Side effects of alpha-interferon therapy and impact on health-related quality of life in children with chronic viral hepatitis

BACKGROUND: Interferon (IFN) is standard therapy for chronic viral hepatitis in children. The aim of this study was to evaluate the side effects of alpha-interferon (IFN) in 94 consecutive children (58 males; age range, 3 to 14 years) affected by chronic viral hepatitis treated with different schedules ranging from 3 to 10 MU and from 3 to 12 months, and the impact of this therapy on health-related quality of life. METHODS: Side effects were evaluated with clinical and laboratory examinations and were recorded on a diary card. The health-related quality of life was evaluated with a modified version of the Sickness Impact Profile. RESULTS: All patients experienced at least one adverse reaction to IFN treatment; 80% had more than five side effects. There were no life-threatening reactions. Three children experienced severe reactions (febrile seizure, severe hypertransaminasemia and relapsing episodes of epistaxis, respectively) that required permanent IFN withdrawal. Another child had a febrile seizure requiring temporary IFN withdrawal. In seven children the neutrophil count fell below 1000/mm3 and promptly increased when IFN was temporarily discontinued. The remaining children had mild or moderate clinical and/or laboratory adverse reactions. Age, sex, viral etiology of chronic hepatitis and response to therapy were not significantly associated with the appearance of side effects. The pre-IFN health-related quality of life was good in all children; it deteriorated significantly during IFN therapy and returned to basal standards within 3 months after IFN withdrawal. No patient required suspension of IFN therapy because of worsening of health-related quality of life. CONCLUSION: Children have a low risk of developing severe IFN-induced side effects. Adverse reactions and worsening of health-related quality of life were tolerable and did not seem to be a limiting factor for IFN therapy in young candidates.     

Neurovisual impairment: a frequent complication of alpha-interferon treatment in chronic viral hepatitis

Following our earlier observation of clinically evident optic tract neuropathy in patients receiving low-dose interferon (IFN) therapy, we prospectively evaluated 53 consecutive patients treated for chronic hepatitis B or C with a median dose of 3 MU of IFN-a2b thrice weekly. Measurements included routine ophthalmologic evaluation and recordings of visual evoked responses (VER), electroretinograms (ERG), visual acuity, and visual fields, before, at the end of IFN treatment, and at follow-up visits. Baseline P100 latencies of VERs (base-VER) were abnormally prolonged in 24 patients (32 of 106 eyes, 30.2%); age was the only significant covariate associated with increased risk for an abnormal base-VER by multiple logistic regression (relative risk [RR] 5.3 per each 5-year increase in age). In 45 patients (74 eyes) with normal baseline P100 latencies, the end-of-treatment VERs (end-VER) were significantly prolonged compared with baseline, becoming abnormal in 11 (15 of 74 eyes, 20.3%) (138.8+/-8.7 vs. 117.7+/-5.2 ms, P < .001). This subgroup had older age (59.1+/-11.0 vs. 47.5+/-15.3, P=.007) and reduced visual sensitivity compared with their own pretreatment measurements (24.5+/-1.6 vs. 23.0+/-1.2db, P=.019). Changes of end-VERs by age had a sigmoid distribution with a steep increase of values beyond the 5th decade (R2=.326, P < .001). In a logistic regression model, significant predictors of abnormal end-VERs were, patients' age (RR 5.6 per each 5-year increase), presence of hepatitis B virus (HBV) infection (RR 15.1 compared with hepatitis C virus [HCV] infection) and serum cholesterol levels above 240 mg% (RR 7.1 compared with values < 240 mg%). Subconjunctival hemorrhages were seen in 2 cases and funduscopic examination revealed cotton wool spots in one other. ERG recordings and the P100 amplitude remained unchanged. After stopping IFN, the treatment-associated neurovisual abnormalities reversed to normal in 7 patients (10 of 15 eyes) and persisted in 5 (5 of 15 eyes, 33.3%) for up to 37 (median 7.3) months observation, all patients remaining clinically asymptomatic. In conclusion, subclinical neurovisual impairment is a frequent, largely unrecognized complication of low-dose IFN therapy, and patients with chronic hepatitis B and older age appear to be most susceptible. This apparently innocuous complication is long lasting, possibly irreversible in some patients, with yet undetermined consequences on visual function.     

