The use of Chinese herbal medicines associated with reduced mortality in chronic hepatitis B patients receiving lamivudine treatment
Der-Shiang Tsai1, Mei-Hsuen Huang1, Yuan-Shiun Chang1 , Tsai-Chung Li2,3, Wen-Huang
Peng1,*
1 Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources,
College of Pharmacy, China Medical University, Taichung, Taiwan
2 Graduate Institute of Biostatistics, College of Public Health, China Medical
University, Taichung, Taiwan
3 Department of Health Care Administration, College of Health Science, Asia
University, Taichung, Taiwan
* Corresponding author: Taiwan. Tel: 886-2-2205-3366-5505 Email address: whpeng@mail.cmu.edu.tw
Abbreviation:
Chinese herbal medicines (CHMs); Chronic hepatitis B (CHB); National Health Insurance (NHI); National Health Insurance Research Database (NHIRD) Jia-Wei-Xiao-Yao-San (JWXYS)
Chemical compounds studied in this article: Lamivudine (PubChem CID: 60825)
Keywords:
Lamivudine, National Health Insurance Research Database, Jia-Wei-Xiao-Yao-San
Conflict of interest:
I. Introduction
Chronic hepatitis B (CHB) virus infection is a common cause of cirrhosis and hepatocellular carcinoma, and an estimated 240 million people chronically infected with hepatitis B in the world . The disease occurs most frequently in the Middle East, Africa and Asia, and is most frequently transmitted from mother to newborn or as are result of close contacts during childhood .
There is no way to cure the patients chronically infected with HBV. Interferon and nucleot(s)ide analogues were the generally approved treatment for chronic hepatitis B . Lamivudine was the first oral antiviral therapy approved for the treatment of CHB. Lamivudine is a nucleoside analogue that rapidly and profoundly suppresses HBV replication through inhibition of viral DNA synthesis . Lamivudine monotherapy is effective for suppressing HBV replication and improving liver disease, with HBeAg seroconversion rates of up to 50% after 5 years of treatment in HBeAg-positive patients and response rates of up to 70% after 1 year of treatment in HBeAg-negative patients . Unfortunately, cumulative rate of lamivudine resistance in patients with CHB after 5 years treatment increased up to 70% . At this time, adding adefovir to LAM or switching to tenofovir monotherapy are the first-line recommendations for rescue therapy .
In Taiwan, National Health Insurance (NHI) offers two kinds of medical service, including Western medicine and traditional Chinese medicine. Insurant may receive these two kinds of healthcare simultaneously. NHI, the only national and official health insurance in Taiwan has established since 1995, covers nearly all inhabitants Thus, the NHI research database (NHIRD) is a platform for understanding the
utilization of traditional Chinese medicine therapies by traditional medicines (CHMs) seem effective as alternative remedies for patients with CHB . As early as 2008, scholar Chen reported that Jia-Wei-Xiao-Yao-San (JWXYS) was the second most frequently prescribed herbal formulas used to treat chronic hepatitis in Taiwan . Moreover, another earlier study also found that JWXYS combined with lamivudine therapy showed the better effect in HBV DNA clearance rate compared to lamivudine monotherapy in a one year follow-up research . JWXYS is prescribed mainly to pacify the liver, spread liver Qi, strengthen the spleen, nourish blood and Yin, regulate menstruation, sedate the heart and clear heat. To the best of our knowledge, it has not been reported by a large-scale clinical trial on mortality in patients with CHB using CHMs who receive lamivudine treatment. The aim of the study was to evaluate the association of CHMs use with outcome of CHB patients receiving lamivudine treatment, and further to estimate the association of JWXYS use with mortality of those patients.
2. Materials and methods
2.1. Research Database
The NHI system in Taiwan is a compulsory, single-payer program that provides health coverage to nearly every individual in Taiwan. Currently, 99.6% of residents are covered by NHI . The Bureau of NHI allowed a random selection of 1 million representative patient records from the NHIRD (23 million insured individuals) to be distributed for research. Age, sex distribution, and premiums paid were not found to be statistically significant difference between the 1 million insured individuals and the general population . In the current retrospective population-based follow-up
cohort study, we analyzed 1 million patients randomly selected from 23 million beneficiaries in the NHIRD between January 1, 2004 and December 31, 2011. The NHIRD contains outpatient and inpatient information including age, sex, living area, date of visit, date of admission, ICD-9-CM codes, and detailed prescription records. The diagnoses and treatments provided by Western and Chinese medicine physicians were all included. This study was approved by the Joint Institutional Review Board of China Medical University.
