Completion Of Interferon Therapy Research Articles

Topical interferon - A novel treatment for pseudophakic macular edema.

Purpose:The aim of this study was to evaluate the efficacy of topical interferon (IFN) therapy in pseudophakic cystoid macular edema (P-CME).Methods:This is a prospective, interventional case series of patients with P-CME. Patients presenting with P-CME were given the option of topical IFN therapy against conventional treatment with oral, topical, intravitreal, and periocular steroid therapy and antivascular growth factors. Patients who consented for the same were advised to use the IFN drops four times/day. Commercially available injection IFN alfa-2b was reconstituted to prepare the eye drops (1 MIU/ml). Optical coherence tomography (OCT) was done at the baseline and on each review visit until complete resolution of P-CME.Results:Eight eyes of eight patients diagnosed with P-CME were studied. Mean central macular thickness (CMT) on OCT at the presentation (n = 8) and at 4 weeks post topical IFN therapy (n = 6) was 560.1 μm (range: 349–702 μm) and 344.33 μm (range: 250–390 μm), respectively. All eyes except one had posterior capsular rent (PCR). Five patients had regular follow-up until resolution. The mean duration of complete first resolution of P-CME was 5 weeks (range: 4–7.1 weeks) in those patients. Relapse was seen in three patients who responded after resuming or continuing the therapy. Case 1 had 9 months follow-up after completion of IFN therapy, and no recurrence was noted. No ocular or systemic side effects related to the topical IFN therapy were noted clinically, except papillary conjunctivitis in one patient.Conclusion:Topical IFN therapy can be a noninvasive, economical, and effective choice of treatment for P-CME, especially in the case of PCR, and where steroids are contraindicated.

Natural history of chronic hepatitis B virus infection in childhood and efficacy of interferon therapy

Objectives. In short-term observations, interferon (IFN) therapy has been shown to be effective in producing both biochemical and virological responses in children with chronic hepatitis B virus (HBV) infection. However, in long-term follow up, no studies have shown a clear advantage of IFN therapy during childhood. We conducted a retrospective study on the sustained effect of IFN therapy among a Japanese pediatric population. Methods and subjects. A retrospective study was performed on 155 children with chronic HBV infection who were followed in two affiliated hospitals during the period from 1986 to 2013. Results. The 155 patients comprised 97 males and 58 female. Infection route was maternal transmission in 96/155 patients. HBV genotype was A in 17, B in 6, and C in 51 patients. IFN therapy was performed in 48 patients. One year after the completion of IFN therapy, normalization of alanine aminotransferase (ALT) and lower viral levels (<104 copies/ml) was observed in 43 and 29 patients, respectively. The sustained effects of IFN therapy were evaluated by comparison between 43 hepatitis B e-antigen (HBeAg)-positive patients treated with IFN and 67 patients with chronic hepatitis B observed without IFN therapy. A Cox’s proportional hazard analysis showed a higher seroconversion rate in the IFN group than in the untreated group (p = 0.003). Similarly, there were higher rates of ALT normalization and lower viral levels in the IFN group than in the untreated group (p = 0.001 for both). Conclusion. IFN therapy showed sustained effects for achieving ALT normalization and HBeAg seroconversion and for reducing the viral load in children with chronic hepatitis B.

Hepatocarcinogenesis in chronic hepatitis C patients achieving a sustained virological response to interferon: significance of lifelong periodic cancer screening for improving outcomes

