Original Article Adefovir dipivoxil combined with lamivudine in the treatment of hepatitis B cirrhosis
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Int J Clin Exp Med 2020;13(6):4202-4210 www.ijcem.com /ISSN:1940-5901/IJCEM0108864 Original Article Adefovir dipivoxil combined with lamivudine in the treatment of hepatitis B cirrhosis Jian Fu, Yi Gao, Panpan Li Department of Infection, Hainan General Hospital, Haikou, Hainan Province, China Received February 7, 2020; Accepted March 3, 2020; Epub June 15, 2020; Published June 30, 2020 Abstract: Objective: To compare the differences between lamivudine alone and adefovir dipivoxil combined with lamivudine in the treatment of hepatitis B cirrhosis in therapeutic effect. Hepatitis B virus (HBV)-DNA negative con- version rate, hepatitis Be antigen (HBeAg) negative conversion rate, liver function changes, quality of life score, and incidence of adverse reactions were investigated. Methods: A total of 70 patients with hepatitis B cirrhosis were selected as subjects. The patients were divided into an observation group and a control group, with 35 patients in each group. All patients were given routine treatment. During one year of treatment, the patients in the control group were treated with lamivudine alone, while those in the observation group were treated with adefovir dipivoxil combined with lamivudine. Results: After one year of treatment, compared with control group, the total effective rate of the observation group was significantly higher (91.4% vs 71.4%; P
Adefovir dipivoxil combined with lamivudine treatment hepatitis B cirrhosis
significantly improve the treatment effects [9]. pated and actively cooperated with the imple-
Therefore, it is of great value to find a method mentation of this study. Exclusion criteria: (1)
of drug combination with clear curative effects Patients with dysfunction of heart, kidney, lung
and less recurrence. and other important organs; (2) Patients com-
bined with malignant tumor diseases such as
Adefovir dipivoxil, as a new antiviral drug, and it liver cancer; (3) Patients combined with other
also belongs to nucleoside drugs. It can not types of hepatitis such as autoimmune hepati-
only inhibit reverse transcriptase, but also tis; (4) Patients with cirrhosis due to other
reduce the activity of DNA polymerase. A study causes; (5) Patients who used antiviral drugs
has shown that adefovir dipivoxil has a low drug before; (6) Patients with mental illness; (7)
resistance rate and a good effect in the pro- Patients who were allergic to drugs such as
cess of anti-HBV [10]. Thus, lamivudine and lamivudine or adefovir dipivoxil. According to
adefovir dipivoxil have their own advantages in the inclusion criteria and exclusion criteria,
anti-HBV, but the effects of lamivudine and patients were divided into an observation group
adefovir dipivoxil in combination on anti-HBV and a control group. Patients in the control
may be different, and no unified conclusion has group were treated with lamivudine alone, while
been formed. In one study, the therapeutic patients in the observation group were treated
effect was used as the monitoring index to with adefovir dipivoxil combined with lamivu-
compare the difference between lamivudine dine. This study was approved by the Ethics
and adefovir dipivoxil combined therapy and Committee of Hainan General Hospital, and all
other anti-HBV drugs such as entecavil [11]. the enrolled patients and their families signed
What’s more, the effects of lamivudine and the informed consent.
adefovir dipivoxil combined on liver function
indexes and HBV negative conversion rate in Treatment methods
patients with hepatitis B cirrhosis were ana-
lyzed before and after treatment [12]. At pres- All patients received symptomatic treatment,
ent, there are few reports on comparing the including liver protection, jaundice reduction,
effect of lamivudine combined with adefovir maintenance of internal environment stability,
dipivoxil and lamivudine alone on hepatitis B and nutritional support. In terms of anti-HBV,
cirrhosis. In this context, this study selected 70 patients in the control group only took lamivu-
patients with hepatitis B cirrhosis, and used dine (GlaxoSmithKline Pharmaceutical Co.,
liver function, therapeutic effect, QOL, adverse Ltd.) at a dose of 100 mg once a day; patients
reactions, HBV DNA negative conversion rate in the observation group were treated with ade-
and hepatitis Be antigen (HBeAg) negative con- fovir dipivoxil (GlaxoSmithKline Pharmaceutical
version rate as monitoring indexes to explore Co., Ltd.) and lamivudine. The dose of lamivu-
the anti-HBV effect of lamivudine combined dine was the same as that of control group. The
with adefovir dipivoxil. The results of this study dose of adefovir dipivoxil was 10 mg once a
will provide experimental basis and theoretical day. The treatments both lasted for 1 year.