2.2. Study Population
Lamivudine treatment in patients with chronic hepatitis B can only be used if authorized by specialist gastroenterologist and/or supported by pathology examination reports in our NHI policy. The selection of study subjects from the random sample of one million individuals was performed as follows (Figure 1). First, patients with chronic hepatitis B who first received lamivudine treatment during 2004 to 2011 were retrieved from NHIRD. Second, in order to strengthen the validity of our result, participants with pre-existing medical conditions (e.g. hepatoma) and enrolled cases that previously received anti-virus therapy (e.g. interferon) were excluded. Therefore, the cases with (1) first lamivudine treatment date after Dec.31, 2010, (2) previous diagnosis of hepatoma, (3) ever received interferon therapy, (4) ever diagnosis of alcoholic hepatitis, and (5) age <20 years were excluded. Third, we further divided these cases into CHMs users and nonusers to evaluate the association of CHMs therapy with all-cause mortality in cases followed up until the end of 2011. The time of cases receiving lamivudine treatment was defined as the index date.
registry for beneficiary files, including age, sex, urbanization, hepatitis C or D infection, and cirrhosis status was determined according to the index date. The baseline comorbidities were determined using the modified version of the Elixhauser comorbidity index according to the patient medical records 2 years before the index date . These comorbidities include diabetes mellitus, hypertension, coronary artery disease, congestive heart failure, stroke, chronic lung disease, chronic kidney disease and drug abuse. The type of treatment was considered as the management that a patient with chronic hepatitis B received after the index date until the end of the follow-up period, including anti-virus medicines (entecavir, adefovir, telbivudine, and ribavirin), silymarin, immune system modulator (interferon), and CHMs.
2.3. Exposure to CHMs
The NHIRD records detailed prescribing information for both CHMs and Western medicines, including drug name, dose, start date, frequency, duration, and method of administration. All CHMs covered by the NHI were prescribed by board-certified Chinese medicine physicians who received rigorous training in both Chinese and Western medicines in medical schools and through residency programs in hospitals. These physicians must also pass the national licensing examinations. CHMs are prescribed by Chinese medicine physicians according to traditional Chinese medicine symptom patterns. Patients ever using CHMs due to diagnosis of chronic hepatitis B were defined as CHMs users, whereas others were considered as CHMs nonusers. Moreover, to observe a dose response relationship, we further grouped CHMs users into two groups: one group used CHMs <240 days whereas the other group used CHMs for ≧240 days. Same as above mentioned, JWXYS also divided into two groups by whether the duration over 90 days or cumulative defined daily doses (DDDs) over
210 g or not to observe a dose response relationship.
2.4. Study outcome
The study outcome was all-cause mortality (overall) during the 8 year follow-up. The patient’s date of death was determined according to the Registry of Catastrophic Illness Database of the NHIRD. The analysis period began from the index date and ended at the death of a patient, withdrawal from NHI, or the end of 2011, whichever occurred first.
2.5. Analysis
The continuous variables were summarized using means and standard deviations, whereas the categorical variables were summarized using counts and percentages. The continuous variables of the baseline demographic characteristics were analyzed using a Student t test, and the categorical variables were analyzed using a Chi-Square or Fisher exact test. The cumulative probability of survival for CHMs users and nonusers was estimated using a Kaplan-Meier estimator with a log-rank test used to compare the survival curves between the groups. Cox proportional hazards models were applied to estimate the crude and adjusted hazard ratio (HR) and 95% confidence intervals (CI). The study endpoint was all-cause mortality. Patients who were alive at the time of last follow-up were censored at the date of withdrawal from NHI or the end of the study period, whichever came first. To verify the dose-response relationship between CHMs use and mortality, we treated CHMs use category as a continuous variable to calculate the P value of the trend. All analyses were performed using SAS statistical software (version 9.3; SAS Institute Inc, Cary, NC).