Due to advances in interferon (IFN) therapy for chronic hepatitis C, most elderly patients, and even many of those with advanced hepatic fibrosis, now achieve a sustained virological response (SVR). However, carcinogenesis remains problematic in these patients. Hence, we aimed to elucidate risk factors for hepatocarcinogenesis in SVR patients and to present an appropriate follow-up protocol for improving outcomes. We retrospectively studied 562 consecutive SVR patients for a median observation period of 4.8 years. Hepatocellular carcinoma was diagnosed in 31 patients (5.5%). Respective cumulative incidences were 3.1, 10.1, and 15.9% at 5, 10, and 15 years after completion of IFN therapy. The proportional hazards model identified moderate or advanced fibrosis stage, advanced age, habitual alcohol consumption, and alpha-fetoprotein elevation as determinants of carcinogenesis, with hazard ratios of 10.7 (p < 0.001), 4.1 (p < 0.01), 3.9 (p < 0.01), and 2.6 (p < 0.05), respectively. Carcinoma was diagnosed in 26% of patients more than 10 years after completion of IFN therapy. Unexpectedly, F2 fibrosis was detected in 42% of these patients. The 5-year survival rate was 93% in the patients who had received periodic cancer screening but only 60% in those who had not. We recommend that SVR patients be observed at 6-month intervals, at a minimum, to facilitate diagnosis at an early stage, for as long as possible after completion of therapy even if not at an advanced stage of fibrosis.

Prolonged Psychosis Associated With Interferon Therapy in a Patient With Hepatitis C: Case Study and Literature Review

Although rare, psychosis can emerge during interferon (IFN)-alpha therapy and persist after therapy is completed. The authors report the case of a 30-year-old man with hepatitis C infection treated with IFN-alpha and ribavirin who developed acute psychosis with persecutory delusions and auditory hallucinations, resulting in a suicide attempt. The patient was treated with amisulpride for 6 weeks and then with risperidone for 6 weeks. There was no improvement in symptoms until the patient was treated with quetiapine; he then had a marked recovery from the psychotic symptoms. The duration of the psychosis was 28 weeks. Hepatitis C can be successfully treated with IFN therapy, and the risk of IFN-induced psychosis is low, with psychotic symptoms resolving in most cases after completion of IFN therapy with or without antipsychotic treatment. In prolonged psychosis induced by IFN, quetiapine might also be of benefit.

Adjuvant Antiangiogenic Therapy for Giant Cell Tumors of the Jaws

To further evaluate a novel treatment protocol for the management of aggressive giant cell lesions (GCLs) consisting of enucleation followed by adjuvant subcutaneous interferon alpha therapy. Using a retrospective case series study design, a sample of patients with aggressive GCLs was enrolled between April 1995 and June 2006. Lesions were enucleated with preservation of vital structures. Postoperatively, the patients received daily subcutaneous interferon alpha (3 million units/m2 of body surface area). Interferon treatment continued with regular clinical and radiographic follow-up until the surgical defects filled in with bone, as demonstrated by panoramic radiographs and confirmed by computed tomography. Side effects, such as fever, fatigue, weight loss, decreased white blood cell count, decreased platelet count and elevated liver enzymes, were monitored. After completion of interferon therapy, patients followed for 2 years without evidence of recurrence were considered cured of disease. The study sample was comprised of 26 subjects (65% female) with a mean age of 18.5 years. At the time of this writing, 16 of the subjects have completed the protocol and are cured of disease, 6 are in remission, and 4 are in active treatment. Four subjects experienced significant side effects from the interferon, requiring modification of treatment. Enucleation of aggressive GCLs with preservation of vital structures and adjuvant interferon is an excellent strategy for managing aggressive GCLs. Approximately 15% of subjects developed significant side effects limiting interferon administration and necessitating alternative therapies.

Development of hepatocellular carcinoma in patients with chronic hepatitis C who had a sustained virological response to interferon therapy: a multicenter, retrospective cohort study of 1124 patients

