Doses Of IFN Research Articles

The proximal interferon-stimulated response elements are essential for interferon responsiveness: a promoter analysis of the antiviral MxA gene.

Interferon (IFN)-inducible human MxA protein mediates resistance against influenza and several other RNA viruses. The MxA gene is under the control of type I IFN and, in certain cell types, is also directly activated by viruses. Here we show that in human macrophages, MxA mRNA levels are upregulated by very low doses of IFN-alpha in a dose-dependent manner. A similar, albeit much weaker, dose-dependent induction was seen with IFN-gamma. The induction was rapid and independent of protein synthesis. Interleukin-6 (IL-6) or tumor necrosis factor-alpha (TNF-alpha) did not influence MxA mRNA levels alone or in combination with IFNs, in spite of the presence of putative response elements of these cytokines in the MxA promoter. We show that the promoter of the MxA gene contains two functional IFN-stimulated response elements (ISRE) near the transcription start site and one homologous ISRE-like element, which is apparently nonfunctional, further upstream. The two proximal ISRE sites are essential for IFN-alpha-induced transcription and appear to be binding sites for IFN-stimulated gene factor 3 complex. In addition, EMSA and DNAse I footprinting analysis demonstrated that Spl binds with high affinity to a region encompassing nucleotides -25 and -50 and, thus, may provide means of interaction with the basal transcriptional machinery.

Quality-of-life-adjusted survival analysis of interferon alfa-2b treatment for advanced follicular lymphoma: an aid to clinical decision making.

To evaluate the trade-off of toxicity versus improved clinical outcome with interferon alfa-2b (IFN) administered concomitantly with a doxorubicin-containing regimen for the treatment of advanced follicular lymphoma. A quality-of-life-adjusted survival analysis (Quality-Adjusted Time Without Symptoms or Toxicity [Q-TWiST]) was applied to the Groupe d'Etude des Lymphomes Folliculaires (GELF) trial 86, which compared a regimen of cyclophosphamide, doxorubicin, teniposide, and prednisone (CHVP) versus CHVP plus IFN in 242 patients with confirmed follicular lymphoma. CHVP was administered monthly for 6 months then every other month for 12 months. The IFN dosage was 5 x 10(6) U three times weekly for 18 months. After a median follow-up duration of 72 months, the IFN group gained a mean of 12.3 months of progression-free survival (PFS) and 7.4 months of overall survival (OS), but also experienced additional time with grade 3 or worse toxicity compared with the CHVP group. Sensitivity analysis demonstrated that CHVP plus IFN provided a greater amount of quality-adjusted survival regardless of the relative quality-of-life valuations placed on time with toxicity due to CVHP alone, time with toxicity due to CHVP plus IFN, and time following disease progression. This gain was significant (P < .05) in all cases except for patients who consider time with toxicity to have a low relative value and time following disease progression to have a high relative value. In patients with advanced follicular lymphoma, the clinical benefits of concomitant IFN can significantly offset the associated grade 3 or worse toxic effects. The magnitude of this clinical benefit depends on an individual patient's relative quality-of-life valuations for time with toxicity and time following disease progression.

Local immune response after intravesical interferon gamma in superficial bladder cancer.

