Low-dose interferon alpha combined with zidovudine in patients with AIDS-associated Kaposi's sarcoma

Abstract. Forty patients with AIDS-associated Kaposi's sarcoma (KS) treated with the combination of interferon alpha-2b (IFN-α) 10–20 MU day^?1 and zidovudine (ZDV), 500–800 mg day^?1, were evaluated for safety and efficacy. Eighteen patients (45%) had an overall response (CR + PR) at 3 months and a response persisting for a median of 14 (3–27) months. Patients with a CD4 count of less than 300 mm^?3, prior to opportunistic infections or constitutional symptoms, were less likely to respond. However, between 28.5% and 36% of patients with a low CD4 count did respond to combined therapy. This is higher than would be predicted from single agent IFN-α therapy. Twelve of 28 patients (42.8%) receiving 10 MU day^?1 of IFN-α (low dose) had an overall response. In addition, patients tolerated this dose of IFN-α better, presenting fewer flu-like symptoms and displayed a trend toward less anaemia, p24 antigen decreased in six out of nine evaluable cases, four of whom were treated with low-dose IFN-α. Low-dose IFN-α plus ZDV seems to be a useful and well-tolerated therapy for KS with antitumoral and antiviral activity. Patients without ‘bad prognostic markers’ are most likely to show improvement.     

Effectiveness and complications of combination therapy with interferon alpha and ribavirin in patients with chronic hepatitis C]

BACKGROUND/AIMS: The effectiveness of combination therapy with conventional or pegylated interferon alpha and ribavirin in patients with chronic hepatitis C is well understood. However, the profound investigation about complications of the treatment has been rarely reported in Korea, where patients have broader spectrum of disease manifestations. The aim of this study was to evaluate the effectiveness and complications of the combination therapy of interferon alpha and ribavirin in patients with chronic hepatitis C. METHODS: Two hundred and forty patients with chronic hepatitis C were included. All patients were treated with interferon alpha (3 million units thrice a week) in combination with ribavirin (800-1,200 mg, depending on body weight). Patients were treated for 6 or 12 months according to the genotypes (genotype 1; 12 months, non-1; 6 months). We retrospectively evaluated ETR (end of treatment response) and SVR (sustained virologic response) on the basis of intent-to-treat in patients completing the therapy. RESULTS: In 154 patients who had completed the therapy, ETR was 79.2% and SVR was 61.0%. Multivariate analysis showed that genotype and early virologic response at 3 months of treatment were independent predictive factors of SVR. Due to insufficient response, 11.3% of the patients discontinued the therapy. In addition, 24.5% of the patients prematurely discontinued the therapy due to adverse events including aggravated liver function (15.4%), failure to return (7.9%), and others (1.2%). Dose modifications of interferon alpha or ribavirin were required due to anemia (15.4%), neutropenia (8.8%), or thrombocytopenia (4.6%). CONCLUSIONS: The overall SVR of patients who had completed the combination therapy with interferon alpha and ribavirin was 61.0%. However, about one third of the patients discontinued the therapy prematurely due to insufficient response, adverse events and/or noncompliance.     

Treatment of chronic delta infection with recombinant human interferon alpha 2c at high doses

Superinfection by hepatitis delta virus (HDV) in hepatitis B virus chronic carriers is normally associated with a progressive liver injury. For this reason, the aim of the present study was to determine the efficacy of recombinant interferon alpha (rIFN-alpha) treatment of chronic delta hepatitis, by giving high doses of rIFN-alpha 2c during a prolonged period. A total of 20 HBsAg, anti-HD carriers with a chronic active hepatitis were randomly allocated in two groups: (I) n = 10, control and (II) n = 10, treated with 10 MU/m2 body surface of rIFN-alpha, twice weekly, intramuscularly (im) during 6 months. Basally, all patients presented HDAg in the liver and serum IgM anti-HD. Serum HDV-RNA was positive in 8 and 7 patients from groups I and II, respectively. The interferon therapy was well tolerated and all patients finished the treatment period. During the first 6 months, a decrease in ALT levels among treated patients (255 +/- 98 vs. 193 +/- 117) was observed. In addition, a transient drop in HDV-RNA levels was also observed. No changes in anti-HD titer, IgM anti-HD and HBsAg concentration were detected. At the end of the follow-up period (15 months) two treated patients had lost IgM anti-HD. In addition, another two patients were HDV-RNA negative. In conclusion, no permanent antiviral effects of rIFN-alpha 2c in chronic delta hepatitis, using this schedule, was achieved.     