Interferon (IFN) improves hepatic inflammation/fibrosis and reduces the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CH-C). However, HCC develops in some patients who have a sustained virological response (SVR) to IFN therapy. We designed this study to establish a follow-up protocol for patients with CH-C who have SVR to IFN therapy. We retrospectively studied 1124 patients with CH-C who received IFN. HCC developed in 3.5% of patients with SVR to IFN. As compared with SVR patients without HCC, SVR patients with HCC were predominantly male (P=0.003), older at the initiation of IFN therapy (P=0.002), and at a more advanced histologic stage of disease (P<0.001). However, three of the 13 SVR HCC patients had mild fibrosis. The mean interval from IFN therapy to the detection of HCC in SVR HCC patients was 5.8 years and did not differ significantly from that in non-SVR HCC patients (P=0.304). Although most patients with HCC received curative therapy, the prognosis of some SVR HCC patients was poor, probably because of insufficient follow-up, resulting in delayed detection of HCC. SVR patients with CH-C who are elderly, male, or have an advanced histologic stage are at a high risk for the development of HCC after IFN therapy. We recommend that SVR patients should be observed carefully for more than 10 years after the completion of IFN therapy, even if they only have early fibrosis.

Accumulation of 8-n itroguanine in the liver of chronic hepatitis C patients without sustained virological response after completion of interferon therapy

To the Editor: Nitric oxide has been suggested to play a crucial role in chronic inflammation-mediated carcinogenesis.1,2 We previously reported that nucleic acid damage by reactive nitrogen and oxygen species in the liver of patients with chronic hepatitis C (CHC) may contribute to inflammation-related hepatocellular carcinogenesis.3 We demonstrated that 8-nitroguanine is a useful biomarker for evaluating the severity of hepatitis C virus (HCV)induced chronic inflammation in relation to hepatocellular carcinoma (HCC), and that interferon (IFN) therapy decreases the accumulation of 8-nitroguanine in the liver. In addition, we evaluated the association between 8-nitroguanine accumulation and the time interval following the completion of IFN therapy during a second biopsy in nonresponders (NR). In the NR group (n = 12), the number of 8-nitroguanine-positive and 8-hydroxy-2′deoxyguanosine (8-OHdG)-positive hepatocytes before treatment with IFN [26.5 (9.0–170.0)/105μm2 and 37.8 (10.0–113.7)/ 105μm2, respectively; data are expressed as median and range] did not decrease after IFN therapy [36.3 (8.7–62.6)/105μm2 and 76.2 (11.3–99.3)/105μm2, respectively]. Each NR patient showed a different duration of 8-nitroguanine accumulation after IFN therapy. The number of 8-nitroguanine-positive hepatocytes tended to increase after IFN therapy [before, 26.5 (9.0–170.0)/ 105μm2; after, 36.3 (8.7–62.6)/105μm2], and the time interval following IFN therapy was significantly correlated with the number of 8-nitroguanine-positive hepatocytes (r = 0.635, P = 0.0351). However, the number of 8-OHdG-positive hepatocytes was not correlated with the time interval following IFN therapy (Fig. 1). This result suggests that improvement of liver inflammation by IFN therapy in NR patients persists for several years. Several clinical studies have suggested a preventive effect of IFN on HCC development in patients with HCV-related cirrhosis4 and CHC.5–8 Ikeda et al.6 reported that the rate of HCC in IFN-treated and -untreated patients with CHC is 2.1% and 4.8% in the fifth year, and 7.6% and 12.4% in the tenth year, respectively (P = 0.0036). In the IFN-treated NR group, the rate of HCC increases during the time following the completion of IFN therapy.4–7 The relationship between 8-nitroguanine accumulation and time after IFN therapy in NR patients supports the idea that temporary reduction of chronic inflammation in the liver by IFN therapy decreases the production of reactive nitrogen species. Accumulation of 8-nitroguanine in the liver increases during the time following completion of IFN treatment (Fig. 1). Arase et al.7 reported that long-term IFN therapy in patients with chronic HCV infection is effective in preventing hepatocarcinogenesis. Long-term IFN therapy in patients may decrease the accumulation of 8-nitroguanine in the liver. Our present study showed that IFN therapy induced temporary suppression of 8-nitroguanine accumulation even in the NR group, suggesting that IFN therapy may prevent hepatocarcinogenesis in HCV-induced chronic inflammation.