To investigate the lymphocyte subpopulations (T4, T8 and macrophages) and major histocompatibility (MHC) II antigens in patients with superficial bladder cancer before and after intravesical instillations of recombinant interferon-gamma (IFN-gamma). Four intravesical weekly instillations of either 1.3 mg (20 patients, group A) or 0.7 mg (11 patients, group B) IFN-gamma were administered in 31 evaluable patients (28 men and three women, mean age 68.5 years). The CD4+, CD8+, CD68+ and HLA-DR antigens were detected immunohistochemically in tumours and a marker tumour before and after intravesical instillations. The median number of T4 lymphocytes increased from 15 per high-power field (HPF) to 27.5 in group A (P = 0.0029) and to 45 in group B (P = 0.0117). Macrophages increased from 6 cells/HPF to 15 cells/HPF in group A (P = 0.0029) and from 2 to 8.75 cells/HPF in group B (P = 0.0117). The T8 lymphocyte subpopulation decreased from 4 to 3 cells/HPF (P = 0.0231) in group A and from 5 to 2 cells/HPF (P = 0.0759) in group B. The median percentage of HLA-DR antigens increased from 1.5% to 18% in general, (P < 0.001), from 2.5% to 15% in group A (P = 0.0064) and from 0% to 20% in group B (P = 0.0077). The induction of HLA-DR antigens was statistically significant in those receiving the lower dose (from 0% before instillation to 20% afterward, P = 0.0277), while it was not with the higher dose (from 0% to 5%, P = 0.068). Irrespective of the dose of IFN used. T4 lymphocytes and macrophages increased significantly after treatment in patients in whom the tumour HLA-DR antigens were either up-regulated or remained stable. The median net increase in T4 cells was 17.5 and 30 cells/HPF for groups A and B, respectively (P = 0.0429). T4 lymphocytes, macrophages and HLA-DR antigens increased after intravesical IFN-gamma in patients with superficial bladder cancer, but T8 lymphocytes decreased. Irrespective of the drug dose used, patients with either upregulated or stable HLA-DR antigens after treatment showed the same pattern of changes in the lymphocyte subpopulations. The two doses generally had the same effect on the immunological variables assessed but the lower dose was more effective in inducing HLA-DR antigens and in increasing the number of T4 lymphocytes in the tumours.

Development of neutralizing antibodies in patients with relapsing-remitting multiple sclerosis treated with IFN-beta1a.

Sixty-eight patients with relapsing-remitting multiple sclerosis (RRMS) were treated with 3 million or 9 million i.u. of recombinant interferon-beta1a (recIFN-beta1a) s.c. three times a week for 2 years. Their sera were tested for antibodies neutralizing the IFN (NAb) in a bioassay. Sera with titers > or = 1:20 were considered positive. We detected NAb in 3.2%, 13.8%, and 15.9% of the patients in sera obtained at 3, 6, and 24 months, respectively. The incidence was not related to the IFN dose. Interestingly, during the 6 month baseline period before the start of the study, relapse rates, baseline disability, and the volume of lesions on T2-weighted images were significantly higher in patients who developed NAb during treatment. Because of interpatient variability, no definitive relationship was observed between NAb formation and loss of clinical or magnetic resonance imaging (MRI) response.

Cutaneous sarcoidosis in a patient with philadelphia‐positive chronic myelogenous leukemia treated with interferon‐α

A patient with Philadelphia-positive (Ph+) chronic myelogenous leukemia (CML) was diagnosed with cutaneous sarcoidosis after treatment with interferon-alpha (IFN-α). Following IFN-α dose reduction, the skin lesions disappeared. Few cases of sarcoidosis associated with IFN treatment have been reported, and only in one patient with pre-existing CML. Our patient was unique in that (1) the sarcoidosis was induced by the IFN-α treatment alone, (2) it developed de novo, and (3) it was confined to the skin. Am. J. Hematol. 58:80–81, 1998. © 1998 Wiley-Liss, Inc.

Biphasic viral clearance of HCV genotype 1 (GENO 1) during high dose IFN induction treatment

Biphasic viral clearance of HCV genotype 1 (GENO 1) during high dose IFN induction treatment

Alpha interferon treatment in myasthenia gravis: Effects on natural killer cell activity

The efficacy of recombinant interferon-alpha (rIFN α), on natural killer (NK) cell cytotoxic activity, CD3+, CD4+, CD8+, CD56+, HLA−DR+ lymphocyte counts, anti-acetylcholine receptor antibody (AChR Ab) levels, single fibre electromyography findings (SFEMG) and clinical course were evaluated in patients with myasthenia gravis (MG). During the IFN α treatment (3 mu, subcutaneous, 3 times a week), NK cell cytotoxicity and CD4+/8+ ratio increased, NK cell count remarkably decreased, and no significant clinical or SFEMG changes were observed. This preliminary open study in MG patients has demonstrated enhanced NK activity per unit NK cell after IFN α therapy. Although lymphocyte phenotypes and NK function approached normal levels during therapy, a higher dose of IFN α may be required for a significant clinical response. It has been also concluded that 6 months of IFN α therapy seems to be safe in MG, though in patients with malignancy, IFN α may cause increased autoimmunity, AChR positivity and MG.

