Interferon alfa incidence

Interferon gamma is an activator of macrophages. Its anti-viral activity is limited compared to that of interferon alfa. Human recombinant interferon gamma restores, at least in part, macrophage cytotoxicity and with that decreases the incidence of infections in patients with chronic granulomatous diseases. Its adverse effects consist mainly of flu-like syndrome skin rashes may occur. 

A recent meta-analysis of clinical trials in patients with chronic HBV infection showed that treatment with interferon alfa is associated with a higher incidence of hepatitis e antigen (HBeAg) seroconversion and undetectable HBV DNA levels than placebo. The addition of the pegylated moiety results in further increases in the proportion of patients with HBeAg seroconversion ( 30%) and a decline by approximately 4 log copies/mL (99.99%) in HBV DNA after 1 year. 

The possibility of a positive correlation between the development of thyroid dysfunction and the probability of a favorable tumor response has been debated (7,9,14). The incidence of thyroid dysfunction did not correlate with the dose or the underlying disease, but increased with treatment duration (6). In a large survey of 281 cancer patients receiving low-dose (72 000 IU/kg) or high-dose (720 000 IU/kg) aldesleukin, up to 41% of previously euthyroid cancer patients developed thyroid dysfunction (15). Combined immunotherapy was also associated with more frequent thyroid disorders. Aldesleukin plus interferon alfa produced thyroid dysfunction in 20-91% of patients (6), and the incidence of laboratory thyroid dysfunction reached 100% in patients given five or six cycles of both cytokines (11). Aldesleukin plus interferon alfa also tended to be a risk factor for the development of biphasic thyroiditis (9). 

Data on interferon alfa-associated thyroid disease have been comprehensively reviewed (512,513). There was a mean prevalence of 6% for incident thyroid dysfunction, and treatment for malignancies was associated with the highest prevalence (11%). 

In addition to the underlying disease, there are many potential susceptibility factors (499,519). There is as yet no definitive evidence that age, sex, dose, and duration of treatment play an important role in the development of thyroid disorders. However, patients with previous thyroid abnormalities are predisposed to develop more severe thyroid disease (SEDA-20, 328). The incidence of thyroid disease was not different between natural and recombinant interferon alfa. Although this should be taken into account, a previous familial or personal history of thyroid disease was generally not considered a major risk factor. Finally, only pre-treatment positivity or the development of thyroid antibodies during treatment seem to be strongly associated with the occurrence of thyroid dysfunction. 

The immunological predisposition to thyroid disorders has been studied in 17 of 439 Japanese patients who had symptomatic autoimmune thyroid disorders during interferon alfa treatment (521). There was a significantly higher incidence of the human leukocyte antigen (HLA)-A2 hap-lotype compared with the general Japanese population (88 versus 41%), suggesting that HLA-A2 is a possible additional risk factor for the development of interferon alfa-induced autoimmune thyroid disease. 

Psychiatric symptoms have been prospectively examined in 104 patients with chronic hepatitis C, of whom 84 received interferon alfa-2b 15 MU/week and 20 were not treated (338). The incidence of clinically relevant scores for depression, anxiety, or anger/hostility increased from 23% of patients before interferon alfa to 58% of patients during treatment, and returned to 30% and 19% of patients 4 weeks and 6 months after withdrawal respectively. In contrast, there were no significant changes in the reference group. There were also significantly higher scores in the 40 patients who took concomitant ribavirin. Six patients successfully received antidepressant therapy, but withdrawal because of untreatable psychiatric symptoms was needed in 8.3% of patients, i.e. about half of the patients who had interferon-induced major depressive disorders. 

Although depressive symptoms are usually ascribed to interferon alfa alone, ribavirin could also contribute to their occurrence. Among 162 patients with chronic hepatitis C treated with peginterferon alfa-2b (1.5 micrograms/ kg once weekly) plus weight-based or standard-dose ribavirin and prospectively evaluated for the incidence and... 

Castera L, Zigante F, Bastie A, Buffet C, Dhumeaux D, Hardy P. Incidence of interferon alfa-induced depression in patients with chronic hepatitis C. Hepatology 2002 35(4) 978-9. 