Partial splenic embolization facilitates completion of interferon therapy in patients with chronic HCV infection and hypersplenism

Partial splenic embolization facilitates completion of interferon therapy in patients with chronic HCV infection and hypersplenism

Efficacy of 6-month interferon therapy in chronic hepatitis B virus infection in Japan

In Japan, there are few studies of long-term (more than 1 month) interferon (IFN) therapy for chronic hepatitis B (CHB). In this retrospective study, we investigated the efficacy and predictors of response to 6-month IFN therapy. We analyzed 66 Japanese patients with CHB who were treated with IFN for 6 months. They comprised patients who were hepatitis B e antigen (HBeAg)-positive (n=45) and -negative (n=21). One (2%), 8 (12%), and 51 (77%) patients were infected with hepatitis B virus (HBV) genotypes A, B, and C, respectively. Responders in patients positive for HBeAg were defined as those who showed normalization of serum alanine aminotransferase (ALT) level, HBeAg loss, and HBV DNA negativity at 6 months after completion of IFN therapy. In patients negative for HBeAg, responders were defined as those patients who showed normalization of ALT level and HBV DNA negativity at the same 6-month time point. Of the 45 patients with HBeAg at the commencement of IFN therapy, 9 (20%) were responders. Young patients, especially those with a high serum ALT level, were significantly more likely to respond to IFN therapy. Of the 21 patients negative for HBeAg, 13 (62%) were responders. There were no significant differences in clinical characteristics between responders and nonresponders among patients negative for HBeAg. Multivariate analyses identified HBeAg negativity and young age as independent factors associated with a positive response to 6-month IFN therapy. However, long-term follow-up of the treated patients showed a fall in the response rate. The response rate to 6-month IFN therapy among HBeAg-positive patients was low. However, young patients may require long-term IFN therapy.

Efficacy of interferon retreatment after relapse for chronic hepatitis C patients with biochemical response after first interferon therapy.

With respect to interferon (IFN) treatment for chronic hepatitis C, normalization of alanine aminotransferase (ALT) as well as clearance of hepatitis C virus (HCV)-RNA after IFN therapy is important. It has been shown that the incidence of hepatocellular carcinoma (HCC) in patients with normal ALT is significantly lower than that in those with elevated ALT after IFN therapy. We assessed the efficacy of IFN retreatment for chronic hepatitis C patients who had a biochemical response (BR) after the first IFN therapy and reelevated ALT during follow up, by a case control study. Fifteen patients (case group; group 1) enrolled in this study showed a BR after the first IFN therapy and reelevated ALT during follow up. Next, we retrospectively selected 30 patients (control group; group 2) with no response (NR) after the first IFN therapy. Group 2 patients were matched 1 : 2 with group 1 patients for sex and age. All patients were given intramuscular injections of human lymphoblastoid IFN alpha daily (6 MU) for 8 weeks and then three times a week for 16 weeks. We compared the clinical and biological differences between group 1 patients and group 2 patients. Virological response (VR) was defined when serum HCV-RNA showed negativity more than 6 months after the completion of IFN therapy. BR was defined when ALT values remained normal during more than 6 months in spite of positive serum HCV-RNA, by reverse-transcription nested polymerase chain reaction, 3 and 6 months after the completion of IFN therapy. NR was defined as any response except for VR or BR. The rate of patients showing VR in this study was 6.7% (1/15) in group 1 and 13.3% (4/30) in group 2. There was no significant difference between the groups with respect to VR. BR occurred in 73.3% (11/15) of patients in group 1, but in only 3.3% (1/30) of patients in group 2 (P = 0.0002). We conclude that IFN retreatment is one of the effective strategies with which to achieve BR again in HCV-positive patients who had a BR after their first IFN therapy and reelevation of ALT during follow up.

