C), European, and Japanese studies. [10], [11], [25] Moreover, the annual risk of developing HCC was within the reported range of 1.51-7.14% in several international studies, including the HALT-C trial. [11], [25] However, other clinical outcome rates such as any event of clinical decompensation, ascites or variceal bleeding were slightly higher than those reported in the HALT-C study [11]. The last finding could be explained by the inclusion of compensated patients with a CP score7 (64 of 402 patients) in our cohort. Once the CP score became elevated, the incidence of clinical outcomes increased substantially.
Our annualized rate of new variceal development (7.3%) was well within the reported range of 6.5-10% in the HALT-C study and other two important studies evaluating the natural history of variceal development in patients treated or not with ß-blockers [26], [27], [28].
Only two recent studies have evaluated the existence of esophageal varices as a risk factor for long-term clinical outcomes in HCV-related compensated cirrhosis [7], [10]. Bruno et al. reported that the cumulative incidence of mortality, HCC and decompensation was significantly higher in compensated patients who had varices at baseline. Unfortunately, they did not report the annual rates for patients with or without varices; therefore, it is not possible to compare these findings with our results.
The presence of esophageal varices among compensated cirrhotic patients is an indirect marker of the degree of portal hypertension, which is linked to an elevated risk of mortality, HCC, and clinical decompensation. The presence of varices at baseline identifies patients with a longer duration and a more aggressive course of the disease; therefore, the screening for varices should be routinely adopted in clinical practice as a useful prognostic tool. [13] This approach may allow a more efficient targeting of the population that would be suitable for testing new strategies of prevention of major clinical outcomes.
The presence of gastroesophageal varices and a CP score7 at baseline were the most universal and independent risk factors of liver-related mortality, HCC development and new-onset of clinical decompensation. Many known factors such as INR1.5, albumin≤35, total bilirubin35, cholesterol≤3.2, and sodium≤134 were independent predictors of liver-related mortality or liver transplantation. In addition to the previous predictors, a platelet count≤120 and HCC were retained within the risk factors of hepatic decompensation. A subsequent analysis in patients with no varices showed that platelets≤120, HCC and a previous history of hypertension were independent predictors of decompensation. In contrast, when varices were present at baseline, the prognostic markers were similar to the overall patient's cohort, thereby reflecting the clinical usefulness of these predictors in patients with varices or more advanced disease. However, the difference between hazard ratios for prognostic markers of decompensation in patients with stages 1 and 2 should be considered if prognostic rules are needed to develop in the clinical practice.
In general, predictors of hepatic decompensation and death reflect the degree of portal hypertension and hepatocellular dysfunction; therefore, a more stringent follow-up may be implemented when these conditions are present.
Our data also showed that the incidence of death and decompensation significantly increased after HCC development. Once HCC is present, the liver function promptly deteriorates with a marked increase of the likelihood of decompensation and death.
Interestingly, a history of high-blood pressure also served as a negative predictor of liver-related mortality and clinical decompensation. A previous study reported that patients with cirrhosis and arterial hypertension appear to be protected from vasodilatory complications. These patients are hyperdynamic and central hypovolaemic, but have no signs of overall peripheral vasodilatation [29].
In addition to varices at baseline and CP score7, platelets≤120, older patients (60), MELD score15, and sodium≤134 were identified as predictors of HCC. Several studies have identified the presence of varices, older patients and variables reflecting the grade of liver failure or portal hypertension as independent predictors of HCC [4], [9], [10], [30].
Our study identified a significant association between male gender, platelets≤120, sodium≤134, cholesterol≤3.2, and development of gastroesophageal varices. Recently, subject race, baseline serum albumin, and hyaluronic acid levels have been found as significantly associated with development of varices in patients with HCV-related cirrhosis [26]. Another factor associated with the probability of developing varices in prior studies, such as a low platelet count, has also been linked to the likelihood of developing varices in our patients [27], [31], [32].
Our data also showed that serum sodium≤134 was a consistent predictor of overall clinical outcomes in compensated patients. Hyponatremia has been well described in associations with hepatorenal syndrome, ascites, circulatory dysfunction, and liver-related mortality [33], [34]. Thus, its presence is considered a surrogate marker for liver dysfunction.
Approximately 1/3 of our cirrhotic patients received antiviral treatment during follow-up. Although significant reductions of major clinical outcomes were reported in patients with SVR, they did not reach statistical significance. The effect of the antiviral treatment on major clinical outcomes was not a predefined objective, and the decision to treat was done on an individual patient basis. Therefore, new data from prospective and randomized studies are required to determine the effect of SVR on major clinical outcomes [15].
This is the first report validating the concept of clinical stages [13] in a single and large group of Hispanic or Latin-American patients with compensated HCV-related cirrhosis. Our patient cohort was prospectively followed during a sufficient period to detect a necessary number of outcomes with very few patients lost during follow-up. The current study had four outcome events per predictor variable [35]. Primary and secondary clinical outcomes were adequately selected and standardized according to the current recommendations for the evaluation of prognosis in cirrhotic patients [13]. Overall patients were systematically monitored every 8weeks during the study, and all outcomes were reviewed independently by three experienced hepatologists. The other strengths of this report were the inclusion of two categories of cirrhotic patients with apparently different probabilities of outcomes. The early use of this clinical classification in two stages could be useful in determining the prognosis of patients with HCV-related compensated cirrhosis. Patients with varices (stage 2) may be monitored more cautiously than those without varices, thus the use of resources could be allocated more efficiently. The classification into two clinical stages (varices vs. no varices) should be validated (major limitation of the study) in further studies focusing on larger and heterogeneous populations of cirrhotic patients. Therefore, further studies are needed to validate the concept of stages either in compensated or decompensated cirrhosis. In conclusion, the cumulative and annual rates of mortality or transplantation, HCC, and hepatic decompensation, including ascites, variceal hemorrhage and encephalopathy, were significantly higher in compensated cirrhotic patients with varices, reflecting a more accelerated course of the disease. Therefore, the classification of compensated patients in two clinical stages should be routinely implemented in current clinical practice. Thus, special attention must be offered to these patients for better monitoring and prevention of clinical complications.
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