An escalating dose regime of recombinant interferon-alpha 2A in the treatment of chronic hepatitis C

doi:10.1016/S0168-8278(05)80029-7

Journal of Hepatology

Volume 17, Issue 2, 1993, Pages 146-149

https://doi.org/10.1016/S0168-8278(05)80029-7 Get rights and content

Interferon-alpha (IFN-α) has proven useful in the treatment of chronic hepatitis C, but a relapse in response is frequently observed. The possible benefit of daily administration of recombinant IFN-α2A at an escalating (from 1.5 to 9 MU) regime depending on the evolution of serum aminotransferase (ALT) levels was evaluated in 31 adult patients with chronic hepatitis C. At the end of the first month with 1.5 MU of rIFN-α2A, 9/31 (29%) had normal ALT values. Then, 22 patients were given 3 MU daily and at the second month 4 patients (18%) normalized ALT values. The 18 non-responders received 6 MU and 4 of them (22%) normalized ALT values (1 patient dropped out). Finally, the remaining 13 non-responders were given 9 MU and in 4 (30%) ALT fell to normal ranges. Three non-responders to 1.5 MU normalized ALT values when the dose of rIFN-α2A was increased (n=2, 3 MU; n=1, 9 MU). The overall response achieved was 68%. Within 3 months after cessation of treatment, 12/20 (60%) responder patients had a relapse in ALT levels. Therefore, although daily administration of rIFN-α2A does not improve the results obtained with a thrice-weekly schedule, a proportion of non-responders could benefit from an escalating dose to a high amount (63 MU/week) of rIFN-α2A.

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Cited by (36)

