The long-term efficacy of interferon alfa in chronic hepatitis C patients: A critical review

With current therapeutic regimens, sustained responses occur in no more than 25% of patients with chronic hepatitis C who are treated with interferon. Relapses occur usually within 6 months from therapy suspension, but clinical and virologic recurrencies can be observed as late as after 3 years of follow up. The rate of long-term responses seems to depend on the dosage and the period of administration of interferon, but the best therapeutic protocol remains unknown. As a direct marker of permanent recovery is not available, indirect signs of disease resolution are: (i) continuously normal alanine aminotransferase levels; (ii) clearance of HCV-RNA; (iii) disappearance of anti-C100/NS4; and (iv) significant histological improvements assessed at least 2 years after therapy withdrawal. Known baseline predictive features of long-term response are the absence of cirrhosis, low viraemic levels and infection with HCV of type III or IV genotype (Okamoto's classification). According to recent reports, the lower the heterogeneity of the hypervariable region of the envelope 2 gene of HCV, the higher the chance of a sustained remission. There is not yet any consensus on the efficacy of a second therapeutic course of interferon in inducing a permanent response, and controlled trials are needed to clarify this issue.     

Clinical study on long-term treatment of chronic hepatitis C with interferon

We treated 41 chronic hepatitis C patients with recombinant interferon alpha 2a, 6 X 10(6) IU/day, for three weeks daily followed by intermittent therapy, 3 X 10(6) IU/day, three times weekly for 6 months and more. After 6 months of intermittent therapy, serum aminotransferases (AST, ALT) decreased to normal or nearly normal levels in 29 of 41 patients (70.7%) with histological improvement. The HCV (C100-3) antibody disappeared during and after IFN therapy in 7 of 34 HCV antibody positive patients (20.6%). Serum aminotransferases levels of all such patients were normalized or nearly normalized. The IFN antibody was detected in 8 of 41 patients (19.5%) including one whose IFN antibody was already present before starting IFN therapy. IFN treatment was discontinued in 22 of 41 patients (53.7%) because they responded completely or nearly completely to IFN therapy. All of the 22 patients have been maintaining normal aminotransferase levels for 1 to 24 months (mean, 12 months) after the treatment period. We conclude that long-term IFN therapy is greatly beneficial in controlling hepatic inflammatory changes in chronic hepatitis C.     

Virological, immunological and histological aspects in adult beta-thalassemic patients with chronic hepatitis C virus infection.

OBJECTIVES: Multitransfused adult beta-thalassemic patients constitute a population with high prevalence of hepatitis C virus (HCV) infection, because of transmission of HCV from infected blood donors prior to the introduction of anti-HCV screening. The aim of this study was to compare them with otherwise normal patients with HCV infection. METHODS: Forty-two adult multitransfused beta-thalassemics and 49 otherwise normal patients of the same age, with chronic HCV infection were studied. Viral parameters, autoimmunity indices and liver histology were evaluated. RESULTS: Serum HCV RNA levels were found significantly lower in thalassemic (median: 65,150 international units per milliliter (IU/ml); range: 3 059 380 IU/ml) than in non-thalassemic (NT) patients (median: 580,000 IU/ml; range: 10,956,000 IU/ml; P=0.001). The most prevalent genotype in thalassemic group was genotype 4 (32.4%) while in NT group was genotype 3a (59.2%). Cryoglobulins were detected in 8/42 (19%) thalassemic patients and in 12/49 (24.5%) NTs. Thalassemic patients had significantly lower levels of C3 and C4 components of complement and higher incidence of anti-nuclear antibodies than those without thalassemia. In patients with thalassemia a lower grading score was noted in liver biopsy compared with those without thalassemia (4.41+/-1.98 vs 5.38 +/- 2.09, P=0.038). On the contrary, thalassemic patients were found to have a higher staging score (3.08 +/- 1.51 vs 2.33 +/- 1.34, P=0.024). CONCLUSIONS: Adult beta-thalassemic patients, compared with other patients with HCV infection, present lower necroinflammatory activity and lower viral load but higher staging score. Autoimmune features are marginally different. Age of acquiring the infection, iron overload and modulation of immune system by transfusions are the proposed causes of these differences.     

