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Toxic lopinavir concentrations in an HIV-1 infected patient taking herbal medications
[Correspondence]
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AIDS:Volume 22(10)19 June 2008p 1243-1244
Beukel van den Bout-van den, Carolien JPa,c; Bosch, Marjolein EWa,c; Burger, David Mb,c; Koopmans, Peter Pa,c; van der Ven, Andre JAMa,c
aDepartment of General Internal Medicine, The Netherlands
bClinical Pharmacy, The Netherlands
cNijmegen University Center for Infectious diseases, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
The use of natural health products, such as herbal medicines, is common among individuals with HIV [1,2]. Surveys revealed that 26-100% of HIV infected patients used natural health products (NHP); 16-26% of patients reported the use of herbal medicines [1-3]. A cross-sectional study among HIV infected patients showed that 67% of patients who were receiving antiretroviral (ARV) treatment were also taking an NHP: 24% of this sample reported the use of herbal medications [3].
Usage of herbal medicines concomitant to ARVs can cause significant drug interactions. Protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs) are mainly metabolized by cytochrome P450 enzymes (CYPs). Herbs are often also substrate of CYPs. In addition, protease inhibitors and NNRTIs have a small therapeutic index [4]. Herbal medicines can interact with ARV metabolism by induction or inhibition of CYPs. Inhibition of CYPs might lead to high ARV plasma levels and the subsequent risk of serious side effects, whereas induction might lead to subtherapeutic plasma levels, leading to therapeutic failure and an enhanced risk of developing ARV drug resistance. We describe a case of an HIV-1 infected patient taking evening primrose, colayur and rheum frangula concomitant to lopinavir (LPV), which resulted in a toxic LPV level.
In April 2004, HIV-1 infection was diagnosed in a 47-year-old man because of oligoarthritis and hypergammaglobulinemia. The patients' CD4 lymphocyte count was 120 cells/μl and his viral load was more than 100 000 HIV RNA copies/ml. Treatment with stavudine (40 mg twice a day), lamivudine (150 mg twice a day) and lopinavir/ritonavir soft gel capsules (533/133 mg twice a day) was directly started. Later on stavudine was changed to tenofovir (245 mg once daily) because of lipodystrophy. His CD4 lymphocyte count recovered to 220 cells/μl, and the viral load became undetectable (<40 copies/ml). Every 3 months, random LPV plasma levels were checked and ranged between 4 and 9 mg/l (normal: 5-10 mg/l). In July 2006, the patient presented with persistent diarrhea (>5 times per day), which was interfering with daily life. The patient turned out to have a high LPV level of 15.2 mg/l 6.75 h after intake (time-adjusted population level: 9 mg/l). The patient's history revealed that he was taking herbal medications including efamol (two tablets TID), rheum frangula (two tablets twice a day) and colayur (one teaspoon a day) for 2 months and he has had persistent diarrhea since then. Six weeks after discontinuation of the herbals, his trough LPV plasma level recovered to 5.3 mg/l and all his complaints disappeared. We rechallenged the patient with efamol for 1 week and his trough LPV plasma level increased from 6.69 to 8.11 mg/l. Thereafter, the patient discontinued herbal medications and his LPV levels remained within normal range at the consecutive visits. There were no adverse events reported by the patient during the week of rechallenge.
This case illustrates a potential herbal medicine-LPV interaction. The patient developed diarrhea and toxic LPV levels when he was taking herbal medicines, then recovered upon discontinuation of the herbal medications. Before usage of the herbal medicines, his LPV levels were always within normal ranges and remained within normal ranges during all consecutive determinations after rechallenge.
Diarrhea in this patient can possibly be accounted for by the high LPV levels [5], although rheum frangula and/or colayur, which are laxative intestinal cleaners, could also have been responsible.
Lopinavir is metabolized through CYP3A4 and, to a lesser extent, CYP2D6 [5]. Evening primrose (Oenothera biennis), an ingredient of efamol, has be found to inhibit both CYP3A4 and CYP2D6 in vitro [6]. Inhibition of CYP3A4 by evening primrose could be a plausible explanation for the toxic LPV level, although, during rechallenge, only a slight rise in the LPV level was observed. The patient discontinued the primrose after 1 week, so we do not know what would have happened after longer combined administration in this rechallenge.
Evening primrose is a frequently used herbal medicine, appearing on the 12th place of the 20 top-selling herbal dietary supplements in the US [7]. Nothing is known on usage of rheum frangula or colayur.
Numerous commonly used herbal supplements, especially those in Africa, have not been studied for potential clinical interactions with ARVs [8]. Many HIV infected patients on antiretroviral therapy use herbal medicines, but often do not report usage of these agents to their physician [9]. As a result, there is a great potential for interactions between ARVs and herbal medicines. Physicians should be aware of the risk for herb-ARV interactions and should routinely discuss the usage of concomitant herbal medications with their patients. Two recent reviews on clinical [10] and potential [8] interactions between herbs and ARVs might be helpful in this. Furthermore, there is a demand for rigorous clinical research to investigate whether commonly used African and Western herbal medicines interact with ARVs in vivo.
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