What are the comorbidities influencing the management of patients and the response to therapy in chronic hepatitis C?
Alfredo Alberti, Venetian Institute of Molecular Medicine, Via Orus, 2, 35128 Padova, Italy
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The natural history of chronic hepatitis C has been defined in several retrospective and prospective studies conducted in the last 20 years. These studies have clearly demonstrated that the outcome of chronic hepatitis C virus infection is profoundly influenced by a variety of cofactors and comorbidities. Many of the cofactors that affect the course of liver disease in hepatitis C also have a significant influence on the result of antiviral therapy. Unfortunately, comorbidities that have been shown to negatively influence the course and outcome of liver disease often reduce the chance of achieving a sustained virological response with pegylated interferon (PEG-IFN) and ribavirin treatment. The most important and frequent comorbidity influencing the course of chronic hepatitis C and the response to antiviral therapy is represented by the metabolic syndrome, and by the associated state of insulin resistance. Other comorbidities that have a negative influence on the progression of hepatitis C and on the response to antiviral therapy include excess alcohol intake, human immunodeficiency virus and hepatitis B virus co-infection and a number of conditions that reduce the benefit of therapy by affecting negatively compliance and/or adherence to adequate PEG-IFN or ribavirin doses.
The management and treatment of chronic hepatitis C depend on a number of virus and host parameters and should be individualized. Virus-related factors that influence the management of patients with hepatitis C virus (HCV) and particularly the decision to observe or to treat and the schedule of pegylated interferon (PEG-IFN) plus ribavirin combination to be used are the serum viral load and the HCV genotype.
The host factors that need to be taken into consideration primarily include age, stage of liver disease and all the many comorbidities that may influence the course of disease and the response to antiviral treatments. The decision to monitor the patients without therapy or to start antiviral treatment should be based on the integrated evaluation of prognostic factors in terms of the progression of disease and the probability of achieving a sustained virological response (SVR) and of contraindications to IFN and ribavirin. Young individuals infected with ‘easy-to-treat’ virus genotypes such as HCV-2 and HCV-3 are usually treated even with no or mild liver disease while, on the other side of the spectrum, elderly patients with high viraemia and HCV-1 are proposed for treatment only in the presence of progressive and/or advanced liver damage.
A number of comorbidities have been shown to influence the course of chronic hepatitis C in a significant manner, and many of them also affect the probability of achieving a SVR with PEG-IFN plus ribavirin combination therapy. Unfortunately, most of the cofactors that negatively influence the natural course of liver disease, being associated with more rapid progression to cirrhosis and to end-stage complications, also influence negatively the response to antiviral therapy by reducing the probability of achieving SVR.
The comorbidities that have been shown to affect the course of hepatitis C (some of which can be modified or attenuated by intervention) consist ‘in primis’ of co-infection with hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) and of the metabolic syndrome inclusive of obesity, of insulin resistance and of overt type 2 diabetes. Other cofactors affecting both the course of the disease and the response to therapy are excess alcohol abuse and conditions favouring an iron overload. Finally, a group of comorbidities specifically affect the response to antiviral therapy by reducing adherence to adequate dosing and compliance. The most frequent in clinical practice are depression and a number of neuropsychiatric conditions, cardiovascular diseases, anaemia and other conditions that reduce the tolerability and safety of PEG-IFN and ribavirin administration.