Effects of long-term interferon-alpha treatment on glucose tolerance in patients with chronic hepatitis C.

BACKGROUND/AIMS: Interferon-a has been reported to acutely induce insulin resistance and glucose intolerance. The effects of long-term treatment with interferon-a on glucose metabolism remain unclear. METHODS: Thirty-two Japanese patients with chronic hepatitis C were given interferon-a (6x10(6)U/day) daily for 2 weeks and thereafter 3 times weekly up to 6 months. The patients received a 75-g oral glucose tolerance test before the treatment. Fifteen patients also had an intravenous glucose tolerance test for an assessment of insulin sensitivity with Bergman's minimal model. These tests were repeated 3 months after the treatment. RESULTS: Insulin sensitivity was not affected by the treatment (5.7+/-3.8 vs 5.2+/-3.8 10(-4) x min(-1) x mU(-1) x l , not significant) and a statistically significant but minimum decrease in area under the curve of plasma glucose (1012+/-332 vs 928+/-282 mmol x l(-1) x min, p<0.01) in a 75-g oral glucose tolerance test was noted. Acute insulin response to intravenous glucose tolerance tests (214+/-275 vs 294+/-334 mU x l(-1) x min, p<0.05) increased slightly. CONCLUSION: Contrary to the known acute metabolic effects, interferon-a therapy for 3 months in patients with chronic hepatitis C did not have deleterious effects on insulin sensitivity and glucose tolerance.     

Interferon treatment of cirrhotic patients with chronic hepatitis C

SUMMARY. Hepatitis C virus (HCV) infection is one of the more important infectious diseases yet to be conquered. An estimated 3.5 million people in the USA have chronic HCV. Each year, 8000 to 10000 of these chronically infected patients die of a liver-related complication of their infection. The introduction of effective blood screening assays has resulted in a remarkable decrease in the incidence of post-transfusion HCV infection. Nonetheless it is essential to have a treatment programme for chronic HCV disease that prevents the development and the progression of compensated cirrhosis to either decompensated cirrhosis or hepatocellular carcinoma, as many individuals present to the health care system with chronic active hepatitis or cirrhosis. A completely safe and effective treatment strategy for chronic HCV, with or without cirrhosis, remains to be developed. Of the various treatment alternatives currently available, only interferon (IFN) has been evaluated extensively. IFN therapy has been shown to induce remissions of the hepatic inflammatory process and also to eliminate the viral infection in some treated cases. As a result, the selection of patients for treatment and the dose and the duration of therapy with IFN are still controversial issues. It is widely held that cirrhotic individuals do not respond to IFN therapy and that treatment of decompensated cirrhotic individuals with HCV infection is dangerous. Here we review data regarding the available experience with IFN treatment of HCV-positive individuals with cirrhosis and compare the response rates of cirrhotics to those reported for individuals with chronic active HCV.     

不同方法阿德福韦酯治疗耐拉米夫定的慢性乙型肝炎患者长期疗效观察

目的观察不同方法阿德福韦酯治疗拉米夫定耐药慢性乙型肝炎（CHB）长期疗效。方法 63例服用拉米夫定耐药的代偿期CHB患者,随机分为两组。A组,无限期拉米夫定联合阿德福韦酯治疗,6个月之内,HBV DNA下降2 log10或病毒检测不到者继续观察。B组,拉米夫定联合阿德福韦酯3～6个月,HBV DNA下降2 log10或病毒检测不到,停拉米夫定,单用阿德福韦酯,继续观察。所有患者定期检测肝功能,每3个月检测HBV DNA,每半年检测拉米夫定耐药位点（rtA173T/V和rtL180M）及阿德福韦酯耐药位点（rtA181T/V和tN236T）。结果 A组在防止再次乙型肝炎病毒（HBV）耐药的发生及预防病毒学和生化学突破要明显优于B组。结论无限期拉米夫定联合阿德福韦酯治疗能明显降低再次HBV耐药的发生,预防病毒学和生化学突破。     

