Comparison of thrice weekly vs daily human leucocyte interferon-alpha therapy for chronic hepatitis C. TVVH Study Group

Standard treatment for chronic hepatitis C currently consists of 3–6 million units (MU) of interferon-α (IFN-α) given thrice weekly (t.i.w.) for 12 months, obtaining rates of sustained response (SR) that usually do not exceed 15–25%. Some recent reports have suggested that daily administration of IFN-α may be more efficacious. More than 7 years ago, when standard therapy for hepatitis C was usually given for 6 months, we conducted a randomized clinical trial comparing daily vs t.i.w. treatment. In this study, 149 patients with chronic hepatitis C were randomized to received 3 MU of IFN-α either t.i.w. for 6 months or daily for 3 months followed by t.i.w. for 3 months. All patients were treated with human leucocyte IFN-α and were followed-up for up to 72 months after inclusion. Overall, patients treated daily or t.i.w. had similar rates of virological response after 3 months of induction [24/49 (50%) vs 40/100 (40%)], at the end of therapy [15/49 (31%) vs 36/100 (36%)] and at the end of follow-up [6/49 (12%) vs 9/100 (9%)]. However, when patients infected with HCV types other than HCV-1 were studied, there was a trend favouring the daily schedule that was associated with a higher [5/20 (25%) vs 5/48 (10%)] rate of long-term SR. All patients with a virological response – hepatitis C virus (HCV) RNA negative in serum as determined using the polymerase chain reaction – at 6 months after therapy remained in biochemical and virological remission at long-term follow-up, while seven of eight subjects who had normal alanine aminotransferase (ALT) levels but were serum positive for HCV RNA at 6 months, relapsed later, indicating that serum HCV RNA is better than ALT at predicting long-term cure after IFN-α therapy in chronic hepatitis C.     

Human leucocyte interferon-α in chronic hepatitis C resistant to recombinant or lymphoblastoid interferon-α: a randomized controlled trial

Patients with biopsy-proven chronic hepatitis C, who failed to respond to a previous course of either recombinant (rIFN-α) or lymphoblastoid (LyIFN-α) interferon-α, were randomized to receive either leucocyte (Le) IFN-α (patients) or a second course of the same IFN-α (controls), to compare the efficacy and safety of these treatment schedules. All patients received the same dose of IFN-α as was used during their previous treatment (3 million units (MU) or 6MU three times weekly) for 6 months. Patients with a normal alanine aminotransferase (ALT) value at month 6 were treated for a further 6 months. All patients were followed-up for 12 months after treatment. A total of 69 patients were enrolled, 44 in the LeIFN-α group and 25 in the control group. At the end of the treatment period, 13 of the 44 patients (29.5%) in the LeIFN-α group had a biochemical response (normal ALT) and six of 44 (13.6%) patients had undetectable serum hepatitis C virus (HCV) RNA. At the end of the follow-up period, 10 patients (22.7%) had normal ALT values and serum HCV RNA was undetectable in three (6.8%). None of the patients in the control group showed normal ALT values at any time. Genotype 1b tended to be more frequent among non-responders (61 vs 45%); basal γ-glutamyl transpeptidase (γ-GT) values were lower in responders than in non-responders (33.3±11.70 Ul^–1 vs 58.4±33.04; P =0.01). LeIFN-α was well tolerated by all patients. These results support the use of LeIFN-α in patients with chronic hepatitis C who are non-responders to a previous treatment with recombinant or lymphoblastoid IFN-α.     

