DOI: 10.1111/j.1468-1293.2008.00610.

x
r 2008 British HIV Association HIV Medicine (2008), 9, 653–659

ORIGINAL RESEARCH

Potential health risks of complementary alternative

medicines in HIV patients
D Ladenheim,1 O Horn,2 U Werneke,3,4 M Phillpot,5 A Murungi,5 N Theobald5 and C Orkin1
1
St Bartholomew’s Hospital, London, UK, 2Academic Department of Psychological Medicine, Institute of Psychiatry, King’s
College London, UK, 3Sunderby Hospital, Luleå, Sweden, 4Department of Clinical Sciences – Psychiatry, Umeå University,
Umeå, Sweden and 5Chelsea and Westminster Hospital, London, UK

Objectives
To determine the prevalence and purpose of complementary alternative medicines (CAMs) use in
people receiving treatment for HIV infection. To identify and quantify potential health risks of CAM
use in this population and to explore options for improved pharmacovigilance.
Methods
Cross-sectional questionnaire survey of 293 patients receiving antiretroviral (ARV) therapy at three
specialist HIV out-patient clinics in central London, UK. The use of herbal medicines and
supplements was explored, and potentially adverse side effects or significant drug interactions with
conventional therapies were identified.
Results
Of the 293 patients included, 61% (n 5 179) were taking herbal remedies or supplements and 35%
(n 5 103) were using physical treatments. Twenty-seven per cent (n 5 80) used a combination of
both. Twenty per cent (n 5 59) potentially compromised their HIV management through using CAM
therapy. Ten per cent (n 5 29) were advised to stop their CAMs and 15% (n 5 43) were made aware of
potential drug interactions and adverse effects and were advised to monitor their care.
Conclusions
There are potentially significant health risks posed by the concomitant use of CAMs in patients
taking ARV therapy. Medical practitioners need to be able to identify CAM use in HIV-positive
patients and recognize potential health risks. Patients should be encouraged to disclose CAM use to
their clinicians and other healthcare professionals.
Keywords: adverse effects, antiretroviral drugs, drug interactions, echinacea, prevalence
Received: 29 January 2008, accepted 29 April 2008

women in Tanzania [14]. Indeed, patients living in some

Introduction
The use of complementary alternative medicines (CAMs) in
patients living with chronic illnesses and their associated
physical and psychological problems is well documented
[1–3]. Depending on the definitions and inclusion criteria,
estimates of the reported prevalence of CAM use in HIV-
positive patients range from 16 to 95% [4–13] (Table 1).
Some authors suggest that CAMs can be of benefit to
HIV-positive patients. For instance, multivitamin supple-
mentation was found to reduce the risk of progression to
late-stage disease and death in HIV-infected pregnant
Correspondence: David Ladenheim, St Bartholomew’s Hospital (Barts), West
Smithfield, London EC1A 7BE, UK. Tel: +44 (0) 207 601 8675; fax: +44 (0)
207 601 7341; e-mail: ladenheim@hotmail.com
low- and middle-income countries may not have access to
antiretroviral (ARV) drugs at all and thus may rely
exclusively on CAMs in their fight against HIV. In broader
terms, CAM use in HIV patients has been shown to provide
relief of disease-related symptoms, help manage ARV-
related side effects and increase the sense of hope and
empowerment [15,16]. However, CAM use is not without
risks in patients who take systemic medication. In a
previous study of cancer patients, 12% of patients were
issued with health warnings. Additionally, in this study
11% took supplements in doses higher than the recom-
mended levels [17].
Standard treatment for patients living with HIV infection
involves the administration of combinations of ARV drugs
to provide potent highly active ARV therapy (HAART), in

653
654 D Ladenheim et al.

