Membranous nephropathy induced by pegylated interferon alpha-2a therapy for chronic viral hepatitis B

Interferon is used to treat chronic viral hepatitis because of low drug resistance and a high remission rate. However, its propensity to induce and modify autoimmunity has been reported. We used pegylated interferon α-2a to treat a patient with chronic viral hepatitis B. After 5 months of this therapy, the patient developed membranous nephropathy. Complete remission of his nephrotic syndrome was achieved after 1 year of cyclosporine and corticosteroid therapy. During this same period, his chronic viral hepatitis B was controlled by entecavir. To our knowledge, this is the first case in which membranous nephropathy developed during pegylated interferon α-2a therapy for chronic hepatitis B. The autoimmune modulation induced by interferon is the most likely mechanism for this complication.     

Randomized trial of pegylated interferon alpha-2b monotherapy in haemodialysis patients with chronic hepatitis C.

BACKGROUND: Chronic hepatitis C infection is prevalent among haemodialysis patients. The goal of our study was to determine the efficacy and safety of pegylated interferon alpha-2b in haemodialysis patients with chronic hepatitis C. METHODS: We conducted a trial which randomized haemodialysis patients with chronic hepatitis C to 1.0 or 0.5 microg/kg of pegylated interferon alpha-2b subcutaneously, weekly for up to 48 weeks. End-points were sustained viral response and adverse events. Data were analysed as intention to treat and as intended per protocol. RESULTS: After 16 patients were enrolled, the study was terminated because of adverse events and modifications needed in the study design. Nine subjects were randomized to the 1.0 microg/kg group and seven subjects were randomized to the 0.5 microg/kg group. Serious adverse events requiring discontinuation of therapy occurred in five (56%) subjects in the 1.0 microg/kg group and in two (28%) subjects in the 0.5 microg/kg group (P = 0.36). The most common adverse events were hypertension and infection unrelated to neutropenia. Two (22%) subjects in the 1.0 microg/kg group, both genotype 1, had a sustained viral response, and none of the subjects in the 0.5 microg/kg group had a sustained viral response (P = 0.47). Five subjects in the 1.0 microg/kg group were able to complete 24 weeks or longer of therapy as per protocol and two (40%) were sustained responders. CONCLUSIONS: In our study group, pegylated interferon alpha-2b was poorly tolerated and was associated with substantial side effects. Sustained response rates seen with pegylated interferon in our study do not appear to be better than rates reported for standard interferon alpha-2b.     

Pegylated interferon alpha-2b plus ribavirin in the treatment of post-liver transplant recurrent hepatitis C

BACKGROUND: Histological recurrence of the hepatitis C virus (HCV) occurs in the majority of persons transplanted for cirrhosis as a result of HCV. Herein we analyze our experience with the use of both conventional and pegylated (PEG) interferon (IFN) in combination with ribavirin (RBV) in liver transplant recipients with recurrent HCV. Methods: Patients transplanted between 1992 and 2001 with post-orthotopic liver transplantation (OLT) histological recurrence of HCV, and who were treated with at least 6 months of IFN or PEG-IFN in combination with RBV were included in this analysis. A retrospective chart review was performed. Results: A total of 31 patients were included. Fifteen were treated with IFN/RBV and 16 with PEG-IFN/RBV. Of these 16, 11 had been begun on IFN/RBV and were changed to PEG-IFN/RBV because of persistent viremia. Three patients (20%) in the IFN/RBV group and six patients (37.5%) in the PEG-IFN/RBV group experienced a virologic response (VR) on therapy. Of the six patients experiencing VR in the PEG-IFN/RBV group, three (50%) were IFN/RBV non-responders. There were two sustained VRs (SVR). The 65.6% of all patients experienced a biochemical response (BR) on therapy. Seven deaths were observed. Dose modifications of IFN or PEG-IFN (87.1%) and RBV (80.6%) and the requirement for hematopoietic growth factors were frequent. Conclusions: Treatment of recurrent HCV infection with combination of IFN or PEG-IFN and RBV produced an on-therapy VR in 29% and BR in 65% of patients. Hematologic toxicity and dose modifications were frequent. Our experience with antiviral therapy for HCV post-OLT remains disappointing but PEG-IFN + RBV appears to produce VR in a sizable portion of IFN + RBV non-responders.     

