Traditional Herbal Medicine Use Associated with Liver Fibrosis in Rural Rakai, Uganda

Uganda. PLoS ONE 7(11): e41737. doi:10.1371/journal.pone.0041737 Traditional Herbal Medicine Use Associated with Liver Fibrosis in Rural Rakai, Uganda Brandon J. Auerbach 0 Steven J. Reynolds 0 Mohammed Lamorde 0 Concepta Merry 0 Collins Kukunda-Byobona 0 Ponsiano Ocama 0 Aggrey S. Semeere 0 Anthony Ndyanabo 0 Iga Boaz 0 Valerian Kiggundu 0 Fred Nalugoda 0 Ron H. Gray 0 Maria J. Wawer 0 David L. Thomas 0 Gregory D. Kirk 0 Thomas C. Quinn 0 Lara Stabinski 0 on behalf of the Rakai Health Sciences 0 John E. Tavis, Saint Louis University, United States of America 0 1 Infectious Diseases Institute, College of Health Sciences, Makerere University , Kampala , Uganda , 2 Harvard Medical School , Boston , Massachusetts, United States of America, 3 Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda , Maryland, United States of America, 4 Division of Infectious Diseases, Department of Medicine, School of Medicine, Johns Hopkins University , Baltimore , Maryland, United States of America, 5 Department of Pharmacology and Therapeutics, School of Medicine, University of Dublin, Trinity College , Dublin, Ireland , 6 St James's Hospital , Dublin, Ireland , 7 Department of Medicine, College of Health Sciences, Makerere University , Kampala , Uganda , 8 Department of Botany, Makerere University , Kampala , Uganda , 9 Rakai Health Sciences Program, Entebbe, Uganda, 10 Department of Population, Family, and Reproductive Health, Bloomberg School of Public Health, Johns Hopkins University , Baltimore , Maryland, United States of America, 11 Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University , Baltimore, Maryland , United States of America Background: Traditional herbal medicines are commonly used in sub-Saharan Africa and some herbs are known to be hepatotoxic. However little is known about the effect of herbal medicines on liver disease in sub-Saharan Africa. Methods: 500 HIV-infected participants in a rural HIV care program in Rakai, Uganda, were frequency matched to 500 HIVuninfected participants. Participants were asked about traditional herbal medicine use and assessed for other potential risk factors for liver disease. All participants underwent transient elastography (FibroScanH) to quantify liver fibrosis. The association between herb use and significant liver fibrosis was measured with adjusted prevalence risk ratios (adjPRR) and 95% confidence intervals (CI) using modified Poisson multivariable logistic regression. Results: 19 unique herbs from 13 plant families were used by 42/1000 of all participants, including 9/500 HIV-infected participants. The three most-used plant families were Asteraceae, Fabaceae, and Lamiaceae. Among all participants, use of any herb (adjPRR = 2.2, 95% CI 1.3-3.5, p = 0.002), herbs from the Asteraceae family (adjPRR = 5.0, 95% CI 2.9-8.7, p,0.001), and herbs from the Lamiaceae family (adjPRR = 3.4, 95% CI 1.2-9.2, p = 0.017) were associated with significant liver fibrosis. Among HIV infected participants, use of any herb (adjPRR = 2.3, 95% CI 1.0-5.0, p = 0.044) and use of herbs from the Asteraceae family (adjPRR = 5.0, 95% CI 1.7-14.7, p = 0.004) were associated with increased liver fibrosis. Conclusions: Traditional herbal medicine use was independently associated with a substantial increase in significant liver fibrosis in both HIV-infected and HIV-uninfected study participants. Pharmacokinetic and prospective clinical studies are needed to inform herb safety recommendations in sub-Saharan Africa. Counseling about herb use should be part of routine health counseling and counseling of HIV-infected persons in Uganda. - Funding: The study was primarily funded by the United States National Institutes of Health (NIH) Bench to Bedside Program. Additional support was provided by the Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health. Support was also provided by the National Institute on Drug Abuse (PI: DLT, R01-AI-16078) and the American Cancer Society (PI: GDK, MRSG-07-284-01-CCE). The study was jointly conducted and benefited from close collaboration of researchers from the intramural NIH Laboratory of Immunoregulation, Johns Hopkins University, the Infectious Diseases Institute of Makerere University, and the Rakai Health Sciences Program. Support for the RHSP HIV Care Program was provided by the Presidents Emergency Fund for AIDS Relief (PEPFAR) and support for the Rakai Community Cohort Study was provided by the Department of the Army, United States Army Medical Research and Material Command Cooperative Agreement DAMD17-98-2-8007; grants R01 A134826 and R01 A134265 from the National Institute of Allergy and Infectious Diseases; grant R01 016078 (DLT) from the National Institute on Drug Abuse; and grant 5P30HD06826 from the National Institute of Child and Health Development. BJA and ASS were funded by the Fogarty International Clinical Research Scholars (FICRS) program of the NIH, administered by the Vanderbilt University Institute for Global Health (R24 TW007988). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Traditional herbal medicines are commonly used for HIV/ AIDS and other health conditions in Uganda and sub-Saharan Africa, often in parallel with programs that provide antiretroviral therapy (ART). In the 1990s an estimated 80% of Ugandans living in rural villages used traditional healers for primary health care [1]. A study of 137 HIV-infected Ugandans receiving ART found that 60% used herbs concurrently with ART [2]. In Uganda traditional herbal medicines are usually boiled extracts of herbs taken orally [3]. Some potentially hepatotoxic traditional herbal medicines used in Uganda and sub-Saharan Africa include Hoodia gordoni [4], kava [5], Phytolacca dioica [6], and herbs from the Asteraceae family [7]. Little is known about the hepatotoxicity of other commonly used herbs or the contribution of herbs to the burden of liver fibrosis and hepatocellular carcinoma in sub- Saharan Africa, including when used concomitantly with ART. Data on the specific types of herbs taken by HIV-infected persons in Uganda is limited, as is information about their components, side effects, toxicities, and ART interactions [8]. In Rakai, Uganda, liver toxicity associated with herbal medicine may be of particular concern given the high prevalence of significant liver disease (17%) among HIV-infected persons in Rakai recently identified by transient elastography (FibroScanH, Echosense, Paris, France) [9]. In the aforementioned study, reported herbal medicine use was associated with a two-fold increased risk of significant liver disease, defined as a transient elastography score equivalent to METAVIR liver fibrosis stage 2 (...truncated)