3. Results
Of the 1 million people randomly selected from the NHIRD between 2004 and 2011, 1,325 patients were diagnosed with chronic hepatitis who received lamivudine. We further excluded 69 cases with first lamivudine treatment date before Dec. 31, 2010 and 174 cases with diagnosis of hepatoma, 5 cases who ever received interferon therapy, 45 cases with diagnosis of alcoholic hepatitis, and 10 cases with age <20 years. Of the remaining 1,037 eligible patients, 531 were CHMs nonusers, whereas the remaining 506 patients were CHMs users, including 260 users who took CHMs below 240 days and 246 users who used it for over 240 days (Fig 1).
Demographic characteristics of the study population of survival, such as age, sex, urbanization, baseline decompensated status, baseline hepatitis B or C infection, baseline comorbidity included diabetes mellitus, coronary artery disease, congestive heart failure, stroke, chronic lung disease, drug abuse, types of Western medicine treatment and CHMs use are shown in Table 1. The mean follow-up period for the patients was 5.26yrs ± 2.21 years; 88 deaths occurred and the all-cause mortality rate in the 8-year follow- up period was 8.5% during the analysis period. CHMs users had 21 deaths (23.7%) and CHMs nonusers had 67 deaths (12.6%). The Kaplan-Meier survival curve and log-rank test in overall survival revealed a statistically significant difference between the survival curves of the groups (log-rank, p<0. 0001) (Fig. 2).
The independent predictors of increased all-cause mortality included age (aHR=4.48, 95% CI: 2.12-9.48 for age 40-59 years; aHR=12.13, 95% CI: 5.21-25.81 for age 60-79 years; aHR=46.4, 95% CI: 12.15-179.62 for age ≧80 years) with
dose-response relationship and chronic kidney disease (aHR=2.11, 95% CI: 1.10-4.02) (Table 2). Either in univariate or multivariate model, lamivudine showed dose-response relationship on mortality in patients with CHB. (aHR=0.49, 95% CI: 0.26-0.93 for 180-359 DDDs; aHR=0.17, 95% CI: 0.09-0.33 for 360-539 DDDs; aHR=0.13, 95% CI: 0.26-0.93 for ≧540 DDDs; Cochran-Armitage test for tend, p<0.0001).
The unadjusted Cox regression analysis demonstrated a strong association between the use of CHMs and a decrease in mortality (Table 3). Compared with CHMs nonusers, CHMs users had reduced mortality by 70% (95% CI: 0.18-0.49). On the multivariate Cox model controlling for all confounders, the use of CHMs remained highly associated with decreased mortality (aHR= 0.45, 95% CI: 0.27-0.76). Further analysis demonstrated a dose-response relationship between CHMs use and mortality. The adjusted HR was 0.51 (95% CI: 0.27-0.98) and 0.39 (95% CI: 0.20-0.80) for patients with CHMs use <240 days and ≧240 days, respectively. The longer the duration of CHMs use, the lower the mortality rate (Cochran-Armitage test for trend,
p<0.0001).
We further replaced the variables traditional Chinese medicine use with prescribed Chinese herbal product containing JWXYS. It was found that there was a significant difference between JWXYS users and JWXYS nonusers after adjusting all other risk factors. Further analysis showed no dose-response relationship after grading with the estimated days or doses of prescribed Chinese herbal products containing JWXYS. Variable classified by days, non-JWXYS CHMs users had reduced mortality by 47% (95% CI: 0.30-0.92), JWXYS CHMs users for prescribing <90 days had statistical significance in reducing mortality by 83% (95% CI: 0.04-0.71) and JWXYS CHMs users for prescribing over 90 days had no statistical significance in reducing
mortality by 54% (95% CI: 0.06-3.46, p=0.45) after adjusting all other risk factors. Only 24 users in group of prescribing JWXYS over 90 days might affect the result. Variable classified by gram, non-JWXYS CHMs users had reduced mortality by 49% (95% CI: 0.30-0.88), JWXYS CHMs for prescribing <210 g had statistical significance in reducing mortality by 89% (95% CI=0.02-0.82) and JWXYS CHMs users for prescribing ≧210g had no statistical significance in reducing mortality by 67% (95% CI: 0.05-2.45,
p=0.28) after adjusting all other risk factors. Only 41 users in group of prescribing
Figure 1
Flow chart illustrating the selection of cases. NHIRD refers to National health insurance research database.
