Peginterferon alpha-2b plus ribavirin vs interferon alpha-2b plus ribavirin for chronic hepatitis C in HIV-coinfected patients

Treatment of chronic hepatitis C in human immunodeficiency virus (HIV)-infected patients is associated with low response rates and high incidence of side effects. One hundred twenty-one hepatitis C virus (HCV)-HIV-coinfected patients were randomized to receive interferon alpha-2b (3 MU thrice weekly; n = 61) or peginterferon alpha-2b (1.5 microg/kg/week; n = 60), plus ribavirin (800 mg daily), for 24 (genotype 2 or 3) or 48 weeks (genotype 1 or 4). We assessed early virological response at 4, 8 and 12 weeks to predict sustained virological response (SVR). Safety assessment included frequent blood lactate measurement and relative quantitation of mitochondrial DNA (mtDNA) content in peripheral blood mononuclear cells. In intention-to-treat analysis, the SVR rate was higher in the peginterferon group (55%vs 26%; P = 0.002). The difference for HCV genotypes 1 and 4 was 45%vs 14% (P = 0.009) and 50%vs 27% (P = 0.387), respectively, and for genotype 2 or 3, 71%vs 43% (P = 0.12) Viral response at 4, 8 and 12 weeks of treatment was highly predictive of SVR. Among genotype 3 patients, 17 of 20 (85%) whose HCV RNA was already undetectable at 4 weeks had an SVR after 24 weeks of treatment. Hyperlactataemia occurred in 22 patients and was clinically significant in six, two of whom died. mtDNA decreased significantly 4-12 weeks after the start of treatment in patients developing clinically significant hyperlactataemia. Peginterferon alpha-2b plus ribavirin was more effective than interferon alpha-2b plus ribavirin in HIV-coinfected patients. Frequent monitoring of virological response may be very helpful to optimize treatment compliance, to tailor treatment duration and to minimize side effects.     

Interferon-α plus low-dose cytosine arabinoside in advanced phase chronic myelogenous leukaemia patients

Abstract: Twenty-nine late chronic and accelerated phase chronic myelogenous leukaemia (CML) patients were entered in a pilot study designed to test the therapeutic efficacy of treatment with interferon-α (IFN-α) and low-dose cytosine arabinoside (ARA-C). IFN-α was administered at a dose of 2–10 × 10⁶ IU/day and ARA-C at 15 mg/m²/day for 14 days each month. The treatment was well tolerated by 73% of the patients. Side effects were mainly asthenia, anorexia, anaemia and piastrinopenia. Haematological and cytogenetic responses were evaluated in the 19 patients who received more than 6 cycles. Four complete haematological response, 7 partial haematological response, 6 minor haematological response, 2 stable disease were obtained in this patient group. Two complete cytogenetic responses and 2 minor cytogenetic responses were detected in these patients. Suppression of secondary Ph' positive clones which appeared during the previous IFN-α treatment was documented in 3 accelerated phase patients after ARA-C was added to their IFN-α treatment. It would therefore seem that late chronic and accelerated phase CML patients benefit from combined IFN-α/ARA-C treatment and achieve haematological and cytogenetic responses not obtained during previous treatment without being exposed to undue toxicity. However, we cannot judge whether it offers any advantage in terms of survival.     

Treatment of chronic hepatitis C in HIV-infected patients with interferon alpha-2b plus ribavirin

