Effect of ribavirin in genotype 1 patients with hepatitis C responding to pegylated interferon alfa-2a plus ribavirin

BACKGROUND & AIMS: Pegylated interferon alfa-ribavirin combination is the standard treatment for chronic hepatitis C, but the mechanisms by which ribavirin enhances the rate of sustained hepatitis C virus (HCV) eradication remain unknown. We aimed to investigate the role of ribavirin in HCV clearance during therapy and to evaluate the consequences of ribavirin discontinuation in patients infected with genotype 1 hepatitis C who cleared HCV RNA at week 24. METHODS: A total of 516 patients were treated with pegylated interferon alfa-2a, 180 microg/wk, plus ribavirin, 800 mg/day. Seventy percent were RNA negative at week 24. They were randomized to continue with the combination or receive pegylated interferon alone. RESULTS: Responders at week 24 who stopped ribavirin had a significantly higher rate of breakthroughs during, and relapses after, therapy (sustained virologic response, 52.8% vs 68.2%; P = .004), but their side-effect profile and quality of life tended to improve. Multiple logistic regression analysis in the pegylated interferon alfa monotherapy group allowed identification of responders at week 24 who could stop ribavirin without losing their chance of a sustained virologic response, based on baseline viral load and age. Forty-eight weeks of ribavirin may not be needed when HCV RNA is undetectable at week 2. CONCLUSIONS: We made 3 conclusions from this study. First, ribavirin primarily acts by sustaining the virologic response to pegylated interferon alfa; second, ribavirin must be administered for the full treatment duration in most genotype 1-infected patients who respond; third, baseline parameters may help identify patients who could discontinue ribavirin or reduce the dose without losing their chance of success.     

Customizing treatment to patient populations

Combination treatment with pegylated interferon plus ribavirin is the most effective therapy for patients with chronic hepatitis C virus (HCV); however, responses are less than optimal in some subpopulations of patients. Emerging insights are suggesting that viral kinetics can be used to predict response. The rapidity of response has been shown to be a more important predictor of sustained virologic response than the duration of therapy. In patients with HCV genotype 2 or 3, shorter durations of treatment might be sufficient in rapid responders and could minimize the risk of toxic effects. Weight-based dosing of ribavirin has emerged as another important consideration. This strategy seems to be most important for difficult-to-treat patients with HCV genotype 1 or advanced fibrosis, and for African-Americans, and is possibly important for patients who have genotype 3 and a high viral load. Re-treatment of nonresponders with interferon-based therapy has been associated with low rates of sustained virologic response. Consensus interferon might offer a new option for patients who do not achieve an early treatment response to standard or pegylated interferon plus ribavirin.     

Quasispecies as Predictive Response Factors for Antiviral Treatment in Patients with Chronic Hepatitis C

The object of this study was to evaluate the viral factor, especially the quasispecies, as predictive of sustained virologic response. We studied the quasispecies, genotype, viral load, and hepatitis C (HCV) cAg in 41 patients with chronic hepatitis C treated with interferon and in 84 with interferon and ribavirin. In the interferon group, responders presented a lower viral load. From logistic regression analysis of patients treated with interferon plus ribavirin, independent predictors for sustained virologic response were genotype 3a, a low baseline viral load and ≤3 bands quasispecies. Genotype and viral load presented higher specificity and positive predictive value than did quasispecies. In patients with genotype 1, viral load ≤5 × 10⁵ IU/mL and ≤3 quasispecies were predictive for sustained virologic response. In conclusion, the predictive factors of virologic response are genotype, viral load, and quasispecies. Quasispecies did not improve on the genotype or the viral load as predictors of virologic response.     

Serum alanine aminotransferase flares during interferon treatment of chronic hepatitis B: is sustained clearance of HBV DNA dependent on levels of pretreatment viremia?