Current therapeutic trends in therapy for chronic viral hepatitis

Hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis delta virus (HDV) are associated with clinically significant chronic infection that may lead to the development of cirrhosis or even hepatocellular carcinoma (HCC). Intervention at the earliest possible stage is needed to prevent such untoward sequelae. Currently, interferon (IFN) is the only approved and widely used agent for the treatment of these infections, including in HBV patients with precore mutant hepatitis or decompensated cirrhosis, but its efficacy is far from satisfactory. Corticosteroid priming has been shown to increase the efficacy of IFN therapy in HBV patients with low abnormal serum transaminase levels, but only a few responders will clear serum hepatitis Bs antigen (HBsAg). Ongoing randomized controlled trials of thymosin alpha 1, lamivudine and famcyclovir have demonstrated encouraging preliminary results. Therapeutic vaccines, such as polypeptides with human leucocyte antigen (HLA)-specific hepatitis B core antigen (HBcAg) epitopes, are under phase II/III clinical trial. For HDV infection, the use of IFN in the early phase of acute superinfection tends to prevent chronic progression. For HCV infection, IFN used at higher doses for a longer period of time is associated with a higher sustained response, but overall it is still not satisfactory. The combined use of ribavirin or corticosteroid priming may improve the effect of IFN therapy by enhancing the durability of the response. Interferon in the acute phase of HCV infection may also prevent chronic progression. There is evidence to suggest that IFN therapy, when associated with response, tends to reduce the risk of cirrhosis or HCC and prolongs survival. There is no doubt that satisfactory treatment of chronic viral infection will require more effective agents and demand optimal treatment strategies, many of which are yet to be found.     

Depression during interferon therapy in chronic hepatitis C patients--a prospective study

The number of patients treated with interferon (IFN) has increased markedly in Japan since 1992, when the Health and Welfare Ministry approved the use of IFN for treating chronic active hepatitis C. It is important to identify and treat depression, which is one of the psychiatric complications of IFN therapy and often leads to discontinuation of the therapy, in patients with chronic hepatitis C. In this study we prospectively investigated the incidence of depression during IFN therapy in patients with chronic active hepatitis C. The psychiatric status of 85 patients (53 men, 32 women; mean age 49.1 years) with chronic active hepatitis C who began receiving IFN at Showa University Hospital was assessed before and 2, 4, 12 and 24 weeks after the start of IFN therapy, using the major depressive episode diagnostic criteria listed in the DSM-III-R and the Hamilton Depression Scale HDS). All of the patients provided informed consent prior to participation in this study. IFN therapy was discontinued in 5 cases (5.9%) because of physical side effects and in 4 cases (4.7%) because of depression. Two, 11, 14, 25 and 16 patients were diagnosed as having major depressive episodes before and 2, 4, 12 and 24 weeks after the start of IFN therapy, respectively. The number of patients who were asymptomatic before the start of IFN therapy but were diagnosed as having a major depressive episode at least once during IFN therapy was 31 (31/83 = 37.3%). The mean HDS scores at 2, 4, 12 and 24 weeks (5.4, 6.0, 8.8 and 6.6) were significantly higher than that before the start of IFN therapy (3.0). The patients whose first diagnosed major depressive episodes occurred more than 4 weeks after the start of IFN therapy tended to be more severely depressed than those in whom it occurred less than 4 weeks after the start of IFN therapy. Compared to the 47 patients who completed 24 weeks of IFN therapy without experiencing depression, the 31 patients who were diagnosed as experiencing major depressive episodes during IFN therapy had significantly higher neuroticism scores determined using the Eysenck Personality Questionnaire, showed a more severely depressed mood and experienced more severe sleep disturbances before the start of IFN therapy. The latter group of patients also tended to have comorbid chronic physical disorders such as hypertension or diabetes mellitus and the histories of mental disorders before the IFN therapy; however these differences were not statistically significant. There were no differences between the two groups in patient age or sex, the severity of hepatitis before the IFN therapy, the type of IFN used in the therapy or the efficacy of IFN in the treatment of the hepatitis C. Our results indicate that the decision as to whether to treat chronic active hepatitis C with IFN should be made carefully and that early intervention and careful monitoring of depression are required during IFN therapy in the treatment of chronic active hepatitis C.     

Lymphoblastoid alpha-interferon for chronic hepatitis C: a randomized controlled study

The orientation of the sella nasion (SN) line in lateral skull radiographs is important for accurate assessment of antero-posterior and vertical facial relationship. Lateral skull radiographs of a random sample were traced and digitized to produce a mean shape template of the sample, with the craniofacial centroid line (CFC) used as a base for superimposition of the sample. A geometrical triangle was formed using the sella nasion line, craniofacial centroid line and the mandibular plane as the sides of the triangle. Simple geometric calculations were done to re-orient both the mandibular plane and sella nasion line in cases with balanced clinical profiles, while the S-N-A and S-N-B measurements indicate otherwise.     

