Hepatitis C virus RNA kinetics during the initial 12 weeks treatment with pegylated interferon-alpha 2a and ribavirin according to virological response

SUMMARY: To optimize treatment of chronic hepatitis C early identification of patients who will not achieve a sustained virological response (SVR) is desirable. We investigated hepatitis C virus (HCV) RNA kinetics at day 1 (in 15 patients; genotypes 1 and non-1, 9 and 6 respectively) at weeks 1, 4 and 12 (in 53 patients; genotypes 1 and non-1, 19 and 34, respectively) during treatment with pegylated interferon alpha-2a and ribavirin. Patients with SVR had a significantly more pronounced mean log10 decline from baseline in HCV RNA levels at weeks 1 and 4 compared with patients who failed to achieve SVR (1.99 vs 0.85 at week 1, P = 0.0003 and 2.89 vs 1.72 at week 4, P = 0.0159), whereas no difference was noted after day 1. For patients with a 2-log10 decrease in HCV RNA levels at day 7, the positive predictive value (PPV) for a SVR was 92%, whereas week 12 was the best time point for predicting a later nonresponse [negative predictive value (NPV) 92%] in patients failing to achieve a 2-log10 drop. For patients with genotype non-1 and a 2-log10 decrease in HCV RNA levels the PPV for a SVR was 89% week 1, and 79% weeks 4 and 12. The corresponding NPV for patients with genotype non-1 were 43, 40 and 100% respectively. During treatment with pegylated interferon alpha-2a plus ribavirin the HCV RNA decline at week 1 was an accurate predictor of SVR in patients who had achieved a 2-log10 drop in HCV RNA levels, whereas the lack of such decline week 12 was an accurate marker of a nonresponse.     

Treatment of hepatitis C virus-associated inflammatory polyneuropathy with pegylated interferon-alpha and ribavirin

Peripheral neuropathy is common in patients with hepatitis C virus infection and cryoglobulinemia. Here, we report a patient with axonal polyneuropathy associated with type III mixed cryoglobulinemia and hepatitis C virus infection without significant liver disease, who was successfully treated with pegylated interferon-alpha-2a and ribavirin. This case illustrated that clinical improvement was paralleled by a decrease of cryocrit but not necessarily by a decrease of viral replication rate. Treatment of hepatitis C virus-cryoglobulinemia-associated neuropathy should therefore be continued even if response of viral replication is lacking or delayed as long as a clinical benefit can be observed.     

Pioglitazone in chronic hepatitis C not responding to pegylated interferon-alpha and ribavirin

BACKGROUND/AIMS: Insulin resistance reduces the response to interferon alfa-based therapy of chronic hepatitis C patients. It has been speculated that improvement of insulin sensitivity might increase the chances of responding to treatment of such individuals. METHODS: We started a multicenter clinical trial of retreatment of chronic hepatitis C patients, who had failed to respond to the pegylated interferon alfa/ribavirin combination, with a triple therapy consisting in these same antivirals plus an insulin-sensitizer (pioglitazone) (The INSPIRED-HCV study). RESULTS: None of the first five patients fulfilling the inclusion criteria and included in the trial achieved a satisfactory virological response after 12 weeks of retreatment, despite the fact that in at least three of them the insulin resistance score improved. As a result, the study was terminated. CONCLUSIONS: Different schedules are warranted to improve insulin sensitivity prior to attempting retreatment of chronic hepatitis C patients with insulin resistance.     

Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups

Psychiatric disorders or drug addiction are often regarded as contraindications against the use of interferon alfa (IFN-alpha) in patients with chronic hepatitis C. Our aim was to obtain prospective data on adherence to as well as efficacy and mental side effects of treatment with IFN-alpha in different psychiatric risk groups compared with controls. In a prospective trial, 81 patients with chronic hepatitis C (positive hepatitis C virus[HCV] RNA and elevated alanine aminotransferase[ALT] level) and psychiatric disorders (n = 16), methadone substitution (n = 21), former drug addiction (n = 21), or controls without a psychiatric history or drug addiction (n = 23) were treated with a combination of IFN-alpha-2a 3 MU 3 times weekly and ribavirin (1,000-1,200 mg/d). Sustained virologic response (overall, 37%) did not differ significantly between subgroups. No significant differences between groups were detected with respect to IFN-alpha-related development of depressions during treatment. However, in the psychiatric group, significantly more patients received antidepressants before and during treatment with IFN-alpha (P <.001). Most of those who dropped out of the study were patients with former drug addiction (43%; P =.04) compared with 14% in the methadone group, 13% in the control group, and 18% in the psychiatric group. No patient in the psychiatric group had to discontinue treatment because of psychiatric deterioration. In conclusion, our data do not confirm the supposed increased risk for IFN-alpha-induced mental side effects and dropouts in psychiatric patients if interdisciplinary care and antidepressant treatment are available. Preexisting psychiatric disorders or present methadone substitution should no longer be regarded as contraindications to treatment of chronic hepatitis C with IFN-alpha and ribavirin in an interdisciplinary setting.     

Hepatitis C viral kinetics in plasma and peripheral blood mononuclear cells during pegylated interferon-alpha2a/ribavirin therapy

BACKGROUND/AIMS: Analysis of hepatitis C virus (HCV) RNA kinetics in compartments other than plasma may help in understanding HCV replication and identifying clinically significant patterns of treatment response. METHODS: After 6 weeks of pegylated interferon-alpha2a/ribavirin therapy, 74 chronic hepatitis C patients were randomized to individualized or standard treatments for another 42 weeks. HCV RNA was quantified in peripheral blood mononuclear cells (PBMCs) by TaqMan-based real-time PCR and compared to plasma HCV RNA. RESULTS: HCV RNA declines in PBMCs and plasma were comparable during the initial 12 weeks of therapy (Spearman's rank correlation range over different time points, 0.73-0.97). However, a delay of HCV RNA decay in PBMCs, expected if kinetics in PBMCs only reflected kinetics in plasma, was rarely observed. For many patients, HCV RNA decline in PBMCs started as early as in plasma and for some of them the kinetics strongly differed in the two compartments, hinting at a compartment-specific HCV replication and treatment effect. Fast viral decay in PBMCs was associated with sustained virological response, but viral kinetics in PBMCs added only minor predictive information compared with kinetics in plasma. CONCLUSIONS: Future kinetics studies of HCV RNA during therapy with new antivirals should take into account their compartment-specific effect.     

Staphylococcus aureus bacteremia in patients receiving pegylated interferon-alpha and ribavirin for chronic hepatitis C virus infection

Bacteremia has rarely been reported in patients receiving treatment for hepatitis C virus (HCV) infection. We describe the features and investigation of four cases of Staphylococcus aureus bacteremia occurring between 3 November 2004 and 10 January 2005 in patients on therapy for chronic HCV infection. The unusual occurrence of S. aureus bacteremia in a series of patients led to an epidemiologic investigation and molecular typing methods were employed to assess the relatedness of cases. The mean time of bacteremia onset was week 10 of HCV treatment. No patient had neutropenia previously. The average duration of bacteremia was 2.6 days and complications included acute renal failure (2/4), disseminated intravascular coagulopathy (DIC) with sepsis syndrome (1/4), septic arthritis (1/4), spinal epidural abscess (1/4) and endocarditis (1/4). Two patients were in the same weight class for dosing, but no other epidemiologic links were found. One patient admitted to intravenous drug use (IVDU) and a second was suspected of IVDU. The two other patients were cirrhotic, but had no further identifiable risk factors. All bacterial isolates were methicillin-susceptible. By pulsed-field gel electrophoresis, two cases were found to have identical bacterial strains. However, fluorescent-based amplified fragment-length polymorphism analysis demonstrated distinct band patterns in all four cases. The epidemiologic data and molecular analysis of this cluster of S. aureus bacteremia cases among patients receiving combination therapy for treatment of chronic HCV infection suggest that these cases were not related. Additionally, IVDU and cirrhosis, but not neutropenia, are identified as potential risk factors for this uncommon complication of HCV therapy.     