Changes in virus loads and precore mutations in chronic hepatitis B patients treated with 4 weeks of daily interferon alfa-2a therapy

Interferon (IFN) alfa-2a was administered to 23 patients with chronic hepatitis B daily for 4 weeks and the relation between the efficacy of the treatment and changes in total hepatitis B virus (HBV) DNA and precore mutant levels was investigated. At 6 and 12 months after the completion of IFN therapy, 39.1% (9/23) and 36.8% (7/19) of patients, respectively, showed alanine transaminase (ALT) normalization; 31.3% (5/16) and 50.0% (7/14), respectively, became negative for HBe-antigen (HBeAg); and 42.1% (8/19) and 41.2% (7/17), respectively, became undetectable for HBV DNA. All 18 of the patients who were positive for HBeAg at baseline nevertheless had the precore mutation. The level of precore mutant as a proportion of the total HBV DNA level was constant at baseline, and 3 and 6 months after the completion of therapy. Thus, the investigation showed that in chronic hepatitis B, the precore mutation occurs at a constant proportion beginning in the HBeAg-positive phase, and IFN therapy inhibits the growth of the wild-type and precore mutant viruses equally.

Sustained Negativity for HCV-RNA over 24 or More Months by Long-Term Interferon Therapy Correlates with Eradication of HCV in Patients with Hepatitis C Virus Genotype 1b and High Viral Load

Objective: We assessed whether sustained negativity for HCV-RNA over 24 or more months by long-term interferon (IFN) therapy correlates with eradication of HCV in patients with hepatitis C virus genotype 1b and high viral load or not. Methods: The number of patients with HCV-genotype 1b and high viral load exceeding 1 Meq/ml who received 6 MU of natural IFN-α daily for 2–8 weeks, followed by three times/week for 16–22 weeks and negativity for HCV-RNA during IFN administration was 403. Forty-one of 403 patients received 6 MU of natural IFN-α three times/week for more than 18 months after the initial IFN therapy (long-term-IFN-group). Three hundred and two patients did not receive any IFN treatment for 6 months after the termination of the 6-month course (6-month-IFN-group). Sustained virological response (SVR) was defined as negative HCV-RNA at both 3 and 6 months after the completion of IFN therapy. Results: SVR was noted in 73.2% (30/41) of long-term-IFN-group and 18.2% (55/302) of 6-month-IFN-group. Multivariate analysis showed that long-term IFN therapy was the most significant contributor to SVR (p < 0.0001). Conclusion: Sustained negativity of HCV-RNA for 24 or more months by long-term IFN therapy correlated with SVR in patients with genotype 1b and high viral load.

Efficacy of IFN therapy based on duration period of negative HCV-RNA during IFN administration

We assessed the relationship between the duration period of negative hepatitis C virus (HCV)-RNA during interferon (IFN) therapy and the efficacy after prolonged IFN therapy in patients with HCV-genotype 1b and high virus load of more than 1 mega equivalents/ml (Meq/ml) retrospectively. A total of 100 patients who had HCV-genotype 1b and a high virus load of more than 1 Meq/ml and were treated with natural IFN-α for more than 12 months were enrolled in this trial. These patients were given 6 MU of IFN daily for 8 weeks, followed by three times weekly for another more than 44 weeks. The HCV-RNA pattern during IFN therapy according to negative or positive of the serum HCV-RNA by reverse transcription nested polymerase chain reaction (RT-nested PCR) from 2 months after the initiation of IFN to the termination of IFN were classified as follows: group 1: constant negative HCV-RNA ( n=41 cases), group 2: constant positive HCV-RNA ( n=35 cases), group 3: HCV-RNA pattern except for group 1 or group 2 ( n=24 cases). A complete response (CR) was defined as negative HCV-RNA by RT-nested PCR at two points, 3 and 6 months after the completion of IFN therapy. CR rate was 58.5% (24 cases) in group 1, but CR rate in group 2 or group 3 was 0%. In group 1, the CR rate was 100% (10/10) in patients with negative HCV-RNA constantly for period of more than 24 months during IFN therapy. On the other hand, all patients who had positive HCV-RNA 2 months after the initiation of IFN did not get CR. In conclusion, it seems to us that the attainment of constantly negative HCV-RNA for the period of more than 24 months during IFN therapy is highly related to CR.