basis for the treatment of hepatitis B cirrhosis. During the treatment period, if the patients had
side effects of drugs, could not recover after
Materials and methods symptomatic treatment, such that affected the
continuation of this study, they were withdrawn
Patients from this study.
A total of 75 patients with hepatitis B cirrho- Outcome measures
sis admitted to Hainan General Hospital from
January 2016 to December 2017 were select- Main observation indexes: The main observa-
ed in this research. Inclusion criteria: (1) Pa- tion indexes in this study included therapeutic
tients over 18 years old who met the diagnostic effect and HBV DNA negative conversion rate.
criteria for hepatitis B cirrhosis [13]; (2) Patients
who received anti-HBV treatment for the first The therapeutic effects of the two groups were
time for one year; (3) Patients whose HBeAg compared. After one year of treatment, the
and HBV DNA were positively expressed accord- evaluation criteria for the therapeutic effect of
ing to laboratory examination results before the patients were shown in Table 1 [14]. The
treatment; (4) Patients who voluntarily partici- total effective rate of treatment of each group
4203 Int J Clin Exp Med 2020;13(6):4202-4210Adefovir dipivoxil combined with lamivudine treatment hepatitis B cirrhosis Table 1. Evaluation criteria of therapeutic effect in patients with hepatitis B cirrhosis Therapeutic effect Evaluation criteria Ineffective There was no improvement in clinical symptoms and liver function indexes, or the decrease of liver function index was less than 50% of the index before treatment. Effective The clinical symptoms were relieved significantly, and the decrease of liver function index was more than 50% of the index before treatment. Markedly effective The clinical symptoms basically disappeared and the liver function returned to normal. 4204 Int J Clin Exp Med 2020;13(6):4202-4210
Adefovir dipivoxil combined with lamivudine treatment hepatitis B cirrhosis
Table 2. Comparison of general information The difference of liver function
Observation Control indexes between the two groups
Group t/χ2 P were compared before treatment
group (n=35) group (n=35)
Male/female (n) 22/13 20/15 0.238 0.626 and one year after treatment.
Age (year) 47.1 ± 3.8 45.8 ± 3.3 1.528 0.131
Venus blood, 3-5 mL was extract-
ed from elbow vein in the morning
Course of disease (year) 5.9 ± 0.7 6.2 ± 0.9 1.557 0.124
under fasting conditions and liver
Albumin (g/L) 28.7 ± 3.1 28.4 ± 2.9 0.418 0.677
function indexes (alanine trans-
Prothrombin activity (%) 45.7 ± 6.8 45.3 ± 5.9 0.263 0.794
aminase (ALT), aspartate trans-
Hypertension (n) 6 8 0.357 0.550 aminase (AST) and total bilirubin
Diabetes (n) 5 4 0.128 0.721 (TbiL)) were detected by the fully-
Child-Pugh classification 0.596 0.742 automatic biochemical analyzer
A 22 21 (purchased from Beckman Kurt
B 10 9 Co., Ltd., USA).
C 3 5
QOL scores were compared be-
tween the two groups before tre-
was calculated as: total effective rate of treat- atment and 3 months, 6 months and 1 year
ment = (1 - number of ineffective cases/total after treatment [15]. The QOL of patients was
number of cases) * 100%. evaluated by the simple scale of QOL measure-
ment. This scale is formulated by the World
The serum HBV DNA negative conversion rate Health Organization, and the items assessed
was compared between the two groups. At 3 mainly include psychological state, physiologi-
months, 6 months and 1 year after treatment, cal state, environmental field and social rela-
according to the operation steps in the instruc- tionship field. In a total score of 100, the lower
tions of HBV DNA fluorescence quantitative the score is, the worse the QOL is, and vice
PCR kit (Thermo Fisher Company, USA), the versa.