Hepatitis C: viral and host factors associated with non‐response to pegylated interferon plus ribavirin

Treatment for chronic hepatitis C virus (HCV) infection has evolved considerably in the last years. The standard of care (SOC) for HCV infection consists in the combination of pegylated interferon (PEG‐IFN) plus ribavirin. However, it only induces a sustained virological response (SVR) in half of genotype 1‐infected patients. Several viral and host factors have been associated with non‐response: steatosis, obesity, insulin resistance, age, male sex, ethnicity and genotypes. Many studies have demonstrated that in non‐responders, some interferon‐stimulated genes were upregulated before treatment. Those findings associated to clinical, biochemical and histological data may help detect responders before starting any treatment. This is a very important issue because the standard treatment is physically and economically demanding. The future of HCV treatment would probably consist in the addition of specifically targeted antiviral therapy for HCV such as protease and/or polymerase inhibitors to the SOC. In genotype 1 patients, very promising results have been reported when the protease inhibitor telaprevir or boceprevir is added to the SOC. It increases the SVR rates from approximately 50% (PEG‐IFN plus ribavirin) to 70% (for patients treated with a combination of PEG‐IFN plus ribavirin plus telaprevir). Different elements are associated with non‐response: (i) viral factors, (ii) host factors and (iii) molecular mechanisms induced by HCV proteins to inhibit the IFN signalling pathway. The goal of this review is to present the mechanisms of non‐response, to overcome it and to identify factors that can help to predict the response to anti‐HCV therapy.     

Hepatitis C virus eradication followed by HBeAg to anti-HBe seroconversion after pegylated interferon-alpha2b plus ribavirin treatment in a patient with hepatitis B and C coinfection

In hepatitis B or hepatitis C endemic areas, the number of patients with dual infections is substantial. In such patients, interferon-alpha plus ribavirin can achieve sustained hepatitis C virus (HCV) clearance and hepatitis B e antigen (HBeAg) seroconversion. Pegylated interferon (PegIFN), an established treatment for hepatitis C, is currently increasingly recognized as an efficient therapy for hepatitis B. No case of successful use of PegIFN plus ribavirin has yet been reported, however, in hepatitis B virus (HBV) and HCV coinfection.We report on a 32-year-old man, of Kampuchean origin, with chronic hepatitis B, as documented by the presence of hepatitis B surface antigen with HBeAg, who was coinfected with HCV genotype 1. On therapy with PegIFN-alpha2b plus ribavirin, HCV RNA became undetectable at week 17. At the end of the 48 weeks of treatment, HCV RNA was still undetectable, HBV DNA was reduced and HBeAg remained positive. Twelve weeks after the end of treatment, HBV DNA reduction was followed by HBeAg to anti-HBe seroconversion. Two years after the end of treatment, HCV RNA and HBV DNA were still undetectable, and HBeAg to anti-HBe seroconversion was maintained. We conclude that the combination of PegIFN plus ribavirin may induce suppression of both viral infections.     

Efficacy and safety of pegylated interferon-alpha2b plus ribavirin for the treatment of chronic hepatitis C in HIV-infected patients

Low response rates and concerns about safety have limited the implementation of treatment for chronic hepatitis C (CHC) in patients with HIV infection. The efficacy and safety of pegylated interferon (peg-IFN) plus ribavirin in HIV-infected patients with CHC were evaluated in a prospective, open-label, multicenter study. Sixty patients with persistently high transaminases, positive HCV-RNA, CD4 count > or = 300 cells/microl, and HIVRNA <10,000 copies/ml were included. Patients were given peg-IFN 80-150 microg/week plus ribavirin 800-1200 mg/day. Treatment was scheduled for 24 weeks for genotypes 2/3 and 48 weeks for genotypes 1/4. In an intent- to-treat analysis, 16 (26.7%) patients achieved a sustained virological response (SVR). Twenty patients (33.3%) discontinued treatment prematurely, but only in 10 (16.6%) was discontinuation due to adverse events. Negative predictive values for SVR on the basis of HCV-RNA decline between baseline and week 4 were 100% for 1- and 2-log10 fall, and positive predictive values were 40% and 58.3% for 1- and 2-log10 fall, respectively. CD4 fell by a median of 216 cells during treatment, but no HIV-associated complications occurred. In conclusion, treatment with peg-IFN alpha-2b plus ribavirin is safe and clears RNA-HCV in about one-quarter of HIV-infected patients with CHC. Efforts should be focused on optimizing management of side effects and counseling to improve adherence and to keep patients on treatment. Assessment of HCV-RNA at week 4 may help guide early therapeutic decision making.     