Aldesleukin given alone or aldesleukin plus interferon alfa produced a high incidence of vitihgo in patients with metastatic melanoma, irrespective of whether or not they had received chemotherapy (102-104). A possible correlation between aldesleukin-induced vitihgo and a favorable tumor response was found (102) but has also been disputed (103). 

Recombinant aldesleukin-binding antibodies were detected in the half of 205 patients with metastatic cancer but there were neutralizing antibodies in only 7% (113). No significant difference in incidence was found between subcutaneous and continuous intravenous administration. In another study, none of the patients receiving aldesleukin alone developed neutralizing antibodies, whereas 18% of patients treated with aldesleukin and interferon alfa-2b had antibodies (114). Whatsoever, the clinical relevance of recombinant aldesleukin-neutralizing antibodies has not been accurately evaluated and a loss of response was apparently documented in only one patient (115). 

An unexpected high incidence of type I allergic reactions to cisplatin and dacarbazine has been observed, several hours after administration to patients on a combination of aldesleukin and interferon alfa (127). The reactions occurred at least after the first cycle and increased in incidence thereafter, suggesting that immunotherapy can sensitize patients to several chemotherapeutic agents. 

In a randomized comparison of recombinant interferon alfa-2b and interferon alfa n-3 (9 MU/week for 1 year) in 168 naive patients with chronic hepatitis C, there was no significant difference in clinical outcomes and the incidence or type of adverse effects between the groups (9). There was a non-significant trend toward more severe leukopenia and a higher incidence of severe thyroid disorders in patients who received recombinant interferon alfa-2b. 

The adverse effects of interferon alfa have mostly been reported after systemic administration, as intranasal use was not associated with more frequent adverse effects than placebo (13). Almost aU patients treated with interferon alfa have experienced adverse effects, most of which are mild to moderate in intensity and easily manageable without withdrawal of treatment (14). The incidence and profile of adverse effects reported with the available tjfpes... 

Although generalized tonic-clonic seizures have occasionally been described during trials of high doses of interferon alfa, they have also been reported after the use of intermediate or even low doses (67-69). There was a 1.3% incidence of generalized seizures in a retrospective study of 311 patients treated with low doses for chronic viral hepatitis (70). In another study, tonic-clonic seizures were identified in 4% of children treated for chronic hepatitis B (71). As seizures occurred only in children under 5 years of age with fever or potential perinatal nervous system injury, immaturity of the nervous system was suggested to be an additional factor for interferon alfa-induced neurotoxicity in children. 

In a prospective study, the overall incidence of biochemical thyroid disorders was 12% in 254 patients with chronic hepatitis C randomized to receive ribavirin plus high-dose interferon alfa (6 MU/day for 4 weeks then 9 MU/week for 22 weeks) or conventional treatment (9 MU/week for 26 weeks) (165). There was no difference in the incidence or the time to occurrence of thyroid disorders between the groups. Of the 30 affected patients, 11 (37%) had positive thyroid peroxidase autoantibodies (compared with 1% of patients without thjroid dysfunction), nine developed symptomatic thjroid dysfunction, and only three had to discontinue treatment. There was no correlation between the viral response and the occurrence of thyroid disorders, and only female sex and Asian origin were independent predictors of thyroid disorders. 

The occurrence of thyroid dysfunction in 72 patients treated with interferon alfa plus ribavirin (1.0-1.2 g/day) has been compared with that of 75 age- and sex-matched patients treated with interferon alfa alone for chronic hepatitis C (177). Of the former, 42 patients, and of the latter, 40 patients had received previous treatment with interferon alfa alone. There was no difference in the rate of thjroid autoimmunity (antithyroglobuUn, antithjroid peroxidase, and thyroid-stimulating hormone receptor antibodies) between the two groups, but the patients who received interferon alfa plus ribavirin developed subclinical or overt hypothyroidism more often (15 versus 4%). Similarly, the incidence of hypothjroidism increased to 19% in patients who underwent a second treatment with interferon alfa plus ribavirin compared with 4.8% after the first treatment with interferon alfa alone, while the incidence remained essentially the same in patients who had two consecutive treatments with interferon alfa alone... 