Long-term interferon alpha maintenance therapy for chronic hepatitis C infection in a patient with common variable immune deficiency.

A 46-year-old woman with common variable immune deficiency acquired acute non-A, non-B hepatitis from contaminated intravenous gamma globulin in 1983. For 6 years she had fluctuating elevations of her serum aminotransferase levels. In 1990 her serum was documented to be hepatitis C virusribonucleic acid positive by polymerase chain reaction, and her liver biopsy revealed chronic hepatitis with early cirrhosis (Knodell score, 15 points). Hepatitis C virus genotyping indicated that she had been infected with the type 3 genotype. She subsequently underwent treatment with interferon alpha (IFN-alpha) for 1 year and experienced biochemical, virologic, and histologic (Knodell score, 9) suppression. She was continued on maintenance therapy for an additional 7 years, with sustained biochemical and virologic suppression. During the sixth year of therapy, complications of portal hypertension were noted with mild ascites and eventually bleeding esophageal varices. This case report documents a favorable biochemical, virologic, and histologic response to IFN-alpha therapy in this setting; supports the notion that the natural progression of hepatitis C virus infection may be more aggressive in patients with common variable immune deficiency; and, although complications of portal hypertension eventually occurred, the suppressive maintenance IFN therapy may have delayed their onset. The future establishment of the long-term effects of IFN therapy on important clinical outcomes is necessary to understand better its therapeutic benefit in chronic hepatitis C infection.     

Acute inflammatory demyelinating polyneuropathy associated with pegylated interferon α 2a therapy for chronic hepatitis C virus infection

The combination of pegylated interferon （Peg-IFN） and ribavirin is the standard of care for chronic hepatitis C virus （HCV） infection treatment. In general, common side effects related to this combination therapy are mild and are very well tolerated. However, peripheral neuropathy including demyelinating polyneuropathy related to Peg- IFN is extremely rare. We present the first case of an acute inflammatory demyelinating polyneuropathy （AIDP） associated with Peg-IFN-α 2a （Pegasys） after 16 wk of a combination therapy with Pegasys and ribavirin in a 65-year-old woman with chronic HCV infection. She developed tingling, numbness, and weakness of her upper and lower extremities and was hospitalized for acute neurological deficits. Her clinical course, neurological findings, an electromyogram （EMG）, nerve conductions studies （NCS）, muscle biopsy, and a sural nerve biopsy were all consistent with AIDP likely related to Pegasys use. The patient recovered completely with the use of intravenous immunoglobulin （IVIG） including physical therapy and neurological rehabilitation. It is very important that gastroenterologists and/or hepatologists recognize this rare neurological complication related to Peg-IFN treatment very early, since it requires a prompt discontinuation of therapy including an immediate referral to a neurologist for the confirmation of diagnosis, management, and the prevention of long-term neurological deficits.     

Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial

BACKGROUND, AIM, AND METHODS: Alpha interferon is the generally approved therapy for HBe antigen positive patients with chronic hepatitis B, but its efficacy is limited. Lamivudine is a new oral nucleoside analogue which potently inhibits hepatitis B virus (HBV) DNA replication. To investigate the possibility of an additive effect of interferon-lamivudine combination therapy compared with interferon or lamivudine monotherapy, we conducted a randomised controlled trial in 230 predominantly Caucasian patients with hepatitis B e antigen (HBeAg) and HBV DNA positive chronic hepatitis B. Previously untreated patients were randomised to receive: combination therapy of lamivudine 100 mg daily with alpha interferon 10 million units three times weekly for 16 weeks after pretreatment with lamivudine for eight weeks (n=75); alpha interferon 10 million units three times weekly for 16 weeks (n=69); or lamivudine 100 mg daily for 52 weeks (n=82). The primary efficacy end point was the HBeAg seroconversion rate at week 52 (loss of HBeAg, development of antibodies to HBeAg and undetectable HBV DNA). RESULTS: The HBeAg seroconversion rate at week 52 was 29% for the combination therapy, 19% for interferon monotherapy, and 18% for lamivudine monotherapy (p=0.12 and p=0.10, respectively, for comparison of the combination therapy with interferon or lamivudine monotherapy). The HBeAg seroconversion rates at week 52 for the combination therapy and lamivudine monotherapy were significantly different in the per protocol analysis (36% (20/56) v 19% (13/70), respectively; p=0.02). The effect of combining lamivudine and interferon appeared to be most useful in patients with moderately elevated alanine aminotransferase levels at baseline. Adverse events with the combination therapy were similar to interferon monotherapy; patients receiving lamivudine monotherapy had significantly fewer adverse events. CONCLUSIONS: HBeAg seroconversion rates at one year were similar for lamivudine monotherapy (52 weeks) and standard alpha interferon therapy (16 weeks). The combination of lamivudine and interferon appeared to increase the HBeAg seroconversion rate, particularly in patients with moderately elevated baseline aminotransferase levels. The potential benefit of combining lamivudine and interferon should be investigated further in studies with different regimens of combination therapy.     

Comparison of long-term effects of lymphoblastoid interferon alpha and recombinant interferon alpha-2a therapy in patients with chronic hepatitis B

To compare the long-term effect of natural lymphoblastoid interferon-alpha (IFN-alpha nl) and recombinant IFN-alpha 2a therapy in patients with chronic hepatitis B, 210 patients in two trials were followed-up for 1.1-15.5 years following the end of therapy. They included 34 patients who received placebo (control), 67 treated with IFN-alpha nl (36 after prednisolone priming) and 109 treated with IFN-alpha 2a (56 after prednisolone priming). The cumulative sustained response was higher in patients who had been treated with IFN-alpha nl after prednisolone priming than was exhibited using IFN-alpha nl alone, IFN-alpha 2a alone or the placebo (P < 0.05), or IFN-alpha 2a following prednisolone priming (P = 0.052) at the end of 11 years. Hepatocellular carcinoma (HCC) was detected in 1.5% of the IFN-alpha nl group, 3.7% of the IFN-alpha 2a group and 14.7% of the control group (control vs IFN-alpha nl or IFN-alpha 2a, P < 0.05). The cumulative HCC development was higher in the control group than in the IFN-alpha nl group (P < 0.002) and the IFN-alpha 2a group (P = 0.06). The cumulative survival rate was lower in the control group than in the IFN-alpha nl group (P < 0.01) and the IFN-alpha 2a group (P = 0.02). Multivariate analysis revealed that IFN-alpha nl therapy and female gender are significant predictors of sustained response; preexisting cirrhosis, age at entry and IFN therapy are significant factors in both HCC development and survival. In conclusion, IFN-alpha nl treatment may have a better long-term effect on hepatitis B virus (HBV) clearance than IFN-alpha 2a and placebo, and IFN therapy may provide better long-term beneficial effects than placebo in terms of HBV clearance, reduction of HCC and prolonged survival.     

Successful interferon desensitization in a patient with chronic hepatitis C infection

Treatment of hepatitis C, even when absolutely necessary, is almost impossible when interferon cannot be administered for any reason. We report a 65-year-old patient with chronic hepatitis C virus （HCV） infection and fibrosis, who was unable to receive interferon because of systemic hypersensitivity. The patient was desensitized successfully through gradual incremental exposure to interferon, and HCV infection was eradicated after a complete course of treatment, with no further allergic reactions. This case report that describes successful eradication of hepatitis C in a patient with advanced liver disease after desensitization to interferon revealed that desensitization may not necessarily damage the therapeutic efficacy of the drug.     