One million random sample of NHIRD, N=1,000,000
Evaluate the association of Chinese herbal medicines therapy with all-cause mortality in cases followed up until the end of 2011
Eligible cases, N=1,037
All new cases with chronic hepatitis B receiving lamivudine therapy during 2004-2011, N=1,325
Exclusion of
69 cases with first lamivudine treatment date after Dec. 31, 2010,
174 cases with diagnosis of hepatoma, 5 cases who ever received interferon therapy, 45 cases with diagnosis of alcoholic hepatitis, and 10 cases with age <20
Figure 2
Kaplan-Meier curves of overall survival in patients with chronic hepatitis B after lamivudine treatment according to Chinese herbal medicines (CHMs) use during the follow-up period. (log-rank, p<0.0001)
CHMs user
Table 1
Demographic characteristic of the study by survival
---Total(N=1037) Survival (N=949) Decease (N=88)
--- ---
---Characteristic Mean±SD or NO. (%) Mean±SD or NO. (%) Mean±SD or NO. (%) p
---Age (mean, yrs) 44.9±14.9 42.2±13.6 59.8±14.34 <0.0001
Age <0.0001 20-39 469 459 (48.4) 10 (11.4) 40-59 431 394 (41.5) 37 (42.0) 60-79 130 94 (9.9) 36 (40.9) ≧80 7 2 (0.2 5 (5.7) Male 729 671 (70.7) 58 (65.9) 0.35 Urbanization 0.03 Low 647 600 (63.2) 47 (53.4) Moderate 328 297 (31.3) 31 (35.2) High 62 52 (5.5) 10 (11.4) Hepatitis virus 0.06 Only B 958 874 (92.1) 84 (95.5) B + C 28 28 (3.0) 0 (0.0) B + D 48 44 (4.6) 4 (4.5) Others 3 3 (0.3) 0 (0.0) Cirrhosis 0.01 No 795 745 (78.5) 50 (56.8) Compensation 97 81 (8.5) 6 (6.8) Decompensation 145 123 (13) 12 (13.6) Comorbiditya DM 138 114 (12.0) 24 (27.3) <0.0001 Hypertension 206 172 (18.1) 34 (38.6) <0.0001 CAD 84 71 (7.5) 13 (14.8) 0.02 CHF 27 21 (2.2) 6 (6.8) 0.01 Stroke 40 30 (3.2) 10 (11.4) 0.0001 CLD 218 188 (19.8) 30 (34.1) <0.01 CKD 61 47 (5.0) 14 (15.9) <0.0001 Drug abuse 14 11 (1.2) 7 (8.0) <0.0001 Type of treatment Lamivudine (DDDs)b
<90 95 71 (7.5) 24 (27.3) <0.0001 90-179 88 71 (7.5) 17 (19.3) 180-359 201 181 (19.1) 20 (22.7) 360-539 371 355 (37.4) 16 (18.2) ≧540 282 271 (28.6) 11 (12.5) Adfovir 6 0 (0.0) 6 (6.8) <0.0001 Entecavir 25 23 (2.4) 2 (2.3) 0.93 Telbivudine 20 19 (2.0) 1 (1.1) 0.57 Tenofovir 6 6 (0.6) 0 (0.0) 0.45 Interferon 20 0 (0.0) 29 (33.0) <0.0001 Silymarin 543 508 (53.5) 35 (39.8) 0.01 CHMs userc 506 485 (51.1) 11 (23.9) <0.0001 JWXYS CHMs userd 143 140 (14.8) 3 (3.4) <0.0001
---a DM refers to Diabetes Mellitus, CAD refers to coronary artery disease, CHF refer s to congestive heart failure; CLD refers to
chronic lung disease, CKD refers to chronic kidney disease
b DDDs refers to defined daily doses.