Hepatitis C virus and renal failure
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Monitoring response during a randomised controlled trial of escalating interferon dose for chronic hepatitis C infection: Predictive value of quantitative and qualitative HCV RNA assays
2001, Journal of Clinical Virology
Background: In chronic hepatitis C infection, raising the interferon dose in initial non-responders may increase the generally poor sustained response rates. Monitoring virological response is essential in this kind of individual patient based approach. Quantitative HCV RNA assays are increasingly used for this purpose. However, their additional value as compared to strictly qualitative HCV RNA assays should be evaluated before they are implemented as a routine measurement, since these assays are more expensive and time consuming than qualitative assays. Objectives: Goals of this study were (1) to test the hypothesis that increasing interferon dose in initial non-responders results in permanent viral clearance in more patients and (2) evaluation of the predictive value of quantitative versus qualitative HCV RNA assays before and during treatment. Study design: 63 patients were treated in a randomised controlled trial of escalating interferon dose. In the standard treatment group patients received 6 MU alpha-2a thrice weekly for 3 months followed by 3 MU thrice weekly for 3 months. In the experimental group interferon dose was escalated at 6 weeks to 9 MU if HCV RNA was still detectable at 4 weeks. Predictors of response were analyzed at various time points before and during treatment and the predictive value of quantitative HCV RNA measurements was compared to that of qualitative HCV RNA assays. Results: No significant difference in sustained response rate was found between the treatment groups at the end of follow-up. At baseline, the strongest independent predictor for a sustained response was a viral load level below 10⁶ copies/ml and age younger than 40 years. During treatment a negative HCV RNA status at week 4 was the strongest predictor of a sustained response. Viral load levels during treatment did not independently predict a sustained response. Conclusions: While on treatment, qualitative HCV RNA assays should be used to monitor response.
New drugs for hepatitis C virus (HCV)
2000, Bailliere's Best Practice and Research in Clinical Gastroenterology
Lack of efficacy and significant side effects have severely limited the use of interferon-α (IFN-α) as the standard therapy for non-A non-B hepatitis (NANBH) caused by hepatitis C virus (HCV) and alternative, improved therapies are urgently sought. Attempts have been made to improve the potency and tolerability of IFN-α by adjusting dosing regimens, methods of delivery and length of treatment. Furthermore, a number of different agents have been used in combination with IFN-α and, from these studies, therapeutic options have been galvanized by the synergistic effects of IFN-α and ribavirin. Nevertheless, the majority of patients with HCV still do not sustain lasting therapeutic benefit from this combination and continuing research is required to identify new therapeutic candidates that will have more potent anti-viral activity and less severe side effects. This review focuses on the progress that has been made in this area and the prospects for new effective therapies in the near future.
A multicenter, randomized trial of daily high-dose interferon-alfa 2b for the treatment of chronic hepatitis C: Pretreatment stratification by viral burden and genotype
2000, American Journal of Gastroenterology
Citation Excerpt :
Attempts to improve the response rates have included the use of higher doses of interferon. Studies that have evaluated dose escalation in patients who had no initial response to interferon failed to demonstrate an impact on sustained response rates (9, 10). Similarly, a large study that treated patients with 3, 5, or 10 million units (MU) also did not show an improvement in response with either initial higher doses or an increment in dose in nonresponding patients when interferon was administered t.i.w.(11).
OBJECTIVES:
The aim of this study was to determine prospectively whether an intensive regimen of daily, high-dose interferon would improve the response rate for the treatment of chronic hepatitis C in patients with unfavorable virological characteristics.
METHODS:
A total of 104 patients with chronic hepatitis C were randomized at eight centers to receive interferon alfa-2b at a dose of 5 million units (MU) daily or 3 MU t.i.w. for a period of 24 wk. Patients were prospectively randomized by low or high viral burden and stratified by genotype. HCV RNA was measured by quantitative polymerase chain reaction, and response rates were compared between the dosage regimens.
RESULTS:
HCV RNA levels dropped more rapidly to lower levels in the group treated with 5 MU daily. In this group, the initial virological response (IR) at wk 12 and the end-of-treatment response (ETR) at wk 24 were double that of patients treated with standard interferon (66% vs 33% and 48% vs 24%, p < 0.01). Sustained response rates were low for both dose groups (14% vs 4%, p = 0.08). Genotype-related differences in initial response rates were present in the standard dose group (63% non-1 genotype vs 24% genotype 1; p = 0.005) but not in those treated with 5 MU daily (66% vs 67%, p = NS). Using multivariate analysis, only the interferon dose was associated with IR and ETR (p = 0.002).
CONCLUSIONS:
Daily, high dose interferon rapidly dropped HCV RNA and increased initial and end-of-treatment response rates when compared to t.i.w. regimens. This effect, independent of viral burden and genotype, suggests that patients with unfavorable viral characteristics might benefit from an intensive regimen that promotes rapid viral clearance. These data support further study of the use of high-dose induction regimens. However, improvements in sustained response rates will require additional therapeutic maneuvers such as prolonged therapy or the adjunctive use of ribavirin.
Early addition of ribavirin to interferon in chronic hepatitis C not responsive to interferon monotherapy
2000, Journal of Hepatology
Background/Aim: Persistence of HCV-RNA in serum early in treatment is a strong predictor of failure of α-interferon therapy for chronic hepatitis C. Therefore, we compared the efficacy of ribavirin addition to α-interferon with a doubling of the dosage of α-interferon in case of lack of early virological response to α-interferon therapy.
Methods: Sixty patients were administered interferon α2b at the dosage of 3 million units 3 times a week. After the first 4 weeks of therapy, serum HCV-RNA was evaluated. The patients with negative HCV-RNA test received the same treatment for a further 11 months, while those with detectable HCV-RNA were randomized to receive either the same dosage of α-interferon plus ribavirin (1000 mg/day) or double dosage of α-interferon (6 million units tiw) for 11 months. We considered sustained response to be the maintenance of normal alanine aminotransferase and negativity at HCV-RNA testing until the end of a 6-month post-treatment follow-up.
Results: After the first 4 weeks of treatment, 12 (20%) patients showed virological response and 48 patients (80%) remained positive on HCV-RNA testing. Sustained response was observed in 5/12 (42%) patients with early virological response, in 10/24 (42%) patients without early virological response who were administered ribavirin and α-interferon, and in only 1/24 (4%) patients who were administered the double dosage of α-interferon (p=0.006).
Conclusions: This study shows the efficacy of the addition of ribavirin to α-interferon and the lack of efficacy of doubling the dosage of α-interferon in patients without clearance of hepatitis C virus early on in treatment.
Hepatitis C
2000, Infectious Disease Clinics of North America
Citation Excerpt :
Side effects are common, and include fatigue, malaise, myalgias, arthralgias, flulike symptoms, depression, suicidal ideation, irritability, thyroid disorders, hair loss, leukopenia, and thrombocytopenia. Because of the high rate of relapse after treatment, and the high rate of nonresponse to initial treatment, researchers investigated higher doses of interferon, either by using a higher stable dose,144,145 induction dosing,100,250 or dose escalation.26,152 Shiffman reviewed pertinent studies that used high-dose interferon, and concluded that although the end-of-treatment response (ETR) appeared improved compared to standard interferon, the sustained response rate (SR) was not significantly improved.231
The transmissibility of viral hepatitis by blood products has been recognized for decades.²⁰ In the latter half of the 20th century, the discovery of the etiologic agents of hepatitis A and hepatitis B led to important medical advances in the diagnosis and treatment of these viral illnesses.22, 77 Nevertheless, it was soon apparent that an unidentified, non-A, non-B (NANB) infectious virus was responsible for most cases of posttransfusion hepatitis.78, 209 Several important studies resulted in information about the epidemiology, transmissibility, and risk factors for the acquisition of this disease. In 1989, Choo et al discovered the elusive causative agent, named hepatitis C virus (HCV), using serum isolated from a patient with NANB hepatitis.³⁹ An assay to detect the circulating antibodies to this virus subsequently was developed,¹³² paving the way for scientific and clinical studies that have culminated in our current understanding of the virus. This article reviews the prevailing knowledge of the hepatitis C virus, which afflicts millions worldwide in what has been called “the silent epidemic.”

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Regular PaperAn escalating dose regime of recombinant interferon-alpha 2A in the treatment of chronic hepatitis C

Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome

Science

Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis

N Engl J Med

Randomised controlled trial of interferon alfa (lymphoblastoid interferon) in chronic non-A, non-B hepatitis

Br Med J

Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial

N Engl J Med

Recombinant interferon alfa therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial

N Engl J Med

Prolonged treatment (18 months) of chronic hepatitis C with recombinant α-interferon in comparison with a control group

J Hepatol

Regular Paper
An escalating dose regime of recombinant interferon-alpha 2A in the treatment of chronic hepatitis C