SYNOPSIS: Use of Chinese herbal medicine was associated with a significantly lower risk of developing hepatocellular carcinoma in patients receiving antiviral medication for chronic hepatitis B infection.

SOURCE: Tsai TY, et al. Associations between prescribed Chinese herbal medicine and risk of hepatocellular carcinoma in patients with chronic hepatitis B: A nationwide population-based cohort study. BMJ Open 2017;7:e014571. doi: 10.1136/bmjopen-2016-014571.

Approximately 350 million people worldwide are chronic carriers of hepatitis B infection and, as such, are at higher risk of developing hepatocellular carcinoma.^1,2,3 Nucleoside/nucleotide analogs (lamivudine, tenofovir, and entecavir) delay disease progression and reduce the risk of hepatocellular carcinoma in patients chronically infected with hepatitis B and represent the current standard of care for patients who can afford the costs of these medications.^4,5,6 Traditional Chinese medicine practitioners use more than 300 botanical and animal product medicines in the treatment of hepatitis B.⁷ These are used as single-herb products or multi-herb products, depending on the clinical presentation. Chinese herbal medicine is used both as an adjunctive treatment to the current standard of care or as an alternative to the standard of care and represents 30-50% of the total medicine consumption for chronic hepatitis B treatment in mainland China.⁸ An estimated 80% of patients with chronic hepatitis B in China and Taiwan have received Chinese herbal medicine treatments.⁷

Unfortunately, there is limited information available on the outcomes of patients with chronic hepatitis B who use Chinese herbal medicines. One meta-analysis showed that Chinese herbal medicine enhanced the antiviral activity of interferon and lamivudine and improved liver function in patients with chronic hepatitis B infection.⁸ In another single study, researchers found that Chinese herbal medicine may improve prognosis in patients with hepatocellular carcinoma.⁹

Tsai et al evaluated the effect of any Chinese herbal medicine on the risk of developing hepatocellular carcinoma in patients chronically infected with hepatitis B. For the purposes of this study, Tsai et al used the Longitudinal Health Insurance Database, a dataset nested within the National Health Insurance Program, and includes 1 million randomly sampled people who were alive in the year 2000, to evaluate the relationship between Chinese herbal medicine and the risk of hepatocellular carcinoma in patients chronically infected with hepatitis B.¹⁰

The database included claims data (ICD-9-CM) and registry prescription drugs. In Taiwan, only certified practitioners of Chinese medicine are licensed to prescribe Chinese herbal products. A definition cutoff of 30 days of Chinese herbal medicine use was used to differentiate between users and nonusers of Chinese herbal medicine for hepatitis B.

Inclusion criteria included patients ≥ 20 years of age who were diagnosed with chronic hepatitis B infection (recorded on three outpatient visits or one in-patient visit) and received treatment with nucleotide or nucleoside analogues, including lamivudine, adefovir, telbivudine, entecavir, or tenofovir between 1998 and 2007. The authors excluded 876 patients with chronic hepatitis B who had a prior diagnosis of hepatocellular carcinoma or who had a follow-up period of less than three months. Following application of these exclusion criteria, 21,020 patients with chronic hepatitis B were retained for further analysis.

The researchers found 8,640 patients with chronic hepatitis B took Chinese herbal medicine and 12,380 did not. Chinese herbal medicine users were more likely to be women, younger, and have a lower monthly income. A total of 1,329 hepatocellular carcinoma events occurred among all study participants. Further analysis showed that the 1,329 cases of hepatocellular carcinoma represented 371 non-Chinese herbal medicine users and 958 Chinese herbal medicine users during the follow-up period (70,203.05 and 94,122.45 person-years, respectively). The incidence rate of hepatocellular carcinoma was lower among users compared to nonusers (5.28 vs. 10.18 per 1,000 person years; adjusted hazard ratio, 0.63; 95% confidence interval, 0.56-0.72]. A multivariate analysis (adjusted for age, gender, and mediation use) showed that the cumulative incidence of hepatocellular carcinoma for those receiving Chinese herbal medicine treatment for more than 180 days was significantly lower than for those not receiving Chinese herbal medicine (4.25 vs. 10.18 log rank test; P < 0.001). Overall, the beneficial effect of Chinese herbal medicine on reducing hepatocellular carcinoma was greater in patients ≤ 50 years of age with chronic hepatitis B, regardless of gender.

Patients in the database received both single-herb and multi-herb products. Eight herbal products (four single-herb and four multi-herb products) were associated with lower risk of hepatocellular carcinoma. (See Table 1.) A multivariate analysis factored in the potential effect of nucleotide or nucleoside analogs on the protective effects of Chinese herbal medicine. A sensitivity analysis, which was limited to those patients with chronic hepatitis B plus Chinese herbal medicine use but without receiving nucleoside/nucleotide analogs, revealed that the protective benefits of Chinese herbal medicines were still in effect (adjusted hazard ratio, 0.65; 95% CI, 0.55-0.71).

The investigators concluded that use of prescribed Chinese herbal medicine is associated with a significantly reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B infection. Overall, the results suggested that the integration of Chinese herbal medicine into the treatment of chronic hepatitis B is associated with 37% lower risk of developing hepatocellular carcinoma.

COMMENTARY

The key strength of this study is that the data came from a comprehensive national database over a 15-year follow-up period. Also, the investigators tried to minimize the risk of a diagnostic error by requiring a recorded diagnosis of hepatitis B on three outpatient visits or one inpatient visit; nonetheless, the diagnosis was based on ICD-9 codes rather than laboratory or clinical findings.

No information was available on relevant cofactors such as alcohol consumption. The rates of alcohol drinking among men and women in Taiwan are low at 25% and 0.4%, respectively, suggesting that alcohol consumption may not be a relevant confounder in this analysis. The authors did not comment on the safety and tolerability profile of the Chinese herbal medicine used. Although only certified practitioners are entitled to prescribe Chinese herbal medicine in Taiwan, the study design did not allow the investigators to definitively rule out herbal medicine use in patients classified as nonusers. Finally, the researchers listed eight herbs found to be beneficial in hepatitis B but the design failed to capture the art and complexity of traditional Chinese medicine, which tailors the treatment to the patient infected with the virus and not just the virus.

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