During interferon treatment of chronic hepatitis B, an alanine aminotransferase (ALT) flare may herald a sustained loss of viral replication, but the relationship between virologic response, the extent of a flare, and pretreatment hepatitis B virus (HBV) DNA level has not been defined. We retrospectively examined the impact of an ALT flare on sustained virologic response in 121 interferon-treated patients and 42 untreated controls with either low-level (<100 pg/mL) or high-level (> or =100 pg/mL) viremia. The degree of ALT flare was classified as mild (increase in ALT of 86-171 IU/L above baseline), moderate (increase of 172 to 343 IU/L above baseline), and severe (increase of > or =344 IU/L above baseline). Undetectable serum HBV DNA and hepatitis B e antigen (HBeAg) loss were significantly more likely at the end of follow-up in patients having a flare (P =.0001 and.001, respectively). In the high viremia group, a proportionate increase in virologic response was observed as the degree of flare increased. By multivariate analysis, high baseline HBV DNA, high pretreatment ALT, and both moderate and severe ALT flare were independently predictive of a virologic response with severe flare being the most powerful predictor for a sustained loss of serum HBV DNA (odds ratio, 5.3; P =.004). Severe flare was predictive of a virologic response in the high but not low viremia group. We conclude that a virologic response in patients with high-level viremia is dependent on the degree of ALT flare. Induction of a robust flare may enhance virologic response when high-level viremia is detected.     

Treatment of HCV infection with pegylated interferons

The past decade has seen advances in the treatment of chronic hepatitis C infection. Therapy with interferon alpha was disappointing, with only 15% of patients achieving longterm viral clearance. Combination therapy with interferon alpha and ribavirin therapy more than doubled sustained virologic response (SVR) rates. The pegylated interferons are a recent development that have improved the outlook for patients with chronic hepatitis C virus (HCV). Pegylated interferons are produced by the binding of polyethylene glycol to interferon alpha, which results in a compound with improved pharmacokinetic properties with increased efficacy. Combination therapy with pegylated interferon alpha and ribavirin is the optimal treatment for chronic HCV infection. Up to 80% of patients with genotype 2/3 infection and up to 50% of patients with genotype 1 infection achieve SVR with treatment. For the first time, the majority of patients with chronic HCV who are treated can anticipate a long-term cure.     

Treatment of hepatitis C virus infection

Acute and chronic hepatitis C virus （HCV） infection remains a serious health problem worldwide, however, there has been advancement in the treatment of HCV infection due to standard treatment using pegylated interferon and ribavirin. The literature indicates that therapy for HCV is becoming more individualized. In addition to considering genotype and viral RNA levels before treatment, achievement of an early virologic response （EVR） and a rapid virologic response （RVR） is now possible during therapy. Moreover, problem patients, such as non-responders, relapsers, HIV or HBV coinfected patients, patients with liver cirrhosis, and preor post-liver transplantation patients are an increasing fraction of the patients requiring treatment. This article reviews the literature regarding standard treatments and problem patients with acute and chronic HCV infection. It also includes discussion on contraindications and side effects of treatment with interferon and ribavirin, as well as new drug development.     

Chronic hepatitis C responds poorly to combination therapy in chronic hepatis B carriers

BACKGROUND: The effect of conventional interferon-based therapy of hepatitis B virus (HBV) and hepatitis C virus (HCV) dual infection is controversial. Yet, no studies have been carried out into pegylated interferon treatment for chronic HBV/HCV coinfection. We aimed to evaluate the response rate and side effects of conventional or pegylated interferon combined with ribavirin on chronic HBV/HCV coinfection therapy. METHODS: The study included 36 chronic hepatitis patients (M/F: 28/8, mean age 47+/-12 years) who were positive for HBsAg and anti-HCV. They were tested for the presence of HBV-DNA by hybridisation assay, and the samples giving negative results were retested by polymerase chain reaction (PCR). All patients were tested for HCV-RNA using PCR, and the HCV genotype was determined. RESULTS: Nineteen patients were given standard interferon either alone or in combination with ribavirin, whereas 17 were given pegylated interferon and ribavirin combination therapy. None of the patients had HBV-DNA positivity; however, all had HCV-RNA detectable by PCR. All the patients had HCV genotype 1b. The mean alanine aminotransferase and aspartate aminotransferase levels were 118+/-65 U/l and 90+/-95 U/l respectively. Five patients in each group discontinued the treatment due to side effects. Only two patients (one from each group) reached sustained virological response. CONCLUSION: Neither pegylated nor conventional interferon based regimes were effective for HBV/HCV coinfection, in which the dominant virus was HCV. Pegylated interferon and ribavirin therapy was not superior to conventional interferon based regimes in the treatment of HBV/HCV coinfection.     