The cooperative effect of interferon- α and ribavirin on subacute sclerosing panencephalitis (SSPE) virus infections, in vitro and in vivo

We studied the effects of two antiviral agents, human interferon- α (IFN- α) and ribavirin, on subacute sclerosing panencephalitis (SSPE) virus infections in hamsters. By intracranial administration, IFN- α alone improved the survival of infected hamsters by 20% at a dose of 6×10 4 IU/kg every other day for 10 days. When the dose of IFN- α was increased incrementally to 6×10 6 IU/kg, the survival rate increased by 70% in a dose-dependent manner. The combination of IFN- α and ribavirin had a synergic inhibitory effect on the replication of SSPE virus in cell culture. Combination of IFN- α (at a dose of 6×10 5 IU/kg) with ribavirin (at a dose of 1 mg/kg) completely prevented mortality. This was significantly better than either IFN- α or ribavirin monotherapy ( p<0.05). Under the conditions used, IFN- α did not enhance the toxicity of ribavirin in hamsters. Intraventricular administration of high dose IFN- α and ribavirin may have potential usefulness in the treatment of patients with SSPE.

Maintenance Therapy with Interferon Alfa 2b in Hodgkin Disease

We performed a randomized clinical trial to assess the efficacy and toxicity of interferon alfa 2b (IFN) as maintenance therapy in patients with advanced Hodgkin's disease in complete remission (CR) after conventional chemotherapy. One hundred and thirty-five patients (stage IIIB-IV B) were initially treated with EBVD (epirubicin, bleomycin, vinblastine, dacar-bazine). IF CR was achieved they were randomly assigned to receive either maintenance therapy with IFN 5.0 MU three times a week for one year or no further treatment (control group). Clinical and laboratory characteristics at diagnosis were quite similar in both groups. After a median follow-up of 74.3 months (range 49 to 108), 61 out of 68 patients (91%; 95% confidence interval (CI): 76% to 97%) remain in first complete remission in the IFN-treated group compared to 38 out of 67 (58%; 95% CI: 49% to 71%) in the control group (p >. 01). Overall survival was also better in the IFN treated group: 62 patients (92%; 95% CI: 82% to 97%) are alive free of disease at 7-years compared to 40 patients (67%, 95%: 55% to 76%) in the control group (p >. 01). Toxicity secondary to IFN administration was mild and no dose modification was necessary during treatment. All patients received the planned dose of IFN. This was not an intent-to treat analysis. IFN administration as maintenance therapy was appears to be the only cause of improvement in outcome in these patients. We feel that IFN should be considered as maintenance therapy in patients with advanced Hodgkin's disease because this treatment improves the final outcome without the excessive toxicities of more aggressive therapeutic approaches such as bone marrow transplantation during first CR. We hope that IFN will be considered in future randomized clinical trials in order to define it's role in the treatment of Hodgkin's disease.

Retreatment of chronic hepatitis C (CHC) with sequential interferon-ribavirin combination (IFN-RIBA) therapy

