Prior studies had suggested that interferon therapy in patients with CHC that did not clear virus may lead to histological improvement (12
). As a result, several large randomized controlled trials of peginterferon therapy were initiated with the hope that the anti-inflammatory and anti-fibrotic effect of treatment in persistently viremic patients would slow the rate of disease progression. However, the HALT-C Trial and other studies have failed to demonstrate any significant benefit regarding clinical and histological disease progression with maintenance interferon therapy (7
). Previous studies have also demonstrated that administration of interferon to cirrhotic patients with CHC can lead to a reduction in portal pressure (17
). Although reductions in portal pressure were consistently greatest in patients with an initial or sustained virological response, some non-responders with improved liver histology also experienced improved portal pressures. Therefore, we hypothesized that antiviral therapy would be associated with a reduction in the rate of development of de novo
varices as well as a reduced rate of variceal progression compared to no treatment.
Overall, 26.2% of the HALT-C Trial patients without baseline varices developed de novo
varices during a median follow-up of 4 years. As expected, patients that developed varices were also significantly more likely to experience a clinical outcome or histological progression compared to patients without de novo
varices (). The majority of these new esophageal varices were small (76%) and only 1% of patients developed variceal hemorrhage. The annualized rate of new varices formation of 6.5% per year is slightly lower compared to that reported in a randomized controlled trial of beta-blockers (8.9% per year) as well as in a natural history study of variceal development (10% per year) (5
). Of note, all of the patients in the latter studies had cirrhosis and underwent annual endoscopy whereas only ~ 33% of the HALT-C patients at risk for varices had cirrhosis and an endoscopy was repeated at 4 years (). Also, the HALT-C Trial patients who did not undergo a follow-up endoscopy had clinical profiles that suggested they were at greater risk of developing varices. Thus, our observed rates of variceal formation may be underestimates. Interestingly, African American patients in the HALT-C Trial were at a reduced risk of developing de novo
varices compared to Caucasians while Hispanics were at the highest risk (). These data are consistent with our prior analysis demonstrating that African Americans are also less likely to have varices on screening endoscopy after controlling for disease severity and liver histology (8
). The reduced risk of developing varices amongst African Americans may be related to their tendency to have less severe necroinflammation or hepatic steatosis compared to Caucasians with HCV at initial presentation and during follow-up (20
). The increased risk of Hispanic patients to develop varices should be interpreted with caution due to the small number of Hispanics enrolled (i.e. only 6% of HALT-C patients but 13.3% of general US population). Nonetheless, the increased prevalence of metabolic syndrome, hepatic steatosis, and advanced fibrosis reported in cross-sectional studies of Hispanic compared to Caucasian patients with CHC may, in part, explain our findings (22
). In support of this, the frequency of significant hepatic steatosis (i.e ≥ 2) was 32.5% in the African Americans, 42.5% in Caucasians, and 54.8% in Hispanic HALT-C patients (p = 0.002). When we controlled for subject BMI and liver histology, Hispanic ethnicity remained an independent risk factor for developing varices. Additional longitudinal studies of larger numbers of Hispanic and African-American HCV patients are eagerly awaited to follow-up on these findings.
Baseline serum albumin and hyaluronic acid levels were also significantly associated with an increased risk of developing varices which is consistent with prior studies demonstrating that these analytes correlate with the extent of hepatic fibrosis and disease severity in patients with CHC (23
). Increases in serum hyaluronic acid levels are believed to be due to reduced endothelial clearance of HA from hepatic sinusoids as well as from increased hepatic stellate cell production with advancing fibrosis. A number of laboratory parameters associated with the likelihood of developing varices in prior studies (e.g. platelet counts, total bilirubin levels, serum AST/ ALT) were also associated with the likelihood of developing varices in our patient population () (24
). However, their lack of independent contribution to our model likely reflects their collinearity with serum albumin and hyaluronic acid levels. Similarly, histological markers of disease severity were also associated with the risk of developing varices on univariate analysis but were not on multivariate modeling presumably for the same reasons.