Four-week pegylated interferon a-2a monotherapy for chronic hepatitis C with genotype 2 and low viral load：A pilot,randomized study

AIM：To assess the efficacy and advantages of 4-wk pegylated interferon a-2a（peg-IFN-a2a） monotherapy for chronic hepatitis C patients with strong predictors of sustained virologic response（SVR）.METHODS：Patients（n = 33） with genotype 2 and low viral load（〈 100 KIU/mL）,who became HCV RNA negative after 1 wk of IFN treatment,were randomly allocated to receive a 4-or 12-wk treatment course at a ratio of 2：1,respectively,with a subsequent 24-wk follow-up period.Peg-IFN-a2a was administered subcutaneously at a dose of 180 μg or 90 μg once weekly.SVR was defined as absence of serum HCV RNA at the end of the follow-up period.RESULTS：All patients completed the treatment schedule,and more than half were symptom-free during the treatment.In the 4-wk treatment group,20 of 22（91%） patients achieved SVR.Two patients relapsed,but achieved SVR following re-treatment with peg-IFN-a2a alone.In the 12-wk treatment group,11 of 11（100%） patients attained SVR.CONCLUSION：Our results show that a 4-wk course of peg-IFN-a2a monotherapy can achieve a high SVR rate in ＂IFN-sensitive＂ patients,without negatively affecting outcome.     

Treatment of patients with dual hepatitis C virus and hepatitis B virus infection: Resolved and unresolved issues

Dual hepatitis C virus (HCV)/hepatitis B virus (HBV) infection is not uncommon in HCV or HBV endemic areas and among subjects at risk of parenteral transmission. In patients dually infected with hepatitis C and B, the disease manifestations are usually more severe than those with either virus infection. In the past decade, the following issues have been resolved. In dually infected patients with active hepatitis C, combined pegylated interferon alfa plus ribavirin was effective, the treatment outcomes being similar to patients with HCV monoinfection. During long‐term follow‐up, the HCV response was sustained in around 97% of patients; and the long‐term outcomes including the development of hepatocellular carcinoma and liver‐related mortality were improved. However, several clinical issues remain to be resolved. First, host and viral factors influencing the long‐term outcomes and treatment options in patients with dual HCV/HBV infection await further studies. Second, about 60% of dually infected patients with baseline undetectable serum HBV DNA levels develop HBV reactivation after the start of treatment. How to prevent and treat HBV reactivation should be clarified. Third, about 30% of dually infected patients lose hepatitis B surface antigen at 5 years after the end of combination therapy; the mechanisms need further investigations. Fourth, the optimal treatment strategies for dually infected patients with active hepatitis B or established cirrhosis should be explored in future clinical trials. Finally, the role of new direct‐acting antiviral‐based therapy for the treatment of patients with dual HCV/HBV infection also remains to be evaluated.     

Pegylated interferons: What role will they play in the treatment of chronic hepatitis C?

The primary therapy for patients with chronic hepatitis C virus (HCV) infection is interferon. Unfortunately, standard interferon, because of its very short half-life and side-effect profile, has limited efficacy in most patients with this disease. Pegylated interferons are produced by attaching the inert polymer, polyethylene glycol, to the standard interferon alpha protein. This process enhances the biological activity of interferon, primarily by prolonging the half-life, when compared with the native protein. To date, two types of pegylated interferon alpha have been developed. Both of these products have been shown to be superior to standard interferon, at both eradicating HCV RNA during therapy and at achieving a sustained virologic response. When combined with ribavirin, treatment with pegylated interferon can achieve sustained virologic response in approximately 42% of patients infected with HCV genotype 1 and 80% of patients with HCV genotypes 2 or 3.     