Most patients with CHC have transient response (Relapsers-R) or no response (NR) when treated with IFN. To assess efficacy of IFN-RIBA in these patients, 50 R and 50 NR after IFN therapy were randomized to be retreated with IFN alone or with IFN-RIBA. IFN was given to all cases at 6MU tiw and at 2 mo patients were randomized to continue with IFN alone or to add RIBA 1800-1200 mglday) for 6 mo. ALT and HCV-RNA (PCR) End Theraov Resoonse and Sustained (12 mo) Resoonse are shown in the table. Previous NR (ALT) ETR(RNA) (ALT) SR (RNA) IFN monotherapy (24) 5(21 %I 3(12%) 0 0 IFN-RIBA (241 12(50%) 4(16%) 1(4%1 0 Previnus R IFN monotherapy (26) 1 16(61X) 10(38%) 1 6(23%) 4(15%) IFN.RIBA (28) 1 22(85%1 18(69%) 1 14(54%) 12(46%) IFN-RIBA significantly improved rate of SR in R (P=O.O3) but not in NR, in which only ALT ETR was improved. IFN-RIBA vs IFN improved SR by 27% with HCV-1 and by 4% with HCV-213. SR rates were 27% and 40% respectively with IFN alone and IFN.RIBA in R after 3MU x 6 mo IFN while the corresponding figures for R after higher/longer IFN therapy were 7% and 57%. Addition of RIBA to IFN improved SR only in patients with normal ALT at randomization. In conclusion, IFN-RIBA combination therapy was superior to IFN monotherapy in retreating previous IFN relapsers, particularly those with HCV-1 and those who had already being treated with high dose IFN during the I” cycle. Our schedule of IFN.RIBA was not effective in previous IFN non responders. A NOVEL HEPATITIS E (HEY) ISOLATED FROM A PATIENT WITH ACUTE nA-C HEPATITIS IN ITALY L. Roman& E. Tanzi. A. Zanetti. G. Sl *Viral Discovery Group, Abbott Laboratories, USA Objective: To assess the aetiological role of HEV in acute nA-C hepatitis and to characterize a viral isolate from a patient with no history of travel to areas where HEV is endemic. P&t&s and methods: We studied 216 patients with nA-C hepatitis (negativity for IgM anti-HAV, HBsAg, IgM anti-HBc, anti-HCV, HCV-RNA and exclusion of autoimmunity, alcohol or hepatotoxic drugs). All sera were tested by EIA for both IgG (Abbott Labs) and IgM (in house assay) anti-HEV. Sera and stools (when available) collected during the acute phase were examined by nested RT-PCR using primers derived from the ORFl region. Oligonucleotide primers based on the 5’-end of the ORFl of HEV-US1 were used to identified an isolate from a patient with no known risk factors. Results: 22/216 (10.2%) patients were found HEV-RNA and IgM positive during acute phase (ALT mean peak 2768 IUil, range 396-12290). The acute disease had a benign course with ALT normalization in 3-5 weeks in 20 (91%) patients. One patient with a history of chronic hepatitis C died from fulminant hepatitis and 1 patient (co-infected with HAV) had a clinically severe course (ALT 12290 IU/l, AST 17870 IUil) with ALT normalization within 8 weeks. 17 (77.3%) acute hepatitis E infections occurred in patients who travelled in endemic areas and 5 (22.7%) in patients with no history of travel. Pairwaise alignments of the nucleotide sequence from a HEV F’CR positive patient with no history of travel indicate that the isolate is significantly divergent from the two original isolates of HEV Burma and Mexico (79.9 and 80.7% respectively) and also significantly divergent from the new US isolates (85.8-88.6%). Phylogenetic analysis indicates that the Italian isolate represents a fourth branch distinct from those represented by the Burmese, Mexican and US isolates. Conclusions: HEV is responsible of about 10% of acute nA-C hepatitis in Italy. The identification of a new HEV variant may be important in understanding the epidemiology of HEV infection in our country.

Subcutaneous Low Doses of Interleukin-2 and Recombinant Interferon Alpha with Carboplatin and Vinblastine in Patients with Advanced Melanoma1

Twenty-three patients with advanced melanoma were treated with a combination of subcutaneous recombinant human interleukin-2 (IL-2), and recombinant interferon alpha-2a (IFN-α) with chemotherapy consisting of four cycles of carboplatin (300 mg/m², day 1) and vinblastine (6 mg/m², day 1), every 28 days (CV-IL-IF). IL-2 was given at a dose of 4.5 × 10⁶ U twice daily on days 3–6 and days 21–24 of each cycle; IFN-α dose was 4.5 × 10⁶ U, starting on day 2, thrice weekly. Immunotherapy was intended to continue for 6 months. Of the 23 analyzed patients, 4 (17%) achieved an objective response, including 1 complete and 3 partial responses, in nonvisceral metastatic disease. The median time to progression was 5 months and the median survival from onset of the treatment 6 months (range 1–14 months). Four patients discontinued the treatment, due to nonhaematologic toxicity; 3 for severe weakness and the 4th patient for long-lasting CNS side-effects. Other grade 3–4 toxicities included weight loss (22%), nausea and vomiting (17%) and alopecia (13%). The haematologic toxicity was acceptable. No toxic death was noted. It is con cluded that the CV-IL-IF regimen has limited activity and moderate toxicity.

