35 4 2014 7 ( ) JOURNAL OF SUN YAT-SEN UNIVERSITY(MEDICAL SCIENCES) Vol.35 No.4 Jul. 2014 72 1, 2, 1, 1, 1, 1, 1, 1* ( 1., 510630;2., 510090) : (TDF) (NA) (CHB) TDF 31 TDF NA 24 CHB, 4 12 24 36 48 72 HBV DNA HBV DNA,HBV DNA ALT HBV DNA HBV DNA ALT (P : 0.05;0.700;0.664) HBV DNA TDF TDF NA (P = 0.720) CK 2 ( P > 0.05),HBV DNA HBV DNA, 24 ( P < 0.05), ALT 36 ( P < 0.05) CHB,TDF TDF NA HBV DNA, ALT, : ; ; :R512.6 + 2 :A :1672-3554(2014)04-0520-05 DOI:10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).2014.0087 Comparison of Efficacy of Tenofovir Monotherapy and in Combination with Other Nucleoside Analogue for Nucleoside-analogues Experienced Chronic Hepatitis B Patients for 72 Weeks HUANG Ming-xing, LI Xing-hua, WU Yuan-kai, SHI Hong, TAO Lin, ZHENG Xiao-yan, CHONG Yu-tian * (Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China) Abstract: Objective To compare the clinical efficacy and safety of Tenofovir Disoproxil Fumarate (TDF) monotherapy and in combination with other Nucleoside-Analogues (NA) for NA experienced chronic hepatitis B patients (CHB). Methods A total of 31 NA-experienced CHB patients treated with TDF monotherapy and 24 NA-experienced CHB patients treated with TDF in combination with other NA in our follow-up clinic were retrospectively investigated. HBV DNA levels, the rate of undetectable HBV DNA and the multivariate analysis of HBV DNA negative conversion, ALT normalization rate and incidences of adverse events were evaluated at week 0, 4, 12, 24, 36, 48, and 72. Results The differences between the two groups in HBV DNA levels, the rate of undetectable HBV DNA, ALT normalization rate were not statistically significant (P > 0.05; 0.700; 0.664). Multivariate analysis of HBV DNA negative conversion showed that difference between TDF monotherapy and in combination with other NA was not statistically significant (P = 0.720). Creatine Kinase (CK) of more than two times upper limit normal (2 ULN) in two groups were comparable (all P > 0.05). HBV DNA levels persistent declined and the rate of undetectable HBV DNA continued rise in each group and the differences were statistically significant before in the first 24 weeks (all P < 0.05),the same as ALT normalization rate in the first 36 weeks (all P < 0.05) treatment, Creatine Kinase (CK) were more than two times upper limit normal in 9.18% patients and were comparable at each time point (all P > 0.05). All patients have a normal serum creatinine. Conclusions For CHB patients with NA experienced, both TDF monotherapy and in combination with other NA can suppress HBV DNA replication very quickly, with a high rate of ALT normalization and lower rate of adverse events. Key words: hepatitis; hepatitis B virus; chronic; tenofovir [J SUN Yat-sen Univ(Med Sci),2014,35(4):520-524] :2014-03-24 : (2012ZX10004-902) :,, :,E-mail:kindentstar@126.com; * :,, E-mail: ytchong2005@126.com