Factors predicting interferon treatment response in patients with chronic hepatitis c: late viral clearance does not preclude a sustained response

OBJECTIVES: Because of the suboptimal efficacy, cost, and adverse effects of interferon in chronic hepatitis C (HCV), predictors have been sought to detect patients with a good treatment response. Also, markers for determining a poor response early in the course of therapy, such as the lack of early viral clearance, have been proposed. METHODS: Ninety-seven patients with chronic hepatitis C were enrolled to receive leukocyte alpha-interferon according to a stepped-care management protocol. The final virological treatment response was evaluated in 74 patients after a 6-month post-treatment follow-up. The relationship between pretreatment and during-treatment variables and the long-term response was assessed. RESULTS: Non-1 viral genotype, higher pretreatment ALT levels, and lower gamma-glutamyl transferase (GGT)/ALT ratios and GGT as well as younger age were significantly associated with a sustained response; a trend was also detected for lower serum ferritin levels. Normalization of ALT by 3 months was also a significant predictor of a long-term response. Of the 27 patients carrying the HCV genotype 3a, seven (26%) were still HCV RNA positive at 6 months. Of these patients, however, five (19%) still achieved a sustained virological response after treatment for up to 12 months. CONCLUSIONS: In contrast to some previous reports, our results suggest that a late viral clearance after 6 months of interferon monotherapy may not preclude a favorable long-term response after a 12-month treatment, especially in patients carrying a non-1 HCV genotype. A low pretreatment GGT/ALT ratio is a predictor of a good treatment response.     

Antiviral therapy for chronic hepatitis C: past, present, and future

Antiviral therapy for chronic hepatitis C has dramatically advanced since the discovery of the hepatitis C virus (HCV) in 1989 and the introduction of interferon (IFN) monotherapy in the early 1990s. The current standard therapy uses a combination of pegylated IFN and ribavirin. The duration of therapy and response to therapy are HCV genotype-specific. Genotype 1 patients require 48 weeks of the combination therapy for 50% successful viral elimination, while genotype 2 patients require 24 weeks of therapy for 80% or 90% viral elimination. Early viral kinetics after the initiation of therapy is a useful predictor of the sustained virologic response (SVR), which is formally determined at 24 weeks after completion of the treatment. For example, an early virologic response, which is determined by a 2-log reduction of HCV RNA or viral elimination at 12 weeks after the initiation of therapy, is a strong negative predictor of SVR in genotype 1 patients. In contrast, a rapid virologic response of HCV RNA-negative at 4 weeks after the initiation of therapy identifies genotype 2 “super-responders,” who may require a shorter period of therapy. Adherence to therapy is one of the most important factors for successful viral clearance. Hematopoietic growth factors such as epoetin and granulocyte-colony stimulating factor help reduce therapy-mediated cytopenia and improve patient compliance, thereby leading to better viral clearance. New types of anti-HCV agents such as HCV protease and polymerase inhibitors are needed for those patients that do not respond to combination therapy.     

Predictors of response of US veterans to treatment for the hepatitis C virus

The currently recommended treatment for hepatitis C virus (HCV) infection is pegylated interferon alfa (PEG-INF) and ribavirin, which can be difficult to tolerate. More information about predicting sustained virologic response (SVR) may allow more informed treatment decisions to be made. This retrospective observational cohort study identified predictors of SVR to PEG-INF and ribavirin in routine medical practice at 121 Department of Veterans Affairs facilities. Among 5,944 patients infected with HCV genotypes 1, 2, or 3 who had been treated with PEG-INF and ribavirin, SVR rates were 20%, 52%, and 43%, respectively, and discontinuation rates were 68% (prior to 48 weeks), 34% (24 weeks), and 41% (24 weeks), respectively. In multivariate analysis, significant predictors of decreased likelihood of genotype 1 patients having an SVR were being African American, clinical liver disease, diabetes, low cholesterol, low hemoglobin, low platelet count, and treatment at a low-volume facility. Predictors of increased likelihood of genotype 1 patients having an SVR were low-level HCV viremia, elevated ALT quotient, and receiving PEG-INF 2A (rather than 2B). For genotype 2 patients, increasing body mass index, prior use of interferon, and low platelet count were negative predictors; only low-level HCV viremia was a positive predictor. For genotype 3 patients, only receiving PEG-INF 2A affected the likelihood of an SVR; its effect was positive. CONCLUSION: Among patients for whom HCV treatment is initiated during routine medical care, multiple factors including form of PEG-INF received affect the SVR rate for genotype 1 patients. Few of these factors affect the rate for genotype 2 patients, and even fewer do so for genotype 3 patients.     