One hundred six HIV-infected patients with chronic hepatitis C virus (HCV) infection were randomized to receive ribavirin (RBV) 400 mg bid plus interferon alpha-2b (IFN-alpha) at two different doses, 3 mU tiw (control arm) or 5 mU daily for the first 6 weeks, followed by 3 mU tiw until completing 6 months of therapy (induction arm). All patients had CD4 counts above 350 cells/microl and 89% were taking antiretroviral therapy. Adverse effects leading to treatment discontinuation occurred in 12.3% of patients, a rate quite similar to that seen in HCV-monoinfected patients. Negative serum HCV-RNA values (< 60 IU/ml) were recorded in 24.7% and 35.5% of patients at 3 and 6 months of therapy. However, in the intent-to-treat analysis, sustained response was reached by only 16% of patients (22.4% in the on-treatment analysis). No differences between treatment arms were noticed. Patients with HCV genotypes 2 or 3 had a 7-fold higher response rate than those with HCV genotypes 1 or 4. Therefore, early, end-of-treatment, and sustained response rates are lower in HIV/HCV-coinfected patients treated with RBV/IFN-alpha combination therapy. Since HCV-related liver disease is currently one of the leading causes of morbidity and mortality among HIV-infected patients, new treatment options are urgently needed for coinfected individuals.     

Combination therapy with interferon-alpha-2b and hydroxyurea in patients with chronic myelogenous leukemia

Background: Interferon-α-2b (INF-α) has been able to achieve hematological and cytogenetic remission in chronic myelogenous leukemia (CML) patients and has a beneficial effect in patients who have relapsed after bone marrow transplantation (BMT). Hydroxyurea (HU) is the optimal conventional drug for treatment of CML in the chronic phase. IFN-α-based combinations have attempted to improve the results of single agent trials. Methods: Thirty previously untreated patients (16 males and 14 females, 26–70 years old), newly diagnosed as having CML (Philadelphia chromosome-positive) from a single hematology center, were treated with a combination of IFN-α and HU. The initial dose of IFN-α was 3×10⁶ daily (not corrected for body surface). HU was administered at a dose of 40 mg/kg daily. The maintenance dosage was adjusted to the white blood cell (WBC) count. Results: The median observation time was 5.2 years. Twenty-seven patients maintained the prescribed dose of IFN-α, while three patients received IFN-α at a dose of 5×10⁶ due to persistent elevated WBC count. Complete hematological remission was achieved in 20 patients (66.6%) and partial remission in the other 10 patients (33.3%). Two patients achieved complete cytogenetic remission and three patients partial cytogenetic remission. During the study period, 20 patients died (median survival 5.1 years). The youngest patient (26 years old) died during BMT. Ten patients are still alive (median survival 5.37 years). Side effects from IFN-α included fever (100%) and flu-like syndrome (80%); two patients had tumor cell lysis syndrome. Conclusions: Combination INF-α and HU therapy is well tolerated and effective for the treatment of CML patients, resulting in a rapid control of the disease with only minor side effects.     

干扰素α-2b联合小剂量阿糖胞苷治疗CML的临床研究

目的：探讨干扰素α-2b（IFNα-2b）和小剂量阿糖胞苷（LD Ara-C)联合治疗慢性粒细胞白血病（CML）的血液学和细胞遗传学缓解率，寻找治疗CML的新途径。方法：采用IFNα-2b（300万U/d)和Ara-C(20mg/m^-2.d^-2)，每月用10d)联合治疗CML慢性期患者17例，检测治疗后血液学缓解和Ph染色体阳性细胞下降情况，并与IFNα-2b治疗组和羟基脲（Hu)治疗组作对照。结果：IFNα-2bLD Ara-C治疗组治疗6个月，CHR率和总CHR率分别为76．47％和88．24％，47．06％的患者治疗7－32个月（中位数14个月），pH染色体阳性细胞下降至38％－90％，仅1例（5．88％）在34个月发生急变，治疗6个月CHR率，总CHR率和Ph染色体阳性细胞下降病例百分数均显著高于IFNα-2b治疗组（P＝0．0095，P＜0．005和P＝0．043）和Hu治疗组（P＝0．014，P＜0．005和P＜0．005），CML急变发生率较低（P＝0．03和P＜0．05），而且发生急变的时间较晚，结论：对CML慢性期患者采用IFNα-2b和LD Ara-C联合治疗，可显著提高CML患者的CHR率，减少Ph染色体阳性细胞，提高CML患者的细胞遗传学解率，延长CML患者的生存期。     