Interferon retreatment of patients with chronic hepatitis C. A long-term follow-up

BACKGROUND/AIMS: We retrospectively evaluated the long-term efficacy of interferon retreatment in patients with chronic hepatitis C, who did not have a sustained response to a 1st cycle of treatment. METHODOLOGY: Sixty-six patients, 43 non-responder and 23 relapser to alpha interferon treatment, were retreated with alpha interferon, 6 MU thrice weekly for 12 months. Response was defined as negative HCV viremia. Responders underwent long-term follow-up (27-43 months). RESULTS: The response rates were 14% and 35% at the end of retreatment, 7% and 22% at 6 months, and 2% and 13% at long-term follow-up in non-responders and relapsers respectively. The outcome of retreatment was not statistically influenced by age, cirrhosis, viral genotype, dose and duration of previous treatment. CONCLUSIONS: Interferon retreatment, for sustained viral eradication, is not effective in non-responders and useful in few relapsers. Whereas, retreatment could prove effective in slowing down the activity of the disease and reducing the incidence of hepatocarcinoma, since some relapses occur late during the follow-up. Therefore, retreatment should be confined to relapsers with contraindications to new more efficient therapeutic strategies.     

Excess mortality in patients with advanced chronic hepatitis C treated with long-term peginterferon

Chronic hepatitis C virus infection can cause chronic liver disease, cirrhosis and liver cancer. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial was a prospective, randomized controlled study of long-term, low-dose peginterferon therapy in patients with advanced chronic hepatitis C who failed to respond to a previous course of optimal antiviral therapy. The aim of this follow-up analysis is to describe the frequency and causes of death among this cohort of patients. Deaths occurring during and after the HALT-C Trial were reviewed by a committee of investigators to determine the cause of death and to categorize each death as liver- or nonliver-related and as related or not to complications of peginterferon. Rates of liver transplantation were also assessed. Over a median of 5.7 years, 122 deaths occurred among 1,050 randomized patients (12%), of which 76 were considered liver-related (62%) and 46 nonliver-related (38%); 74 patients (7%) underwent liver transplantation. At 7 years the cumulative mortality rate was higher in the treatment compared to the control group (20% versus 15%, P = 0.049); the primary difference in mortality was in patients in the fibrosis compared to the cirrhosis stratum (14% versus 7%, P = 0.01); comparable differences were observed when liver transplantation was included. Excess mortality, emerging after 3 years of treatment, was related largely to nonliver-related death; liver-related mortality was similar in the treatment and control groups. No specific cause of death accounted for the excess mortality and only one death was suspected to be a direct complication of peginterferon. CONCLUSION: Long-term maintenance peginterferon in patients with advanced chronic hepatitis C is associated with an excess overall mortality, which was primarily due to nonliver-related causes among patients with bridging fibrosis.     

聚乙二醇干扰素联合利巴韦林治疗慢性丙型肝炎疗效观察

目的评价聚乙二醇干扰素联合利巴韦林治疗慢性丙型肝炎的临床疗效。方法使用聚乙二醇干扰素α-2a(派罗欣)联合利巴韦林(800~1200mg/d)治疗58例慢性丙型肝炎患者,疗程48周,分别于治疗12周、24周和48周及治疗结束后24周评价疗效,并观察药物副作用。结果基因1型和非基因1型患者早期应答率分别为57.1%和76.7%(P>0.05),持续应答率分别为53.6%和80.0%(P<0.05);HCV RNA高水平组和低水平组之间持续应答率分别为56.3%和80.8%,具有显著性差异(P<0.05)。结论在慢性丙型肝炎患者的治疗中,基因1型患者疗效低于非基因1型,HCV RNA低水平组的疗效优于高水平组。     