The new occurrence or exacerbation of hchen planus is a well-known comphcation of interferon alfa, but this has been a source of a considerable debate (SED-13, 1095) (SEDA-20, 330) (SEDA-22, 402). Indeed, most patients have received interferon alfa for chronic hepatitis C, an underlying disease that is controversially thought to be associated with a spontaneously higher incidence of lichen planus (290). In addition, complete reversibility of previous lichen planus was sometimes... 

Both binding and neutralizing antibodies to interferon alfa can be detected in interferon alfa-treated patients, and the incidence or clinical significance of these antibodies is the subject of continuous controversy, which has been addressed in a number of studies or general reviews (SED-13, 1096) (SEDA-20, 330) (SEDA-21, 373) (156,323-325). 

Two studies have provided insights into the incidence and risk factors of the immune-mediated comphcations of interferon alfa in patients with chronic myeloid leukemia. In the first study, 13 of 46 patients had autoimmune manifestations consisting of a combination of autoimmune thyroiditis in four, a direct antiglobulin test without hemolysis in eight, cryoagglutinins in one, Raynaud s phenomenon in two, and chronic autoimmune hepatitis in one (343). Overall, six patients had chnically symptomatic manifestations after a median of 15 months of treatment. In the second study, there were autoimmune diseases in seven of 76 patients after a median of 19 months of treatment, including hypothyroidism in one, immune-mediated hemolysis in two, systemic lupus erythematosus in two, Raynaud s phenomenon in one, and mixed connective tissue disease in one (344). In... 

The early impression that interferon alfa, alone or in combination with ribavirin, could reactivate or cause new subcutaneous sarcoid nodules and pulmonary or generalized sarcoidosis, has been confirmed by several reports, with prompt recovery after interferon alfa withdrawal (SED-13, 1097) (SEDA-20, 330) (SEDA-22, 404). The incidence may have been underestimated in one series, 3 patients out of 60 who received interferon alfa alone or combined with ribavirin developed pulmonary sarcoidosis (351). In a review of 27 cases, the time to onset was 15 days to 30 months, and there were dermatological signs in 50% (352). Five patients had also taken ribavirin, but an enhanced T cell immune reaction from the combination of interferon alfa plus ribavirin is speculative. However, the association of cutaneous or systemic sarcoidosis with interferon alfa, alone or in association with ribavirin, has been exemplified by various reports (353,354), including one patient whose sarcoidosis resolved with prednisone despite continued interferon alfa treatment (355). 

There was an unexpectedly high incidence of rheumatoid and lupus-like symptoms (27 of 137 patients), namely arthralgia, arthritis, myalgia, and Raynaud s phenomenon, in patients with myeloproliferative disorders taking interferon alfa alone or combined with interferon gamma (365). However, only a minority of affected patients fulfilled the diagnostic criteria for systemic lupus erythematosus. By contrast, systemic autoimmune diseases appeared to be genuine but very rare complications of interferon alfa in chronic hepatitis C, with only one case of lupus-like syndrome and two cases of polyarthritis in a survey of 677 patients (18). 

There are still uncertainties about the possible relation between interferon alfa and an increased incidence or severity of acute graft-versus-host disease after bone marrow transplantation. Late-onset, severe, atypical chronic graft-versus-host disease has been attributed to interferon alfa (383). 

Compared with untreated patients and patients treated with busulfan or hydroxyurea, interferon alfa produced a significantly higher frequency of clonal aberrant cytogenetic abnormalities and chronic clonal evolution in patients with chronic myeloid leukemia (386). However, the possible role of interferon alfa in the secondary occurrence of hematological malignancies is purely speculative. Only isolated cases of myeloproliferative syndrome, leukemia, or lymphoma have been attributed to interferon alfa (SED-13, 1098) (SEDA-20, 331) (SEDA-21, 373). There was no increased incidence of second cancers in patients treated for hairy cell leukemia (SEDA-20, 331). 

There was an increased incidence of adverse skin effects, mostly eczema, malar erythema, and lichenoid eruptions, in 33 patients who received combination of interferon alfa with ribavirin compared with 35 patients treated with interferon alfa alone (416). 

In 13 patients with metastatic renal cell carcinoma, the combination of interferon alfa-2a (27 MU/week) and thalidomide produced severe neurological toxicity in four patients, an incidence that was considered to be far greater than would be expected with either drug alone (417). 

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