Sarcoidosis induced by interferon therapy for chronic myelogenous leukaemia

A 31-year-old male was diagnosed as having chronic myelogenous leukaemia and has been treated with hydroxyurea and interferon-α since February 1995. After 16 months, he complained of low-grade fever and a cough. Bilateral hilar lymph node enlargement was detected on the chest X-ray film and multiple subcutaneous erythematous nodules appeared. A skin biopsy revealed subcutaneous sarcoid granuloma. Two months after the cessation of interferon therapy, the subcutaneous nodules and the hilar lymph node enlargement resolved. It is possible that continuous interferon administration can promote granuloma formation in sarcoidosis by activating T cells and macrophages.     

Comparison of a 6-month course peginterferon alpha-2b plus ribavirin and interferon alpha-2b plus ribavirin in treating Chinese patients with chronic hepatitis C in Taiwan

Previous studies in Caucasian patients showed treatment of chronic hepatitis C with pegylated interferon/ribavirin was well tolerated, and produced a higher response rate especially in genotype 1 infections. However, it is unknown whether this conclusion can be extrapolated to patients with Chinese ethnic origin. A total of 153 patients with biopsy-proven chronic hepatitis C were randomly assigned to receive either weekly injection of peginterferon alpha-2b 1.5 mcg/kg plus oral ribavirin (1000 or 1200 mg/day, depending on body weight) (PEG group, n = 76) or 3 MU of interferon alpha-2b t.i.w. plus ribavirin (IFN group, n = 77) for 24 weeks. Sustained virological response (SVR) was defined as the sustained disappearance of serum hepatitis C virus (HCV) RNA at 24 weeks after the end of treatment by polymerase chain reaction assay. Baseline demographic, viral and histological characteristics were comparable between the two groups. Using an intent-to-treat analysis, HCV genotype 1 patients showed a significantly higher SVR in patients receiving PEG-IFN rather than IFN (65.8%vs 41.0%, P = 0.019), but no difference was found in genotype non-1 patients (PEG vs IFN: 68.4%vs 86.8%, P = 0.060). Genotype 1 patients (28.6%) in the PEG-IFN group relapsed, as compared with 52.9% in the IFN group (P = 0.040). Multivariate analyses showed early virological response at week 12 of therapy and genotype non-1 were significant predictors to SVR. As compared with the IFN group, patients receiving PEG-IFN had a significantly higher rate of discontinuation, dose reduction, fever, headache, insomnia, leucopenia and thrombocytopenia. In genotype 1 chronic hepatitis C Chinese patient, PEG-IFNalpha2b ribavirin had significantly better SVR and lower relapse rate when compared to IFN/ribavirin. Both regimens can be recommended for genotype non-1 chronic hepatitis C Chinese patients. However, a higher rate of adverse events and discontinuance of therapy were noted in patients treated with PEG-IFNalpha2b ribavirin.     

Peginterferon alpha-2b plus ribavirin compared with interferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C in Saudi patients commonly infected with genotype 4.

AIM: Comparing the efficacy of peginterferon alpha-2b plus ribavirin with interferon alpha -2b plus ribavirin in Saudi patients with chronic hepatitis C virus (HCV) commonly infected with genotype 4. METHODS: A total of 96 patients with chronic HCV infection were randomly assigned to two treatment groups. Forty-eight patients received once weekly 100 microg of peginterferon alpha-2b plus ribavirin given orally 800 mg/day (peginterferon group). Another 48 patients received thrice weekly 3 million units of interferon alpha-2b plus ribavirin 800 mg/day (interferon group). At the end of treatment (48 weeks) and sustained (72 weeks) biochemical and virologic responses were determined. RESULTS: In the peginterferon group, 70.8% (34/48) patients attained both biochemical and virologic responses at the end of the treatment as against 52.1% (25/48) patients in the interferon group. (P=0.09 for both). Similarly, sustained biochemical and virologic responses in the peginterferon group were attained in 52.1% (25/48) and 43.8% (21/48) patients as against 43.8% (21/48) and 29.2% (14/48) patients in the interferon group, respectively (P=0.54 and 0.20, respectively). The sustained virologic response rates in patients with genotype 4 were 42.9% (12/28) in the peginterferon group and 32.3% (10/31) in the interferon group (P=0.43). Patients in peginterferon group had higher, although statistically not significant adverse reactions. CONCLUSIONS: Saudi patients with chronic HCV attained a higher, although statistically not significant sustained virologic response with pegylated interferon plus ribavirin compared with interferon plus ribavirin.     