New treatment strategies in non-responder patients with chronic hepatitis C

There is solid evidence that retreatment of non-responders with standard regimens of interferon monotherapy is of no clinical value. On the other hand, combination therapy with interferon and ribavirin now produces sustained response rates in non-responders similar to those of interferon monotherapy in untreated patients. Consequently, retreatment of non-responders with the combination of interferon-ribavirin appears to be a valid treatment option. The efficacy of retreatment with the interferon-ribavirin combination can probably be increased by modifying the first weeks of interferon therapy from standard (3 MU tiw) to induction (10 MU daily), and by extending the treatment period to 12 months. In the next few years, the additive value of amantadine to interferon or to interferon-ribavirin combination in inducing sustained viral clearance should be explored. For the many patients who still do not respond with viral clearance despite these new approaches, the goal of therapy might be shifted towards persistent ALT normalization in order to reduce the progression of liver disease. Drugs that can normalize serum ALT such as interferon, ursodeoxycholic acid, ribavirin and glycyrrhizin should be evaluated for this objective.     

长期应用恩替卡韦治疗拉米夫定耐药的慢性乙型肝炎患者临床疗效及安全性分析*

目的 分析长期应用恩替卡韦治疗拉米夫定耐药的慢性乙型肝炎患者的临床疗效及安全性。 方法 2007年1月~2009年1月我科收治的98例对拉米夫定耐药的慢性乙型肝炎患者,应用恩替卡韦1.0 mg口服,1次/d,长期治疗至今。对27例在治疗期间患者出现病毒学反弹者,则停药,使用阿德福韦酯联合拉米夫定治疗。观察患者临床疗效、病毒学反弹、治疗后HBV DNA阴转、HBsAg和HBeAg血清阴转、ALT复常和不良反应发生情况。 结果 在治疗24周,应答率达到88.8%,随着治疗时间的延长,临床应答率逐渐升高,在192周时,为92.9%,之后其水平保持稳定;在治疗8周和24周时,未出现病毒学反弹情况,在治疗48周时,6例出现病毒学反弹,随着治疗时间的延长,病毒学反弹发生率逐渐升高,到8年观察结束时达到27.6%;在治疗8周时,出现HBV DNA阴转,在治疗96周时,血清HBV DNA阴转率达到46.9%,之后在治疗过程中阴转情况升高,到观察结束时血清HBV DNA阴转率为60.2%;在治疗48周之前无血清HBeAg和HBsAg阴转,在治疗48周时出现了血清HBeAg和HBsAg阴转情况,并且随着治疗时间的延长,出现的例数在逐渐增多,到观察结束时共出现31例（31.6%）血清HBeAg阴转,12例（12.2%）血清HBsAg阴转;随着治疗时间的延长,98例患者血清ALT水平明显下降,到治疗12周时 ALT水平逐渐恢复正常,直到观察结束;在治疗过程中,25例（25.5%）出现不良反应,其中8例患者出现乏力,6例患者出现心动过速,10患者出现恶心,1例患者尿液中检出白细胞。 结论 长期应用恩替卡韦治疗对拉米夫定耐药的慢性乙型肝炎患者具有显著的临床疗效,且治疗后未出现明显的不良反应,但用量需加倍。     

α-干扰素治疗慢性乙型肝炎疗效预测因素研究进展

α-干扰素主要通过抑制病毒复制和调节免疫功能而发挥抗病毒作用。在实际临床应用中,α-干扰素治疗慢性乙型肝炎的总有效率仅为30％～40％。研究发现,宿主血清丙氨酸氨基转移酶水平、肝脏病理学损害程度、机体免疫状态、遗传背景以及病毒基因分型、病毒变异、血清HBV DNA、HBsAg、HBeAg、HBcAb水平可以预测干扰素的疗效。采用多因素联合对α-干扰素疗效进行预测,可以优化治疗、提高疗效,以获得最大价格效益比。     