慢性乙型肝炎抗病毒治疗的停药问题

随着核苷（酸）类似物在慢性乙型肝炎（CHB）治疗中的长期应用,其停药方面的问题较为突出.首先,在定义治疗目标、治疗终点及停药标准上,如何掌握理想和现实的停药标准、最佳停药时机、使广大CHB患者获得最大疗效等问题都是当前值得我们关注和研究的热点课题.现将有关研究进展介绍如下.     

Single-blind, multicenter, placebo controlled, parallel study to assess the safety and efficacy of intralesional interferon alpha-2B for minimally invasive treatment for Peyronie's disease

PURPOSE: We investigated the efficacy and safety of intralesional interferon alpha-2b for the treatment of Peyronie's disease. MATERIALS AND METHODS: A total of 117 consecutive patients with a mean age of 55.1 years who had Peyronie's disease were enrolled in a single-blind, multicenter, placebo controlled, parallel study to determine the efficacy and safety of intralesional interferon alpha-2b therapy (Schering, Kenilworth, New Jersey), including 62 who received placebo and 55 who received interferon alpha-2b. Saline (10 ml) in controls and interferon alpha-2b (5 x 10(6) U) were administered biweekly for 12 weeks. Each patient was evaluated for penile curvature, plaque size and density, penile pain, erectile function and penile hemodynamics before and after study completion. Improvement in these parameters was statistically compared between the groups. RESULTS: A total of 53 patients in the control arm and 50 in the interferon alpha-2b arm completed the study. Improvement in penile curvature, plaque size and density, and pain resolution was significantly greater in patients treated with interferon alpha-2b vs placebo. The increase in mean International Index of Erectile Function scores was not significantly different between the groups. Penile blood flow improvement was observed in interferon alpha-2b treated patients but not in those who received placebo. The decrease in the number of penile vascular pathologies was significantly higher in interferon alpha-2b cases. Side effects, mostly flu-like symptoms, which were frequently noted in patients on interferon alpha-2b, were mild to moderate in degree and of short duration. CONCLUSIONS: This single-blind, multicenter, placebo controlled, parallel study demonstrates that intralesional interferon alpha-2b at a dose of 5 x 10(6) units biweekly for 12 weeks is effective and safe as minimally invasive therapy for Peyronie's disease.     

Natural leukocyte interferon alfa for the treatment of chronic viral hepatitis in heart transplant recipients

BACKGROUND: A more rapid and aggressive course of hepatitis B virus (HBV)-related and hepatitis C virus (HCV)-related infection in organ transplant recipients has been described. Interferon alfa is the most accepted drug for treating HBV and HCV chronic infections. However, the use of interferon alfa-N3 has been contraindicated in heart transplant (HTx) recipients because of the hypothesized greater risk of triggering acute cellular rejection. The aim of this clinical pilot study was to evaluate tolerability, safety, and efficacy of natural leukocyte interferon alfa in the treatment of chronic HBV and HCV in HTx recipients. METHODS: Seven HTx recipients were enrolled in the study: two with HBV, four with HCV, and one with combined HBV-HCV chronic infection. The patients had a mean follow-up after heart transplantation of 8.5+/-3 years, before starting interferon alfa-N3 treatment at a dose of 6 MU three times per week, intramuscularly for 12 months. RESULTS: All patients completed the treatment with no major side effects. No unexpected episodes of acute cellular rejection were observed during the treatment. Mean aminotransferase serum levels were significantly lower than before transplantation at 3 (P<0.03), 6 (P<0.02), and 12 (P<0.02) months of treatment and at the 12-month follow-up (P<0.02). A complete and sustained response was achieved in all subjects with HBV-related chronic hepatitis, whereas sustained virologic response was observed in one of four HCV patients. CONCLUSIONS: The preliminary data emerging from our study indicate that natural leukocyte interferon alfa-N3 can be safely administered in HTx recipients with chronic HBV or HCV viral hepatitis. Further studies with larger numbers of patients are needed to assess the efficacy of interferon alfa-N3 on HCV virologic response.     

