Widespread use of herbal medicines by people living with human immunodeficiency virus and contamination of herbal medicines with antiretrovirals in Nigeria

Abstract

Herbal medication use amongst people living with human immunodeficiency virus (PLWH) is widespread and understudied. This study aimed to evaluate the prevalence of herbal medicine use amongst PLWH and possible contamination with antiretrovirals (ARVs). Countrywide collection of herbal samples sold by street vendors in Nigeria for the following indications: human immunodeficiency virus (HIV), acquired immune deficiency syndrome, fever and general weakness. Samples were screened using a validated liquid chromatography-mass spectrometry/mass spectrometry method for the presence of the following ARVs: efavirenz, nevirapine, lopinavir, darunavir, ritonavir, atazanavir, emtricitabine, tenofovir and lamivudine. A survey was conducted among 742 PLWH attending four HIV clinics in Nigeria. Data were collected using a structured questionnaire and analysed using IBM SPSS statistics version 22.0 (IBM Corp., 2013, Armond, NY). Of the 138 herbal medicines sampled, three (2%) contained detectable levels of tenofovir, emtricitabine and/or lamivudine. Additionally, of the 742 PLWH surveyed, 310 (41.8%) reported herbal medicine use. Among the users, 191 (61.6%) started taking herbals after commencing HIV therapy while herbal medicine use preceded ARVs treatment in 119 (38.4%) PLWH. We found herbal use to be widespread among PLWH in Nigeria, with increasing use after commencing ARV. Three herbal preparations were also found to contain detectable levels of ARVs. This is a concern and should be studied widely across the region and countries where herbal medicine use is prevalent and poorly regulated.

Keywords

Herbal medicines antiretroviral therapy human immunodeficiency virus tenofovir lamivudine emtricitabine

Introduction

Prevalence of herbal medication use among people living with human immunodeficiency virus (PLWH) and contamination with medicinal products and certain pharmaceutical agents has previously been reported,¹ though understudied. Herbal contamination has not been described for antiretrovirals (ARVs), despite suspicion and poor regulations of herbal practices in sub-Saharan Africa (SSA).^2,3

Globally, several studies have reported the use of herbal medicines among PLWH either as part of complimentary medicines or as a component for treating other ailments⁴ but few reports described the impact of herbal medication use on patient safety, adherence and health outcomes.^5,6 Widespread use of herbals among PLWH sabotages the intensified efforts to end the human immunodeficiency virus (HIV) epidemic by 2030.⁷ Use of herbal medicines could be associated with toxicities, reduced ARV adherence and poor health outcomes.^5,6,8 In a Ugandan study, 63.5% of PLWH reported herbal medicine use after HIV diagnosis and 32.8% use herbals concomitantly with other pharmaceutical products including ARVs.⁹ Similarly, a Nigerian study reported 27.5% herbal use among PLWH prior to starting ARVs and 4.25% concomitant use with ARVs.^9,10

Nigeria and South Africa account for over 40% of the HIV burden in SSA and over three million PLWH in 2016 were living in Nigeria.^11,12 Poor access to healthcare, lack of qualified healthcare personnel, healthcare cost, economic status, education and cultural beliefs promote dissatisfaction with health services and use of herbal medicines even while taking ARVs.^13–15 Other challenges of healthcare in Nigeria include: infrastructural, administrative and logistics challenges. Marked variability in ARV access across the country and complex peculiarities of the HIV programmes pose a significant challenge to PLWH and promote utilisation of herbal medicines by patients.¹¹

Although conflicting information have previously been reported by some studies on the relationship between concomitant use of herbal medicines and ARV adherence,^10,14,16 herbal use in HIV treatment should be discouraged because of unknown constituents of the herbal and potential drug interactions with ARVs.¹⁷

Use of herbals in relation to timing of ARV initiation or safety is not well characterized.^9,18 Users and practitioners erroneously consider herbal medicines to be safe without any safety prior evaluation.^19,20 Furthermore, practitioners often have little or no understanding of the modern approaches to evaluate the safety of medicinal products.^19,21

We sought to evaluate the prevalence of herbal medicine use by PLWH attending one rural and three urban HIV clinics in Nigeria, and related this to the time of ARV initiation. In addition, samples of traditional herbal medicines were collected from street vendors across Nigeria and were screened for the presence of ARVs using liquid chromatography-mass spectrometry (LC-MS).