Maintenance therapy for chronic hepatitis C

Major progress has been made in the treatment of chronic hepatitis C virus (HCV) infection over the 18 years since Hoofnagle et al. initially documented response of non-A non-B hepatitis to interferon alfa. Current optimal therapy with pegylated interferon alfa (PEG-IFN) and ribavirin results in sustained virologic response rates of just over 50%. With an estimated 2.7 million Americans with active HCV infection, we can anticipate a large number of potential treatment failures with the current standard of care. At this time, no therapy is approved by the US Food and Drug Administration for treatment failures of PEG-IFN and ribavirin. Maintenance interferon therapy with the goal of prevention of disease progression rather than viral eradication appears to offer an option for HCV treatment failures with advanced disease. Alternative medical strategies to reduce hepatic fibrosis are also under investigation. With the relatively static number of available organs for transplantation, prevention of disease progression and decompensation is essential for an impact to be made upon the predicted rates of HCV morbidity and mortality in the next 10 to 20 years.     

Viral kinetics and duration of hepatitis C therapy

Treatment for hepatitis C is aimed at eliminating the virus and thus preventing the development of cirrhosis. The effectiveness of antiviral therapy with pegylated interferon and ribavirin is based upon inhibition of viral replication and successful viral clearance while maintaining minimal toxicity. Therapy as short as 12 to 16 weeks duration may be adequate for those with genotypes 2 or 3, and 24 weeks may be sufficient for those with genotype 1 and low viral load who achieve rapid virologic response. On the other hand, extension of therapy beyond 48 weeks may be necessary for those with genotype 1 and slow response or those with a high pretreatment viral load who do not achieve rapid virologic response. As new viral kinetic data emerge with pegylated interferon and ribavirin, the tailoring of hepatitis C virus treatment will allow shorter durations of therapy for some patients and a greater chance of sustained response in others who are treated for longer durations.     

Association between insulin resistance and sustained virologic response in hepatitis C treatment,genotypes 1 versus 2 and 3: systematic literature review and meta-analysis

Background/aimsControversial results have been found in literature for the association between insulin resistance and sustained virologic response to standard chronic hepatitis C treatment. This study aims to provide a systematic literature review with meta-analysis, in order to evaluate if insulin resistance interferes with sustained virologic response in patients infected by the HCV genotype 1 versus HCV genotypes 2 and 3, undergoing treatment with interferon and ribavirin or pegylated interferon and ribavarin.MethodsSystematic search was performed on main electronic databases until May 2012. Primary outcome was sustained virologic response, defined as undetectable levels of HCV-RNA six months after the end of treatment. Meta-analytic measure was estimated using Dersimonian and Laird's method, using Stata software.ResultsThirteen studies involving 2238 infected patients were included. There was a statistically significant association between insulin resistance and lower sustained virologic response rate, and this difference occurred in HCV genotype G1 (OR: 2.23; 95% CI: 1.59–3.13) and G2/G3 (OR: 4.45; 95% CI: 1.59–12.49). In addition, a difference was seen in the cut-offs used for defining insulin resistance by Homeostasis Model Assessment of Insulin Resistance. To minimize this limitation, sub-analysis that excluded the studies that did not use 2 as a cut-off value was performed and the results still demonstrated association between insulin resistance and sustained virologic response, for both genotypic groups.ConclusionThis meta-analysis provides evidence that elevated Homeostasis Model Assessment of Insulin Resistance is associated with a lower sustained virologic response rate in patients with hepatitis C treated with interferon and ribavirin or pegylated interferon and ribavarin, regardless of their genotype.     

Current issues in the management of paediatric viral hepatitis

Viral hepatitis poses important problems for children. In preschoolers, hepatitis A virus (HAV) infection frequently causes acute liver failure. Vaccinating toddlers against HAV in countries with high endemicity is expected to decrease mortality. HAV vaccine demonstrates efficacy (comparable to immunoglobulin) as post‐exposure prophylaxis. A recently developed vaccine against hepatitis E virus (HEV) may benefit fetal health, because pregnant women are most prone to acute liver failure as a result of HEV. Hepatitis B vaccine continues to demonstrate value and versatility for preventing serious liver disease. With chronic infection, undetectable levels of serum HBV DNA complement e‐seroconversion as the preferred outcome measure; suppressed viral load correlates with long‐term complications better than HBeAg status. Among Taiwanese children, low pretreatment HBV DNA (<2 × 10⁸ copies/ml) strongly predicted response to interferon‐α. Future paediatric studies must incorporate HBV DNA levels. The rationale for routine treatment of immunotolerant hepatitis B during childhood remains uncertain. Any treatment of chronic hepatitis B in childhood requires consideration of the risks and benefits. Childhood hepatitis C virus (HCV) infection results mainly from mother‐to‐infant transmission. Babies of HCV‐infected women should be tested for serum HCV RNA at 1 month of age. If negative, confirmatory anti‐HCV antibody testing may be performed between 12 and 15 months of age. Children with chronic hepatitis C may develop progressive fibrosis/cirrhosis, particularly in the setting of obesity and insulin resistance. Treatment of children chronically infected with genotype 2 or 3 is highly successful: combination therapy of pegylated interferon‐α and ribavirin is well tolerated and superior to pegylated interferon‐α alone.     