Table 1 Reported prevalence studies of complementary alternative The completed questionnaires were scrutinized for drug
medicines (CAMs) and use of antiretroviral drugs in HIV-positive interactions and adverse effects. Such effects included a
patients potentially clinically significant change of serum concen-
Study Country Sample size CAM use (%) trations of ARV drugs, inappropriate stimulation of the
immune system, risk of hepatotoxicity and changes in
Josephs et al. [4] USA 914 16
Bica et al. [5] USA 642 60
coagulation factors.
Hsiao et al. [6] USA 2466 53 In cases of potential adverse events or drug interactions,
Furler et al. [7] Canada 104 89 a pharmacist or dietician contacted the patient and the
Wiwanitkit [8] Thailand 160 95
De Visser et al. [9] Australia 924 55
prescribing physician within 48 h. Where an identified health
Colebunders et al. [10] Europe 517 63* risk was judged to be potentially serious, patients were
Duggan J et al. [11] USA 191 67 advised to stop their CAM use. In other cases, patients were
Barton et al. [12] UK 190 38
Anderson et al. [13] USA 184 40
advised to exercise caution and appropriate monitoring.
The data were entered into an Access database and
*Only vitamins and minerals surveyed. analysed descriptively using SPSS version 13 (SPSS Inc.,
Chicago, IL, USA). All patients gave written consent before
accordance with national guidelines. Standard combina- participation in the study. The study received ethical
tion therapy includes two drugs from the nucleoside approval from both East London and The City (for Bart’s
reverse transcriptase inhibitor (NRTI) class of ARV drugs and the London NHS Trust) and The Riverside (for Chelsea
and one other drug from another class, either a non- and Westminster Hospital) research ethics committees.
nucleoside reverse transcriptase inhibitor (NNRTI) or a
protease inhibitor (PI). Because the PI and NNRTI classes
are metabolized via the cytochrome P450 (CYP450) path- Results
ways, CAM use in such populations may be of concern
Three hundred and seventy-three patients were issued with
because of potential interactions between CAMs and ARV
a questionnaire. Twenty-two had withdrawn consent or
drugs.
returned an incomplete questionnaire and 58 were
While the extent of CAM use in people living with HIV
excluded because they were not taking ARV drugs at the
has been described, there is no published data on the
time. Questionnaires from 293 patients were included in
potential risks of CAM use in this population. The purpose
the study, a response rate of 79%. Of these, 61% (n 5 179)
of this study was to investigate the prevalence of CAM use
were taking herbal remedies or supplements and 35%
in HIV-positive patients taking ARV therapy and to
(n 5 103) were using physical treatments. Twenty-seven
quantify the risk of potentially serious interactions and
per cent (n 5 80) used a combination of both.
adverse reactions associated with CAM use.
In total, 179 patients took 93 different oral CAM agents.
One patient took 19 different oral CAM remedies (Fig. 1).
Supplements were the most common form of CAM used
Patients and methods and 102 patients took supplements only. Only two patients
took just herbal medicines. Seven patients used other
We conducted a cross-sectional survey of patients attend-
ing three HIV out-patient clinics in London, using a
checklist questionnaire to estimate the prevalence and
100
purpose of herbal medicines and supplement use. In
addition, respondents were asked whether they were
undertaking any physical therapy.
Frequency

Patients attending the Andrewes Unit, the Grahame

Hayton Unit and the Kobler Clinic (at St Bartholomew’s, 50
Royal London, and Chelsea and Westminster Hospitals,
respectively) were invited to participate. Patients who did
not return their questionnaires, patients not taking ARV
drugs and those who had not completed the questionnaire
fully were excluded. Following a 1-week pilot, a pharmacist, 0
0 5 10 15 20
dietician or doctor issued questionnaires to HIV-positive
Number of agents taken
patients attending the three out-patient departments on
randomly selected days. Fig. 1 Frequency of taking complementary alternative medicines.

r 2008 British HIV Association HIV Medicine (2008) 9, 653–659

 CAM use in HIV patients 655

Table 2 Frequency of use of complementary alternative medicine Table 3 Frequency of use of complementary alternative medicines
agents by substance class (n 5 293) according to likely indication (n 5 293)

n % n %

Supplements (n 5 371) Antioxidants: multivitamins, vitamin C, selenium, minerals, 225 76

