Re-Evaluation The Efficacy Of Interferon On HBeAg-Positive Chronic Hepatitis B

Objective: Hepatitis B virus (HBV) infection is the commonest cause of Chronic liver disease in China. The pathogenesis of chronic hepatitis B (CHB) is still unclear because of lacking of proper animal model for human HBV replication. Carriers of HBV are at increased risk of developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC), which will lead to serious sequelae during their lifetime and bring about heavy economic, familial and social burden. Morbidity and mortality in CHB are linked to persisitence of viral replication and the immune injury caused by viral antigens. Therefore, the main goal of therapy is to inhibit replication of HBV and halt the progression of liver inflammation to fibrosis, cirrhosis or hepatocellular carcinoma. Current treatment options for CHB consist of interferons (IFN) and nucleo(s)tide analogues(NA). The off-treatment outcomes are dissatisfactory for both managements. NA therapy offers oral administration, rapid suppression of viral replication and well tolerated. However, it is uncertain whether oral antiviral therapy can be discontnued, thus necessitating indefinte therapy in most patients, which may poses a risk for antiviral resistance and unknown long-term saftey. It is very difficult to reach their aims for yong generations who want to have chlidren by NA treatment in a short duration. IFN with immunomodulatory effects has higher sustained rates of HBe and HBs seroconversion, absence of reistance, and finite duration, which is especially important for yonger patients who will have children after treatment. Nevertheless, response to IFN-related therapy depends on many factors such as HBV genotype, HBV DNA concentration, status of the host immunity, IFN dosage and duration, etc. As we know, not every HBV patient has indication for therapy and can achieve off-treatment sustained response, even if they stricktly obey the standard straitegy. Some progresses have been made about the optimal dosage and duration of IFN treatment of chronic hepatitis B patients, especially use of pegylated interferon, which allows a more convenient once-weekly dosing interval and increases the compliance of the patients. The aims of our study are to investigate pretreatment and on-treatment factors, such as serum HBV concentration, alanine aminotransferase level(ALT) , that allow the selection of patients who are likely to achieve a sustained response to conventional IFN therapy in order to avoid the side-effects and costs associated wih unnecessary treatment. We also try to address if peginterferon therapy treatment efficacy is equal or superior to that of conventional IFN by comparing treatment results, and provid evidence for future clinical practice. Patients and study methods:Conventional interferon group: HBeAg-positive CHB patients from July 2005 to December 2009 with elevated ALT were enrolled in conventional interferon group. Key Inclusion criteria were: Age 16-35 years. HBsAg positive for at least 6 months, HBeAg positive, detectable HBV-DNA (patients had a serum HBV DNA concentration 1.0×105-1.0×108 copies/mL) and negative anti-HBe and anti-HBs. Elevated serum ALT levels of 2-10 times the upper limit of nomal(ULN) on three occasions within 12 weeks prior to enrollment. Important exclusion criteria: antiviral therapy history, presence of viral coinfections, preexisting cytopenia, or decompensated liver cirrhosis. Treatment comprised of IFN 50-60ug daily for the first week, and every other day for the rest of 6 or 12 months according to on-treatment response and patients'compliance. Patients attended the outpatient clinic at least every month for routine examinations and laboratory assessments (including blood routine test, liver function, HBV DNA level, HBV markers, thyroid gland function and side effects) during both the treatment and the post treatment follow up phase. Treatment duration or strategy was decided according to on-treatment response, tolerance to side effects and patients'compliance at the first 3 or 6 month. If HBV-DNA quantification was below the minimum detection limit or decrease from baseline by more than 2 logs after 3 month therapy (defined as early virological response, EVR), the duration lasted for 12 month. If HBV-DNA concentration decreased less than 2 logs after 3 months therapy, the patient continued to administer IFN to 6 months. If HBV DNA decrease was more than 2 logs at 6 month, the patient should finish 12 months treatment. However if HBV DNA decrease was less than 2 logs after 6 month therapy, treatment was considered as no virological response (NVR) . By means of the factors of baseline and in the early phase of treatment, the study try to find whether some benchmarks were able to guide individualized decisions concerning therapy continuation.Pegylated interferon group: HBeAg-positive CHB patients were enrolled in an investigator-initated multicenter randomized controled trial and a subsequent 6 months follow-up.Group A: A phase III