C CHMs refers to Chinese herbal medicines
Table 2
Association between demographic characteristics and mortality
---Univariate analysis Multivariate analysis
---
---Variable HR (95% CI) p aHR (95% CI)a p
---Age 20-39 1 1 40-59 4.45 (2.21-8.95) <0.0001 4.48 (2.12-9.48) <0.001 60-79 16.50 (8.18-33.28) <0.0001 12.13 (5.21-25.81) <0.0001 ≧80 45.93 (15.63-135.00) <0.0001 46.40 (12.15-179.62) <0.0001 Cochran–Armitage test for trend, p<0.0001
Male 0.79 (0.51-1.23) 0.29 1.18 (0.73-1.88) 1.17 Urbanization Low 1 1 Moderate 1.32 (0.84-2.07) 0.24 1.20 (0.74-2.00) 0.45 High 2.34 (1.18-4.63) 0.02 1.23 (0.59-2.55) 0.59 Virus Only B 1 1 B + C - -B + D 0.93 (0.34-2.54) 0.89 1.07 (0.38-3.04) 0.90 Others - - - -Cirrhosis No 1 1 Compensation 2.89 (1.64-5.07) <0.001 2.20 (1.18-4.12) 0.01 Decompensation 2.48 (1.5-4.1) <0.001 1.61 (0.92-2.81) 0.09 Comorbidityb DM 2.62 (1.64-4.19) <0.0001 1.72 (0.96-3.07) 0.07 Hypertension 2.82 (1.83-4.33) <0.0001 0.69 (0.38-1.25) 0.22 CAD 2.15 (1.19-3.88) 0.01 0.90 (0.47-1.73) 0.76 CHF 3.06 (1.33-7.01) <0.001 0.81 (0.32-2.09) 0.67 Stroke 3.75 (1.94-7.26) <0.0001 1.11 (0.51-2.43) 0.79 CLD 2.07 (1.33-3.22) <0.01 1.20 (0.73-1.98) 0.47 CKD 3.46 (1.95-6.13) <0.0001 2.11 (1.10-4.02) 0.02 Drug abuse 3.02 (1.00-9.57) 0.06 2.78 (0.79-9.78) 0.11 Type of treatment Lamivudine (DDDs)c
<90 1 1
90-179 0.70 (0.38-1.30) 0.26 0.89 (0.45-1.75) 0.74 180-359 0.32 (0.18-0.58) <0.001 0.49 (0.26-0.93) 0.03 360-539 0.13 (0.07-0.25) <0.0001 0.17 (0.09-0.33) <0.0001
≧540 0.12 (0.06-0.25) <0.0001 0.13 (0.06-0.28) <0.0001 Cochran–Armitage test for trend, p<0.0001
Adfovir - - - -Entecavir 0.92 (0.23-3.75) 0.92 1.98 (0.47-8.43) 0.36 Telbivudine 0.56 (0.08-4.04) 0.56 0.54 (0.07-4.14) 0.55 Tenofovir - - - -Interferon 0.55 (0.08-3.92) 0.55 0.49 (0.06-3.96) 0.50 Silymarin 0.55 (0.36-0.84) <0.01 0.73 (0.46-1.15) 0.17
---a Adjusted all variables listed.above
b DM refers to Diabetes Mellitus, CAD refers to coronary artery disease, CHF refer s to congestive heart
failure; CLD refers to chronic lung disease, CKD refers to chronic kidney disease, CHM refers to Chinese herbal medicines
Table 3
Association between Chinese herbal medicines use and mortality
---Univariate analysis Multivariate analysis
---
---Variable HR (95% CI) p aHR (95% CI)a p
---CHMs useb No 1 Yes 0.3 (0.18-0.49) <0.0001 0.45 (0.27-0.76) <0.01 CHMs user (day) No 1 <240 0.34 (0.18-0.62) <0.001 0.51 (0.27-0.98) 0.04 ≧240 0.26 (0.13-0.53) <0.001 0.39 (0.20-0.80) 0.01 Cochran–Armitage test for trend, p<0.001
JWXYS CHMs userc
No 1 1
Yes 0.20 (0.06-0.64) <0.01 0.26 (0.08-0.83) 0.02 JWXYS CHMs user (day)
Non-CHMs user 1 1 Non-JWXYS CHMs user 0.34 (0.20-0.58) <0.001 0.53 (0.30-0.92) 0.02 JWXYS CHMs user <90 0.12 (0.03-0.48) <0.01 0.17 (0.04-0.71) 0.02 ≧90 0.29 (0.04-2.10) 0.22 0.46 (0.06-3.46) 0.45 JWXYS CHMs user (g) Non-CHMs user 1 1 Non-JWXYS CHMs user 0.35 (0.21-0.58) <0.001 0.51 (0.30-0.88) 0.02 JWXYS CHMs user <210 0.08 (0.01-0.55) 0.01 0.11 (0.02-0.82) 0.03 ≧210 0.18 (0.02-1.24) 0.08 0.33 (0.05-2.45) 0.28
---a Adjusted all variables in Table 2.
