Treatment-emergent depression and anxiety between peginterferon alpha-2a versus alpha-2b plus ribavirin for chronic hepatitis C

Chronic infection with hepatitis C virus (HCV) is a serious health problem worldwide. Chronic hepatitis C increases the risk of morbidity and mortality from sequelae such as liver cirrhosis and hepatocellular carcinoma [1]. The purpose of treatment is the prevention of complications of chronic HCV infection, which is principally achieved by eradicating the infection [2]. A combination of weekly subcutaneous injections of long-acting peginterferon alfa (PegIFN-α) and oral ribavirin greatly improves the efficacy of antiviral treatment and represents the current standard of care for patients with chronic hepatitis C [2]. Depression is one of the most common neuropsychiatric complications during antiviral treatment for chronic hepatitis C [3‐7]. A meta-analysis has found that around 25% of chronic hepatitis C patients who receive interferon and ribavirin treatment will develop a treatment-induced major depressive episode [6]. Although interferon exposure is clearly associated with an increased incidence of depression, the relationships of the frequency and magnitude of depression with the specific type of interferon used have seldom been evaluated [5].

The two available licensed products of PegIFN-α are peginterferon alfa-2a (PegIFN-α-2a) and peginterferon alfa-2b (PegIFN-α-2b), which differ in their pharmacokinetics and chemical properties; both are cost-effective and recommended for use in combination with ribavirin for treating chronic hepatitis C [8]. Several researchers have found that, when combined with ribavirin (RBV), PegIFN-α-2a yields a higher virological response rate than does PegIFN-α-2b, [9, 10]. However, one review article indicated that PegIFN-α-2a and PegIFN-α-2b exhibit similar degrees of effectiveness and tolerability, with few clinical differences [11], while investigations have suggested similar sustained virological response (SVR) rates and frequencies of adverse events upon treatment with PegIFN-α-2a to those with -2b [11‐13]. Compared to those treated with PegIFN-α-2a plus RBV, some clinical trials have indicated that patients treated with PegIFN-α-2b plus RBV have similar incidence rates of depression [14, 15], whereas one revealed that patients administrated with PegIFN-α-2b plus RBV have higher probability of depression [16]. To date, no conclusive evidence has established that one PegIFN-α is superior to the other, or that one type of PegIFN-α is more likely to induce depression than the other when combined with RBV in the treatment of chronic hepatitis C.

This study investigates the differences in depression and anxiety between patients with hepatitis C who receive PegIFN-α-2a plus RBV and those who receive PegIFN-α-2b plus RBV. The factors that are associated with depression and anxiety are examined.

This study involved 55 patients with hepatitis C infection who underwent combination treatment with PegIFN-α-2a plus RBV (Group 1) and 26 patients who underwent combination treatment with PegIFN-α-2b plus ribavirin (Group 2). Table 1 summarizes the baseline demographic characteristics and mood statuses of the two patient groups. At the beginning of combination therapy 14 (25.5%) of patients in Group 1 and 3 (11.5%) of patients in Group 2 have been classified as depression cases (HADS-D ≥ 8), and 21 (38.2%) of patients in Group 1 and 6 (23.1%) of patients in Group 2 have been classified as anxiety cases (HADS-A ≥ 8). The mean dose of RBV that was co-administrated for hepatitis C treatment was higher for Group 1 (1048.2 mg/day) than for Group 2 (958.3 mg/day). There was no significant difference in other variables.

Of the 55 patients in Group 1, 52 (94.5%), 51 (92.7%) and 36 (65.5%) remained in the study until weeks 4, 12 and 24, respectively. Of the 26 patients in Group 2, 22 (84.6%), 19 (73.1%) and 15 (57.7%) remained in the study until weeks 4, 12 and 24, respectively. After six months of treatment, 22 (61.1%) patients in Group 1 and nine (60%) patients in Group 2, respectively, were SVR (HCV RNA-negative). The attrition rates (χ ²  = 0.46, p = 0.499) and treatment response (SVR) rates (χ ²  = 0.10, p = 0.753) did not differ significantly between the two groups at the endpoint.