Long-term follow-up of sustained responders to interferon therapy, in patients with chronic hepatitis C.

Interferon (IFN) therapy has been proven to induce the normalization of serum alanine aminotransferase (ALT) levels and to eradicate the hepatitis C virus (HCV) in some patients with chronic hepatitis C, and these patients are usually defined as 'sustained responders'. However, there have been some reports of hepatocellular carcinoma (HCC) in these patients, and the development of HCC remains life-threatening in patients who clear HCV. We analysed the long-term prognoses of patients with chronic hepatitis C in whom HCV was eradicated with IFN. We investigated 392 sustained responders to IFN therapy, from 1,277 patients with chronic HCV infection who received IFN treatment at one of our institutions between April 1989 and March 1999. We analysed the medical records and looked for the development of HCC. About 30% of the sustained responders had been lost to follow-up 3 years after the end of IFN therapy, and the follow-up rate of sustained responders was significantly lower than that of non-sustained responders (P < 0.0001). HCC were found in eight patients: in seven patients HCC developed within 5 years after completion of IFN therapy; but in one patient, a single HCC less than 3 cm in diameter was detected between 7 and 8 years after completion of IFN. Of the five patients who had regular medical follow-up, the HCC was solitary, and the patients survived without any evidence of recurrence. Of the three patients who had not been followed-up, two died from HCC and HCC recurred in the third. These results suggest that HCC can develop in sustained responders and that sustained responders should be followed-up closely after completion of IFN so that HCC may be detected at an early stage. The optimal duration of the follow-up period of the sustained responders remains unclear. Additional prospective studies are required in order to establish an appropriate follow-up protocol for sustained responders to IFN.

Increased response rate to interferon therapy after a second course in hepatitis C patients who show relapse after the initial course.

Some patients with chronic hepatitis C become HCV-RNA seronegative during interferon (IFN) therapy. However, about one-half of these patients show a relapse, evident by high serum alanine aminotransferase (ALT) level. In some patients with biochemical relapse, the serum HCV-RNA level becomes low immediately after the ALT relapse. Here, we assessed the changes in serum HCV-RNA level in patients with ALT relapse after IFN therapy, and evaluated the efficacy of a second course of IFN, started at the recovery stage after ALT relapse. Two hundred and seventy-seven patients who showed HCV-RNA seronegativity by reverse transcription nested-polymerase chain reaction (RT nested-PCR) and normalization of ALT during the initial IFN therapy, and had positive HCV-RNA with ALT relapse (> 100 IU/l) within 3 months after completion of the initial IFN course were enrolled in this retrospective study. Two hundred and sixty patients were followed-up without further IFN retreatment after the ALT relapse (group 1), and 17 patients received another 6-month course of IFN after the ALT relapse (group 2). The median level of serum HCV-RNA, determined with a branched DNA probe assay (version 1; Chiron-Dai-ichi Kagaku Tokyo, Japan), in group 1 was 3.1 Meq/ml before IFN therapy, 1.3 Meq/ml at the time point of the ALT peak after the completion of IFN therapy, and 0.7 and 2.6 Meq/ml at 2-4 and 6-8 weeks after the ALT peak, respectively. The serum HCV-RNA level at 2-4 weeks after the ALT peak was lower than that before IFN therapy. The eradication rate of HCV-RNA (complete response; CR) in group 2 (47.1%; 8/17) was significantly higher than that in group 1 (1.5%; 4/260; P < 0.001). In conclusion, our data suggested that: (1) patients who showed biochemical relapse after initial IFN therapy had a significantly lower serum HCV-RNA level at recovery after ALT relapse compared with that before initial IFN therapy. (2) A high response rate was noted after a second course of IFN administered at the recovery stage of the ALT relapse, compared with patients without IFN retreatment.