b CHMs refers to Chinese herbal medicines c JWXYS refers to Jia-Wei-Xiao-Yao-San
4. Discussion
This population-based cohort study suggests that CHMs uses associated with reduced all-cause mortality in patients with chronic hepatitis B who received lamivudine treatment. Furthermore, we also found JWXYS associated with a similar effect. This is the first study to our limited knowledge conducted in National Health Insurance Healthcare System where patients receive almost all care within this system, and information on chronic hepatitis risk factors, lamivudine therapy, use of CHMs are available. This research has a number of strengths that deserve attention compared with previous population-based studies. First, to minimize the selection bias, the current data extracted from a single, large nationwide database with 1 million representative beneficiaries. Second, to mitigate CHMs prescription information bias, the full records adapted from NHIRD, including drug names, dose and days of administration. Third, to reduce confounding bias of less chronic hepatitis severity, we restricted the study population to those with chronic hepatitis receiving lamivudine. Finally, all lamivudine prescriptions ordered only by gastroenterological specialist and CHMs prescription only by board certified Chinese medicine physicians.
Currently, the approved remedies worldwide for patients with CHB are interferon and nucleos(t)ide analogues (e.g. lamivudine, adefovir, entecavir, telbivudine, and tenofovir) . However, the overall therapeutic efficacy of interferon is limited by its inconvenient parenteral route of administration, unpleasant side effects and expense. Although patients treated with lamivudine or other nucleoside analogues generally respond well to the medication and experience fewer side effects, in many cases the HBV replication increases markedly as soon as the treatment is stopped .
Furthermore, the emergence of drug resistance and viral variation limit their efficacy as therapeutic agents for CHB, and the newer nucleoside analogues are prohibitively expensive for many countries. Lamivudine was the first antiviral agent applied to treat CHB virus in Taiwan since 2004, and was currently one of the largest usage of West remedies for treatment of CHB. In our analysis, lamivudine markedly improve the mortality in CHB patients with dose-response relationship. The results are similar to other studies that reported long-term nucleoside therapy potential improve the mortality in CHMs patients . The longer the use of lamivudine, the lower the mortality rate.
Age also offered a predictive factor. Our data showed that the earlier the use of lamivudine, the lower the mortality rate, which is similar to another study . In our data, 23.3 % of the total cases were cirrhosis (Appendix table 1). The mortality was still higher in CHB patients with cirrhosis than without cirrhosis, even after lamivudine therapy.
The prevalence of CHMs use in our country from 1,000,000 random sample cases was about 26% (Appendix figure 1a). About 49 % of CHB patients used CHMs (Appendix table 2) during the study periods. CHMs users had less mortality compared to CHMs nonusers in CHB patients. Our data showed a dose-response relationship between these two groups, both in univariate and multivariate analysis. The longer the use of CHMs, the lower the mortality rate. While we found association between CHMs use and survival of patients with CHB receiving lamivudine treatment, it remains debate that CHMs cannot work in chronic hepatitis B. The basic pharmacological data have provided relatively strong evidences and suggested some CHMs have anti-HBV effect in cell and animal models. Nine extracts
isolated from 18 Chinese herbs showing strong inhibitory effect on HBV DNA, HBeAg or HBsAg release with low cytotoxicity in HepG2.2.15 cells and agents from 12 Chinese herbs showing the highest inhibition rates of plasma duck HBV DNA of more than 50% in duck HBV-infected ducks . Of course, these studies on the anti-HBV effect in cell and animal models provided potential perspective in the understanding of CHMs in the treatment of hepatitis B, and may not apply to humans.
Our results are similar to at least two published large systemic analytical review studies (observational study) that reported obvious association between CHMs use and survival in patients with CHB. One of these large analytical review studies by Liu and colleagues found some CHMs may work in patients with CHB, including Fuzheng Jiedu Tang (compounds of herbs) show significantly positive effects on clearance of serum HBsAg, HBeAg and HBVDNA; Polyporus umbellatus polysaccharide on serum HBeAg and HBV DNA; Phyllanthus amarus on serum HBeAg . The other observational study by Zhang et al. also reported that CHMs had a similar beneficial effect when compared with LAM for CHB on antiviral activity as evidenced by the loss of serum HBeAg and HBV DNA; and traditional Chinese medicine enhanced LAM anti-viral activities and improvements of liver function . More over one small case-control study concluded that JWXYS in combination with lamivudine had better HBV DNA clearance rate when compared with lamivudine monotherapy alone.