聚乙二醇化干扰素α-2b联合核苷（酸）类似物治疗低水平乙型肝炎病毒表面抗原慢性乙型肝炎患者的临床疗效及影响因素

目的评估聚乙二醇化干扰素α-2b（PegIFNα-2b）联合核苷（酸）类似物（NAs）治疗低水平乙型肝炎病毒表面抗原（HBsAg）慢性乙型肝炎（CHB）患者的临床疗效及影响因素分析。 方法本研究为前瞻性、非随机对照的真实世界研究,选取2018年1月至2020年5月东部战区总医院收治的使用NAs治疗1年以上,血清HBsAg ≤ 1 500 IU/ml、HBV DNA < 50 IU/ml的CHB患者,于原NAs治疗基础上联合PegIFNα-2b治疗,收集患者治疗0周、12周、24周、36周及48周丙氨酸氨基转移酶（ALT）、天门冬氨酸氨基转移酶（AST）、HBV血清标志物以及HBV DNA定量等。根据停止注射PegIFNα-2b时HBsAg是否阴转,分为治愈组（13例）和未愈组（32例）,运用广义估计方程比较两组患者HBsAg、ALT和AST水平;多因素Logistic回归模型分析HBsAg清除影响因素并绘制受试者工作特征曲线（ROC）,评估相关影响因素对HBsAg清除的预测价值。 结果共纳入CHB患者45例,完成PegIFNα-2b治疗48周患者共21例,其中临床治愈10例（治愈率为47.6%）;提前终止PegIFNα-2b治疗患者共24例,其中临床治愈3例（治愈率为12.5%）。治愈组和未愈组患者HBsAg定量较基线水平均显著下降（Z =－2.201、P = 0.028;Z = －3.17、P = 0.011）。入组48周时,治愈组患者ALT水平与基线差异无统计学意义（Z =－1.412、P = 0.158）;AST水平与基线差异有统计学意义（Z =－2.90、P = 0.004）。未愈组患者ALT和AST水平与基线差异均无统计学意义（Z =－1.97、P = 0.122,Z = －1.05、P = 0.421）。广义估计方程分析组间比较结果显示,调整年龄及性别后,两组患者在入组48周时,ALT和AST水平差异无统计学意义（χ² = 0.837、P = 0.36,χ² = 0.005、P = 0.945）,而HBsAg差异具有显著统计学意义（χ² = 24.161、P < 0.001）。多因素Logistic回归分析显示,基线HBsAg（OR = 0.073、95%CI：0.007~0.803、P = 0.032）,年龄（OR = 0.883、95%CI：0.781~0.998、P = 0.047）,PegIFNα-2b使用疗程（OR = 1.027、95%CI：1.001~1.053、P = 0.038）均为影响48周HBsAg清除的因素。基线HBsAg、年龄联合PegIFNα-2b疗程对HBsAg清除预测的ROC曲线面积为0.978（95%CI：0.883~0.993）,敏感性和特异性分别为96.44%和88.95%。 结论PegIFNα-2b联合NAs对低水平HBeAg CHB患者具有较好的临床疗效。基线HBsAg、年龄联合PegIFNα-2b疗程对48周HBsAg清除具有一定预测价值。     

Pilot study of interferon alpha-2b tolerance in patients with stage III melanoma

GOAL: Evaluation of interferon alpha-2b adjuvant treatment (INF alpha-2b) toxicity by monitoring biologic parameters in patients with stage III melanoma. METHOD: Between January 7th till October 29th 1998, we administered 674 injections of INF alpha-2b to eight patients who previously had undergone surgery for stage III melanoma. Patients received 20 MU/m2/d IV for a month and 10 MU/m2/d sub-cutaneously three time a week for 48 weeks. All these patients were followed with at least one complete blood count and hepatic profile every week. Interferon alpha-2b doses were changed accordingly. RESULTS: Patients received on average 51.5% of the total dose. Doses were decreased in patients with neutropenia or hepatic profiles anomalies. Only one patient could received 100% of the total regimen. In four patients treatment was discontinued. In three out of four patients this was due to disease progression, and in one out of four patients this was due to hepatic toxicity. CONCLUSION: INF alpha-2b is less well tolerated than initially thought. Dosage was frequently decreased due to hematologic and hepatic toxicities. This could compromise the treatments efficacity. The minimal dose required to obtain an optimal response will thus have to be defined.     