Expert opinion on the treatment of patients with chronic hepatitis C

Summary.  The current preferred treatment for patients with hepatitis C virus (HCV) is combination therapy consisting of pegylated interferon alfa and ribavirin (RBV) for 24–48 weeks. Although this approach appears to be highly effective for patients with HCV genotypes 2 or 3, who have a sustained virological response (SVR) of approximately 80%, the treatment algorithm is less effective for patients with HCV genotype 1, as these patients have SVR rates of just 40–50%. In order to improve treatment outcomes, this article explores potential approaches for the optimization of treatment for patients with HCV genotype 1: considering shorter treatment periods for patients with a rapid virological response (RVR), increasing treatment periods for slow responders, and increasing RBV dose are all suggestions. Results from clinical trials suggest that approximately 20% of the HCV genotype 1-infected population are slow responders, and around 15% of all HCV genotype-1 infected patients could benefit from a shorter treatment duration without compromising the SVR rate. Interest has also focused on whether treatment duration could be individualized in some patients with genotype 2 and 3 infection. Here all the findings from recent studies are translated into practical advice, to help practitioners make evidence-based treatment decisions in everyday clinical practice. Although there are areas where currently available data do not provide conclusive evidence to suggest amending treatment approaches, there is clearly potential for individualized treatment in all aspects of hepatitis treatment in the future.     

A long-term follow-up study of interferon treatment for chronic hepatitis C in Japanese patients with congenital bleeding disorders

Abstract: Twenty-one HIV negative Japanese patients with chronic hepatitis C who had congenital bleeding disorders, 15 hemophilia A, 3 hemophilia B, 1 von Willebrand's disease, 1 afibrinogenemia and 1 thrombasthenia, were treated with 9 million units 3 times a week of natural interferon (IFN)-α for 6 months. They were followed, biochemically and virologically, for at least 18 months after therapy discontinuation to evaluate the long-term results. Liver biopsy, hepatitis C virus (HCV) genotyping and quantification of viral load by polymerase chain reaction (PCR) were performed to identify the predictors of a favorable response to IFN treatment. One male patient with hemophilia A dropped out because of general fatigue and was excluded from evaluation. Ten (50.0%) patients continued to be HCV RNA negative in serum together with normal ALT levels throughout the study. Subtype 1b and a high level of viremia significantly associated with an unfavorable outcome on the response to IFN although liver histology was not definitive for predicting the response. We concluded that a 6-month treatment with high doses of natural IFN-α was effective in inducing a long-term response without relapse of viremia in 50% of chronic hepatitis C patients with congenital bleeding disorders and that HCV subtype and pretreatment level of viremia were useful predictors of the response to IFN in treating such patients.     

Initial experience with treatment of chronic hepatitis C in HIV-positive patients

A 30 years old man originating from Ukraine was infected by the human immunodeficiency virus (HIV) and virus of hepatitis C (HCV) due to injection administration of drugs of abuse in his own country before coming to Czech Republic. He was infected by genotype 3 of HCV and the infection became chronic. Under the influence of a three-combination anti-retrovirus therapy his conditions related to HIV infection became stable and it proved to be possible to apply a combined treatment by alpha-interferon and ribavirin at commonly used doses for the period of 12 months. In the course of therapy the HCV nucleic acid (HCV RNA) disappeared from serum and serum activity of alanine aminotransferase (ALT) became normal. However, two months after the therapy ended a relapse of the disease occurred--HCV RNA reappeared in serum and ALT activity increased. The therapy was well tolerated. A rapid decrease of hemoglobin level during the first four weeks of therapy was stopped by reduction of ribavirin dose.     