HBV DNA level of each group was detected by
ABI 7500 fluorescence quantitative PCR instru- Statistical analysis
ment (purchased from American Applied Bio-
SPSS 22.0 software was used to analyze the
systems Company), and finally the HBV DNA
experimental data. The measurement data
negative conversion rate of each group was cal-
were expressed as mean ± standard deviation,
culated. HBV DNA negative conversion rate =
and the enumeration data were expressed as
HBV DNA negative conversion cases/total ca-
percentage (%). Comparison between the two
ses * 100%. groups was performed by independent sample
t-test. Paired t-test was used for comparison
The serum HBeAg negative conversion rate
before and after treatment. Comparison be-
was compared between the two groups. At 3
tween different time points in the same group
months, 6 months and 1 year after treatment,
was conducted by ANOVA of repeated measure-
HBeAg level in each group was measured by
ment, and the post test was conducted by
the fully automated AXSYM SYSTEM immuno-
Bonferroni method. Chi-square test is used for
analyzer (purchased from Abbott Company, comparison between two groups. There was a
USA) according to the procedures in the enzy- significant difference at P0.05),
The secondary observation indexes of this stu- and there was comparability between the two
dy included liver function and QOL score. groups (Table 2). During the follow-up period, 1
4205 Int J Clin Exp Med 2020;13(6):4202-4210Adefovir dipivoxil combined with lamivudine treatment hepatitis B cirrhosis
group, 1 patient was lost to
follow-up and 1 patient wi-
thdrew from the study due
to cardiac insufficiency. Fi-
nally, 70 patients were en-
rolled in this study, including
35 in the observation group
and 35 in the control group.
Comparison of liver function
Figure 1. Comparison of ALT, AST indexes
and TBiL between the two groups.
A: AST; B: ALT; C: TBiL. Compared
with the same group before treat- Before treatment, there we-
ment, *PAdefovir dipivoxil combined with lamivudine treatment hepatitis B cirrhosis
Table 4. Comparison of QOL scores before and after treatment
Before At 3 months At 6 months At 1 year after
Group F P
treatment after treatment after treatment treatment
Observation group 59.8 ± 7.5 67.2 ± 6.8* 75.4 ± 7.1* 88.7 ± 8.6* 94.610Adefovir dipivoxil combined with lamivudine treatment hepatitis B cirrhosis
Table 6. Comparison of HBV DNA negative conversion rate and HBeAg negative conversion rate (n
(%))
HBV DNA negative conversion rate HBeAg negative conversion rate
Group At 3 months At 6 months At 1 year after At 3 months after At 6 months after At 1 year after
after treatment after treatment treatment treatment treatment treatment
Observation group 12 (34.3) 18 (51.4) 27 (77.1) 6 (17.1) 9 (25.7) 20 (57.1)
Control group 10 (28.6) 15 (42.9) 19 (54.3) 5 (14.3) 7 (20.0) 11 (31.4)
χ2 0.265 0.516 4.058 0.108 0.324 4.690
P 0.607 0.473 0.044 0.743 0.569 0.030
Note: HBV, hepatitis B virus; HBeAg, hepatitis Be antigen.