Prospective study of sequential reduction in immunosuppression, interferon alpha-2B, and chemotherapy for posttransplantation lymphoproliferative disorder

BACKGROUND: Several interventions can cure posttransplant lymphoproliferative disease (PTLD); a sequential approach is usual, starting with reduction in immunosuppressives (RI). The efficacy of RI remains poorly defined, particularly in adults. We assessed an algorithm starting with a defined course of RI in all patients, escalating to interferon (IFN) alpha2b, and finally to chemotherapy, in a prospective multicenter phase II study of adult solid organ transplant recipients. The design predated rituximab. METHODS: Reduction in immunosuppressives: cyclosporine or tacrolimus reduction by 50% for 2 weeks; a further 50% reduction for 1 week if not in complete remission (CR). Intravenous acyclovir was given for the duration of all RI. Patients with less than CR, or any rejection, resumed immunosuppressives and proceeded to IFN 3 MIU/m(2)/day for up to 3 months; if less than CR, ProMACE-CytaBOM chemotherapy. RESULTS: Twenty patients were registered over 60 months; 16 patients with biopsy-proven PTLD were eligible (13 heart, 3 kidney recipients). Median age was 47 (24-75) years. Reduction in immunosuppressives resulted in only 1 of 16 partial responses (12.5%), no CR. Progressive disease occurred in 8 of 16 (50%) and 6 of 16 (38%) experienced rejection. Only 1 of 13 (7%) patients achieved durable CR with IFN. Seven eligible patients received ProMACE-CytaBOM chemotherapy, five of seven (67%) achieving CR, four of five durable beyond 2 years. CONCLUSIONS: Reduction in immunosuppressives produced no CR, progressive disease and rejection were frequent; response to IFN was rare. A strong case can be made for adding rituximab to RI as initial therapy. Chemotherapy resulted in 57% durable CR, data that are relevant for the up to two thirds of PTLD patients who are refractory to rituximab.     

Safety and efficacy of venlafaxine in the treatment of premature ejaculation: a double-blind, placebo-controlled, fixed-dose, randomised study

Venlafaxine is a serotonin-noradrenaline reuptake inhibitor antidepressant. Two hundred and twenty-two married men (mean age, 34 years) with premature ejaculation (PE) were randomly assigned to receive 75 mg of venlafaxine extended release (n = 112) (group 1) or placebo (n = 110) (group 2) for 12 weeks. Pre-treatment evaluation included history and physical examination, geometric mean intravaginal ejaculatory latency time (IELT) and International Index of Erectile Function (IIEF). The efficacy of two treatments was assessed every 2 weeks during treatment, and at the end of study, using responses to IIEF, IELT evaluation, mean intercourse satisfaction domain, mean weekly coitus episodes and adverse drug effects. At the end of treatment period, the geometric mean IELT in venlafaxine and placebo group demonstrated 1.7-fold (95% CI: 0.76-1.96) and 1.6-fold (95% CI: 0.87-1.84) increase respectively (P = 0.1). The mean weekly intercourse episodes increased from pre-treatment values of 1.2 and 1.18 to 2.1 and 1.9 for venlafaxine and placebo respectively (P = 0.08). Baseline mean intercourse satisfaction domain values of IIEF 12 and 12 reached to 13 and 12 at 12-week treatment in groups 1 and 2 respectively (P = 0.07). Mean number of adverse events was 32 for venlafaxine and 8 for placebo (P = 0.02). Venlafaxine is not better than placebo in treatment of PE.     