Response to interferon-α of Egyptian patients infected with hepatitis C virus genotype 4

Summary. Hepatitis C virus (HCV) genotype 4 is the principal HCV genotype found in Egypt and the Middle East. Little is known concerning its propensity to cause disease and the frequency with which infected individuals respond to interferon-α (IFN-α). We have investigated the response to treatment in a cohort of 100 chronic hepatitis C patients infected with genotype 4. All patients had biopsy-proven chronic active liver disease. Each was treated with 3 million units (MU) IFN-α, thrice weekly. Response was monitored, in 92 patients who completed treatment, by alanine aminotransferase (ALT) measurements and by polymerase chain reaction (PCR) for HCV. ALT levels remained abnormal in 64 patients during treatment (69.6%). Of the 28 patients who showed a biochemical response during treatment (30.4%), 18 maintained this over the 6-month post-treatment period. Amongst the sustained biochemical responders, HCV RNA was cleared from serum in only four of the 18 (22.2%) in this period. Histological improvement was observed in 26/51 (50.9%) of the patients who had a second biopsy.
Hence, patients infected with HCV genotype 4 show a poor response to IFN-α therapy compared with genotypes 2 and 3, but a similar response to IFN-α compared with those infected with type 1b HCV. These findings have major implications for treatment strategies in the Middle East, including Egypt, where HCV genotype 4 is widely distributed.     

Ribavirin and interferon-α combination therapy vs interferon-α alone in the retreatment of chronic hepatitis C: a randomized clinical trial

Interferon-α (IFN-α) induces sustained remission of chronic hepatitisC in approximately 25% of patients. In patients who are non-responders to the first course of therapy, retreatment with IFN-α is of limited efficacy. Ribavirin has also been used to treat chronic hepatitisC, but it induces only a transient response. In this study, we evaluated the efficacy of ribavirin and IFN-α combination therapy for IFN-α resistant chronic hepatitisC. Twenty-four IFN-α non-responders and 24 relapsers were randomized to receive either ribavirin (1000mg per day) together with IFN-α (3–6million units (MU) thrice weekly) or the same dose of IFN-α alone, for 6months. Both at the end of treatment and 6months later, normal transaminase levels were more common in the patients receiving combination therapy than in the group receiving IFN-α alone: 17 (70.8%) vs seven (29.2%) patients ( P =0.009) and six (25%) vs one (4.2%) patient ( P =0.034), respectively. At the end of treatment and 6months later, serum HCV RNA was no longer detectable in eight (33.3%) and five (20.8%) patients in the combination therapy group and in six (25%) and one (4.2%) patient in the IFN-α therapy group, respectively. Three patients (12.5%) were withdrawn prematurely from combination therapy because of side-effects; ribavirin therapy was ceased or dosage reduced in six other patients (25%), again because of side-effects. In conclusion, this combination treatment was more effective than retreatment with IFN-α, alone, in inducing sustained biochemical remission of chronic hepatitisC that was resistant to a previous course of IFN-α. The combination treatment, however, was frequently associated with significant side-effects.     

Long-term titrated recombinant interferon-α2a in chronic hepatitis C: a randomized controlled trial

Summary. The efficacy and tolerability of 12-month treatment with titrated doses of recombinant interferon-α2a (IFN-α2a) in chronic hepatitis C were studied in 67 consecutively recruited patients randomly assigned either to a starting dose of IFN-α2a 6 MU, subsequently adjusted to the serum alanine aminotransferase (ALT) response ( n = 35), or to no therapy ( n = 32; controls). End-of-treatment ALT levels were normal and hepatitis C virus (HCV) RNA was negative by nested polymerase chain reaction (PCR) in 17 (49%) treated patients compared to none of the controls ( P < 0.001). During the 12 months after stopping treatment the number of patients who remained in remission was eight (23%) and one respectively (4%) ( P = 0.031). Follow-up liver biopsy showed reduced hepatic inflammation in 80% of treated patients and in 29% of controls ( P < 0.001). The eight sustained responders and 2 7 non-responders or relapsers received similar mean total doses of IFN (565 MU vs 545 MU) and had a similar incidence of anti-IFN neutralizing anti-bodys (13% vs 19%). Absence of cirrhosis was the only independent pretreatment parameter that predicted a sustained response. In conclusion, a mean cumulative dose of IFN 549 MU, titrated over 12 months, was well tolerated, and resulted in the long-term clearance of HCV RNA and normal ALT levels in 23% of patients.     

