Peginterferon has antiviral, anti-inflammatory, and anti-fibrotic effects which led to the hypothesis that prolonged peginterferon treatment would lead to a significant reduction in the rate of liver disease progression in prior non-responders with advanced fibrosis. However, no benefit from low-dose maintenance peginterferon was identified in the 1050 randomized patients prospectively followed for a mean of 3.5 years in the HALT-C Trial (16
). Two other studies using prolonged courses of standard interferon or peginterferon α2b also failed to demonstrate a clinical benefit with maintenance therapy in prior non-responders with advanced histology (28
). When designing the randomized phase of the HALT-C Trial a major concern was the tolerability of peginterferon administered over several years. Interferon is associated with a number of dose-dependent neuropsychiatric side effects, including mood disorders, emotional distress, and symptoms of impaired memory that can be serious and progressive in some (14
). As a result, the cognitive study was implemented at two sites to prospectively assess the frequency and severity of mood and cognitive effects of treatment using a validated battery of objective neuropsychological tests.
Our current study results demonstrate no significant impact of prolonged peginterferon therapy on cognitive function in the 129 randomized patients that were prospectively studied (). Although 28% of the patients had evidence of mild baseline impairment prior to therapy, the frequency and severity of cognitive impairment did not increase in subjects with and without baseline impairment and also was not influenced by treatment (). In fact, the GDS scores of the patients with baseline impairment actually improved over time (). Though the number of patients in the impaired group is small, the improvement in performance most likely reflects regression to the mean but it is possible that practice effects were greater in those who had poorer initial performance. In addition, a significant improvement in the standard scores of several individual tests was noted in both the peginterferon and untreated control patients (). These improvements in test scores were most likely due to practice effects since the subjects were repeatedly tested with the same battery over time. The CVMT, Digit symbol, and Trail’s A tests have been shown to have similar practice effects in prior studies (30
). Although the use of alternate forms and 12 month intervals between test administrations should have minimized practice effects, the relatively high level of education in this study population may, in part, explain a trend towards improved test performance. To be certain that medication adherence did not substantially influence our results, a careful analysis of the dose of peginterferon received and cognitive impairment was undertaken in the treated patients. However, there was no discernible relationship between the cumulative exposure to peginterferon and cognitive function ().
Our prior study demonstrated no evidence of cognitive impairment with 48 weeks of full dose peginterferon and ribavirin therapy (13
). However, many patients complained of “difficulty concentrating” and “indecisiveness” and some developed symptoms of depression which resolved following treatment cessation (13
). The results of the current study are in keeping with our prior findings and demonstrate that low-dose peginterferon given over 3.5 years also does not cause any objective evidence of worsening cognition which is reassuring for patients and practitioners. The rare patient with HCV related cryoglobulinemia or renal disease that requires prolonged peginterferon therapy should not be concerned about potential worsening of cognitive function. However, HCV patients treated with peginterferon in the randomized phase of HALT-C did experience clinically significant decrements in their quality of life and increased symptoms of fatigue and weakness compared to the untreated controls (34
). However, contrary to expectations, BDI-II scores did not significantly worsen over time in the peginterferon treated patients compared to the untreated patients. Therefore, maintenance peginterferon was generally well tolerated with minimal neuropsychiatric side effects during a mean follow-up of 3.5 years. This unexpected finding may, in part, be related to the frequent dose reductions or early discontinuation of peginterferon in the treated patients. In addition, the inclusion of prior non-responders in HALT-C who were capable of tolerating full dose peginterferon and ribavirin may have selected a subgroup of patients who were very tolerant of interferon.
Another aim of our study was to determine the relationship between liver disease progression and changes in cognition over 3.5 years of follow-up. A number of prior cross-sectional studies have demonstrated more frequent and severe cognitive abnormalities in cirrhotic patients with clinical decompensation and advanced portal hypertension compared to patients with compensated cirrhosis (17
). In addition, reductions in perception and conduction of nervous system impulses have been shown. Finally, subjects with minimal hepatic encephalopathy have been shown to have a poorer survival during follow-up presumably due to more severe portal hypertension (35
). However, most of these studies have included a small number of patients who were compared in a cross-sectional manner rather than longitudinally over time. In addition, the criteria for a diagnosis of “minimal” or subclinical hepatic encephalopathy have not been well-characterized and validated. The HALT-C Trial provided a unique opportunity to study serial changes in cognition in a large cohort of well-characterized subjects with a single underlying cause of liver disease.