Multivitamins 100 34 vitamin E, coenzyme Q10, vitamin ACE, vitamin A, b-carotene,
Cod liver/o-3 oil 79 27 grape seed
Vitamin C 47 16 Dyslipidaemia: cod liver/o-3 oil, flax oil/flax, garlic 102 43
Flax oil/flax 13 4 Gastrointestinal problems/diarrhoea: glutamine, liquorice, 49 17
Selenium 21 7 probiotics, acidophilus
Minerals 15 5 Neuropathy: vitamin B compounds, acetylcarnitine, a-lipoic acid 30 9
Vitamin E 13 4 Anti-inflammatory/anti-arthritis: glucosamine, evening primrose 23 8
Vitamin B compounds 13 4 oil, aloe vera
Glutamine 12 4 Immune system stimulation: echinacea, b glucans (maitake/ 21 7
Coenzyme Q10 11 4 shitake)
Acetylcarnitine 10 3 Psychotropic/sleep: Ginkgo biloba, ginseng, melatonin* 17 6
a-lipoic acid 7 2 Muscle wasting: creatine, dihydroepiandrosterone, protein 11 5
Vitamin ACE 7 2 supplements
Vitamin A 6 2 Unspecified: homeopathic remedies, Chinese herbs 9 3
Creatine 5 2
N-acetylcysteine 4 1 Some patients took more than one remedy.
Protein supplements 3 1 *Also a powerful antioxidant.
b-carotene 3 1
Glucosamine 2 1
Single plant remedies (n 5 84)
total cohort were advised to stop their CAM use because of
Echinacea 17 6 concerns about serious drug interaction with ARV therapy
Evening primrose oil 12 4 or adverse effects of the remedy used. Of those asked to
Garlic 10 3
Milk thistle 9 3
discontinue, 23 were asked to stop because of risk of
Aloe vera 9 3 serious adverse effects. These warnings concerned mainly
Ginkgo biloba 8 3 the use of echinacea, which, because of its immune-
Ginseng 7 2
Grape seed 2 1
stimulating effects, could theoretically increase the count
Liquorice 2 1 of infected lymphocytes. Eight patients taking garlic, St
Grape seed 2 1 John’s wort or both were asked to stop because of risk of
b glucans (maitake/shitake) 4 1
Other (n 5 49)
serious drug interaction with their ARV therapy (Table 4).
Probiotics 22 8 Fifteen per cent (n 5 45) of patients were advised to use
Acidophilus 13 4 their remedies with caution and adequate monitoring. Of
Homeopathic remedies 7 2
Dihydroepiandrosterone 3 1
these, five patients were asked to do so because of concerns
Chinese herbs 2 1 about the risk of reduced drug absorption (aloe vera) and
Melatonin 2 1 40 because of potential interactions with the CYP3A4
Some patients took more than one remedy.
system (Table 5).

remedies including probiotics or acidophilus, dihydroe-

piandrosterone, melatonin, homeopathic remedies and
Chinese herbal formulations. One hundred and seventy-
nine patients used combinations of supplements, herbal
remedies and other substances (Table 2). Most patients
using CAMs took antioxidants or immune-stimulants,
presumably in the belief it would boost their immune
system or improve their general health. Others used CAMs
to combat adverse effects of ARV therapy such as
dyslipidaemia and gastrointestinal problems. Some patients
used CAMs to counter detrimental effects of the disease,
such as muscle wasting, HIV-induced neuropathy or
associated psychiatric problems such as loss of energy
and cognitive efficiency or sleep problems (Table 3).
Of all those taking CAMs, 20% (n 5 59) were issued with
warnings owing to CAM usage. Ten per cent (n 5 29) of the
Discussion
In this study, 61% of patients used CAMs and 20% of
patients potentially compromised their HIV management
through their use of CAMs. We identified a potential for
serious health risks in 10% of patients; these patients were
advised to stop their CAM usage. Fifteen per cent of
patients were made aware of potential drug interactions
and adverse effects owing to CAM usage. For these
patients, warnings were issued to monitor ARV therapy
more closely rather than stop the CAM outright. Several
studies have been published on the prevalence of CAM use
in patients living with HIV but, to our knowledge, this is
the first study to try and quantify the associated potential
health risks, thereby adding clinical relevance to the
prevalence data.

r 2008 British HIV Association HIV Medicine (2008) 9, 653–659

656 D Ladenheim et al.

Table 4 Warnings issued to HIV-positive patients taking complementary alternative medicines (CAMs) and advised to stop doing so

CAM Patients (n) ARV drug class Interaction Potential concern

Echinacea 22 Any HIV-positive patient Theoretical stimulation of immune system

resulting in an increase in HIV viral load [18,19]
Garlic 8 NNRTI and/or PI Risk of CYP3A4 enzyme induction Risk of sub-therapeutic ARV levels [20–22]
Kava 1 Any HIV-positive patient Risk of CYP3A4 enzyme inhibition Concerns over hepatotoxicity (withdrawn from
UK market) [23,24]
St John’s wort 2 NNRTI and/or PI Risk of CYP3A4 enzyme induction Risk of sub-therapeutic ARV levels [26–28]

Some patients were issued with warnings for more than one adverse effect or interaction.
ARV, antiretroviral; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor.