Enhanced Radiosensitization with Interferon-α-2b and Cisplatin in the Treatment of Locally Advanced Cervical Carcinoma

Purpose.To evaluate the efficacy and toxicity of interferon-α-2b (IFN-α) and cisplatin given concomitantly with radiation therapy (RT) in the treatment of locally advanced cervical carcinoma. Materials and Methods.Twenty-one patients with stage bulky Ib–IIIb (Ib, 2; IIa, 2; IIb, 8; IIIb, 9) cervical carcinoma were treated with combined IFN-α (5 million IU) subcutaneously three times per week and cisplatin (25 mg/m 2) iv infusion over 2 h weekly for 7 weeks, given concomitantly with RT (4500 cGy of external beam plus 2 brachytherapy procedures). Total radiation doses delivered ranged from 7500 to 9960 cGy (median, 9300 cGy). Follow-up ranged from 16 to 33 months (median, 25 months). Results.The 2-year local control rate was 100%. The only sites of disease recurrence were distant. Freedom from distant metastases, disease-free survival, and overall survival at 2 years was 76%. Late complication rates were high. Grade 4 rectosigmoid, bladder, and small bowel complication rates were 49, 18, and 23% at 2 years. Late toxicity was seen earlier than expected with rectosigmoid complications observed 5 to 11.5 months (median, 8 months) after completion of treatment. Conclusion.Combination IFN-α and cisplatin produced a marked effect of enhanced radiosensitization as evidenced by 100% local tumor control and high late normal tissue complication rates. Due to the unacceptable late toxicity, its routine clinical use cannot be recommended. Further investigation is needed to determine whether a therapeutic window exists such that the use of lower doses of IFN-α, cisplatin, or RT can increase tumor control with more acceptable normal tissue toxicity.

A pilot study on the efficacy of escalating dosage of alpha-interferon for chronic hepatitis C in HIV-infected patients

Chronic liver disease caused by hepatitis C virus (HCV) seems to present a more accelerated course in HIV-infected patients, leading to cirrhosis and liver failure in a shorter period of time than in HIV-negative individuals. As efforts to increase life expectancy in HIV-infected people progress, substantial morbidity and mortality from HCV infection is likely to arise amongst subjects infected parenterally, such as injecting drug users, haemophiliacs and transfusion recipients. Preliminary results have suggested that alpha-interferon (IFN) treatment allows higher rates of response in HIV-infected patients with higher CD4+ lymphocyte counts, suggesting a primary dependence of IFN on a preserved immune system in order to act appropriately. In an open, multicentre, prospective trial we analysed whether the use of larger doses of IFN, through an escalating schedule, might overcome the limits imposed by immune dysfunction. An interim analysis performed in 29 patients concluded that escalating the dosage did not improve the rate of response to IFN. In fact, only one (8.3%) out of 12 patients without response after 3 months of being on IFN therapy achieved response after the dosage was increased from 5 MU to 8 MU s.c. three times a week. Moreover, he relapsed 3 months after completion of treatment for 1 year.

Inactivation of the Fanconi Anemia Group C Gene Augments Interferon-γ–Induced Apoptotic Responses in Hematopoietic Cells

AbstractHematopoietic progenitor cells (HPC) from mice nullizygous at the Fanconi anemia (FA) group C locus (FAC −/−) are hypersensitive to the mitotic inhibitory effects of interferon (IFN-γ). We tested the hypothesis that HPC from the bone marrow of Fanconi group C children are similarly hypersensitive and that the fas pathway is involved in affecting programmed cell death in response to low doses of IFN-γ. In normal human and murine HPC, IFN-γ primed the fas pathway and induced both fas and interferon response factor-1 (IRF-1) gene expression. These IFN-γ-induced apoptotic responses in HPC from the marrow of a child with FA of the C group (FA-C) and in FAC −/− mice occurred at significantly lower IFN doses (by an order of magnitude) than did the apoptotic responses of normal HPC. Treatment of FA-C CD34+ cells with low doses of recombinant IFN-γ, inhibited growth of colony forming unit granulocyte-macrophage and burst-forming unit erythroid, while treatment with blocking antibodies to fas augmented clonal growth and abrogated the clonal inhibitory effect of IFN-γ. Transfer of the normal FAC gene into FA-C B-cell lines prevented mitomycin C–induced apoptosis, but did not suppress fas expression or inhibit the primed fas pathway. However, the kinetics of Stat1-phosphate decay in IFN-γ–treated cells was prolonged in mutant cells and was normalized by transduction of the normal FAC gene. Therefore, the normal FAC protein serves, in part, to modulate IFN-γ signals. HPC bearing inactivating mutations of FAC fail to normally modulate IFN-γ signals and, as a result, undergo apoptosis executed through the fas pathway.