Treatment of chronic viral hepatitis

Recent advances have been made in the treatment of chronic viral hepatitis, mainly with recombinant interferon (IFN) alpha. However, the present treatment of chronic viral hepatitis is not entirely satisfactory because the efficacy is inconstant and/or incomplete. In chronic hepatitis B IFN-alpha induces a sustained interruption of hepatitis B virus (HBV) replication, with a HBeAg to anti-HBe seroconversion in about 30% of patients. Patients most likely to respond are those with no immunosuppression, HBV infection acquired during adulthood or active liver disease with low HBV replication. Responders usually show a significant decrease in serum HBV DNA levels during the first 2 months of therapy, followed by a significant increase in the level of aminotransferases. New nucleoside analogues might be useful in combination with IFN-alpha in the treatment of those who do not respond to IFN therapy. In chronic hepatitis B-D, the rate of sustained response to IFN-alpha therapy is low. To be effective, IFN-alpha must be used at a high dosage (9-10 mega units) with a long duration (1 year). In chronic hepatitis C, IFN-alpha at a dosage of 3 mega units over 6 months, induces a sustained response in about 20% of patients. A higher dosage of IFN (5-10 mega units) and a longer duration of treatment increases the rate of sustained response but is associated with poor tolerance. Non-responders to a first course of IFN do not respond to a second course of treatment. In patients who respond but relapse after treatment, the rate of sustained response after a second course of IFN needs to be assessed. Ribavirin, which has a significant antiviral effect on hepatitis C virus, might be useful in combination with IFN-alpha. At the dosage (3-6 mega units) usually used, IFN-alpha is relatively well tolerated. In about 10% of the patients therapy is interrupted, mainly because of severe fatigue, thyroid dysfunction or depression.     

Management of chronic viral hepatitis

Chronic viral hepatitis is a leading cause of death worldwide. Four of the six identifiable hepatitis viruses are associated with chronic disease. Until recently, the only accepted treatment has been injected interferon alfa. New antiviral medications currently hold promise in the treatment of hepatitis B. Hepatitis C remains more difficult to treat than hepatitis B, but involving the patient in selecting the treatment and identifying patients with better responses to interferon may help the physician direct the management of such patients more successfully.     

Treatment of chronic viral hepatitis

The initial appearance of tyrosine hydroxylase (TH)-, serotonin (5-HT)-, gamma-aminobutyric acid (GABA)-, calcitonin gene-related peptide- (CGRP), substance P-, and synaptophysin-immunoreactivity in the rat pituitary gland, and in the related brain regions was investigated. Several groups of TH-immunoreactive neurons were first detected in the brain stem on day E17, and in the hypothalamus on day E18, followed by TH-immunoreactivity in the median eminence and infundibulum on E19-E20. TH-positive fibers appeared in the posterior lobe on day E20 and in the intermediate lobe on day P0. 5-HT-immunoreactivity was first detected on day E17 in neurons and nerve fibers in the brain stem and in the median eminence, respectively. On day E18, a few 5-HT-immunoreactive fibers were detected in the posterior lobe of the pituitary, although they were consistently seen in the infundibulum from day E19. In newborn rats, some 5-HT-immunoreactive fibers, but no neurons, were seen in the hypothalamus. GABA immunoreactivity appeared on day E17 in several nerve fibers of the infundibulum and the posterior lobe. Some neurons in the cortex and ventral hypothalamus transiently expressed GABA-immunoreactivity on day E17. In newborn rats, a plexus of GABA-immunoreactive fibers was detected for the first time in the intermediate lobe. No CGRP-immunoreactive fibers could be detected in the prenatal pituitary. On day P10, CGRP-immunoreactive fibers were first observed in the anterior lobe. Later their number considerably increased, while only sporadic fibers could be found in the intermediate or posterior lobes. No substance P-immunoreactivity could be detected in any of the lobes in the embryonic or developing postnatal rat pituitary, instead the adult anterior lobe occasionally showed some substance P-immunoreactive fibers. Synaptophysin-immunoreactivity was first detected in the posterior lobe on day E20, followed shortly by its expression in the intermediate lobe in newborn rats. The time course of GABA and 5-HT expression revealed in the present study suggests that these transmitters, which are initially expressed in the developing pituitary clearly before synaptic maturation, may act as trophic molecules during the prenatal period.     

