| BackgroundHepatitis B is widely distributed all over the world,especially in developing countries such as China.As a viral infectious disease that damages the liver,Hepatitis B can cause acute and chronic processes.It is believed to be a"terrible"disease due to the lack of specific treatment.The majority of acute hepatitis B is self-limiting process,however,chronic hepatitis B(CHB)often relapses,thus resulting in liver cirrhosis or even hepatocellular carcinoma(HCC).In the treatment of CHB,anti HBV therapy plays crucial roles.It is more effective and benefit to the prognosis of CHB when compared to other western or traditional Chinese medicines with the role of protecting liver cells,immunomodulation,and anti-liver fibrosis.Anti HBV therapy can improve liver function,alleviate liver lesions and reduce or delay the occurrence of end-stage liver disease through inhibiting viral replication.Current antiviral drugs with definite efficacy include interferon alpha(IFN-alpha)and nucleos(t)ide analogues(NAs).NAs acts on the polymerase region of HBV,and inhibits viral replication by replacing nucleosides with similar structures in the polymerase chain and terminating the extension of the chain.IFN-alpha inhibits viral replication through inducing the host to produce cytokines with antiviral and immunoregulatory activities.Instead of inhibiting viral replication directly,IFN-alpha plays its roles via strengthening immune function thus inducing viral inhibition.Due to different antiviral mechanisms between these two kinds of drugs,their clinical efficacies are different.The course of IFN-alpha antiviral therapy is precise,and the curative effect is obviously related to the choice of cases.The serological conversion rate of hepatitis B surface antigen(HBsAg)and hepatitis B e antigen(HBeAg)of IFN-alpha is higher than those of NAs,but NAs works faster.Though NAs has advantages including fast onset,good tolerance and strong antiviral effect,the course of NAs therapy depends on individual situation and there exists drug resistance.In order to achieve better efficacy,IFN-alpha combined with NAs therapy has been increasingly used in clinical.Meanwhile,adverse drug reaction(ADR)also requires attention in pursuit of curative effect.When IFN-alpha was used,a wide array of ADR could be seen,including influenza-like symptoms,insomnia,alopecia,myelosuppression,neuropsychiatric symptoms and autoimmune diseases.NAs has good safety,but rare adverse effects such as hypophosphatemic osteopathy,myositis,renal insufficiency,rhabdomyolysis,and lactic acidosis were also observed.IFN-alpha combined with NAs can cause the aggravation of ADR or other serious ADR;however,it is lack of research data at home and abroad.Given that IFN-alpha can induce transient peripheral blood cell depletion and adefovir dipivoxil(ADV)may cause renal insufficiency,it remains unclear whether the combination of these two drugs aggravates peripheral blood cell depletion and renal impairment.Moreover,the trend of peripheral blood cell changes during the treatment and whether the impairment of renal function and peripheral blood cell can be reversed after withdrawal are also unknown.Specific aims included:(1)To observe the antiviral efficacy of pegylated interferon-alpha-2b(PegIFN-alpha-2b)alone and in combination with ADV in treating HBeAg-positive CHB patients,and to evaluate whether the combined therapy can improve the antiviral efficacy;(2)To compare the changes of peripheral blood cells between two groups during different antiviral regimens,to evaluate whether the combined treatment aggravates peripheral blood cells depletion,and to guide the safety monitoring of peripheral blood cells in CHB patients during antiviral treatment;(3)To compare the changes of renal function between two groups with different antiviral regimens,to evaluate whether the combined treatment aggravate renal insufficiency,and to guide the safety monitoring of renal function in CHB patients during antiviral treatment.ObjectiveTo investigate the efficacy of PegIFN-alpha-2b alone(51 patients)or PegIFN-alpha-2b combined with ADV(51 patients)in the treatment of HBeAg-positive CHB patients,and to compare their effects on peripheral blood cells and renal function through monitoring liver function,HBV DNA,five quantitative hepatitis B,white blood cells(WBC)count,neutrophil(N)count,lymphocyte(L)count,red blood cells(RBC)count,hemoglobin(Hb),platelet(PLT)count,serum creatinine(Scr),creatinine clearance(Ccr)and glomerular filtration rate(eGFR).MethodsWe performed a multicenter,prospective,open-label,and randomized-controlled trial.A total of 102 HBAg-positive HBV cases were included in 14 hospitals from June 2012to September 2013.After signing informed consents,patients were randomized to the PegIFN-alpha-2b monotherapy group or the PegIFN-alpha-2b+ADV combination group for 48 weeks-treatment.Patients were followed up for another 24 weeks after drug withdrawal.The baseline(0 week),4 weeks,8 weeks,12 weeks,24 weeks,36 weeks,48 weeks,60 weeks and 72 weeks of liver function,HBV DNA,five quantitative hepatitis