compete with dCTP so as to inhibit the replica- er, and have significant antiviral effects and low
tion of HBV and reduce the inflammatory re- incidence of induced drug resistance [21]. Woo
sponse in the liver, thereby preventing the fur- et al. reported that adefovir dipivoxil combined
ther deterioration of the disease and improve with lamivudine can reduce the risk of drug
prognosis [17]. Lee et al. showed that the resistance induced by lamivudine in patients
metabolites of lamivudine can also infiltrate with decompensated hepatitis B cirrhosis, and
into the DNA chain in the synthesis process of the antiviral effect is more significant [22]. The
HBV to interfere with the replication of HBV; but combination of drugs not only improves the
the normal metabolism of deoxy nucleoside effect of clinical treatment, but also avoids the
and the intracellular mitochondrial structure risk of drug resistance induced by monothera-
are rarely affected by this [18]. The results of py. The results of this study also showed that
this study showed that the total effective rate adefovir dipivoxil combined with lamivudine
of lamivudine alone in the treatment of hepati- was more effective than lamivudine alone.
tis B cirrhosis was 71.4%, and the HBV DNA Moreover, compared with control group, liver
negative conversion rate could reach 54.3%. function indexes including AST, ALT and TBiL
Compared with before treatment, using lamivu- levels in the observation group were significant-
dine alone could significantly improve the liver ly decreased, with significant differences. The
function and QOL of patients, and the incidence reason may be that the application of the drugs
of adverse drug reactions was low, which was in combination can inhibit the replication of
basically consistent with the results reported HBV, help to reduce the production of hepatitis
by Jaffe et al. [19]. In addition, another study cells, and transfer them to normal hepatocytes,
has reported that during the long-term antiviral thus improving the liver function of patients. In
therapy of lamivudine alone, drug withdrawal is addition, compared with control group, the QOL
likely to lead to recurrence and increase the score, HBV DNA negative conversion rate and
risk of drug resistance [20]. HBeAg negative conversion rate of the patients
in the observation group were significantly
In order to overcome the deficiency of lamivu- increased. The significant efficacy of combina-
dine, adefovir dipivoxil combined with lamivu- tion therapy compared with lamivudine alone,
dine was used in this study. At present, no sta- is conducive to the improvement of patients’
tistical conclusion has been drawn on the effect QOL, and this is similar to the results reported
of combined antiviral drugs in patients with by Srivastava et al. and Yang et al. [23, 24]. In
hepatitis B cirrhosis. Adefovir dipivoxil, one of addition, in terms of drug safety, both groups of
the acyclic analogs of 5’-monophosphate deo- patients showed mild adverse drug reactions
xyadenosine, is currently believed to have an without significant difference, although the
antiviral mechanism different from lamivudine, observation group showed slightly higher inci-
as it can inhibit the replication of HBV DNA. dence than the control group, indicating that
Mainly, the drug is converted into adefovir the adverse drug reactions of combined drugs
diphosphate by phosphorylation in the body, were acceptable and relatively safe.
and after adefovir diphosphate is integrated
into the HBV DNA, the DNA chain length is ter- There were some limitations in this study in-
minated or the drug competes with dCTP to pro- cluding the small sample size, single-center
duce an antiviral effect. Compared with lamivu- study, lacking of long-term follow-up results, no
dine, adefovir dipivoxil is reported to be cheap- classification comparison, and unclear relevant
4208 Int J Clin Exp Med 2020;13(6):4202-4210Adefovir dipivoxil combined with lamivudine treatment hepatitis B cirrhosis
mechanism. A multicenter controlled study with rhosis 2015. J Gastroenterol 2016; 51: 629-
large sample size and long-term follow-up is 650.
needed for further confirmation in the fu- [5] Tsai MC, Chen CH, Hu TH, Lu SN, Lee CM,
ture. Wang JH and Hung CH. Long-term outcomes of
hepatitis B virus-related cirrhosis treated with
In conclusion, adefovir dipivoxil combined with nucleos(t)ide analogs. J Formos Med Assoc
2017; 116: 512-521.
lamivudine is more effective than lamivudine
[6] Grossi G, Viganò M, Loglio A and Lampertico P.
alone in antiviral treatment for patients with
Hepatitis B virus long-term impact of antiviral
hepatitis B cirrhosis, with high HBV DNA nega- therapy nucleot(s)ide analogues (NUCs). Liver
tive conversion rate, significant improvement in Int 2017; 37: 45-51.
liver function indexes, high QOL, and relative [7] Yue-Meng W, Li YH, Wu HM, Yang J, Xu Y, Yang
safety. The results of this study provide experi- LH and Yang JH. Telbivudine versus lamivudine
mental basis for clinical treatment of hepatitis and entecavir for treatment-naïve decompen-
B cirrhosis. sated hepatitis B virus-related cirrhosis. Clin
Exp Med 2017; 17: 233-241.