The role of hepatitis B virus co-infection in chronic hepatitis C virus carriers
Around 3–6% of HCV carriers are co-infected with HBV (1), the prevalence being higher in high-risk groups and in geographical areas where both infections are endemic. Co-infection with HBV may occur with or without significant HBV replication and three main categories of HCV/HBV-co-infected individuals are recognized: (a) those with HCV dominance (HCV-RNA positive/HBV-DNA negative); (b) those with HBV dominance (HCV-RNA negative/HBV-DNA positive); and (c) those with both viruses in an active phase (HCV-RNA positive/HBV-DNA positive) (2). These profiles can be seen to occur sequentially in the same patients because of different virological phases of virus interference. The virological profile is important in the decision to start antiviral therapy and in the choice of drugs. Independently of the virological profile, patients co-infected with HBV and HCV have been shown in several studies to have a more aggressive and progressive liver disease compared with HBV- or HCV-monoinfected patients (3). This is true both for the risk of developing cirrhosis and for the incidence of progression to hepatocellular carcinoma. For these reasons, patients co-infected with HBV and HCV should be monitored closely and should be considered for antiviral therapy to prevent severe liver complications.
The role of human immunodeficiency virus co-infection in chronic hepatitis C virus carriers
Around 30–50% of HIV-infected patients are co-infected with HCV, the prevalence being significantly higher in drug addicts compared with homosexual and other risk categories (4). There are considerable data indicating that HIV–HCV co-infection has a negative effect on the natural course and response to antiviral therapy for both types of infections. These patients have a more progressive and severe type of liver disease and their response to HCV antiviral therapy is reduced because of reduced tolerability and efficacy. On the other hand, the presence of HCV co-infection and the associated liver disease complicate the course of the HIV disease and the tolerability and efficacy of anti-HIV drugs. For these reasons, the management and treatment of HIV–HCV co-infection remain a challenge, with a number of unsolved issues.
The effect of metabolic syndrome and of insulin resistance in hepatitis C
Several studies have indicated that the presence of metabolic syndrome and of insulin resistance is associated with a poor prognosis in patients with chronic hepatitis C (5).
Patients with chronic HCV infection have increased prevalence of insulin resistance and of type 2 diabetes compared with age-, sex- and liver disease-matched controls. These observations have led to the hypothesis that HCV might be directly diabetogenic, although this is still controversial (6). There have been a number of hypotheses and experimental data that have attempted to explain how HCV infection can lead to the development of type 2 diabetes. Most of these studies agree that HCV infection may induce insulin resistance. On the other hand, insulin resistance has been clearly associated with a more severe and progressive type of liver disease and a reduced response to PEG-IFN and ribavirin therapy in HCV patients.
Several studies have recently confirmed that a SVR is impaired in patients with a high homoeostasis model assessment index (7). The same is true for patients with a high body mass index and for those with liver steatosis. Based on the observation that overweight, insulin resistance and liver steatosis have a negative impact on the course of chronic hepatitis C, being associated with more severe and progressive liver fibrosis, the indication has been given that HCV carriers should avoid weight gain by diet and physical exercise. When initiation of antiviral therapy is considered, high body weight and insulin resistance should be considered as negative predictors of a SVR and all efforts to improve the metabolic status of the patient should be made before starting therapy. This can be attempted by diet and physical exercise. A number of studies are currently addressing the issue of whether the use of insulin sensitizers such as metformin and pioglitazone might improve the response to antiviral therapy in HCV patients but the results obtained so far have been rather controversial and inconclusive (8, 9).
For this reason, the use of these compounds cannot yet be recommended in clinical practice for HCV patients with a high insulin resistance index who are started on antiviral treatment.
The role and management of depression in hepatitis C virus patients treated with pegylated interferon and ribavirin
Interferon-α is the cornerstone of antiviral therapy for chronic hepatitis C and will remain so in the future even with the introduction of new antiviral agents currently under evaluation. Treatment with INF-α induces a variety of central nervous system changes, depression being among those most frequently observed, with a wide range in grade from minimal to severe. Severe depression may require premature withdrawal of antiviral treatment. When PEG-IFN-α 2b plus ribavirin was compared with standard IFN-α 2b plus an identical dose of ribavirin, the frequency of psychiatric symptoms did not differ, and depression, in particular, occurred in 31% of patients treated with 1.5 μg/kg/week of PEG-IFN-α 2b, in 29% in patients treated with a lower dose of PEG-IFN and in 34% of patients treated with standard IFN-α 2b (10). In another large-scale registration trial, treatment with IFN-α 2a plus ribavirin was associated with depression in 22% of the cases, while the rate of depression was somehow higher in a control group treated with standard IFN-α 2b plus ribavirin (11). Other studies that have assessed, with more sophisticated approaches, the rate of depression that developed during standard or PEG-IFN did not find significant differences. Kraus et al. (12) evaluated 98 patients treated with standard or PEG-IFN-α 2b and found no significant differences in depression rate, which was 40% in the former and 33% in the latter group (P=0.49). No differences in depression rates were observed by Neri et al. (13) comparing pegylated α 2a and pegylated α 2b, and this finding has recently been confirmed in the large randomized comparison trial ‘IDEAL’ (14).