Prediction of relapse or sustained response in biochemical responders by serum hepatitis C virus RNA monitoring during interferon therapy

Normalization of serum aminotransferase levels is achieved in ≈ 50% of chronic hepatitis C patients treated with interferon (IFN); however, in about one-half of these patients the hepatitis relapses after therapy. In this study we investigated the efficacy of serum hepatitis C virus (HCV) RNA monitoring during IFN therapy to predict the outcome of a biochemical end-of-treatment (ETR) response. Eighty patients with chronic hepatitis C received leucocyte (natural) IFN-α (13 patients) or recombinant IFN-α2a (67 patients). Antiviral therapy was given for 12 months to 43 (53.7%) responders and this group was analysed further. During follow-up, 15 relapsed and 28 showed a sustained response (median follow-up 50 months, range 39–67 months). Viraemia was monitored at baseline, and at months 1, 3, 6, 9 and 12 of treatment, by nested polymerase chain reaction (PCR) (sensitivity 10–100 copies ml^–1). A combination of positive nested PCR and HCV RNA values at the 3rd and 6th months of treatment was 100% predictive of relapse (sensitivity, 66.6%; specificity, 100%). A combination of negative nested PCR and HCV RNA values at the 1st and 3rd months of treatment was 100% predictive of sustained response (sensitivity, 39.3%; specificity, 100%). In conclusion, serum HCV RNA monitoring is an appropriate and reliable tool for predicting early outcome of the biochemical ETR response after IFN discontinuation. This could be useful in the modulation of therapeutic management of chronic hepatitis C.     

Randomized, placebo-controlled, double-blind trial with interferon-α with and without amantadine sulphate in primary interferon-α nonresponders with chronic hepatitis C

In primary interferon-α (IFN-α) nonresponders with chronic hepatitis C, retreatment with IFN-α has only limited efficacy with sustained response rates below 10%. Therefore, the aims of the present study were to compare the efficacy and safety of IFN-α alone or in combination with amantadine sulphate in nonresponders to previous IFN-α monotherapy. Fifty-five IFN-α nonresponders with chronic hepatitis C (mean age: 46.6 years) received IFN-α 6 MIU thrice weekly for 24 weeks followed by 3 MIU thrice weekly for additional 24 weeks. Amantadine sulphate ( n =26) or a matched placebo ( n =29) was given orally twice daily for 48 weeks. Because of a low initial response rate at week 12 (13/55 patients) and a high breakthrough rate (8/13 patients) after IFN-α dose reduction in week 24, a virological end-of-treatment response with undetectable serum HCV-RNA (< 1000 copies/mL) was achieved in only five patients (IFN-α/amantadine sulphate, one patient; IFN-α/placebo, four patients). After 24 weeks follow-up a sustained virological response was observed in only two patients receiving IFN-α and placebo. Health-related quality-of-life analysis showed a substantial improvement of the Profile of Mood States (POMS) scale concerning the subscales fatigue ( P  < 0.05) and vigor ( P  < 0.05) in patients receiving combined IFN-α/amantadine sulphate treatment compared with those treated with IFN-α alone. IFN-α/amantadine sulphate combination therapy was well tolerated without any serious adverse events. In conclusion, retreatment with IFN-α and amantadine sulphate does not increase the low sustained virological response rates of IFN-α therapy in primary IFN-α nonresponders with chronic hepatitis C, but may lead to a sustained improvement of health-related quality-of-life.     