Disclosure of conflict of interest [8] Lv GC, Yao JM, Yang YD, Zheng L, Sheng JF,
Chen Y and Li LJ. Efficacy of combined therapy
None. in patients with hepatitis B virus-related de-
compensated cirrhosis. World J Gastroenterol
Address correspondence to: Jian Fu, Department 2013; 19: 3481-3486.
of Infection, Hainan General Hospital, No. 19 Xiu- [9] Zhang D, Zhao G, Li L and Li Z. Observation of
hua Road, Xiuying District, Haikou 570311, Hainan combined/optimized therapy of Lamivudine
Province, China. Tel: +86-0898-65380855; Fax: and Adefovir Dipivoxyl for hepatitis B-induced
+86-0898-65380855; E-mail: fujianhn1h@163. decompensated cirrhosis with baseline HBV
com DNA>1,000 IU/mL. Acta Gastroenterol Belg
2017; 80: 9-13.
References [10] Wang GL, Liu Y, Qiu P, Zhou SF, Xu LF, Wen P,
Wen JB and Xiao XZ. Cost-effectiveness of La-
[1] Van Tong H, Hoan NX, Binh MT, Quyen DT, Mey- mivudine, Telbivudine, Adefovir Dipivoxil and
er CG, Song LH, Toan NL and Velavan TP. Inter- Entecavir on decompensated hepatitis B virus-
feron-stimulated gene 20 kDa protein serum related cirrhosis. Eur Rev Med Pharmacol Sci
levels and clinical outcome of hepatitis B virus- 2016; 20: 866-872.
related liver diseases. Oncotarget 2018; 9: [11] Lian JS, Zeng LY, Chen JY, Jia HY, Zhang YM,
27858-27871. Xiang DR, Yu L, Hu JH, Lu YF, Zheng L, Li LJ and
[2] Chen VL, Yeh ML, Le AK, Jun M, Saeed WK, Yang YD. De novo combined lamivudine and
Yang JD, Huang CF, Lee HY, Tsai PC, Lee MH, adefovir dipivoxil therapy vs entecavir mono-
Giama N, Kim NG, Nguyen PP, Dang H, Ali HA, therapy for hepatitis B virus-related decom-
Zhang N, Huang JF, Dai CY, Chuang WL, Rob- pensated cirrhosis. World J Gastroenterol
erts LR, Jun DW, Lim YS, Yu ML and Nguyen 2013; 19: 6278-6283.
MH. Anti-viral therapy is associated with im- [12] Wang M, Yuan L, Qiao B and Li Y. Two rescue
proved survival but is underutilised in patients therapies in lamivudine-resistant patients with
with hepatitis B virus-related hepatocellular chronic hepatitis B in the central China: adefo-
carcinoma: real-world east and west experi- vir monotherapy and adefovir plus lamivudine.
ence. Aliment Pharmacol Ther 2018; 48: 44- Virus Genes 2014; 48: 32-37.
54. [13] The Chinese Medical Association Branch of
[3] Yang SC, Lee CM, Hu TH, Wang JH, Lu SN, Liver Disease and Infection Epidemiology
Hung CH, Changchien CS and Chen CH. Viro- Branch of Chinese Medical Association. Chron-
logical response to entecavir reduces the risk ic hepatitis B prevention guide (2010 edition).
of liver disease progression in nucleos(t)ide Gastroenterology 2011; 16: 351-366.