Clonal B lymphocytes lack bcr rearrangement in Ph-positive chronic myelogenous leukaemia

Philadelphia (Ph) chromosome-positive chronic myelogenous leukaemia (CML) was studied in a subject heterozygous for the X chromosome-linked alloenzyme system of glucose-6-phosphate dehydrogenase (G6PD). Determination of G6PD mosaicism showed homogeneous expression in granulocytes, erythrocytes and platelets. Cytogenetic studies showed the typical Ph translocation in all metaphases from bone marrow and peripheral blood myeloid cells, bcr rearrangement was detected in bone marrow and in granulocytes. B cells were stimulated with Epstein-Barr virus (EBV) in order to evaluate involvement of lymphocytes, EBV-transformed lymphoblastoid cells expressed a single G6PD phenotype and therefore probably derived from the leukaemic stem cell. However they had a normal karyotype and a constitutional bcr restriction pattern. Molecular analysis in this case of CML clarifies the differentiative potential of cells belonging to the leukaemic clone, by demonstrating that clonal Ph-negative B cells maintain normal differentiative capacity and have a bcr gene sequence which is not rearranged.     

Cost effectiveness of peginterferon alpha-2b plus ribavirin versus interferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C

BACKGROUND: Peginterferon alpha-2b plus ribavirin therapy in previously untreated patients with chronic hepatitis C yields the highest sustained virological response rates of any treatment strategy but is expensive. AIMS: To estimate the cost effectiveness of treatment with peginterferon alpha-2b plus ribavirin compared with interferon alpha-2b plus ribavirin for initial treatment of patients with chronic hepatitis C. METHODS: Individual patient level data from a randomised clinical trial with peginterferon plus ribavirin were applied to a previously published and validated Markov model to project lifelong clinical outcomes. Quality of life and economic estimates were based on German patient data. We used a societal perspective and applied a 3% annual discount rate. RESULTS: Compared with no antiviral therapy, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 4.2 and 4.7 years, respectively. Compared with standard interferon alpha-2b plus ribavirin, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 0.5 and by 1.0 years with incremental cost effectiveness ratios of 11,800 euros and 6600 euros per quality adjusted life year (QALY), respectively. Subgroup analyses by genotype, viral load, sex, and histology showed that peginterferon plus weight based ribavirin remained cost effective compared with other well accepted medical treatments. CONCLUSIONS: Peginterferon alpha-2b plus ribavirin should reduce the incidence of liver complications, prolong life, improve quality of life, and be cost effective for the initial treatment of chronic hepatitis C.     

Sequential treatment of Ph-positive chronic myeloid leukemia with interferon gamma and interferon alpha

Several clinical observations have shown that alpha-IFN is presently the most interesting investigational agent for the treatment of Ph+ chronic myeloid leukemia (CML). Gamma-IFN is also effective, and experimental data as well as preliminary clinical observations suggest that the combination of the two IFNs is worth investigating. No comparative data are available on the effects of the two IFNs, given alone, in the same patients. In this study 11 patients with PH+ CML were first treated with gamma-IFN, up to a maximum period of 35 weeks, and after a short rest period were retreated with alpha-IFN. Both IFNs were ineffective in 3 patients in accelerated or instable chronic phase. Both IFNs were equally effective in 8 patients in stable chronic phase, but none of these patients achieved a karyotypic conversion with either IFN. This study did not show any measurable differences in the therapeutic response to gamma-IFN and alpha-IFN given consecutively to the same patients.     