慢性乙型肝炎肝组织中 PD-L1在干扰素治疗中的表达

目的：研究慢性乙型肝炎患者肝组织中程序性死亡分子配体1（PD-L1）在进行聚乙二醇干扰素α-2a 抗病毒治疗前后及不同应答组间的表达变化，以进一步明确其与干扰素抗病毒疗效的相关性。方法15例慢性乙肝患者予以聚乙二醇干扰素α-2a 治疗48周，根据抗病毒疗效分为完全应答组、部分应答组及无应答组，检测治疗前后及不同应答组间 ALT、HBV DNA、HBV 标志物及肝脏病理变化，采用免疫组织化学方法结合图像定量分析系统检测肝组织 PD-L1的表达。结果在长效干扰素抗病毒治疗48周后，完全应答组 ALT 均降至正常，HBV DNA 低于检测下限，HBeAg 出现血清学转换，肝脏炎症程度有所好转，肝脏 PD-L1表达较治疗前明显下降（P ＜0．05）；部分应答组 ALT 降至正常， HBV DNA 较治疗前有所下降，但仍未低于检测下限，HBeAg 未发生血清学转换，肝脏炎症程度有所好转，肝脏 PD-L1表达较治疗前明显下降（P ＜0．05）；无应答组 ALT、HBV DNA、肝脏炎症程度及肝组织 PD-L1的表达较治疗前无明显变化，HBeAg 均未发生血清学转换。结论慢性乙型肝炎患者进行聚乙二醇干扰素α-2a 抗病毒治疗，可通过下调肝组织 PD-L1表达从而抑制病毒复制，改善肝脏炎性反应程度。     

Hepatitis B virus genotype B results in better immediate, late and sustained responses to peginterferon-alfa in hepatitis-B-e-antigen-positive patients

Background and Aims: This study investigated outcome predictors in hepatitis‐B‐e‐antigen (HBeAg)‐positive chronic hepatitis B patients treated with peginterferon alfa‐2a. Methods: A total of 88 HBeAg‐positive patients receiving peginterferon alfa‐2a for 6 months and followed up for at least 24 weeks were prospectively analyzed. Precore and core promoter genes of hepatitis B virus (HBV) were sequenced from the serial serum samples of 88 patients. Results: After 24 weeks of follow up, 38.6% and 28.4% of patients achieved HBeAg clearance and combined response, respectively. Multivariate analysis disclosed that pretreatment HBeAg sample to cut‐off (S/Co) ratio ≤ 200, alanine aminotransferase > 200 IU/mL, HBV genotype B and T1846 were independent factors for HBeAg clearance, and HBeAg S/Co ratio ≤ 200 and HBV genotype B were major determinants for combined response. HBeAg S/Co ratio ≤ 10 at week 12 of therapy was the useful factor for treatment response and had a greater power (P = 0.012) to predict HBeAg clearance than HBV DNA. Patients with HBeAg clearance had a higher frequency of A1896 mutation at baseline and during therapy than those without HBeAg clearance, and the frequency of A1896 decreased during treatment. During follow up, delayed HBeAg seroconversion and reactivation of HBV after HBeAg clearance were observed in eight non‐responders and 20 patients with HBeAg clearance, respectively. HBV genotype B was a significant factor to predict both responses. Conclusions: Pretreatment HBeAg S/Co ratio ≤ 200 and HBV genotype B were major determinants for treatment response to peginterferon. Genotype‐B‐infected patients had higher probability of delayed HBeAg clearance and sustained response. Rapid decrease of HBeAg titer was useful on treatment predictor.