Administration of low dose peginterferonα2a did not reduce the risk of developing new varices (Figure 4A). Although only low doses of peginterferonα2a were used, the likelihood of developing varices was also not influenced by medication adherence amongst the treated patients. Therefore, our results demonstrate that maintenance peginterferon does not reduce the risk of developing varices. These results are consistent with the overall HALT-C Trial results wherein the rate of liver disease progression by clinical and histological assessment was not reduced in treated compared to untreated patients despite improvements in serum aminotransferase and HCV RNA levels (7
). Our study results differ from preliminary reports of other studies of low-dose peginterferonα2b compared to no treatment or colchicine wherein a reduced risk of variceal development and bleeding have been noted (16
). The differing results may, in part, relate to the differing entry criteria of the studies. For example, 100% of the patients in the EPIC3
trial and 83% of the Colchicine versus PegIntron Long-Term (CoPilot) study patients had histological cirrhosis while only 40% of the HALT-C patients had cirrhosis. In addition, Co-Pilot allowed patients with a CTP score of < 8 while HALT-C limited enrollment to patients with a CTP < 7. In addition, the lower reported rate of de novo varices/ variceal progression with peginterferonα2b in CoPilot may relate to the absence of retreatment with full dose peginterferon and ribavirin prior to randomization. This could result in the CoPilot patients receiving peginterferonα2b having a greater chance of virological suppression and reduced necrointlammation compared to those treated with peginterferonα2a in HALT-C. However, both of the trials involving peginterferonα2b also failed to demonstrate a reduction in the overall rate of disease progression and clinical outcomes compared to the control arm (15
A second aim of our study was to determine the rate of variceal progression amongst patients with CHC. Overall, 35.2% of the 210 patients with baseline gastroesophageal varices experienced variceal progression and these patients were also significantly more likely to develop a clinical outcome or histological progression compared to the patients without variceal progression (). The annualized rate of 8.8% per year is similar to that reported in other studies of patients with small varices followed over time (19
). On multivariate analysis, baseline serum AST/ ALT and platelet counts were independently associated with variceal progression. Since the serum AST/ ALT ratio is associated with more advanced hepatic fibrosis in patients with CHC, it is not surprising that this parameter was also associated with variceal progression. In fact, baseline serum AST/ ALT levels are a component of a model developed in the HALT-C cohort to distinguish patients with bridging fibrosis from those with cirrhosis as well as to identify patients at increased risk of clinical outcomes during follow-up (26
) In addition, subjects with variceal progression were more likely to have cirrhosis () although the addition of liver histology parameters did not substantially improve the model’s performance.
Use of these simple and widely available laboratory parameters may be of value to practitioners. For example, the likelihood of developing variceal progression can be categorized as low, medium and high using various platelet levels for a patient with a given serum AST/ ALT level (Supplemental Figure 1
). However, contrary to expectations, maintenance peginterferon therapy was not associated with a reduced likelihood of variceal progression (). In addition, adherence to peginterferon was not associated with a reduced risk of variceal progression amongst the treated patients although the trend was in the expected direction (26% vs 35%, p= 0.33). The lack of an association between subject ethnicity and variceal progression may relate to the limited number of patients with baseline varices in this analysis.
The serial endoscopic data also demonstrated that 17% of patients with baseline varices had a reduction in the size of their varices by at least 1 grade and remarkably 3% had a reduction in variceal size by more than 2 stages (See supplemental material
). It is possible that the regression in varices may relate to inter-observer variability in the grading of varix size which is known to vary by 10 to 15% (28
). Alternatively, the reproducibility of assessing esophageal varices in a given patient due to technical factors of insufflating the esophagus may have also played a role. However, on univariate analysis patients with lower INR levels and higher platelet counts, indicative of less severe liver disease, were more likely to experience regression. Nonetheless, the use of maintenance peginterferon was not associated with variceal regression (). In addition, baseline use of beta-blockers and statins were also not associated with variceal regression.
Strengths of our study include the large number of well-characterized patients with CHC that were prospectively assessed using a standardized endoscopy protocol while being carefully monitored in a multi-center clinical trial. Furthermore, overall patient retention in the HALT-C Trial was excellent at 85% (7
). In addition, the majority of patients with a pretreatment screening endoscopy did undergo a follow-up study as planned (80% of those without varices and 90% of those with varices). However, the subjects without baseline varices who did not get a follow-up endoscopy had more severe liver disease at entry and were significantly more likely to develop a clinical outcome during follow-up leading to a potential underestimation of the rate of varices formation. Similarly, amongst the 272 patients with baseline varices, the excluded subjects that did not undergo a follow-up endoscopy tended to have more severe liver disease at entry and were also more likely to develop a clinical outcome. Additional limitations regarding our study design was the lack of central review of endoscopic findings which may have led to substantial inter-individual variability in grading varices as has been shown in prior studies (28
). To address these concerns, formal training on the grading of varices was undertaken at the initiation of the study and a standardized scoring form was used in all patients at all sites by a limited number of experienced investigators (8
). Finally, direct portal pressure measurements were not obtained at baseline nor during follow-up. Although these measurements are closely associated with the risk of developing new or worsening varices, the incremental risk, cost, and inconvenience of this invasive method precluded us from incorporating it into this trial (1
In summary, 26.2% of HALT-C Trial participants developed new gastroesophageal varices and 35.2% of those with baseline varices experienced variceal progression during a median follow-up of 4 years. The risk of developing varices was significantly influenced by patient ethnicity and laboratory markers of disease severity at entry but not influenced by the use of maintenance peginterferon. Assessment of baseline serum albumin and hyaluronic acid levels can help stratify patients with CHC into low, medium, and high risk of developing varices (). Use of these models may improve patient and physician adherence with recommendations for endoscopic screening and assist in targeting the highest risk patients for the most frequent follow-up. Similarly, determination of serum AST/ ALT and platelet counts in patients with CHC and known varices may help identify those that may benefit from beta-blocker prophylaxis or pre-emptive band ligation as well as more frequent endoscopic surveillance.