Methods

Contamination of herbal medications with ARVs

Herbal medicines were collected across eight states in Nigeria between December 2014 and June 2015. The protocol for sample collection was as follows: (i) street vendors from both urban and rural settings were approached by study investigators or assigned personnel, (ii) herbal medicines were requested for the following indications: HIV, acquired immune deficiency syndrome, fevers or non-specific symptoms (e.g. weakness) known to be associated with HIV, (iii) herbal vendors were not informed that samples were to be used for research purposes to avoid any attempt by the vendors to modify the preparation, (iv) only herbals sold as powders or liquids were purchased, (v) instructions for use were recorded, as was the date and site.

A semi-quantitative screen for ARV contamination of herbal medicines was performed at the University of Liverpool by LC-MS for the following ARVs: efavirenz, nevirapine, lopinavir, darunavir, ritonavir, atazanavir, emtricitabine, tenofovir and lamivudine, using a method adapted from Else et al.²² This method enabled the simultaneous measurement of nine ARVs and was modified based on the suspected solubility of the different ARVs.

Sample pre-treatment

Herbal powders were weighed and dissolved in both water and dimethyl sulfoxide in order to optimise recovery due to different solubility of possible contaminants, at a stock concentration of 10 mg/mL. Working solutions were prepared by further diluting the stock (1:1) with mobile phase. Control (drug-free) mobile phase and blank herbal extracts (herbal controls) were prepared to check the background response of the LC-MS assay. Reference standards spiked with nine ARVs (efavirenz, nevirapine, lopinavir, darunavir, ritonavir, atazanavir, emtricitabine, tenofovir and lamivudine) at two concentrations (50 ng/mL and 100 ng/mL) were prepared.

Semi-quantitative LC-MS/MS

Blanks, reference standards and unknown samples (sourced herbal extracts) were injected (10 µL) onto the LC column coupled to a triple quadrupole mass spectrometer (TSQ Ultra; Thermo Scientific, Hemel Hempstead, UK). Data acquisition and processing was performed using LC Quan™ software (Thermo Scientific, Hemel Hempstead, UK). Herbal contamination was determined by semi-quantitative LC-MS assay (no internal standard or calibrators were used). An estimate of the amount of drug within contaminated samples was derived by comparing chromatographic peak areas of the samples against peak areas of known concentrations of tenofovir, emtricitabine and lamivudine spiked in water after correcting for background signal from a known negative herbal sample. Two rounds of analysis (initial screening using 10 mg/mL and confirmatory tests using 50 mg/mL) were performed before accepting the presence of ARV contamination in the sample. Detectable drug was confirmed if the response (chromatographic peak area; arbitrary units) of the unknown sample was at least five times greater than the response of the blank herbal extract (assay background). A semi-quantitative value per milligram of herbal powder was calculated based on the response of the reference standards minus the assay background interference. For samples that showed presence of drug during screening, additional confirmatory experiments were performed using higher (50 mg/mL) concentrations of herbal extract.

Survey of herbal medication use among PLWH

A clinical survey of PLWH attending ARV facilities in one rural (Rural Hospital, Idong) and three urban HIV facilities (Specialist Hospital, Gombe, Faith Alive Foundation Clinic, Jos, and Dalhatu Araf Specialist Hospital, Lafia) was conducted. Using a non-probability sampling technique, 500 PLWH were surveyed from Faith Alive Foundation Clinic, 199 from Dalhatu Araf Specialist Hospital, 33 from Specialist Hospital Gombe and 10 from Rural Hospital, Idong, respectively. The national prevalence rate of HIV in Nigeria is 3.2%; Kaduna, Gombe, Plateau and Nassarawa states have HIV prevalence rates of 9.2%, 8.1%, 3.4% and 2.3%, respectively. These surveyed clinics attend to over 6000 PLWH and the Faith Alive Foundation Clinic in Jos attends to over 5000 PLWH per month, while Rural Hospital, Idong, a primary healthcare setting, attends to less than 50 PLWH.^23,24

