Clinical Characteristics Of Creatine Kinase Elevation Associated With Telbivudine Treatment In HBV Infected Patients

AIM: An estimated 90 million people are chronically infected with the hepatitis B virus(HBV)in China,chronic hepatitis B was one of the most common infectious disease even now.Antiviral therapy with nucleos(t)ide analogues(NAs)has shown the powerful efficacy by achieving sustained suppression of HBV replication and obvious benefit for HBV-related cirrhosis,liver failure and hepatocellular carcinoma(HCC).In April 2007,a synthetic thymidine β-L-nucleoside called telbivudine was approved for the treatment of chronic hepatitis B(CHB)in China.It is applied in clinical practise widely owed to its antiviral potency,nearly no toxicity to baby and the potential to improve renal function.LdT is recommended to be one of the choice for pregnancy women and chronic kidney disease(CKD)patients accompanied by HBV infection.Although LdT is generally well tolerated,several adverse effects associated with LdT have been reported,such as creatine kinase(CK)elevation,neuropathy,and lactic acidosis.Among these adverse effects,CK elevation,which is an early indicator of muscle injury is most commonly observed.However,few data were available with regard to the clinical characteristics and variation of creatine kinase elevation associated with LdT treatment.The aims of our study were to evaluate the safety profile of LdT by investigating the clinical features and risk factors of CK elevation associated with LdT in CHB patients,pregnancy women and chronic kidney disease(CKD)patients accompanied by HBV infection.METHODS: The clinical data of patients currently treated with LdT(or had a history of prior treatment with LdT)in our hospital between June 2014 and June 2015 were analyzed retrospectively.527 cases of patients met the criteria,including 436 cases of patients treated with LdT alone,of which 58 cases of pregnant women and 19 cases of CKD patients,and 91 cases of patients treated with LdT plus adefovir dipivoxil(ADV).All patients met the following inclusion:(1)diagnosed as chronic HBV infection according to the guidelines for prevention and treatment of hepatitis B in China(2010).(2)treated with LdT more than 6 months(except for pregnant women).(3)followed up every 3-6months.(4)18 to 65 years old.(5)all CKD patients were confirmed by renal needle biopsy.Exclusion criteria:(1)coinfection with HAV,HCV,HDV,HEV,HIV.(2)alcoholic intake/drug induced liver diseases.(3)history of thyroid and neuromuscular diseases.(4)other severe systemic diseases.(5)application of statin and fibrate.The dynamic of CK and muscle symptoms during LdT therapy were the main parameters.CK value>175 IU/L was indicated as CK elevation.Serum creatinine(Cr)and urine protein quantitation were also recorded for CKD patients.RESULTS:CHB patients1.There were 450 of eligible CHB patients were enrolled in this study,including 359 cases of patients treated with LdT alone and 91 cases of patients treated with LdT plus ADV were analyzed.303 cases of patients experienced CK elevation during the period of therapy,and the proportion of patients with grade 1,2,3,and 4 of CK elevation was 38.44%,20.44%,5.33% and 3.11%,respectively.CK elevation in 267 cases of patients(59.33%)first occurred between 1 and 24 months after starting telbivudine therapy.2.14 cases of patients were diagnosed as myositis and no cases of rhabdomyolysis were found in this study.The mean level of CK elevation in patients with myositis was lower than that of patients without muscle symptoms meanwhile with grade 3-4 CK elevation(1139±505.3IU/Lvs1480±737.55 IU,P=0.002).CK elevation in patients with myosistis first occurred between 1 and15 months after starting telbivudine therapy,and the median time to CK elevation was 7.5 months,which was earlier than that of patients without muscle symptoms.3.Most patients(244/265)with CK grade 1-2 elevation did not receive any special intervention and CK level decreased to normal or only slightly higher than normal during the period of observation.22 cases of 38 patients with CK grade 3-4 elevation switched to other antiviral agents,which CK level decreased to 203.05±105.79IU/L in an average of 3.18±1.48 months.Otherwise,the rest patients continued to use LdT,which CK level to 255.28±128.02IU/L in an average of 3.41±2.47 months.There was no significance difference in these two groups(P=0.232).4.Multivariate regression analysis revealed that male(OR=1.975)and higher baseline of CK level(OR=1.015)were the significant risk factors for CK elevation(P<0.005)during LdT therapy.5.No significant differences was found for the therapeutic response between patients with CK elevation and patients without CK elevation in terms of nondetectable viremia(<500 IU/mL)at 88.12% versus 89.12%(P=0.756),ALT normalization at 79.21%vs82.31%(P=0.528)and HBeAg loss at 26.69% versus 31.17%(P =0.307).Pregnant women3.44%(2/58)of the pregnant women developed transient CK elevation after the average 6.5(4-21.25)months of LdT treatment and 1 patient switched to other antiviral agents.The result showed pregnant women who received LdT had lower incidence of CK elevation compared with general CHB population(15.11%vs3.45%,P=0.006).CKD patients1.31.58%(6/19)of the CKD patients developed CK elevation in variable degree after 16.21±7.55 months of LdT treatment.The cumulative incidence of CK elevation at 6,12,18 and 24 months was 0%,5.26%,21.05%,and 31.58%,respectively.CKD patients who use LdT had lower rates of CK elevation in contrast with CHB patients.2.There was no significant difference in baseline estimated glomerular filtration rate(eGFR)between patients with CK elevation or not(P=0.23).Conclusion1.CK elevation associated with LdT therapy is a common adverse reaction.It usually occured within 24 months after starting treatment.CK elevation in most patients with LdT therapy are benign and reversible.Only few patients developed myopathy.The therapeutic response had nothing to do with CK elevation.2.Male patients who use LdT are risk factor to develop CK elevation.3.There is no absolute correlation between the incidence of myositis and the magnitude of CK elevation.CK elevaton in patients who developed myositis occurred within 2 years after starting LdT treatment.So,muscle symptoms and CK level should be closely monitored in this period.4.Patients with CK grade 1-2 elevation should remove inducing factors and monitor the CK level closely.Patients with CK grade 3-4 elevation should adjust the treatment recipe appropriately according to the muscle symptoms,dynamic variation of CK level,patients compliance and so on.As long as patients are closely monitored for CK levels,myopathic symptoms and signs during the period of treatment,LdT is still a safe antiviral drug.5.As to the pregnant women and CKD patients,the incidence of CK elevation related to LdT is lower than general CHB patients.In respect of CK elevation,LdT is safe for pregnant women and CKD patients.