HCV-associated thrombocytopenia: clinical characteristics and platelet response after recombinant alpha2b-interferon therapy

Hepatitis C virus (HCV) has been proposed as a possible causative agent of chronic thrombocytopenia. We investigated HCV infection in a series of 51 unselected Spanish patients with chronic acquired thrombocytopenia. Anti-HCV and HCV viraemia were detected in 13/51 (22·5%) of cases; this prevalence was particularly significant when compared with HCV seropositivity in age-matched controls (0·4%). Anti-HCV-positive patients, four men and nine women with a median age of 59·3 years (range 36–72), had a mean platelet count of 55·8 × 10⁹/l (range 12–96). Only one of our HCV-positive thrombocytopenic patients had hypersplenism. Platelet-associated IgG (PAIgG) was negative, as measured by immunofluorescent flow cytometric analysis in 11/13 HCV-positive thrombocytopenic patients. Thus, thrombocytopenia in our HCV-positive patients appeared to be non-autoimmune mediated. In six patients, a trial of recombinant α2b-interferon (IFN-α) given at a dose of 3 MU three times per week for 6–24 months gave a durable (> 1 year) and significant increase in platelet count in all six patients. The maximum increase occurred after 6 months of IFN-α therapy. In conclusion, the ability of IFN-α to increase platelet counts in HCV-positive thrombocytopenic patients supports mechanisms involving a direct role for HCV inhibiting platelet production.     

Combination low-dose lymphoblastoid interferon and thymosin α1 therapy in the treatment of chronic hepatitis B

SUMMARY. This open label study was initiated to assess the safety and efficacy of lymphoblastoid interferon-α (IFN-α) and thymosin α₁ (Tα₁) in the treatment of 11 patients with chronic hepatitis B, who had failed to respond to standard IFN-α2b therapy, and in four interferon naive patients. These fifteen hepatitis B surface antigen (HBsAg) positive and serum hepatitis B virus (HBV) DNA positive patients were given Tα₁ (1 mg) subcutaneously (sc) on 4 consecutive days. Low-dose lymphoblastoid IFN-α (3 MU) was administered intramuscularly (IM) on the fourth day. Beginning with the second and for the subsequent 25 weeks, patients self-administered Tα₁ twice weekly in the morning followed, 12 h later, by 3 million units (MU) lymphoblastoid IFN-α. Patients were followed-up for 12 months. Nine (60%) of the 15 patients, including six (55%) of the 11 patients previously treated with IFN-α2b, responded by losing serum HBV DNA and normalizing alanine aminotransferase (ALT) values. Six of the nine responders seroconverted to HBsAg negativity. Significant improvements in the Knodell histological activity index were observed in the responders and no significant adverse effects were observed. Combination low-dose lymphoblastoid IFN-α and Tα₁ treatment may provide a safe and potentially effective therapeutic approach in chronic hepatitis B. These results require confirmation in future randomized controlled studies.     

Hepatitis C virus RNA and long-term response to recombinant interferon-α2b in patients with chronic hepatitis C

Summary. The effectiveness of recombinant interferon-α2b (rIFN-α2b) in eradicating hepatitis C virus (HCV) RNA from serum has not been completely assessed. We studied 39 patients with compensated chronic hepatitis C diagnosed by liver biopsy and positive HCV RNA measured by polymerase chain reaction (PCR). Group I consisted of 26 patients treated with 3 MU of rIFN-α2b for 6 months; group II, 13 control patients observed for six months; and group III, 12 out of 13 patients from group n who subsequently received 5 MU of rIFN-α2b for 6 months. In group I, 11 out of 23 (47.8%) patients who completed treatment had an immediate response and five (21.7%) had a sustained response to therapy six months after treatment. No response was observed in patients from group II. In group III, 7 out of 12 (58.3%) patients who completed treatment had an immediate response and none had a sustained response. Considering all patients who completed rIFN-α2b treatment, HCV RNA remained positive at the end of therapy in three of five sustained responders (60%), six of 13 patients who relapsed (46.1%), and in all non-responders (100%). HCV RNA was positive 6 months after therapy in four (80%), 13 (100%). and 17 (100%) patients respectively. All patients with a sustained response had normal aminotransferase levels 18 months after therapy. We conclude that in chronic hepatitis C rIFN-α2b causes a significant immediate response but this is not sustained, only 2.8% of treated patients had a sustained loss of HCV RNA. Normal aminotransferase persist in the long term, despite persistence of HCV RNA.     