Suicidal impulses in patients with chronic viral hepatitis C during or after therapy with interferon alpha

OBJECTIVE: The objective of this study was to evaluate key outcomes of a universal hearing screen/rescreen program for all births with transient evoked otoacoustic emissions in all 8 maternity hospitals in the state of Rhode Island over a 4-year period. STUDY DESIGN: This was a retrospective analysis of the hearing screen/rescreen refer data collected prospectively for 53,121 survivors born in Rhode Island between January 1, 1993, and December 31, 1996. Primary outcomes included the first-stage refer rates, rescreen compliance, diagnostic referral rates, identification rates, and the age of amplification. RESULTS: During this 4-year time period 11 infants were identified with permanent hearing loss, resulting in an impairment rate of 2 per 1000. The mean age of hearing loss confirmation decreased from 8.7 months to 3.5 months, and the age at amplification declined from 13.3 months to 5.7 months. CONCLUSION: We conclude that time and experience are important factors in the development and refinement of a universal hearing screen program. Hearing screen outcome data collected over a 4-year period in Rhode Island reveal a steady improvement in the percent of infants completing the 2-stage screen process, the stage 1 and stage 2 refer rates, compliance with rescreen and diagnostic testing, and significant improvement in the age of identification and age of amplification.     

Autoantibodies before, during and after administration of recombinant interferon-alpha for chronic viral hepatitis

This study was undertaken to investigate the presence of autoantibodies in patients with chronic viral hepatitis B and C, before, during and after interferon-alpha (IFN-alpha) therapy and to study their relation to dose and type of IFN-alpha and response to treatment. Fifty patients with chronic hepatitis were divided in two groups, a control-group of 21 patients (10 type B and 11 type C) who were followed for 6 months without treatment and an IFN-group consisting of 29 patients (8 type B and 21 type C) who received IFN therapy for 6 months. Serum samples were tested for a range of antibodies at the start of the study, during therapy and at the end of the 6 month period. Antibodies tested for included: antinuclear, smooth muscle, antimitochondrial, parietal cell and thyroid microsomal. Four (8%) of the total patient group had autoantibodies at the beginning of the study (two in each group). During the follow-up period no patient in the control group developed antibodies compared with 3 (11%) patients in the treatment group. Autoantibodies developed in patients treated with higher doses of IFN and were found in those patients who tended to show a poor response to IFN-therapy. Further studies are needed to establish the relationship between poor response to IFN-alpha and development of autoantibodies.     

Permanent response to alpha-interferon therapy in chronic hepatitis C is preceded by rapid clearance of HCV-RNA from serum

BACKGROUND/AIMS: Prediction of response to interferon therapy is important in the management of chronic hepatitis C. Pre-therapy data are valuable but they may be inaccurate in some cases. Our aim was to investigate whether the biochemical and virological events that occur early during interferon therapy in chronic hepatitis C may predict the final result of the treatment. METHODS: ALT and serum HCV-RNA were serially measured in 53 HCV-RNA-positive patients who received a standard 6-month course of interferon therapy. Eleven patients with a sustained response, 23 who responded but subsequently relapsed and 19 who did not respond were studied. HCV-RNA was measured with a commercial kit (Amplicor HCV). RESULTS: After 4 weeks of treatment, HCV-RNA became negative in 73% of sustained responders, in 26% of transient responders (p = 0.02) and in none of the non-responders. Corresponding figures after 8 weeks of therapy were 82% in sustained responders, 61% in transient responders and 9% in non-responders. The difference between sustained and transient responders at this time was not significant. After 4 weeks of therapy, 82% of sustained responders, 52% of transient responders and none of the non-responders presented normalization of alanine transferase. The difference between sustained and transient responders was not significant. Corresponding figures for normalization of alanine transferase at 8 weeks were 82%, 96% and 0% respectively. At the end of treatment, all sustained responders, 70% of transient responders and none of the non-responders had cleared HCV-RNA from serum. CONCLUSIONS: A rapid normalization of alanine transferase induced by interferon therapy is associated with response, but does not differentiate between transient and permanent response. In contrast, clearance of HCV-RNA after 4 weeks of treatment, but not after 8 weeks, is significatively associated with sustained response. Testing for HCV-RNA early during interferon administration may be valuable for further decisions concerning therapy in patients with chronic hepatitis C.     