The impact of azathioprine on chronic viral hepatitis in renal transplantation: a long-term, single-center, prospective study on azathioprine withdrawal.

BACKGROUND: In transplanted patients, viral hepatitis progresses to chronic liver disease and patient's death after many years of transplantation. Also, it is well known that azathioprine (AZA) is harmful to the liver of these patients. However, it is unclear whether a low dose of AZA still represents a threat to the viral liver disease. METHODS: A total of 79 patients with hepatitis C, B, or both, transplanted between 1973 and 1990, were grouped according to whether they had AZA either withdrawn from the immunosuppressive regimen [group (G) I, n=45] or a dosage reduction only (group II, n=34). The decision to remove or to keep AZA was restricted to the patient's doctor. Patients records were reviewed by April 1997. RESULTS: After an equal time of follow-up, after the AZA changing (64+/-26 vs. 58+/-29 months), patients in GI showed a significant decrease in the serum liver parameters when compared to baseline [alanine aminotransferase (ALT): P=0.001; gamma-glutamyl transferase (gamma-GT): P=0.001 and total bilirubin: P=0.002], whereas in GII only ALT decreased (P=0.04) although gamma-GT and total bilirubin did not. Compared to baseline, serum creatinine (SCr) increased only in GI (P=0.001) but, at last follow-up, did not differ from GII. The intention-to-perform liver biopsies was equal in GI and GII (16 vs. 14) but the hystological findings of severe chronic liver disease (either chronic active hepatitis or cirrhosis) were more frequent in GII (P=0.004). Death with a functioning graft was much more frequent in GII than in GI (P=0.001). Infection and cirrhosis were more common as a cause of death in GII than in GI. CONCLUSIONS: The use AZA is harmful to renal transplantation patients with both chronic hepatitis C and B and, therefore, should be avoided. AZA withdrawal, but not dose adjustments, diminishes the serum liver enzymes and the progression rate of the chronic viral liver disease as well as the rate of death secondary to infection and cirrhosis.     

Safety and efficacy of mizoribine treatment in nephrotic syndrome complicated with hepatitis B virus infection: a clinical study

Objective The objective of this study is to explore the efficacy and safety of mizoribine (MZR) in treating nephrotic syndrome patients afflicted with hepatitis B virus (HBV). Methods The present study included 36 nephrotic syndrome patients accompanied with HBV infection. A draft of MZR (150–200?mg/d), methylprednisolone (0.6–0.8?mg/kg·d), and entecavir (0.5?mg/d) was administered to study patients over 24 weeks. The serum albumin (AlB), 24-h urine protein (24-U-TP), liver and renal functions, and HBV-DNA were quantified before and at 2, 4, 8, 12, 16, 20, and 24 weeks after the treatment. The adverse responses were recorded. Results The AlB levels of patients increased gradually after comprehensive treatment, while the 24-U-TP, serum cholesterol, and triglyceride (TG) levels declined gradually. The changes at 24 weeks post-treatment were statistically significant. Compared with the levels before treatment, the HBV-DNA, transaminase, and renal functions of the patients were not significantly altered after the treatment. No evident adverse response was found. Conclusion Treatment using MZR in combination with methylprednisolone and entecavir in HBV-positive nephrotic syndrome patients displays significant efficacy with a low incidence of adverse reactions.     

Safety and efficacy of vardenafil versus sertraline in the treatment of premature ejaculation: a randomised, prospective and crossover study

We investigated safety and efficacy of vardenafil and sertraline in premature ejaculation (PE). Seventy-two men graded their primary PE on a scale of 0–8 (0 = almost never, 8 = almost always). Intravaginal ejaculatory latency time (IELT) was measured. Patients were included if they scored their PE as 4 or greater and their IELTs were less than 1.30 min. After 6 weeks of behavioural psychosexual therapy, 49 patients still had a PE of 4 or greater and an IELT less than 1.30 min and they were randomised: 6 weeks vardenafil (10 mg) or sertraline (50 mg). After a wash-out phase for 1 week, medication was changed in a cross-over design. Initially, all 72 men with PE received behavioural therapy. Twenty-three men were satisfied with treatment and excluded. The remaining 49 men graded their PE as 5.94 ± 1.6 and IELT was 0.59 min and patients were randomised. Four men discontinued the study. Vardenafil improved PE grading: 2.7 ± 2.1 ( P  < 0.01) and IELT increased to 5.01 ± 3.69 ( P  < 0.001). PE grading improved 1.92 ± 1.32, ( P  < 0.01) and IELT 3.12 ± 1.89 ( P  < 0.001) with sertraline. It is concluded that vardenafil and sertraline are useful agents in the pharmacological treatment of PE.     