analogue-experienced HBV-infected patients [14] Lai XJ, Lian JS, Chen JY, Zhang YM, Jia HY,
with prior resistant mutants. J Antimicrob Che- Zheng L and Yang YD. Efficacy and safety of
mother 2013; 68: 2154-2163. Entecavir monotherapy switched from Lamivu-
[4] Fukui H, Saito H, Ueno Y, Uto H, Obara K, Sakai- dine combined Adefovir Dipivoxil for chronic
da I, Shibuya A, Seike M, Nagoshi S, Segawa hepatitis B virus-related compensated liver cir-
M, Tsubouchi H, Moriwaki H, Kato A, Hashimo- rhosis. Zhonghua Gan Zang Bing Za Zhi 2018;
to E, Michitaka K, Murawaki T, Sugano K, 26: 113-118.
Watanabe M and Shimosegawa T. Evidence- [15] Keskin G, Gümüs AB and Orgun F. Quality of
based clinical practice guidelines for liver cir- life, depression, and anxiety among hepatitis B
4209 Int J Clin Exp Med 2020;13(6):4202-4210Adefovir dipivoxil combined with lamivudine treatment hepatitis B cirrhosis
patients. Gastroenterol Nurs 2013; 36: 346- [21] Sun Y, Wu K, Shen F, Qiu L, Chen B, Yu L and
356. Chang S. Effects of the combined administra-
[16] Wu CC, Chen YS, Cao L, Chen XW and Lu MJ. tion of entecavir and adefovir dipivoxil to im-
Hepatitis B virus infection: defective surface prove hepatic fibrosis in hepatitis B patients
antigen expression and pathogenesis. World J with interferon resistance. Minerva Med 2017;
Gastroenterol 2018; 24: 3488-3499. 108: 507-512.
[17] Shi H, Han Z, Liu J, Xue J, Zhang S, Zhu Z, Xia J [22] Woo HY, Choi JY, Yoon SK, Suh DJ, Paik SW,
and Huang M. Comparing efficacy of lamivu- Han KH, Um SH, Kim BI, Lee HJ, Cho M, Lee
dine, adefovir dipivoxil, telbivudine, and ente- CK, Kim DJ and Hwang JS. Rescue therapy with
cavir in treating nucleoside analogues naïve adefovir in decompensated liver cirrhosis pa-
for hbeag-negative hepatitis b with medium tients with lamivudine-resistant hepatitis B vi-
hepatitis B virus (HBV) DNA levels. Med Sci rus. Clin Mol Hepatol 2014; 20: 168-176.
Monit 2017; 23: 5230-5236. [23] Srivastava M, Singh N, Dixit VK, Nath G and
[18] Lee KS, Kweon YO, Um SH, Kim BH, Lim YS, Jain AK. Comparative evaluation of long-term
Paik SW, Heo J, Lee HJ, Kim DJ, Kim TH, Lee monotherapies & combination therapies in pa-
YS, Byun KS, Kim D, Lee MS, Yu K and Suh DJ. tients with chronic hepatitis B: a pilot study.
Efficacy and safety of entecavir versus lamivu- Indian J Med Res 2016; 144: 424-432.
dine over 5 years of treatment: a randomized [24] Yang S, Xing H, Wang Q, Wang X, Liu S and
controlled trial in Korean patients with hepati- Cheng J. De novo entecavir+adefovir dipivoxil+
tis B e antigen-negative chronic hepatitis B. lamivudine triple-resistance mutations result-
Clin Mol Hepatol 2017; 23: 331-339. ing from sequential therapy with adefovir dipiv-
[19] Jaffe A and Brown RS Jr. A review of antiviral oxil, and lamivudine. Ann Clin Microbiol Antimi-
use for the treatment of chronic hepatitis B vi- crob 2016; 15: 24.
rus infection in pregnant women. Gastroenter-
ol Hepatol (N Y) 2017; 13: 154-163.
[20] Chao DC and Hu KQ. Update on rescue thera-
pies in patients with lamivudine-resistant
chronic hepatitis B. Drug Des Devel Ther 2013;
7: 777-788.
4210 Int J Clin Exp Med 2020;13(6):4202-4210You can also read