Table 5 Warnings issued to HIV-positive patients taking complementary alternative medicines (CAMs) and advised to monitor and use with caution

CAM Patients (n) ARV drug class Interaction Potential concern

Aloe vera 5 All ARV drugs Increased gastrointestinal transit Reduced drug absorption leading to
therapeutic failure of ARV [45]
Cat’s claw 1 NNRTI and/or PI Risk of CYP3A4 enzyme inhibition Risk of ARV-related side effect [29]
DHEA 2 NNRTI and/or PI Risk of CYP3A4 enzyme inhibition Risk of ARV-related side effect [30]
Ginkgo biloba 6 NNRTI and/or PI Risk of CYP3A4 enzyme inhibition Risk of ARV-related side effect and/or
and/or induction ARV therapeutic failure [31–33]
Ginseng 6 NNRTI and/or PI Risk of CYP3A4 enzyme inhibition Risk of ARV-related side effect [34]
Liquorice 2 NNRTI and/or PI Risk of CYP3A4 enzyme inhibition Risk of ARV-related side effect [29,44]
Milk thistle 6 NNRTI and/or PI Risk of CYP3A4 enzyme inhibition Risk of ARV-related side effect [25]
Red yeast 1 NNRTI and/or PI Risk of CYP3A4 enzyme inhibition Risk of ARV-related side effect [34]
Vitamin C41 g 16 NNRTI and/or PI Risk of CYP3A4 enzyme inhibition Risk of sub-therapeutic ARV levels [46]

ARV, antiretroviral; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; DHEA, dehydroepiandrosterone.

Patients may use CAMs for a variety of reasons. Some
patients use CAMs to treat the underlying immune
deficiency itself; others wish to treat associated problems
or treatment-induced side effects. CAM use may, to a
degree, be independent of the availability of effective
treatments. For instance, two surveys found that the advent
of HAART did not lead to a decrease of CAM use in HIV-
positive patients. Of 190 HIV-positive patients surveyed at
a UK hospital in the pre-HAART era, 72 (38%) had used at
least one alternative treatment since their diagnosis [12]. A
similar survey in the pre-HAART era of HIV-positive
patients in the Philadelphia area reported 74 (40%) using at
least one form of alternative therapy [13]. Thus while CAM
use in HIV-positive patients may not have changed
radically over time, the risk of potential harm may have
increased because some CAMs compromise the effective-
ness of HAART.
Our study was conducted as a clinical survey, sampling
attendees from three HIV units in central London. Seventy-
nine per cent of all questionnaires could be included in the
final analysis; however, even if all of those patients
excluded from the study did not use CAMs, the prevalence
of CAM use would still amount to 48% – well within the
range of reported prevalence figures [4–13]. Equally, the
rate of health warnings would have dropped by only 5–
15% – still a clinically relevant finding. The questionnaire
was based on patients’ self report. No attempt was made to
validate patients’ responses because there was no reason to
believe that participants would give misleading informa-
tion. All had given written informed consent and had been
given the option to withdraw from the study at any time.
Above all, we did not ask about illegal substance use,
which could have resulted in a higher rate of false
responses. The questionnaire was not validated formally:
validation was considered to be of limited value because
the questionnaire was factual in nature. In other words, the
questionnaire was not designed to derive an abstract
concept from the measurement of a variety of attributes. It
was based on a sample questionnaire successfully applied
in a sample of cancer patients [17] and then adapted for use
in HIV patients. This new questionnaire was piloted prior to
conducting the main study.
In issuing health warnings, most of our concerns related
to potential drug interactions between ARV drugs and
CAMs [37,38] and, more specifically, interactions resulting
from potential interference with the CYP system. In this
regard, PIs and NNRTIs are particularly susceptible. The
long-term success of ARV treatment depends upon
maintaining inhibitory concentrations of active drug at
the site of HIV replication sufficient to suppress viral
replication. Reduced serum levels of ARV drugs correlate
with treatment failure and the development of ARV drug
resistance [39–42]. High serum levels of ARV drugs have
been shown to correspond with an increased incidence of