Clinical efficacy of intramuscular human interferon-βvs interferon-α2b for the treatment of chronic hepatitis C

Summary. We have conducted a randomized study to compare the efficacy and tolerance of human interferon (IFN) β vs recombinant IFN-α2b in patients with chronic active hepatitis C. Forty patients were included: 21 received IFN-α (group A) and 19 IFN-β (group B). IFN was administered intramuscularly at a dose of 6 MU three times a week (tiw) for 2 months (induction phase), followed by 3 MU tiw for 4 months. Clinical, epidemiological and pathological features were similar in the two groups. Normal alanine aminotransferase (ALT) values at the end of treatment was regarded as a response to therapy and the response rate was 57% (12/21) in group A and 5.2% (1/19) in group B ( P < 0.01). Both types of IFN induced a significant decrease in mean ALT values by the end of the induction phase ( P < 0.01). When the dose was reduced to 3 MU, a marked, but not significant increase in ALT, was seen in group B, whereas no increase was seen in group A. IFN-β was better tolerated and haematological adverse effects (platelet and leucocyte decrease) were less pronounced with IFN-β. Hence, human IFN-β was less effective than IFN-α in treating chronic hepatitis C virus (HCV). Doses of IFN-β of 3 MU intramuscular (IM) tiw were clearly insufficient and it remains to be established whether higher doses of intramuscularly IFN-β can be useful.     

Interferon-α-2B and ribavirin in combination for chronic hepatitis C patients not responding to interferon-α alone: an italian multicenter, randomized, controlled, clinical study

Objective: The aim of the study was to assess the efficacy of interferon (IFN)-α-2b and ribavirin in combination in the treatment of chronic hepatitis C (CHC) patients unresponsive to a previous treatment with IFN-α−2b alone.
Methods: We conducted a randomized study in 303 CHC patients. One hundred fifty-two patients received subcutaneous administration of recombinant IFN-α−2b (3 MU thrice weekly) and ribavirin (1000–1200 mg/daily per os ), whereas 151 received IFN-α−2b alone (6 MU thrice weekly). Both ribavirin and IFN-α-2b were given for 24 wk, regardless of treatment response. Alanine aminotransferase (ALT) levels and HCV RNA titer were checked during the treatment period and for a further 24 wk.
Results: Normal ALT levels were observed in 64.5% of the patients treated with IFN-α and ribavirin and in 22.6% of the patients treated with IFN-α alone. In the group of patients receiving IFN-α and ribavirin HCV RNA was not detectable in 40% of patients responders and remained undetectable in 44.2% of sustained responders. In the group of patients receiving IFN-α alone HCV RNA was not detectable in 24.2% of patients responders and remained not detectable in 33.3% of sustained responders.
Conclusion: A 24-wk treatment course with IFN-α and ribavirin given to patients with a previous lack of response to IFN-α alone offers a chance of a sustained biochemical and virological response, at least in a subset of such patients. The role of long-term therapy in inducing prolonged remission still remains to be explored.     

Development of a hepatitis C virus relapse model using genome-length hepatitis C virus ribonucleic acid-harboring cells possessing the interferon-α-resistance phenotype