Changes in haemoglobin during interferon alpha-2b plus ribavirin combination therapy for chronic hepatitis C virus infection

Interferon alpha and ribavirin (RBV) combination therapy is associated with decreases in haemoglobin (Hb) concentrations and anaemia. The aim of this analysis was to better characterize the magnitude and frequency of Hb changes and risk factors. This retrospective analysis evaluated treatment‐related changes in Hb in 677 patients who participated in either of two interferon alpha‐2b plus RBV studies for chronic hepatitis C virus (HCV) infection. Study 1 included 192 interferon alpha‐naïve patients randomized to receive RBV 1000–1200 mg/day plus interferon alpha‐2b 3 million IU daily or three times weekly for 48 weeks. Study 2 included 485 interferon alpha‐experienced patients randomized to receive RBV 1000‐1200 mg daily plus interferon alpha‐2b 3 million IU daily or three times weekly for 4 weeks, followed by three times weekly dosing for 44 weeks. More than 50% of all patients experienced a decrease in Hb ≥30 g/L. Women were 4.4 times as likely as men to experience a Hb level of <100 g/L; however, men were at a 40% higher risk to experience a Hb decline of >30 g/L from baseline. Daily use of interferon alpha‐2b did not impact the magnitude of Hb decrease. In this pooled analysis, RBV dose reduction resulted in increases in Hb concentration of approximately 10 g/L. Lower baseline creatinine clearance, higher baseline Hb levels and increased age were independently associated with increased risk of Hb decreases of >27.7%. Lower baseline weight was not associated with increased risk of Hb decrease. Substantial Hb decreases occur frequently with interferon alpha/RBV combination therapy. Sex, the magnitude of the Hb decline and renal function are potentially important factors to consider in patients receiving RBV. Further research is needed to determine the impact on virological response and to develop strategies to manage the medical consequences.     

Cytogenetic remission 10 years after the start of monotherapy with interferon alpha-2b in elderly chronic myelogenous leukemia

A 69-year-old man was found to have leukocytosis and a bleeding tendency, when he underwent surgery for hemorrhoids in November 1992, at the age of 69. The patient was referred to our department for further examination, and was admitted on December 4. On admission, he had hepatomegaly (5 cm) and splenomegaly (12 cm). Laboratory data on admission showed that the leukocyte count was 173,400/microliter, erythrocyte count, 314 x 10(4)/microliter, hemoglobin level, 10.5 g/dl, hematocrit value, 29.7%, and platelet count, 14.4 x 10(4)/microliter, respectively. Peripheral hemogram revealed neutrophilia with a shift to the left to promyelocytes, and the positivity of neutrophil alkaline phosphatase (NAP) was very low. The bone marrow was hyperplastic with a high M/E ratio (5.8). As the chromosome analysis revealed that he had 9:22 translocation in all 20 karyotypes, chronic myelogenous leukemia in the chronic phase, was diagnosed. After the daily intramuscular administration of 9 megaunits interferon alpha-2b was started on December 9, 1992, his leukocyte count stabilized between 5,000 and 8,000/microliter. Thereafter, intramuscular administration of IFN alpha has been continued regularly almost twice a week at the outpatient clinic until now. The leukocyte count ranges from 3,000 to 6,000/ml and he is asymptomatic. In April 1995, complete cytogenetic response was achieved 28 months after the start of interferon alpha therapy. The recent bone marrow chromosomes examination showed Philadelphia-negative metaphases until now, December, 2002, although major bcr-abl still remains positive. This case suggests that treatment with interferon alpha may still be useful in some elderly patients with chronic myelogenous leukemia.