Figure 1 presents the proportion of patients in the two groups with depression and anxiety during the 24 week follow-up. We found the proportion of depression cases significantly increased in both groups (Group 1: χ ²  = 7.89, p = 0.048; Group 2: χ ²  = 7.91, p = 0.044). The post hoc test revealed that the trends of depression in both groups (week 12 > baseline; week 24 > baseline) were similar. The proportion of anxiety cases did not significantly change throughout the overall follow-up period in either group (Group 1: χ ²  = 1.01, p = 0.798; Group 2: χ ²  = 3.45, p = 0.321). The post hoc test revealed that anxiety in Group 2 was more prevalent at week 12 than at the baseline (β = 2.50, p = 0.018). No significant difference was observed in any other pairwise comparisons between time-points or the two groups.

The HADS-D scores in both groups significantly increased over time (Group 1: Wald χ ²  = 12.78, p = 0.005; Group 2: Wald χ ²  = 9.88, p = 0.020). The post hoc test revealed that the HADS-D scores in Group 1 significantly increased after week 4 (p < 0.05) while those in Group 2 significantly increased after week 12 (p < 0.05). The HADS-A scores did not significantly increase over time in either group (Group 1: Wald χ ²  = 3.04, p = 0.385; Group 2: Wald χ ²  = 1.76, p = 0.623). A post hoc test also revealed that HADS-A scores did not differ significantly between time-points or groups.

Table 2 lists the factors that were associated with patients’ depression at week 12 and at 24 week of combination therapy. Alcohol use disorder was consistently associated with depression at week 12 (β = 6.59, p < 0.001) and at week 24 (β = 5.96, p < 0.001). Poor response to combination therapy (HCV RNA positive) was significantly associated with patients’ depression at week 24 (β = 2.43, p = 0.029).

Table 3 shows factors that are associated with patients’ anxiety at week 12 and at week 24 of combination treatment. Patients’ physical comorbidities were positively correlated with their anxiety status at week 12 (β = 1.28, p = 0.038). Nonetheless, no variable was significantly associated with anxiety at week 24.

During 24 weeks of antiviral treatment, the proportion of depression cases significantly increased in both groups over time. Significant differences in depression or anxiety levels were not observed between patients with chronic hepatitis C who underwent 24 week antiviral treatment with PegIFN-α-2a plus RBV and those who underwent such treatment with PegIFN-α-2b plus RBV. A history of alcohol use disorder was an independent predictor of depression at week 12 and week 24 of combined PegIFN plus RBV treatment and a poor virological response to treatment was associated with depression at week 24. Additionally, patients who had more physical comorbidities were more likely to exhibit anxiety at week 12.

During the 24 weeks of antiviral treatment, the proportion of patients with depression significantly increased over time, in line with previous reviews and meta-analysis [5, 6]. Newly developed depression was observed in 33 patients during antiviral treatment. Nevertheless, we found that 8 patients whose HADS depression scores were above the cut-off at baseline had mood improved during treatment. Although the relative efficacies of different forms of PegIFN-α are currently debated, the data herein reveal that neither the virological response rate nor trend in mental health status, differed between patients who were treated with PegIFN-α-2a (Group 1) and those who were treatment with PegIFN-α-2b (Group 2). Notably, this study used non-randomized and open-label methods. At the baseline, patients in Group 2 seemed to have a lower anxiety level, although not significantly, than those in Group 1. Therefore the possibility of selection bias cannot be excluded. Randomized trials have revealed that patients who are given PegIFN-α-2a plus RBV and those who are given PegIFN-α-2b plus RBV exhibit similar incidences of depression [14, 15]. However, one trial demonstrated that patients who were administered PegIFN-α-2b plus RBV were more likely to develop depression than counterparts who were administered PegIFN-α-2a plus RBV [16]. Therefore, a future study which conducted in multi-centre, with randomized controlled design and adequate stratification for controlling the potential confounding variables (e.g. mood status at baseline, HCV genotype, prior psychiatric history) is warranted to determine whether PegIFN-α variants have differently alter mental health.