Aim:  The cure rate of current interferon (IFN) therapy is limited to approximately 50% and most of the relapses after therapy are caused by genotype-1. To develop a relapse model in cell culture, we attempted to obtain genome-length hepatitis C virus ribonucleic acid (HCV RNA) harboring cells possessing the IFN-α-resistance phenotype from previously established OR6 cells, which enabled the luciferase reporter assay for monitoring of HCV RNA replication.
Methods:  The IFN-α-resistant HCV RNA-harboring cells and control cells were obtained by the treatment of OR6 cells with and without IFN-α, respectively. Then, we examined the relapse of HCV in IFN-α-resistant HCV RNA-harboring cells.
Results:  Only type I IFN (α and β) showed significantly different anti-HCV activity between IFN-α-resistant HCV RNA-harboring cells and control cells. There was no significant difference in the anti-HCV activity of IFN-γ, fluvastatin, or cyclosporine A between the two types of cells. Furthermore, we showed that fluvastatin or cyclosporine A in combination with IFN-α could prevent the relapse after therapy in the IFN-α-resistant HCV RNA-harboring cells.
Conclusion:  We developed a HCV relapse model in cell culture using IFN-α-resistant HCV RNA-harboring cells. Thus anti-HCV reagents, which have a mechanism different from IFN-α, were shown to be useful for preventing a relapse of IFN-α-resistant HCV.     

Pegylated interferon-alpha2a/ribavirin treatment of recurrent hepatitis C after liver transplantation

Abstract: Hepatitis C virus (HCV) infection invariably recurs after liver transplantation (LT), leading to significant morbidity and mortality. Although the combination of pegylated interferon-alpha (IFN-α)/ribavirin is the preferred treatment for these patients, the optimal schedule remains undetermined. In an uncontrolled trial, 19 patients with HCV infection recurring after LT received pegylated IFN-α_2a, 180 μg weekly, and ribavirin, 10 mg/kg body weight daily, for 48 weeks. The proportion of patients with undetectable HCV RNA in their serum after 12 weeks of treatment was 53%. Five patients (26%) dropped out of the study due to intolerance (in 2 cases), depression (in 1), or infectious complications (in 2). A sustained virological response (SVR), defined as undetectable serum HCV RNA 24 weeks after the end of treatment, was observed in 9/19 patients (47%). SVR was associated with an early virological response after 12 weeks of therapy ( P <0.001) and a treatment duration >80% ( P =0.02), but not with baseline HCV RNA level or a cumulative dose of pegylated IFN-α_2a or ribavirin >80% of the scheduled dose. All 4 patients with genotype 2 or 3 reached SVR, as compared with 33% of patients with genotype 1 or 4 ( P =0.03). A 48-week course of pegylated IFN-α_2a/ribavirin therapy is effective in patients with recurrent HCV infection after LT.     

Interferon-alpha up-regulates bcl-2 expression and protects B-CLL cells from apoptosis in vitro and in vivo

Summary. The bcl-2 oncoprotein, which is involved in the t(14.18) translocation, protects cells against apoptosis. We examined the effects of interferon-alpha (IFN-α) on bcl-2 protein expression and apoptosis in B-chronic lymphocytic leukaemia (B-CLL) cells. None of 12 patients with B-CLL examined expressed the t(14,18) translocation; however, all these, and seven other patients, expressed significant levels of bcl-2 protein. In vitro , IFN-α (500U/ml over 18 h) increased bcl-2 expression on CLL cells (to 200±23% of control MCF, as determined by indirect immunofluorescence and flow cytometry. n = 10, P < 0.001). All of eight patients who received IFN-α (3 megaunits subcutaneously three times a week) demonstrated an increase in bcl-2 expression on circulating malignant cells. CLL cells undergo apoptotic cell death when cultured in vitro (35.6 ± 10.3% DNA fragmentation after 18 h, n = 10). In the presence of IFN-α, however, DNA fragmentation was reduced to 6.6 ± 5.8% (n = 10, P < 0.001). IFN-α also protected CLL cells against apoptosis induced by hydrocortisone and gamma irradiation (reducing DNA fragmentation from 63.9 ± 12.6% to 10.8 ± 4.5 % and from 80 ± 2.9% to 5.4 ± 1.6%, respectively, P < 0,001 for both). The protective effect of IFN-α was dose dependent, and maintained for up to 24 h. Our data demonstrate that bcl-2 expression and apoptosis of CLL cells can be influenced by cytokines. In addition, it seems unlikely that the observed clinical responses to IFN-a in patients with CLL are due to a direct effect on the malignant cells.     