Effect of interferon therapy on the incidence of hepatocellular carcinoma and mortality of patients with chronic hepatitis C: A retrospective cohort study of 738 patients

The effect of interferon on the long-term clinical outcome of patients with chronic hepatitis C remains unclear. This study included 594 patients with chronic hepatitis C who received interferon-alpha therapy (Interferon group) and 144 patients with chronic hepatitis C who did not receive interferon (Control group). The patients in the Interferon group were classified into the following three groups based on the response of the serum aminotransaminase level of the patient during and after completion of the therapy protocol: sustained responders (n = 175), transient responders (n = 165), and non-responders (n = 254). The age, sex, serum aminotransaminase level, platelet count, histological staging, hepatitis C virus (HCV) subtype, and HCV concentration at baseline were adjusted with the Cox proportional hazards model. The length of follow-up for assessment of the risk for developing hepatocellular carcinoma (HCC) was 57.2 +/- 13.9 months in the Interferon group and 67.7 +/- 28.7 months in the Control group. Multivariate analysis showed that interferon therapy decreased the risk for developing HCC by 48% compared with that in the Control group (P = 0.064). The older the age, being male, having a low platelet count, and higher histological stage were independent factors associated with the development of HCC. The hazard rate ratio for development of HCC in the sustained responders, transient responders, and non-responders was 0.16 (95% confidence interval [CI]: 0.04-0.62), 0.27 (95% CI: 0. 09-0.79), and 0.74 (95% CI: 0.37-1.48), respectively. During follow-up, 18 patients in the Interferon group died (10 from liver-related diseases) and 17 patients in the Control group died (10 from liver-related diseases). No sustained responder or transient responder in the Interferon group died of liver-related disease. The cumulative survival rates of the Interferon and Control groups were nearly identical during the first 5 years following diagnosis. Thereafter, the cumulative survival rate of the Control group declined, resulting in an 8-year survival rate in the Interferon and Control groups of 97% and 81%, respectively (P = 0. 061). Similar trends were seen in the survival analysis of those who had died of liver disease: the 8-year survival rates of the Interferon and Control groups were 98% and 88%, respectively (P = 0. 32). Our study demonstrated that interferon therapy significantly lowered the incidence of HCC among patients with chronic hepatitis C who showed sustained normalization and among patients who showed transient normalization of the serum aminotransferase level after completion of interferon therapy. The survival analyses and determination of cause of death suggested that interferon therapy improves the long-term survival of chronic hepatitis C patients who respond to this therapy, possibly by decreasing mortality from liver-related diseases.

How soon can a virological sustained response be determined after withdrawal of interferon therapy in chronic hepatitis C? Tokyo-Chiba Hepatitis Research Group.

Hepatitis C virus (HCV)-RNA status and alanine aminotransferase (ALT) levels determined shortly after interferon (IFN) therapy in patients with chronic hepatitis C do not predict long-term response. To determine the virological sustained response after the completion of IFN therapy, HCV-RNA was measured at the end of treatment and at 3-4 months and 12 months after the completion of therapy in 537 patients with chronic hepatitis C. In 347 patients, HCV-RNA was not detected by polymerase chain reaction (PCR) at the completion of therapy and 175 of these patients (50%) were still PCR negative 12 months later. In contrast, of the 180 patients who were HCV-RNA negative at 3-4 months after completion of therapy, 99% remained negative at 12 months. Normal ALT levels were found in 80, 93 and 95% of patients who were negative for HCV-RNA either at the end of treatment or at 3-4 months and 12 months after the completion of therapy, respectively. Of patients who were HCV-RNA positive, 30, 15 and 20% were found to have normal ALT levels at the same respective time points. To determine a sustained virological response shortly after the completion of therapy, serum HCV-RNA was serially examined in 66 patients negative for HCV-RNA at the end of therapy. Of 31 patients who relapsed, HCV-RNA reappeared in 33, 80, 97 and 100% of patients by 1, 2, 4 and 8 weeks after the completion of therapy. In conclusion, a sustained virological response could be determined with 97 and 99% certainty at 4 weeks and at 3-4 months after the completion of therapy, respectively.