Contrary to expectations, the GDS scores of subjects with objective evidence of worsening liver disease did not significantly differ over time from the GDS scores of patients with stable liver disease (). In addition, baseline cognition was not associated with liver disease progression and serial assessment of cognition was also not associated with disease progression. These novel findings raise questions regarding prior studies that have associated more advanced liver disease with impaired cognition. The lack of association in our cohort may relate to our ability to control for baseline cognition with a longitudinal study design and the inclusion of a generally well-educated group of ambulatory outpatients. In addition, it is possible that the GDS scores of patients with disease progression may have worsened but that patient drop-out or discontinuation from the study could have biased our results. In support of this, month 48 cognitive testing was not available in 47% of the patients with disease progression compared to 31% of the patients without liver disease progression. We also only measured cognitive function annually during the randomized phase and a test battery could not be administered at the time of actual disease progression. Finally, it is possible that the association between liver disease progression and cognitive decline is better represented by a tipping point rather than a linear function. In other words, cognitive decline may be precipitous at a certain stage of liver failure rather than continuously declining as the disease progresses.
Of note, our study was conducted exclusively in outpatients who were otherwise relatively healthy except for their liver disease. In comparison, many of the studies describing “minimal hepatic encephalopathy” were done in hospitalized or recently hospitalized patients who may have had other acute infectious or inflammatory co-factors leading to poorer test performance (36
). Nevertheless, the baseline pattern of cognitive deficits identified in the current study population with difficulties in verbal encoding and recall as well as complex working memory and slowed reaction to visual stimuli () is similar to more recent conceptualizations of minimal hepatic encephalopathy (37
Strengths of our study include the large number of patients with hepatitis C who were prospectively studied in a standardized manner during a randomized controlled trial. In addition, a battery of validated neuropsychological tests were used that have previously been shown to be sensitive to the effects of neurotoxic medications (e.g. interferons) and progression of chronic systemic diseases (e.g. HIV infection) on cognition (38
). The absence of an increasing frequency or severity of cognitive impairment in the patients receiving prolonged low-dose peginterferon is consistent with our prior results in the patients treated with 24 to 48 weeks of full dose peginterferon and ribavirin (13
). It is possible that the low dose of peginterferon used in the randomized phase of HALT-C may have been insufficient to cause significant cognitive impairment. In addition, fewer than 50% of the treated patients were able to maintain 80% adherence. The use of aggregrate scores to assess cognitive function (i.e. Global Deficit Scores) may have also masked some variation in the individual tests comprising the battery. However, significant changes in individual tests or domains of cognitive function over time were not readily apparent in the peginterferon treated nor untreated control patients (). An analysis of the raw scores also failed to show a difference in the two treatment groups (Data not shown). A final issue to consider is the GDS cut-off score used to define cognitive impairment of ≥ 1 used in our study. Recently, Carey et al demonstrated that a GDS cut-off of ≥ 0.5 improves the overall diagnostic accuracy in asymptomatic HIV patients compared to a cut-off of ≥1 (23
). However, we previously demonstrated that a GDS of ≥ 1 correlated the best with gold standard “clinician ratings” of impairment in HCV patients (21
). Carey et al also noted that the positive likelihood ratio for correctly identifying a patient as impaired was higher when using a GDS of ≥ 1.0 rather than 0.5 (23
). Analysis of our data using a GDS of > 0.5 to define impairment demonstrated generally similar results to the GDS criteria of > 1 regarding the frequency and severity of impairment in treated versus untreated patients over time (data not shown).
The lack of an association between cognitive function and liver disease progression over time is a potentially important finding (). If confirmed in other longitudinal studies, further clarification of the definition of minimal hepatic encephalopathy and other cognitive disorders associated with chronic liver disease may be warranted (38
). For example, a more quantitative and objective analysis of psychomotor slowing and altered executive function may be required for future prospective studies of cognition in patients with chronic liver disease as well as a better-delineated representation of change over time including potential threshold models. Lastly, the lack of discernible cognitive impairment in our patients during a mean follow-up of 3.5 years suggests that maintenance peginterferon can be safely administered for prolonged periods of time if clinically warranted in selected patients.