Traditional Chinese medicines have been used in China for more than two thousand years and are being used increasingly worldwide. CHMs is still used extensively for the treatment in Taiwan. Thousands of different herbs have been used in CHMs formula (mixed of different herbs). These CHMs formula are based on the collective experiences of Chinse clinicians, coupled with centuries of accumulated
wisdom. The general philosophical underpinning of CHMs is that of ‘holistic medicine’. Thus, clinicians treat the person as a whole, including body, mind, and spirit. A wide-spread strategy underlying CHMs treatment of CHB is to relieve anxiety and symptoms, improve the quality of life of the patients, alleviate inflammation, arrest hepatic fibrosis, improve immune function and improve lipid metabolism. Of course, the purported effectiveness of CHMs formula on CHB could be exaggerated if only positive results were published as possibility of publication bias.
One large retrospective cohort study reported that JWXYS was the second most popular prescription products used to treat chronic hepatitis in Taiwan (Chen et al.,2008). JWXYS consists of 10 medicinal herbal preparations, namely,
Angelica sinensis radix [Scientific name: Angelica sinensis (Oliv.) Diels], Bupleurum falcatum radix (Bupleurum falcatum L.), Paeonia albiflora (Paeonia albiflora Pall.), Glycyrrhizae radix (Glycyrrhiza uralensis Fisch.), Moutan Radicis cortex (Paeonia
suffruticosa Andr.), Gardenia fructus (Gardenia jasminoides J.Ellis), Zingiber officinale
rhizome (Zingiber officinale Roscoe), Atractylodis macrocephalae rhizoma (Atractylodis macrocephalae Koidz), Poria cocos [Poria cocos (Schw.) Wolf.], and Mentha arvensis (Mentha arvensis L.) was recorded from “Tai Ping Hui Min He JiJu Fang”, edited by the office of “He JiJu” of the Song Dynasty (A.D. 960-1279). Recent scientific evidences have suggested that JWXYS can treat insomnia , chronic fatigue , menopausal syndromes , functional dyspepsia and chronic hepatitis . The average percentage of JWXYS in all CHMs prescriptions in our country was about 12%, which gradually climbed from 11.6% to 13.4% from 2004 to 2011 (Appendix figure 1b). In the current study, JWXYS could decrease mortality in patients with CHB receiving lamivudine treatment, although without dose-response relationship, and whether the efficiency was conducted directly through inhibiting HBV virus or indirectly
through improving holistic condition warranted further observation. JWXYS seems likely with potentially efficacious therapies for CHB receiving lamivudine.
Several limitations must be considered. First, the NHI program only pays for CHMs prescribed by Chinese medicine physicians, not over-the-counter CHMs. Therefore, the use of CHMs may be underestimated. Second, it is likely that CHMs users were not fully compliant with prescriptions. However, we were still able to demonstrate the mortality benefit from CHMs use. Third, the NHIRD is a claims-based database; therefore, no detailed clinical information regarding virological or biochemical data is recorded. Finally, because the Registry of Catastrophic illness Database of the NHIRD only documents the date of death and not cause of death, the effect of CHMs on liver-specific mortality cannot be analyzed.
5. Conclusions
In conclusion, the results of the current observational study reveal that CHMs lowered the risk of death in patients with CHB receiving lamivudine. Our findings suggest that CHMs appear to be beneficial to those with CHB. Study of JWXYS in the treatment of CHB is warranted in higher quality randomized-controlled trials to validate these observational findings. The use of CHMs is worthy of attention and further research.
Acknowledgements
This study is based on a portion of data from the NHIRD provided by the Bureau of National Health Insurance, Department of Health and managed by National Health
Research Institutes in Taiwan. The interpretation and conclusions contained do not represent those of Bureau of National Health Insurance, Department of National Health Research Institutes. The authors thank pharmacist Huang for herb interpretation and manuscript editing.
Appendix
Supplementary data associated with this article can be found below, include Appendix Figure 1, Table 1 and Table 2.