4,. 72 521 (chronic hepatitis B, CHB) (hepatitis B virus, HBV) (, (HBV, ) DNA),TDF [1] 100 HBV [ 2 ] CHB NA NA HBV [3] HBV 300 mg 1 (Tenofovir disoproxil fumarate,tdf) ( 300 mg )+ ( (Entecavir,ETV) (AASLD) 0.5 mg), 11 ; ( 300 mg)+ (EASL) ( 600 mg), 10 ; ( [3], 300 mg)+ ( 100 mg), 3, 1.4 (NA) Hitachi 7180, Olympus 64,ALT 5 ~ 35 U / L HBV CHB TDF, CHB (IU / ml) : 1 材料和方法 1.1, 2012 1 2013 6, 1.6 55, TDF 31,TDF NA 24, t, χ 2 3 1,,P < 0.05 HBV-DNA 2010 Kaplan-Meier [4] 1 1.2 (1),, 2.1 ;(2) TDF TDF NA 37(24 ~ 60), 40(21 ~ 68) ; ; 17.4 (10.4 ~ 24.7),17.3 CHB (10.9-24.2) ;HBeAg(+) 87.1% (27 / 2012 31) 70.8% (17 / 24);HBV DNA lg ρ / 341, (IU / ml) 5.64 ± 1.48 5.28 ± 1.51, CHB 98, ALT,, 1 ( 1) TDF 31, TDF NA 24, 55 1.3 300 mg 1,TDF DNA ( ) 2 lg ρ / 4 12 24 36 48 72, 1.5 ( ) SPSS 13.0 2 结果 2.2 HBV DNA HBV DNA 4 12 24 36 48 72 HBV
522 ( ) 35 DNA (P = 0.148 ~,TDF 4 12 0.748),,TDF 24 (P < 0.05) 0 4 12 36 48 72, 4 12, 12 (P < 0.05), 24 36 48 72 ( P > 0.05; 1) TDF NA, 24 ( P > 0.05) TDF NA 36 48 72 ( 0 24, P > 0.05) TDF ( 1) 24 36 48 72, 4 12 12 24 (P < 0.05) 24 HBV DNA ( HBV DNA ) 3.50(0.80 ~ 11.6),TDF NA HBV DNA 3.75 (0.80 ~ 13.8) ( 2) 1 TDF TDF NA HBV DNA Fig.1 Comparison of HBV DNA levels between TDF monotherapy and in combination with other NA Fig.2 Comparison of HBV DNA undetectable rates 2.3 HBV DNA between TDF monotherapy and in combination with other TDF TDF NA NA HBV DNA Kaplan- 2.4 ALT Meier HBV DNA, ALT (Log Rankχ 2 =0.148,P=0.700) 2 TDF TDF NA HBV DNA ( 3) Kaplan-Meier Table 1 1 TDF TDF NA CHB The baselines of TDF monotherapy and in combination with other NA of CHB patients Age / years Sex (male,%) Booly mass / kg Follow-up time / months The proportion of alcohol history / % The proportion of smoking history / % Family history of hepatitis B / % ALT baseline / (U / L) HBV DNA baseline / lg ρ / (IU / ml) Rate of Hepatitis B E antigen positive / % TDF monotherapy(n = 31) 37(24-60) 77.4(24 / 31) 53.4 ± 5.7 17.4(10.4-24.7) 38.7(12 / 31) 45.2(14 / 31) 54.8(17 / 31) 244.1 ± 214.3 5.64 ± 1.48 87.1(27 / 31) TDF in combination with other NA(n = 24) 40(21-68) 75.0(18 / 24) 55.6 ± 6.0 17.3(10.9-24.2) 25.0(6 / 24) 41.7(10 / 24) 62.5(15 / 24) 227.0 ± 208.9 5.28 ± 1.51 70.8(17 / 24) P 0.076 0.834 0.169 0.617 0.283 0.796 0.568 0.769 0.374 0.135
4,. 72 523 ALT (Log Rank χ 2 = 0.188,P = 0.664), TDF 12 vs 24, 24 vs 36, 36 vs 48 (P < 0.05), 48 72 (Fisher,P = 0.237) TDF NA, 12 vs 24 24 vs 36, (P < 0.05); 36 48 (χ 2 = 1.613,P = 0.204) 3 TDF TDF NA ALT 2.5 HBV DNA HBV DNA Fig.3 Comparison of ALT normalization rates between (Cox ) 1, TDF monotherapy and in combination with other NA TDF TDF NA HBV DNA 2 HBV DNA Cox (P = 0.462), HBV DNA Table 2 Multivariate survival analysis of HBV DNA ALT e HBV DNA negative rate (Cox regression analysis) ( P > 0.05) Factors B SE Wald