影响丙型肝炎初治患者标准化治疗疗效的相关因素及对策

目前国际国内所有权威指南均明确指出,慢性丙型肝炎(chronic hepatitis C,CHC)的标准治疗是聚乙二醇干扰素α(Peg-IFN α)联合利巴韦林(ribavirin,RBV),基因1型HCV感染患者疗程48周,基因2/3型HCV感染患者疗程24周[1-2].我国最新的全国多中心临床研究结果显示,我国CHC患者经过规范化标准治疗的持续病毒应答(sustainedvirologic response,SVR)率可高达80％以上.     

Pretreatment prediction of interferon-alfa efficacy in chronic hepatitis C patients.

BACKGROUND & AIMS: Interferon has been used widely to treat patients with chronic hepatitis C infections. Prediction of interferon efficacy before treatment has been performed mainly by using viral information, such as viral load and genotype. This information has allowed the successful prediction of sustained responders (SR) and non-SRs, which includes transient responders (TR) and nonresponders (NR). In the current study we examined whether liver messenger RNA expression profiles also can be used to predict interferon efficacy. METHODS: RNA was isolated from 69 liver biopsy samples from patients receiving interferon monotherapy and was analyzed on a complementary DNA microarray. Of these 69 samples, 31 were used to develop an algorithm for predicting interferon efficacy, and 38 were used to validate the precision of the algorithm. We also applied our methodology to the prediction of the efficacy of interferon/ribavirin combination therapy using an additional 56 biopsy samples. RESULTS: Our microarray analysis combined with the algorithm was 94% successful at predicting SR/TR and NR patients. A validation study confirmed that this algorithm can predict interferon efficacy with 95% accuracy and a P value of less than .00001. Similarly, we obtained a 93% prediction efficacy and a P value of less than .0001 for patients receiving combination therapy. CONCLUSIONS: By using only host data from the complementary DNA microarray we are able to successfully predict SR/TR and NR patients for interferon therapy. Therefore, this technique can help determine the appropriate treatment for hepatitis C patients.     

Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP

Chronic immune thrombocytopenic purpura (ITP) is characterized by low platelet counts and mucocutaneous bleeding. In previous studies romiplostim (AMG531), a thrombopoiesis-stimulating protein, increased platelet counts in most patients with chronic ITP. This ongoing, long-term open-label, single-arm study investigated safety and efficacy in patients who completed a previous romiplostim study and had platelet counts less than or equal to 50 [corrected] x 10(9)/L. One hundred forty-two patients were treated for up to 156 weeks (mean, 69 weeks). Platelet responses (platelet count > or = 50 x 10(9)/L and double baseline) were observed in 87% of all patients and occurred on average 67% of the time in responding patients. In 77% of patients, the romiplostim dose remained within 2 microg/kg of their most frequent dose at least 90% of the time. Ninety patients (63%) received treatment by self-administration. Treatment-related serious adverse events were reported in 13 patients (9%). Bone marrow reticulin was observed in 8 patients; marrows were not routinely performed in this study, so the true incidence of this event cannot be determined. Severe bleeding events were reported in 12 patients (9%). Thrombotic events occurred in 7 patients (5%). In conclusion, romiplostim increased platelet counts in most patients for up to 156 weeks without tachyphylaxis and had an acceptable safety profile. (ClinicalTrials.gov Identifier NCT00116688).     

慢性丙型肝炎患者HCV基因型分析

目的研究慢性丙型肝炎患者HCV基因型概况。方法采用基因芯片法检测HCV基因分型;采用PCR法测定HCV RNA定量。结果在570例患者中,HCV RNA阳性552例（95%）,其中1b型400例（72.4%）,2a型63例（11.4%）,3a型20例（3.6%）,3b型20例（3.6%）,1b＋2a型12例（2.1%）,1a型2例（0.4%）,6型7例（1.26%）,1b＋3a型1例（0.18%）,2a＋1b型3例（0.5%）,未定型24例（4.3%）;不同HCV基因型感染者血清HCVRNA水平无统计学差异（P〉0.05）。结论本组患者HCV基因型以1b型为主,2a型次之,多种混合型的出现提示HCV基因型呈现多样化趋势。