Inactivation of the Fanconi Anemia Group C Gene Augments Interferon-γ–Induced Apoptotic Responses in Hematopoietic Cells

Hematopoietic progenitor cells (HPC) from mice nullizygous at the Fanconi anemia (FA) group C locus (FAC −/−) are hypersensitive to the mitotic inhibitory effects of interferon (IFN-γ). We tested the hypothesis that HPC from the bone marrow of Fanconi group C children are similarly hypersensitive and that the fas pathway is involved in affecting programmed cell death in response to low doses of IFN-γ. In normal human and murine HPC, IFN-γ primed the fas pathway and induced both fas and interferon response factor-1 (IRF-1) gene expression. These IFN-γ-induced apoptotic responses in HPC from the marrow of a child with FA of the C group (FA-C) and in FAC −/− mice occurred at significantly lower IFN doses (by an order of magnitude) than did the apoptotic responses of normal HPC. Treatment of FA-C CD34+ cells with low doses of recombinant IFN-γ, inhibited growth of colony forming unit granulocyte-macrophage and burst-forming unit erythroid, while treatment with blocking antibodies to fas augmented clonal growth and abrogated the clonal inhibitory effect of IFN-γ. Transfer of the normal FAC gene into FA-C B-cell lines prevented mitomycin C–induced apoptosis, but did not suppress fas expression or inhibit the primed fas pathway. However, the kinetics of Stat1-phosphate decay in IFN-γ–treated cells was prolonged in mutant cells and was normalized by transduction of the normal FAC gene. Therefore, the normal FAC protein serves, in part, to modulate IFN-γ signals. HPC bearing inactivating mutations of FAC fail to normally modulate IFN-γ signals and, as a result, undergo apoptosis executed through the fas pathway.

Combination therapy with BRMs in cancer and infectious diseases

In recent years many studies have stressed the importance of using biological response modifiers (BRMs) in the treatment of different conditions of immune-impairment correlated with ageing, cancer and infectious diseases. In particular, the use of different BRMs in conjunction with conventional therapies has been extensively explored. Our studies have demonstrated that treatment with Thymosin α-1 and low doses of IFN or IL-2 exert powerful biological effects both in vitro and in vivo. They are highly effective in restoring cytotoxic activities in immunosuppression induced by tumors and/or cytostatic drugs. In addition, when combined with specific chemotherapy, they are able to induce a dramatic inhibition of tumor growth in both experimental models and in humans. Immunotherapeutic treatment also has an application in controlling infectious diseases, especially those occurring in the immuno-compromised host. The advantage of using the combined immunotherapy treatment with antiviral drugs has been recently demonstrated by our group both in a murine experimental influenza model and in patients infected with HBV, HCV and HIV.

Changes of peripheral blood lymphocyte subsets in a long-term survivor with advanced renal cell carcinoma

We present the case of an 11-year survivor with advanced renal cell carcinoma (T4N2M1). This patient received long-term interferon-alpha (IFN-α)-based immunotherapy. Measurement of peripheral blood lymphocyte subsets suggested that reduction of the IFN-α dose might be associated with a marked increase of cytotoxic T cells, suppressor T cells, activated suppressor/cytotoxic T cells, and natural killer cells among the peripheral blood lymphocytes.

EFFECT OF INTERFERON (IFN) TREATMENT OF CHRONIC ITP IN CHILDREN. 180

Long term effect of IFN treatment in paediatric patients with chronic ITP has not yet been established. We treated nine patients with chronic form of disease aged 17-184 monts (median 90 months), M/F 5/4. Conventional therapy with corticosteroids and HDIVIG failed. None of the patients underwent splenectomy. All patients received 12 doses of alfa 2b IFN 3 MU/mq three times weekly, in seven patients we used repeated courses of IFN therapy.