P 2.6 Sex (male) 0.181 0.383 0.224 0.636 Body mass / kg -0.042 0.028 2.277 0.131 TDF Age / years 0.000 0.015 0.000 0.987 (CK) 2 (2 ULN) 5.70% 0 4 12 24 36 48 72 :6.5%(2 / 31) 3.2%(1 / 31), 9.7%(3 / 31) 6.5% (2 / 31) 3.2% (1 / 31) 3.6% (1 / 28) 7.7% (2 / 26), Antivirus lg ρ(hbv DNA) / (IU / ml) ALT baseline / (U / L) E antigen status 0.461-0.034 0.001-0.693 0.627 0.096 0.001 0.404 0.540 0.128 2.100 2.950 0.462 0.720 0.147 0.086 TDF NA Antivirus: TDF monotherapy vs TDF + other NA CK 2 ULN 7.3%, 0 4 12 24 36 48 72 :8.3%(2 / 24),4.2%(1 / 24), 12.5%(3 / 24) 0 12.5%(3 / 24) 4.5%(1 / 22) 9.1%(2 / 22), 2 ~ 4 CK,,, TDF CHB, TDF, TDF, 31 TDF 24 TDF NA, (CR) HBV, 3 讨论, TDF TDF NA CHB TDF CHB,12,24 [6] TDF,, 24 HBV DNA, 2 lg ρ / (IU / ml) HBV ( P > 0.05), HBV TDF TDF NA CHB
524 ( ) 35, Marcellin [6] 48 HBeAg CHB HBV DNA CHB,TDF TDF NA 2.46 lg ρ / (IU / ml), HBeAg CHB HBV DNA 2.31 lg ρ / (IU / ml)(, 2.6 lg ρ / (IU / ml) 24 CHB TDF TDF NA [1] HBV DNA Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis,, B virus DNA level[j]. JAMA, 2006, 295(1): 65-73. HBV DNA [2] Ocama P, Opio CK, Lee WM. Hepatitis B virus, TDF infection: current status [J]. Am J Med, 2005, 118 TDF NA (12): 1413-1415. CHB Berg [7] [3] Davison S. Management of chronic hepatitis B virus, (168 ) infection[j]. J Hepatol, 2012, 57(1): 167-185. TDF TDF [4],. CHB HBV DNA, HBV DNA, ALT :2010 [J]. 24, 2011, 32(4):405-415. Chinese Society of Hepatology and Chinese Society of HBV DNA, HBV DNA Infectious Diseases, Chinese Medical Association, The TDF guideline of prevention and treatment for chronic TDF NA hepatitis B:2010 version [J]. Zhonghua Liu Xing Bing HBV DNA HBV DNA Xue Za Zhi, 2011, 32(4): 405-415. TDF TDF [5] Keskin O, Ormeci AC, Baran B, et al. Efficacy of NA HBV DNA tenofovir in adefovir -experienced patients compared to TDF TDF NA treatment -naive patients with chronic hepatitis B [J]. Antivir Ther, 2014, doi: 10.3851 / IMP2732. CHB, ALT [6] Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir ALT disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B[J]. N Engl J Med, 2008, 359(23): 2442- TDF 48 2455. ALT, 48 [7] Berg T, Zoulim F, Moeller B, et al. Long-term efficacy ;TDF NA 36 and safety of emtricitabine plus tenofovir DF vs. tenofovir, 36 DF monotherapy in adefovir -experienced chronic ALT 36 ~ 48,Pol [8] TDF CHB 24 ~ 36 hepatitis B patients[j]. J Hepatol, 2013, 60(4), 715-722. ALT, ALT [8] Pol S, Lampertico P. First -line treatment of chronic, hepatitis B with entecavir or tenofoir in real -life settings:from clinical trials to clinical practice [J]. J Viral Hepat, 2012, 19(6):377-386. TDF TDF NA [9] Heathcote EJ, Marcellin P, Buti M, et al. Three-year, efficacy and safety of tenofovir disoproxil fumarate CK, treatment for chronic hepatitis B [J]. Gastroenterology, CK 2011, 140(1): 132-143. CR, Heathcote [9] TDF 3 ( 编辑 孙慧兰 )