B,peripheral blood and renal function were measured;Ccr was calculated by Cockcroft-Gault(CG)formula;simplified Modification of Diet in Renal Disease(MDRD)and Chronic Kidney Disease Epidemiology Collaboration(CKD-EPI)formula were used to calculate the eGFR.A linear mixed effects model for repeated measures was used to assess baseline characteristics and eGFR variations of patients at different time points,and evaluate effects of two therapeutic schedules on peripheral blood cells and renal function.Results1 Baseline characteristicsFrom June 2012 to September 2013,102 patients with CHB were screened and qualified.The baseline demographic and clinical characteristics were similar in 93patients who completed follow-up between the two groups.There were no significant differences in age distribution,sex composition,family history of hepatitis B,HBV genotype,HBeAg quantitative median,HBsAg quantitative median,HBV DNA quantitative median and ALT median between the two groups(P>0.05).2 Efficacy evaluationThe virological response rates of PegIFN-alpha-2b monotherapy and combined with ADV antiviral therapy groups were 23.9%and 76.6%,respectively(P<0.001).The mean ALT values at baseline of the eighteen patients in the monotherapy group and thirty-three patients in the combination therapy group were 202.37 U/L and 234.89U/L,respectively.Their ALT returned to normal at 48 weeks and reached biochemical response(BR).At 48 weeks,higher BR(P=0.003)was obtained in the combined treatment group(70.2%)compared with that in the PegIFN-alpha-2b monotherapy group(39.1%).HBeAg seroconversion rate was higher in the combined treatment group when compared to that of the monotherapy group(P=0.293).HBeAg seroconversion occurred in 6 patients in the monotherapy group and 10 patients in the combined treatment group at 48 weeks.The disappearance of HBsAg was inspected in 1 patient in the combined treatment group,whereas it was not observed in the patients treated with PegIFN-alpha-2b monotherapy.There was no significant difference in serum HBeAg negative(P=0.196),virological breakthrough(P=0.202)and biochemical breakthrough(P=0.117)between the two groups at 48 weeks.The two groups showed statistically significant differences in persistent response(4.3%to 21.3%,P=0.015),partial virological response(69.6%to 100%,P<0.001),sustained virological response at 72weeks(4.3%to 19.1%,P=0.027),recurrence(19.6%to 53.2%,P=0.001),and clinical recurrence at 72 weeks of follow-up(0%to 17.0%,P=0.006).3 Effects on peripheral blood cellsThe changes of WBC,N,L,RBC,Hb,PLT at different time points were statistically significantly different(P<0.05);WBC,N,L,RBC and group had no interaction effect(P>0.05);Hb,PLT and group had interaction effects,and the difference was statistically significant(P<0.05).There was no significant difference in WBC,L,RBC,Hb,PLT levels between monotherapy and combination therapy groups(P>0.05).The effect of monotherapy group on N was statistically greater than that of combined treatment group(P<0.05).The N,L,WBC and PLT counts of two groups decreased in varying degrees during the treatment,especially between 0-4 weeks,then turned to be stable during the treatment and returned to normal levels after drug withdrawal.The number of cases with N<0.5×10~9/L and N<0.75×10~9/L,PLT<50×10~9/L and PLT<30×10~9/L during treatment were rare.The decrease of WBC,N,L,RBC,Hb,PLT at 4 weeks had no significant difference between two groups(P>0.05).4 Effects on renal functionThe incidences of renal adverse events were low in both groups,and the combined treatment might aggravate renal impairment at 48 weeks of treatment and 12 weeks after drug withdrawal.After 48 weeks of treatment,there was a significant difference in the number of normal or abnormal Ccr cases(?~2=8.026,P=0.005<0.05),and there was a significant difference in the number of normal or abnormal cases of e-GFR(MDRD)between the two regimens(?~2=7.351,P=0.007<0.05).The difference was statistically significant(?~2=6.861,P=0.009<0.05).and their was statistically significant difference in the number of cases with normal and abnormal e-GFR(CKD-EPI)(?~2=5.291,P=0.021<0.05).At different time points,Scr and Ccr in both groups showed a similar downward trend to that of eGFR.Age,HBV DNA,and ADV administration were important predictors of eGFR decline over time.ConclusionsPegIFN-alpha-2b combined with ADV has advantages in virological response rate,biochemical response rate,serological response rate,sustained response,partial VR and72-week SVR.Peripheral blood WBC,N,L,RBC had a similar downward trend during treatment in the two groups.However,the combined treatment group had an impact on Hb and PLT,which was reversible and could be recovered quickly after drug withdrawal.Close monitor is required during treatment.The incidences of renal adverse events in both groups were low,and the combination therapy may cause delayed,but reversible renal impairment.Older age,high HBV DNA load,and treatment regiments containing ADV were important predictors of eGFR decline. |
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