Long-term administration of interferon-α in non-responder patients with chronic hepatitis C: follow-up of liver fibrosis over 5 years

In chronic hepatitis C, previous data have shown that short-term treatment with interferon-α (IFN-α) can reduce collagen deposition in the liver independently of the viral response. The aim of this work was to determine, in non-responder patients, the long-term effect of IFN-α on liver fibrosis according to the total administered dose and the fibrotic stage. Fibrosis was investigated on liver biopsies from 24 non-responder patients with chronic hepatitis C retreated with successive courses of IFN-α. The degree of liver fibrosis was assessed on three successive biopsies, performed before IFN-α treatment and 1 and 5 years later, in 13 and 11 patients, respectively, treated for less (mean: 7.5 months, 313 MU) and more (mean: 21.8 months, 791 MU) than 1 year. For each biopsy, fibrosis was assessed using a histological semiquantitative fibrosis scoring system and by morphometry after picrosirius red staining. Regardless of the dose and duration of IFN-α therapy, a slight decrease of fibrosis was observed in patients 5 years after starting treatment. In cirrhotic patients, a short treatment induced an improvement followed by a relapse of fibrosis in 57%, and only 43% of patients showed constant collagen regression over the 5 years of follow-up. On the contrary, after prolonged therapy, a progressive and significant decrease occurred throughout the follow-up period in all patients ( P = 0.045). Long-term treatment with IFN-α is therefore associated with regression of liver fibrosis, particularly in cirrhotic patients. These promising results need to be confirmed in a larger series of patients.     

Serum macrophage colony-stimulating factor (M-CSF) levels correlate with clinical response to interferon-alpha in patients with early-stage B-CLL

Summary Interferon-alpha (IFN-α) reduces peripheral lymphocyte counts in B-CLL (CLL). In eight patients with stage 0 CLL on IFN-α therapy, peripheral lymphocyte counts fell to 61·7 19·5% of baseline at week 2 ( P <0·01), while serum M-CSF levels rose from 455 183 U/ml to 686 110 U/ml ( P <0·05). Neopterin levels also showed a significant rise. M-CSF levels were correlated with clinical response in these patients. Increased production of M-CSF and the activation of mononuclear phagocytes may be involved in clinical responses to IFN-α in early-stage CLL.     

Statistical models for predicting response to interferon-alpha and spontaneous seroconversion in children with chronic hepatitis B

To develop prognostic models for identifying children with hepatitis B who are likely to respond to interferon-α (IFN-α) or to spontaneously seroconvert, we evaluated results of a multinational controlled trial comprising 70 children with chronic hepatitis B who received IFN-α and 74 children who did not receive therapy. Prognostic models were developed using SMILES (similarity of least squares), which is a data analysis network that incorporates multidimensional relationships in the clinical data of complex diseases. Commonly collected clinical data included age, gender, serum aminotransferase (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and hepatitis B virus (HBV) DNA levels, and IFN-α dose. Additional data included pretreatment directional information (e.g. increases or decreases in serum aminotransferase and HBV DNA levels), liver biopsy results, race and transmission mode. Using data available prior to initiation of treatment, the SMILES models achieved prospective predictions of 89% for responders, 96% for non-responders, 100% for seroconverters and 93% for non-seroconverters. Although not predictive by themselves, the variables that had the greatest impact on predictions for IFN-α response were HBV DNA pretreatment direction, baseline HBV DNA, IFN-α dose and gender. The variables that had the greatest impact on predictions for spontaneous seroconversion were ALT pretreatment direction, baseline HBV DNA level, age and AST pretreatment direction. Therefore, these models may be useful in determining, in children with hepatitis B, the likelihood of response to IFN-α and spontaneous seroconversion.