HCV-RNA SERUM LEVELS IN CHILDREN WITH CHRONIC HEPATITIS C AND RESPONSE TO INTERFERON THERAPY

Recently it has been reported that low baseline serum HCV-RNA levels and early loss of serum HCV-RNA on IFN therapy can predict a long-term response to IFN therapy in adults with chronic hepatitis C (CHC). Little information is available about viraemic changes during IFN therapy in children with CHC. Aim: to evaluate serum HCV-RNA levels before and during IFN therapy in children with CHC and compare virological and biochemical response rates. Methods: 25 consecutive children (13 males; mean age 7.9 yrs; range 3.6-11.5 yrs) affected by CHC were enroled to receive treatment with recombinant-alfa2b IFN (5MU/m2 t.i.w.) for 12 months. IFN therapy was suspended before time in case of severe side effects including hypertransaminasemia (>6 times the upper reference limit) or if no reduction of ALT after 6 months of therapy occurred. Patients' sera were tested for liver function tests and HCV-RNA serum levels by branched DNA signal amplification (b-DNA) assay (Chiron HCV-RNA 2.0; level of sensitivity 0.2 × 106 Eq/ml) at the following times: 2 and 1 week before IFN therapy, weekly for the first 3 weeks of treatment, and therafter monthly until the suspension of IFN. Results: At the present, 15 patients have completed the entire course of therapy, in remaning 10 patients IFN was suspended before time according to protocol. Before therapy, median HCV-RNA serum levels were 0.90 ×106 Eq/ml (range: 0.10-20.18), median ALT serum levels were 74 IU/L (range: 41-219; normal values <35 IU/L). At the end of treatment 8/25 were considered biochemical responders (BR) because ALT serum levels became normal during the treatment and persisted normal until the suspension, the remaining were biochemical nonresponders (NBR). In 11 patients (5 BR), viremia fell below the level of sensitivity already after the second dose of IFN. During the course of therapy, only 2 patients (both BR) showed undetectable levels of HCV-RNA levels for the whole period of treatment; 7 patients (all NBR) showed HCV-RNA levels persistently elevated; in the remaining patients viremia was fluctuating with phases of reduction below the level of sensitivity of the test. At the end of therapy, 12 patients (7 BR) had undetectable levels of serum HCV-RNA. Although no significant difference between pretreatment values of HCV-RNA serum levels between BR (median 0.29 ×106 Eq/ml; range: 0.10-1.62) and BNR (median 1.04 ×106 Eq/ml; range: 0.15-20.18) was found, none of BR had basal values of HCV-RNA >1.62 × 106 Eq/ml. Conclusions: an early reduction of serum HCV-RNA levels occurred in 44% of CHC patients treated with IFN, but only in 8% persisted for the entire course of therapy; persistent biochemical and virological responses may be predicted by low pretreatment HCV-RNA levels; the present study did not confirm the virological response rates observed in previous studies in whom a single evaluation of HCV-RNA levels was performed at the end of therapy.

A prospective, randomized trial comparing lymphoblastoid to recombinant interferon alfa 2a as therapy for chronic hepatitis C

To compare the long-term effectiveness and tolerability of lymphoblastoid interferon (IFN-alphaN1) and recombinant interferon alfa 2a (IFN-alpha2a) in patients with chronic hepatitis caused by hepatitis C virus (HCV), 234 consecutive patients with HCV-related chronic hepatitis were randomized prospectively to receive titrated doses (starting dose = 6 million units [MU]) of IFN-alpha2a (n = 118) or IFN-alphaN1 (n = 116) for 12 months. HCV RNA was detected by reverse- transcription polymerase chain reaction (RT-PCR), quantified by branched-DNA (bDNA) assay, and genotyped by reverse hybridization assay. Thirty-one patients in the IFN-alpha2a group and 28 in the IFN- alphaN1 group (total, 59 [25%] had normal transaminases and undetectable HCV RNA by RT-PCR after 12 months of therapy, but only 19 in the first group and 20 in the second group (total, 39 [17%]) had biochemical and virological responses 12 months after treatment was discontinued. The two treatment groups differed in terms of prevalence of major drug-related adverse reactions (23% vs. 37%, P = .025). The mean total dose per patient was similar for the two groups, i.e., 502 MU IFN-alpha2a vs. 496 MU IFN-alphaN1, and the cost of each sustained response was $31,800 and $32,440, respectively. By multivariate analysis, pretreatment viremia higher than 0.2 MEq/mL and infection with genotype 1 were independently associated to treatment failure. The outcome of treatment in chronic hepatitis C patients was not improved by the administration of high cumulative doses of lymphoblastoid IFN. (Hepatology 1996 Dec;24(6):1366-70)