r 2008 British HIV Association HIV Medicine (2008) 9, 653–659


drug-related side effects [42,43]. Given the relative lack of
safety and effectiveness data for numerous CAMs, all
judgements regarding its cessation were based on the best
available trade-off between potential benefits and harm.
Garlic and St John’s wort were the two agents that we
advised patients to stop using because of their potential to
reduce the plasma levels of concomitant ARV agents. Garlic
has been shown to significantly reduce therapeutic
concentrations of PIs – notably indinavir and saquinavir
– when administered concomitantly [20]. The precise
mechanism for this interaction is unclear, but is thought
to relate to an increase in hepatic CYP450 activity [21,22].
Similarly, St John’s wort has been shown to adversely
affect serum concentrations of ARV drugs [26,27]. While
the mechanism for this interaction is, again, not fully
understood, it is thought to be caused by effects on either
the CYP450 isoenzyme system or the multi-drug transpor-
ter p-glycoprotein, or possibly both [28].
Kava-kava and echinacea have been restricted from the
UK and other markets because of concerns regarding their
safety and hepatotoxicity [23,24] and immune activation
[18], respectively. Some studies have demonstrated activa-
tion of an immune response following treatment with
echinacea extracts [19], but it is not clear how this might
influence the pathogenesis of individuals infected with
HIV.
In addition to the four agents that we recommended be
discontinued, there were 10 CAM agents for which we
recommended the exercise of caution when used con-
comitantly with ARV drugs. For each of these agents there
are limited data suggesting possible impact on ARV
pharmacokinetics, and little is known on how such a
potential interaction, demonstrated in vitro, might translate
into clinically significant effects. In such circumstances,
additional clinical monitoring is recommended. Where
there is a theoretical risk of increased levels of ARV drugs,
patients should be monitored for adverse drug reactions
associated with the relevant ARV therapy. Conversely,
when an interaction could lead to reduced levels of ARV
drugs, due vigilance should be paid to the risk of
therapeutic failure.
Our research highlights the importance of healthcare
professionals discussing CAM use with their patients and
making them aware of CAM-induced side effects or
interactions. By exploring the reasons behind CAM use in
HIV-positive patients, clinicians may gain a valuable
understanding of their patients’ concerns and symptoms.
They may also gain an insight into their patients’ subjective
experience of their HIV disease.
Patients should be actively encouraged to disclose
information about CAMs to healthcare professionals.
Similarly, healthcare professionals need to employ sensi-
r 2008 British HIV Association HIV Medicine (2008) 9, 653–659
CAM use in HIV patients 657
tivity in tackling the issue of CAM use. It is important not
to alienate patients by making them feel that they are not
being taken seriously or that they are being criticized for
their use of CAMs. Research has shown that patients may
feel deprived of their autonomy if their healthcare
professionals are insensitive when addressing their use of
CAMs [17]. It is recommended that clinicians devote time
to discussing CAM use as part of regular consultation in
out-patient clinics.
The regulation of agents is an important means by which
patient safety can be enhanced for those wishing to use
CAMs. In the UK, the Herbal Medicines Advisory Commit-
tee was set up in 2005 to advise the Medicines and
Healthcare Products Regulatory Agency about safety issues
related to herbal medicines. Because the scope of such
regulation is limited, patients should have access to reliable
specialist resources. Healthcare professionals may need to
advise patients on how they can make informed decisions
should they wish to self-medicate with over-the-counter
CAMs. Health professionals must adopt a robust, evidence-
based approach to advise those patients who need guidance
in their decision-making. Therefore, in the clinical setting,
additional consultation time may be required to ensure that
appropriate CAMs can be used safely.
A significant proportion of HIV-positive out-patients use
CAMs. There are potentially significant health risks posed
by the concomitant use of CAMs in patients receiving ARV
therapy. Effective pharmacovigilance systems, which can
be incorporated easily into routine clinical practice, need to
be developed and expanded. This will ensure safe clinical
practice for HIV-positive patients using complementary
medicines.
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