Ischaemic jejunal vasculitis during treatment with pegylated interferon-alpha 2b and ribavirin for hepatitis C virus related cirrhosis

A 53-year-old male with compensated cirrhosis (Child-Pugh class A5) and mixed cryoglobulinaemia (cryocrit: 2.0%), both hepatitis C virus-related, was treated with pegylated interferon-alpha 2b and ribavirin. After three months of therapy, he developed segmental jejunal vasculitis requiring emergency resection of an ischaemic intestinal loop 60cm long. Pathological examination of the surgical specimen revealed signs of ischaemic injury with haemorrhagic infarction due to arteritis and arterial occlusion. The postoperative course was complicated by progressive liver and renal failure that led to the patient's death six months after surgery. To our knowledge, ischaemic jejunal vasculitis has never been reported during interferon therapy, but the latter treatment may have played causative roles.     

Ischemic colitis during pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C.

Rare cases of ischemic colitis associated with interferon-alpha (IFN-alpha) treatment for chronic hepatitis C (HCV) infection and metastatic cancer have been reported. The present study describes the first case of ischemic colitis attributable to pegylated IFN-alpha and ribavirin combination therapy in an HCV-infected patient after 34 weeks of treatment. The clinical presentation, endoscopic appearance and histopathology of the colon were consistent with ischemic colitis, and the patient's symptoms rapidly resolved with cessation of therapy. The association between the therapy and the pathogenesis of ischemic colitis is unclear, but immunoregulatory, vasospastic and procoagulant mechanisms have been proposed. Physicians should be aware of this complication, and should consider it in any HCV-infected patient taking pegylated IFN-alpha and ribavirin who develops abdominal discomfort and gastrointestinal bleeding.     

Serum hs-CRP was correlated with treatment response to pegylated interferon and ribavirin combination therapy in chronic hepatitis C patients

Background/aims

Serum high sensitivity C-reactive protein (hs-CRP) is a surrogate marker for cardiovascular disease risks and related mortality. However, the features of hs-CRP in chronic HCV infection (CHC) patients have not been fully addressed. This study aimed to elucidate the characteristics of hs-CRP and its correlation with clinical profiles in CHC patients.

Methods

Ninety-five CHC patients and 95 age- and sex-matched healthy controls were enrolled for serum hs-CRP level, biochemical, and metabolic profiles examinations. Sequential changes of hs-CRP levels in CHC patients receiving peginterferon/ribavirin combination therapy were also evaluated.

Results

The mean hs-CRP level of CHC patients was significantly higher than that of healthy controls (0.97 ± 0.11 vs. 0.24 ± 0.07 mg/L, P < 0.001). There was no significant correlation between hs-CRP and both virological and histological factors. CHC patients with a high LDL-C level had significantly higher mean hs-CRP (1.38 ± 0.20 mg/L) than that of patients without (0.59 ± 0.06 mg/L) (P < 0.001). Hs-CRP level was significantly decreased in 83 patients after peginterferon/ribavirin combination therapy (0.24 vs. 0.62 mg/L, P < 0.001), particularly in 68 patients achieving a sustained virological response (0.25 vs. 0.64 mg/L, P < 0.001).

Conclusion

CHC patients had a higher hs-CRP level than healthy controls which could be ameliorated after peginterferon/ribavirin combination therapy.     

Incidence of psychiatric side effects during pegylated interferon- alpha retreatment in nonresponder hepatitis C virus-infected patients.