Negative strand of hepatitis C virus RNA in the liver of patients with chronic hepatitis C after interferon treatment.

In patients receiving interferon therapy for chronic hepatitis C, serum hepatitis C virus (HCV) RNA often reverts from an undetectable to a detectable form after completion of treatment. Detection of the negative strand of HCV-RNA in liver tissue is regarded as an index of viral proliferation. Therefore, we investigated changes in the hepatic negative-strand HCV-RNA following interferon therapy to determine whether this parameter could predict the long-term response to treatment. The subjects of this study were 27 patients with chronic active hepatitis C. Serum positive-strand and hepatic tissue negative-strand HCV-RNA were detected using polymerase chain reaction. At the completion of interferon treatment, serum HCV-RNA was not detected in 21 patients. One year following treatment it remained undetectable in 14 of these patients but it had reverted to a detectable form in seven. The 14 patients in whom hepatic negative-strand RNA was not detected between 2 weeks and 12 months after treatment, had not relapsed after another year. In the 13 remaining patients, negative-strand RNA was found in liver tissue and serum RNA either reverted to a detectable form or remained detectable throughout. From these findings, we conclude that the detection of negative-strand HCV-RNA in liver tissue 2 weeks after the completion of interferon therapy is useful for predicting the long-term effect of therapy.

Utility of Hepatitis C Virus RNA Levels for Predicting the Therapeutic Efficacy of Interferon

We studied the levels of serum hepatitis C virus (HCV)-RNA, the HCV genotype before interferon therapy, and the kinetics of serum HCV-RNA at the initial stages of therapy to determine their utility in predicting the therapeutic efficacy of interferon in 44 patients with chronic hepatitis C infection. We also looked at the efficacy of repeated interferon treatment in relation to the kinetics of serum HCV-RNA. The level of serum HCV-RNA determined by a branched DNA probe assay before interferon treatment and that by a reverse transcription nested polymerase chain reaction assay during the initial stages of interferon administration were useful for predicting the efficacy of treatment. Furthermore, detection of serum HCV-RNA by the reverse transcription nested polymerase chain reaction assay after the completion of interferon therapy indicated relapse at its earliest stage. In patients who experience relapse, repeated treatment with an appropriate dose of interferon before an increase in viral levels may increase the proportion of complete responses.

Response to interferon-alpha 2a in patients with e antigen-negative chronic hepatitis B.

Sixty-eight consecutive patients with chronic hepatitis B received 702 million units of recombinant interferon-alpha 2a. Of the 24 patients negative for hepatitis B e antigen (HBeAg) in serum, the normalization of serum transaminase occurred in 14 (58%) at the completion of interferon therapy and in 13 (54%) at 12 months thereafter; it was normalized in 17 (39%) and 13 (30%), respectively, of the 44 HBeAg-positive patients. Of the HBeAg-negative patients, hepatitis B virus DNA was cleared from serum in six (25%) at the completion and in one (4%) at 12 months thereafter, in contrast to only one (2%, p < 0.05) and none of the HBeAg-positive patients, respectively. The 1896th nucleotide of G (G1896) for codon 28 for tryptophan or A (A1896) for the stop codon 28 in the precore region was determined by restriction fragment length polymorphism. The ten HBeAg-negative patients with A1896 only in the precore region had lower pretreatment levels of viral markers, which decreased more rapidly and extensively after interferon than in the 14 HBeAg-negative patients with a mixture of G1896 and A1896 or in the 44 HBeAg-positive patients. These results indicate that patients with HBeAg-negative chronic hepatitis B may respond better to interferon than HBeAg-positive patients, and that the precore mutant with the stop codon 28 may be sensitive to interferon.