The immunological diagnosis of chronic viral hepatitis

Chronic viral diseases of the liver are associated with changes in immune reactions mediated by T and B lymphocytes and dependent in severity on etiological factor (virus of hepatitis B, delta, C, their combination), the disease stage (hepatitis, cirrhosis), the process activity, kind of immune correction. HBsAg, viral hepatitis B marker, was detected in 21.2% of 1400 cases with chronic active hepatitis and liver cirrhosis. 32% of HbsAg-seropositive patients had antibodies to delta-antigen. Antibodies to HBsAg, HCV were found in 27.7 and 14.9% of the above patients. Chronic viral diseases of the liver with persistence of HBV, HDV and HCV markers are characterized by a complex of immune disorders, including a moderate rise in peripheral blood of IgM, IgG, IgA, IgE, Ig kappa, lambda, immune complexes, cryoglobulins, autoantibodies to subcellular structures as well as changes in regulatory (suppressor, helper) and effector (lymphokine-producing) functions of T lymphocytes, inhibition of phagocytosing capacity. The above shifts in immune status, clinical and biochemical activity of the disease are more pronounced in chronic active hepatitis with HCV markers compared to BHV. Of maximal intensity they were in combined viral infection HBV+HDV or HBV+HCV.     

The risk factor for development of thyroid disease during interferon-alpha therapy for chronic hepatitis C

OBJECTIVES: To determine the risk factors for the development of thyroid diseases during interferon-alpha therapy, we analyzed the patients with chronic hepatitis C who were treated with interferon-alpha. METHODS: One hundred nine patients with chronic hepatitis C (77 men and 32 women, ages 20-72 yr) were treated with interferon-alpha (alpha, 48; alpha 2a, 38; alpha 2b, 23) for 14-40 wk. Thyroid function tests and seven autoantibodies were assessed at the beginning and end of interferon-alpha therapy, and every other month. A logistic multiple regression model was used in the statistical analysis of risk factors for development of thyroid diseases. RESULTS: Among the 106 patients with normal pretreatment thyroid function tests, nine patients (three men and six women, ages 33-62 yr) developed thyroid diseases. However, among three patients with abnormal thyroid function tests, exacerbation of thyroid disease was not observed during interferon-alpha therapy. Logistic multiple regression model revealed that positivity for microsome antibody was a significant risk factor for the development of thyroid disease (p < 0.0001, chi 2 = 20.18). Actually, compared to patients without microsome antibody at the beginning of therapy, the incidence of thyroid diseases in the patients with pretreatment microsome antibody was very high: 3.3% (3/99) versus 60% (6/10), respectively. Six patients developed hyperthyroidism and three patients developed hypothyroidism. The patients with hyperthyroidism had atypical clinical features. CONCLUSION: Our study revealed that positivity for microsome antibody at the beginning of interferon-alpha therapy is a risk factor for thyroid dysfunction.     

Opioid therapy for chronic noncancer back pain. A randomized prospective study

STUDY DESIGN: A randomized, open, long-term, repeated-dose comparison of an anti-inflammatory drug and two opioid regimens in 36 patients with back pain. OBJECTIVES: To examine the long-term safety and efficacy of chronic opioid therapy in a randomized trial of patients with back pain. METHODS: All participants underwent a 4-week washout period of no opioid medication before being randomly assigned to one of three treatment regimens for 16 weeks: 1) naproxen only, 2) set-dose oxycodone, or 3) titrated-dose oxycodone and sustained-release morphine sulfate. All patients then were assigned to a titrated dose of opioids for 16 weeks and then gradually tapered off their medication for 12 weeks. Finally, all participants were monitored for a 1-month posttreatment washout period. Each patient was called once a week for a report on pain, activity, mood, medication, hours awake, and adverse effects and was monitored carefully for signs of abuse and noncompliance. RESULTS: Weekly reports during the experimental phase showed the titrated-dose group to have less pain (P < 0.001) and less emotional distress (P < 0.001) than the other two groups. Both opioid groups were significantly different from the naproxen-only group. During the titration phase, patients also reported significantly less pain and improved mood. Few differences were found in activity or hours asleep, or between average pretreatment and posttreatment phone-interview and questionnaire variables. No adverse events occurred, and only one participant showed signs of abuse behavior. CONCLUSIONS: The results suggest that opioid therapy has a positive effect on pain and mood but little effect on activity and sleep. Opioid therapy for chronic back pain was used without significant risk of abuse. However, tapered-off opioid treatment is palliative and without long-term benefit.