Objective: Evaluate the incidence of mental disorders using pegylated interferon plus ribavirin retreatment in nonresponder hepatitis C virus‐infected patients. Method: The Mini‐International Neuropsychiatric Interview (MINI) was used to evaluate 30 hepatitis C virus‐infected interferon‐nonresponder patients at baseline and following 4, 12 and 24 weeks of pegylated interferon retreatment. Results: During the pegylated interferon/ribavirin retreatment, 5(16.6%) patients developed psychiatric side effects: 3(10%) were diagnosed with major depressive disorder, 1(3.3%) had a brief psychotic disorder and 1(3.3%) presented with panic attacks. Conclusion: This is the first prospective study evaluating the incidence of neuropsychiatric side effects during interferon retreatment of hepatitis C virus‐infected patients, suggesting that the risk of acquiring serious psychiatric symptoms during retreatment with interferon‐α (IFN‐α) may not be higher than during the first antiviral therapy. This finding challenges the hypothesis that during a second treatment with IFN‐α, patients with hepatitis C may be at greater risk for neuropsychiatric side effects than naïve patients.     

Superior response to pegylated interferon and ribavirin in Asians with chronic hepatitis C

Purpose  

Reported sustained virological response (SVR) rates in Asians with chronic hepatitis C (CHC) exceed those of other ethnic groups, but differences in body weight across races potentially confound this observed superior response. Our aim was to determine whether Asian race independently predicts SVR within a multicultural clinic setting.     

聚乙二醇干扰素联合利巴韦林治疗慢性丙型肝炎患者效果的影响因素

目的 分析聚乙二醇干扰素(PEG-IFN)联合利巴韦林(RBV)治疗慢性丙型肝炎患者的病毒学应答情况及其影响因素.方法 入组对象为接受PEG-IFNα-2a或PEG-IFNα-2b联合RBV治疗的慢性丙型肝炎患者130例,收集患者基线、治疗4、12、48周和停药24周的资料,包括年龄、性别、体质指数(BMI)、脾指数(SPI)、门静脉内径(PV)、HCV基因型、HCV RNA载量等.比较获得持续性病毒学应答( SVR)与未获得持续性病毒学应答(NSVR)的情况,对SVR的影响因素进行相关分析.数据处理采用t检验、x2检验和Logistic回归分析.结果 总SVR率为84％ (109/130),其中快速病毒学应答(RVR)率为21％(27/130),早期病毒学应答(EVR)率为72％ (94/130),治疗结束时病毒学应答(ETVR)率为93％(121/130).HCV基因1型患者SVR率为82％(45/55),非基因1型SVR率为87％(13/15);患者年龄、基线HCV RNA载量、BMI、SPI与SVR负相关(回归系数＜0,均OR＜1,均P＜0.05),EVR与RBV总量和SVR呈正相关(回归系数＞0,均OR＞1,均P＜0.05),而RVR、PV及PEG-IFN总量与SVR不相关(均P＞0.05).结论 PEG-IFN联合RBV治疗慢性丙型肝炎患者的SVR率较高,超过80％患者可治愈;年龄大于35岁、既往治疗失败、基线病毒载量高于6×105 IU/mL、BMI＞26 kg/m2、SPI＞40 cm2、RBV累计量不超过标准量80％的患者SVR率较低.     

Hepatitis C virus genotype 4 responds better to pegylated interferon with ribavirin than genotype 1 in HIV-infected patients

We assess the efficacy of pegylated interferon (peg-IFN) with ribavirin (RBV) and the predictors of sustained virological response (SVR) among HIV/hepatitis C virus genotype 4 (HCV-4)-coinfected patients. Thirty-nine (31.5%) of 124 individuals with HCV-4 achieved SVR compared with 103 (22.7%) of 453 individuals with HCV genotype 1 (P=0.046). Only interleukin-28B (IL28B) genotype CC was independently associated with SVR in HIV/HCV-4-coinfected patients. The efficacy of peg-IFN with RBV in coinfected individuals with genotype 4 is significantly higher than in those with genotype 1. IL28B CC genotype is the main predictor of response in this population.