Immunological response in chronic hepatitis C virus infection during interferon alpha therapy

BACKGROUND/AIMS: Chronic hepatitis C infection is a serious therapeutic problem. Interferon therapy is one of the possible methods leading to HCV infection elimination in some patients. The aim of the study was the estimation of administration of interferon alpha 2a and its effect on the lymphocyte subpopulations in peripheral blood in patients with chronic hepatitis C. METHODOLOGY: A cytometric analysis was completed concerning the level of CD19+, CD3+, CD4+, CD8+, CD4+ + HLA DR+, CD16+ + 56+ in 21 patients in the 0, 4, 24, 48 weeks of interferon alpha 2a treatment, with the dose of 18 MU/week/48 weeks. RESULTS: Virus elimination was obtained in 26% of patients (responders, R) and a higher CD8+ level and a decrease in CD4+ was observed during interferon administration in those patients. A slight increased NK cell level was noticed mainly in patients who did not eliminate HCV (non-responders, NR). In R patients, lower lymphocyte values of CD19+, NK, CD3+ + HLA DR+, and CD4+ were observed in comparison to NR, which could suggest that they play a role in the process of HCV elimination. Significant immunological changes in peripheral blood were observed mainly in the first 4 weeks of interferon alpha therapy. CONCLUSIONS: Our studies did not reveal whether any of examined lymphocyte subpopulations in peripheral blood could be considered as a predictive factor of a positive reaction to interferon alpha treatment. However, there are significant differences in the levels of lymphocytes in R and NR.     

Autoimmunization induced by interferon alpha therapy in chronic hepatitis C

We report the case of a 56 year-old woman with post-transfusion chronic hepatitis C who presented with a severe ALT flare up associated with a rapid progression of liver fibrosis during interferon alpha 2b therapy. Several hypotheses were considered to explain the etiology of this ALT flare: there was no viral super infection by other hepatotropic viruses, no toxic hepatitis, no metabolic disease, and no other specific liver diseases could be identified. HLA typing showed a specific profile A1 B8 DR3 (risk factor of auto-immunization during interferon alpha therapy) with antinuclear antibodies and anti smooth muscle antibodies. This case suggests that auto-immunization induced by interferon alpha should be investigated in case of ALT flare that is not followed by an HCV breakthrough.     

Therapy of chronic hepatitis B with recombinant human alpha and gamma interferon

Eight patients with chronic hepatitis B entered a pilot study of gamma interferon and alpha interferon in combination. Gamma interferon alone had minimal inhibitory effects on serum levels of hepatitis B virus as monitored by serum HBV DNA and DNA-polymerase activity. The drug also gave troublesome side effects. In contrast, alpha interferon had more potent inhibitory effects on serum HBV levels and fewer side effects. When combined, the two interferons showed no additive or synergistic effects in inhibiting serum levels of HBV DNA or DNA polymerase. These findings indicate that the addition of gamma interferon to alpha interferon provides no additional antiviral effects but contributes significantly to side effects.     

Long-term results of therapy with interferon alpha for cryoglobulinemia associated with hepatitis C virus infection

Summary We describe the long term results of treatment with interferon (IFN) in two patients with cryoglobulinemia and chronic hepatitis related to Hepatitis C virus (HCV). Our results suggest that interferon may induce long remission in cryoglobulinemia associated with HCV infection and that the effect of IFN is not dependant on the effect on liver function, but results of its antiviral activity.     

Severe thrombocytopenia with probable autoimmune mechanism associated with interferon therapy in a patient with chronic hepatitis C

We describe the case of a 20-year-old man who developed severe thrombocytopenia and hemorrhagic complications 5 months after beginning pegylated interferon therapy for chronic hepatitis C. Interferon therapy was stopped and platelets were transfused, but the platelet count did not increase until treatment with immunoglobulins and intravenous corticosteroids was started. Therefore, we believe this would suggest a possible autoimmune mechanism for the development of thrombocytopenia with interferon therapy. Mild reduction in platelets count is a common adverse effect of this drug. Nevertheless, severe decreases and secondary serious hemorrhagic complications have been infrequently described in the literature.     