The presence of mild/moderate depression at baseline is not considered an absolute contraindication to initiate antiviral therapy with PEG-IFN and ribavirin. However, this condition is certainly associated with a higher risk of developing severe depression during therapy that may lead to higher rates of treatment discontinuation in the absence of adequate antidepressant therapy (15). For this reason, baseline depression has usually been considered to be a risk factor for reduced adherence to an adequate dose of PEG-IFN and ribavirin, which may then compromise the virological response and the chance of achieving a sustained response. With adequate patient selection and counselling and use of antidepressant therapy when needed, the risk of reduced adherence and efficacy of antiviral therapy can be minimized.
Data published in the literature about pretreatment or on treatment depression and response to antiviral therapy have been rather controversial. Several studies concluded that individuals who experience significant worsening in depressive symptoms during IFN therapy are less likely to achieve a virological response during therapy and a SVR after therapy withdrawal. In terms of this, Raison et al. (16) observed virus clearance after 24 weeks of PEG-IFN plus ribavirin therapy in 70% of patients with a delta increase in the Zung self-rating depression scale lower than 10, while patients with delta SDS ≥20 showed only a 33% response rate. This was independent of other variables including the dose and duration of IFN and ribavirin. A negative effect of depression on a SVR to PEG-IFN plus ribavirin combination has been described by Maddock et al. (17). Other studies reported reduced adherence to treatment in patients developing psychiatric adverse effects (18, 19).
Pharmacological intervention has been shown to be effective in the management of IFN-induced depression in a number of studies (20). The most effective and well-studied antidepressants in this setting are those of the selective serotonin reuptake inhibitor class. In particular, citalopram and escitalopram have been investigated in clinical trials of IFN treatment for HCV infection. A prospective, open-label trial of 39 HCV-infected patients undergoing treatment with IFN-α 2b plus ribavirin examined the efficacy of citalopram in managing on-treatment depression (21) The results showed that among 13 patients who developed a major depressive disorder, there was an 85% response rate to treatment with citalopram. In this study, response was defined as ≥50% reduction in the Beck Depression Inventory score. A similar study conducted by Schaefer et al. (22) found that 92% of patients who developed depression during treatment with PEG-IFN-α 2b plus ribavirin responded to 20 mg/day citalopram. Response was defined as ≥40% reduction in the Montgomery-Asberg Depression Rating Scale score following 3 weeks of treatment. Citalopram was also recently analysed in a prospective, double-blind, randomized, placebo-controlled trial of 100 HCV-infected patients on treatment with PEG-IFN-α 2b plus ribavirin (23). In this study, 28% of patients experienced on-treatment clinical depression as defined by an Hospital Anxiety and Depression Scale (HADS) score ≥9 and were randomized to placebo vs 20 mg/day citalopram (n=14 for each arm). After 4 weeks, a significant reduction in HADS scores was observed for patients in the antidepressant treatment arm (P<0.001), but no significant change was observed in the placebo group. Of importance, all patients who received antidepressant treatment were able to complete the full course of IFN therapy, whereas therapy discontinuation was necessitated in five patients in the placebo arm.
Conflicts of interest
The author has not declared any conflicts of interest.