partially double blinded study evaluating the efficacy and safety of 40KD branched pegylated interferon alfa-2a in HBeAg-positive patients with chronic hepatitis B(protocol:WV16240) from Shanghai Roche pharmaceutical company from February 2002 to April 2004. Inclusion criteria:Age≥18years.Positive HBsAg for more than 6 months, positive HBeAg, detectable HBV-DNA (>5.0×105 copies/ml as measured by PCR) and anti-HBs negative. Two times(more than 14 days apart) elevated serum ALT with the level >ULN, but≤10ULN within 6 months, and one time should be less than 35days prior to the first dose, etc. All the patients were treated with PEG-IFNa-2a with the dosages of 180ug for 12 months, and were followed-up after stopping drugs within 6 months.Group B: An open-label, randomized study of pegylated interferon in the treatmeat of HBeAg positive chronic hepatitis B patients (protocol: P05170) from Schering-plough company from April 2007 to December 2009. Inclusion criteria: Age18-65years. Positive HBsAg for more than 6 months, positive HBeAg, detectable HBV-DNA (>1.0×105 copies/ml as measured by PCR) and anti-HBs negative. ALT level before treatment was 2-10ULN, et al. All the patients were treated with PEG-IFNa-2b with the dosages of 1.5μg/kg for 12 months, and were followed-up after stopping drugs within 6 months.Results: 246 patients were recruited to accept conventional interferon therapy. Among them, 2 cases were withdrawn owing to severe alopecia and leukocytopenia in the early phase, respectively. 132 cases in 244 patients got EVR (54.1%). 38 cases did not finish duration because of HBV-DNA decrease less than 2 logs after 6 month therapy. 128 cases in 206 patients got eAg-eAb serum conversion at the end of treatment with a conversion rate 62.1%. 121 cases(58.7%) still kept sustained serum response (SSR), and 165 case with normal liver function after 6 months follow-up.Femal patients had a little higher eAg-eAb serum conversion rate compared to male, but there was no statistic difference (67.5% vs 58.5%;χ2=1.03, P>0.05). Patients with the age of 16-25 years old had a higher conversion rate than patients of 26-35 years old(70.9% vs 52.1%,χ2=7.72, P<0.05). Patients with non-vertical transmission had a higher conversion rate(79.1% vs 33.8%,χ2=42.06, P<0.05). The conversion rate of eAg-eAb for patients with ALT 5-10ULN was higher than with 2-5ULN,(71.1% vs 49.4%,χ2=9.96,P<0.05). Patients with ALT level more than 5ULN elevation in the early three months had a higher conversion rate than less than 5ULN elevation patients(72.9 vs 52.7%,χ2=8.88,P<0.05). Patients whose liver function returned to normal during 6 months interferon therapy had a conversion rates of 70.2%, better than patients with a fluctuation liver function(50.6%),(χ2=8.20,P<0.05). Patients with HBV-DNA quantity less than 1.0×106 copies/ml at baseline had a higher eAg-eAb serum conversion rate than with 1.0×106-1.0×108copies/ml,(74.6% vs 44%,χ2=19.72,P<0.05). Patients with HBV-DNA level reduction by more than 2logs in the early phase after 3 months treatment had higher conversion rate than less than 2logs patients(78% vs 33.8%,χ2=39.46,P<0.05). 52 cases whose ALT level 5-10ULN, HBV-DNA less than 1.0×106copies/ml before treatment, and ALT more than 5ULN elevation, HBV-DNA reduction by more than 2logs in the early phase after 3 months treatment had eAg-eAb serum conversion rate of 82.7%. EVR had a critical value to predict ETSR and SSR with PPV 78%(103/132)and 73.5%(97/132), respectively. Also NPV of ETSR and SSR by NEVR were 77.7% and 78.6%, respectively.60 patients were enrolled in peginterferon group. 28 patients were given treament with peginterferonα-2a, and 32 patients with peginterferonα-2b. 10 cases and 11cases got eAg-eAb serum conversion at the end of therapy with a conversion rate 35.7%(10/28) and 34.4%(11/32), and 25%(7/28) and 28.1%(9/32) still kept serum response after 6 months off-treatment follow up in group A and group B, respectively.All side effects patients complained in conventional interferon group and pegylated interferon group were transient and tolerable, including fever, leukocytopenia and alopecia, etc.Conclusion:1. Higer eAg-eAb serum conversion rate of IFN treatmeat of CHB could be reached by strictly screening patients. Higher ALT level and lower HBV-DNA load at baseline were good predictive factors for higher eAg-eAb serum conversion. Patients with elevated ALT or /and HBV-DNA reduction by 2 logs after 3 months treatment had a higher eAg-eAb serum conversion rate, which were the on-treatment predictors of response. EVR had a critical value to predict eAg-eAb serum conversion. Age and whether vertical transmission also had some effects on therapeutic conversion rate.2. The study indicated that conventional interferon and pegylated interferon could achieve good results in the treatmeat of CHB, with the same treatment efficacy.So it was very important to select proper patients at baseline and monitor therapeutic response during the period of treatment, which may guarantee, to some extent, better outcomes.