拉米夫定治疗慢性乙型肝炎病毒感染者四年或以上耐药及疗效分析

目的通过分析拉米夫定治疗慢性乙型肝炎病毒（HBV）感染者4年或以上的耐药情况及疗效,以优化拉米夫定的治疗。方法 54例入组患者口服拉米夫定100mg/d,若患者HBV DNA载量连续两次（间隔1个月）超出检测下限1.0log10拷贝/ml时,则采用拉米夫定100mg/d联合阿德福韦酯10mg/d长期治疗;而另一部分患者在拉米夫定100mg/d联合阿德福韦酯10mg/d治疗3个月后停用拉米夫定,继续单用阿德福韦酯长期治疗。结果末次随访时,45例患者（83%）HBV DNA低于检测下限,52例患者（96%）丙氨酸氨基转移酶（ALT）复常,31例HBeAg（＋）患者中出现HBeg血清学转换者14例（45%）,无患者进展为肝细胞癌;17例患者在使用拉米夫定过程中出现病毒学突破,需加用或换用阿德福韦酯,在3年内出现病毒学突破需更改治疗方案的患者13例,占需要更改治疗方案患者人数的76%;曾停药患者7例,停药后均出现HBV DNA反弹,其中伴ALT升高者6例,再次服药后全部病例HBV DNA低于检测下限,ALT恢复正常。结论长期使用拉米夫定抗病毒治疗,安全性好,70%以上的病毒学突破发生在治疗3年内,若及时更改治疗方案,可使80%以上的患者维持HBV DNA低于检测下限,90%以上的患者ALT正常;拉米夫定停药后容易复发,但再次使用拉米夫定仍有效。     

Preliminary experience with alpha-2b-interferon therapy of viral hepatitis in liver allograft recipients.

Currently, alpha interferon is the only recognized therapy for chronic viral hepatitis. As a result of its success in several multicenter trials, the agent was approved recently by the FDA for use in the clinical management of patients with chronic hepatitis C. FDA approval for its use in chronic hepatitis B is anticipated. Based upon this experience in nonimmunosuppressed individuals, the efficacy of alpha interferon therapy in patients who are recipients of liver allografts and are receiving chronic immunosuppression was assessed in a preliminary trial of the agent in 30 patients (13 with HBV, 11 with HCV, and 6 with hepatitis non A, non B, non C). Therapy was initiated at a dose of 3 X 10(6) units three times per week and continued for 6 months. Dose reduction in the amount of the alpha interferon administered was determined by a preestablished protocol. Nine percent of those with HCV and 18% of those with hepatitis non A, non B, non C experienced a full response to alpha interferon therapy. No full responses to alpha interferon therapy. No full responses were seen in those with HBV disease. Partial responses were common in all three groups but were most frequent in those with hepatitis non A, non B, non C and least frequent in those with HCV-related disease. This preliminary experience demonstrates the following: 1. Viral hepatitis following OLTx can be treated with alpha-2b-interferon. 2. The complications of alpha-2b-interferon therapy utilized prior to OLTx can be avoided by giving the therapy following successful OLTx. 3. The high rate of partial responses noted suggests that future studies should utilize either higher doses or longer durations of therapy or both. 4. The response rate was greatest for those having non A, non B, non C hepatitis and least for those with HCV hepatitis. 5. In this small preliminary series, no episodes of liver graft rejection could be ascribed to the use of alpha-2b-interferon in the patients so treated.