Suppression of haematopoiesis during therapy of chronic hepatitis C with different interferon alpha mono and combination therapy regimens

BACKGROUND: Treatment of chronic hepatitis C with interferon (IFN)-alpha and ribavirin has haematotoxic effects. We evaluated the effects of four different IFN/IFN-ribavirin treatment regimens on haematopoiesis. METHODS: Haematopoiesis was studied in 133 patients with chronic hepatitis C receiving IFN-alpha2b alone (group A) or in combination with ribavirin (group B), pegylated IFN-alpha2a (group C), or pegylated IFN-alpha2b (group D) in combination with ribavirin. RESULTS: At week 4, haemoglobin levels were diminished in all groups receiving combination therapy. In the monotherapy group, haemoglobin decreased slightly after eight weeks. In all groups, haemoglobin remained diminished throughout therapy. In all patients, leucocytes (while blood cells) decreased after four weeks and remained low during treatment. Platelets (peripheral platelet count (PPC)) were decreased in all groups after four weeks and remained below baseline levels during therapy in group A, C, and D whereas in group B PPC recovered early and reached baseline levels at week 16 of therapy. Concomitantly with the decreases in haemoglobin and PPC, erythropoietin increased in all groups receiving combination therapy and thrombopoietin in all groups. Patients treated with pegylated IFN-alpha2a and those who received pegylated IFN-alpha2b combination therapy differed only in leucopoiesis, whereas erythropoiesis and thrombopoiesis were comparable. CONCLUSION: IFN-alpha based therapies are associated with a decrease in all three haematopoietic lineages, irrespective of the type of therapy used. The stronger suppressive effect of pegylated IFN-alpha2a on leucopoiesis could be due to a dose effect. Overall, concentrations of endogenous haematopoietic growth factors are increased but can only partially alleviate haematotoxicity. Potential uses of exogenous haematopoietic growth factors and their impact on the virological response need to be explored.     

Treatment of chronic hepatitis E in a patient with HIV infection

BACKGROUND: Hepatitis E virus (HEV) infections in immunosuppressed patients can result in chronic hepatitis that rapidly progresses to cirrhosis (1, 2). When immunosuppressed transplant recipients are treated with pegylated -interferon and ribavirin, HEV clears and liver histology improves (2). However, we are not aware of reports about how this therapy works in patients with HIV infection. OBJECTIVE: To describe the clinical and laboratory response to antiviral therapy for chronic HEV infection in a patient also infected with HIV. CASE REPORT: We studied a 48-year-old bisexual male with HIV- 1 infection who was chronically infected with HEV genotype 3a and had several years of painful sensory neuropathy of uncertain cause in the lower limbs (3). He had malaise, persistently abnormal liver function tests, and active inflammation and cirrhosis on liver biopsy (Figure).Before beginning anti-HEV therapy, the patient had an undetectable HIV viral load and a CD4 cell count between 30 and 150 cells/mL for the previous 2 years while receiving combination antiretroviral therapy (abacavir–lamivudine once daily and lopinavir–ritonavir twice daily).     

Sustained hypothyroidism induced by recombinant alpha interferon in patients with chronic hepatitis C.

Thyroid dysfunction has been reported in patients with malignant disease treated with recombinant alpha interferon. Two cases of hypothyroidism in patients with chronic hepatitis C treated with recombinant alpha interferon are reported. In one patient, interferon induced hypothyroidism in the absence of pre-existing thyroid dysfunction and in the other it aggravated a pre-existing thyroid dysfunction. Both patients developed a severe, sustained hypothyroidism requiring thyroxine treatment for one year or more after stopping alpha interferon. Diagnosis of hypothyroidism during treatment can be difficult because of the common side effects of alpha interferon. Thyroid function should be assessed before and during alpha interferon therapy in patients with chronic hepatitis C.