Studies have established that relatively many patients with chronic hepatitis C have alcohol use disorder [21]. Alcohol use disorder is associated with increased use of illicit substances and impulsive behaviors [22] that may increase the likelihood of HCV acquisition [23]. Furthermore, alcohol use can worsen hepatic problems and can lead to a negative effect on adherence to a treatment regimen and responses to antiviral therapy [23]. This study revealed that a history of alcohol use disorder predicted depression during 24 weeks of combination treatment with PegIFN and ribavirin for chronic hepatitis C. Alcohol abuse can worsen hepatic disease and reduce adherence to a treatment regimen. Therefore, the identification and treatment of alcohol abuse in this population is very important.

The results of this study indicated that a poor virological response to combination treatment with interferon and RBV for chronic hepatitis C is associated with depression at week 24. The possibility of a causal relationship between the response to antiviral treatment and depression is intriguing. While treatment with interferon-α is known potentially to cause neuropsychiatric side effects, however, the neuropsychiatric symptoms is reduced in HCV patients achieving an SVR [24]. HCV infection is regarded as a systemic disease because liver disease is accompanied by effects on other organs and tissues. The brain is a favorable site for HCV replication, and the virus may be directly neurotoxic. Other mechanisms that have been proposed to explain the pathophysiology of neuropsychiatric disorders in cases of chronic HCV infection, such as derangement in neurotransmitter circuits, inflammation and autoimmune dysregulation and alterations of metabolic pathways of infected cells. Improvement of neuropsychiatric symptoms in patients achieving SVR following interferon treatment has been noticed [25‐28]. Some other factors may favor depression and the poor outcome of antiviral treatment. For example, depression is associated with poor adherence or early discontinuation of antiviral treatment in cases of chronic hepatitis C [15]. Additionally, patient satisfaction owing to awareness of being cured of hepatitis C may bias the results of this study. Therefore, care should be taken in interpreting the association between depression and a poor virological response to treatment.

The results herein also demonstrate that the number of co-morbid physical illnesses was significantly correlated with anxiety at week 12. Previous studies have found that 24% to 36% of patients who undergo interferon-α treatment for HCV infection suffer from anxiety disorders [29, 30]. However, no specific risk factor for anxiety disorders has been identified [29]. We propose the possible explanation is patients with many comorbidities related physical illnesses, not only having a poorer physical condition, but also suffering from a greater psychological stress. Patients with multiple physical comorbidities may be vulnerable to the adverse effects of PegIFN-α, which are linked to a high probability of anxiety.

Several limitations of this study should be concerned. First, the sample size was small - especially in Group 2, and a smaller sample provides less statistical power to detect potential differences in mental health between treatment groups, and limits the ability to assess change in anxiety score. Second, this study was a naturalistic observational study, rather than a randomized controlled trial, hence the results may be influenced by selection bias. Additionally, the attrition of patients underwent antiviral treatment could be related to lack of effect, adverse effect, poor adherence to the prescription or simply loss of follow up. The sample sizes in the two treatment groups were small and unequal resulting certain attrition rates lead to inability for a subgroup analysis. Third, various important factors that may have affected patients’ mental health were not identified, such as compliance with the PegIFN-α and RBV regimen, the presence of infectious diseases, and the taking of other drugs (such as antidepressants). It is uncertain whether such factors influenced the results of this study. Finally, the assessments that were made using the HADS covered a period of one week, and do not by themselves constitute a psychiatric diagnosis of a major depressive disorder, which requires a depressed mood or anhedonia with other critical associated symptoms that are present for at least two weeks. Cut-off points of the HADS were used to establish depression or anxiety without a formal confirmation of the diagnosis based on DSM-IV-TR criteria through a structured interview, although higher HADS scores commonly correlate with a diagnosis of a major depressive disorder or anxiety disorders [18].

This investigation did not reveal significant differences in depression or anxiety levels of patients with chronic hepatitis C on a 24 week antiviral treatment regimen with PegIFN-α-2a plus RBV and those on such a corresponding regiment with PegIFN-α-2b plus RBV. These two regimens worsened HCV patients’ depression and anxiety. Future research with larger samples and a randomized, controlled design are warranted to verify the findings of this study.