Inclusion criteria were: known HIV-antibody positive patients attending clinic, any age, willing to participate in the survey. For children less than 18 years old, parents were asked for consent and if willing, provided responses to the survey. Hospitalised patients, patients who were acutely unwell and any unconfirmed patient in the clinic were excluded. We utilised a structured questionnaire adapted from Langlois-Klassen et al. who previously evaluated herbal medication use among PLWH.⁹ The questionnaire was modified for our purpose and was applied to evaluate use of herbal medications across age, gender, education, employment status, date of diagnosis, date of starting herbal medications, type of herbal medication, source of recommendation for herbal use, source of procurement of herbal, reasons for use and perceived effectiveness of the herbals. Someone was considered a herbal user if he/she utilises concoctions (from known or unknown plant products) from herbal vendors or plant product recommended by family, friend or anybody. The primary outcome was prevalence of herbal medication use among PLWH. Secondary outcomes were use of herbals in relation to initiation of antiretroviral drugs, differences by gender, by age, by educational attainment, employment status and perception of benefit from herbal use. Herbal sample collection from vendors was random, and collection at different regions of the country was ensured for fair representation of different regions of the country.

Statistical analysis

Data were analysed using IBM SPSS statistics version 22.0 (IBM Corp. Armonk, NY, 2013). Participants who answered positively when asked, ‘Do you use herbal medicine?’ were considered as herbal medicine users. Data on herbal use and baseline social and demographic factors were pooled across all four centres to produce aggregate, descriptive overall frequencies at 5% level of significance (Table 1). We then compared social and demographic factors in PLWH who used or did not use herbal medicines. First, univariate analysis was performed using binary logistic regression with herbal use as the dependent variable. Next, all univariate associations with P≤0.1 were included in the final multivariable model. Groups were compared for relationships and confounders on the dependent variable (use of herbal medication) were resolved using multiple regression models (Table 2).

Table 1.

Prevalence of social and demographic factors in PLWH who use or do not use herbal medicines.

Variable	Use herbal medications (n = 310) n (%)	Do not use herbal medications (n = 432) n (%)
Age (years)
Median (range)	33 (2–91)	32 (13–74)
Gender
Male Female Missing data	119 (38.4)191 (61.6)	162 (37.9) 266 (62.1) 4 (0.9)
Level of education
Little or no education Secondary and tertiary education Missing data	81 (26.1) 217 (70.0) 12 (3.9)	139 (32.1) 285 (66.0) 8 (1.9)
Employment status
Employed Unemployed Missing data	219 (70.7) 88 (28.4) 3 (0.9)	281 (65.1) 140 (32.4) 11 (2.5)
Months since HIV diagnosis
<6 months >6 months Missing data	146 (47.1) 152 (49.0) 12 (3.9)	136 (31.5) 284 (65.7) 12 (2.8)
Commenced ARVs
Yes No Missing data	259 (83.6) 45 (14.5) 6 (1.9)	335 (77.5) 78 (18.1) 19 (4.4)

HIV: human immunodeficiency virus; ARV: antiretroviral.

Table 2.

Source of recommendations, reasons for use, when herbal medication was started and perceived effectiveness among PLWH who use herbal medication (n = 310).

Variable	Use herbal medications (n = 310) n (%)
When did you start using herbal medications?
Pre-HIV diagnosis Post-HIV diagnosis	119 (38.4)191 (61.6)
Who recommended the herbal medications
Family Friends Missing data	209 (67.4)98 (31.6)3 (1.0)
Source of herbal medicines
City vendors Village herbalist Others Missing data	108 (34.8)145 (46.8)15 (4.8)42 (13.6)
Reasons for herbal medication use
To relieve symptoms To achieve cure of disease Others Missing data	108 (34.8) 145 (46.8)15 (4.8)42 (13.6)
Perceived effectiveness of herbal medication
No help Moderate relief of symptoms Completely relieved symptoms Cures disease (HIV) completely Missing data	125 (40.3)89 (28.7)43 (13.9)14 (4.5)39 (12.6)

HIV: human immunodeficiency virus.

Ethical approval

Ethics approval for the survey was obtained from Dalhatu Araf Specialist Hospital, Lafia, Faith Alive Foundation Hospital and PMTCT Centre, Jos (protocol assigned number: FAFHREC/08/34/5) and parental consent for including children was sought from parents before interviewing the parents for their children’s information. Only verbal consent and permission from hospital management was obtained from patient in primary healthcare Idong and Gombe Specialist Hospital.

Results

A total of 742 (approximately 12% of patients receiving treatments in these facilities) consecutively-attending PLWH aged between 2 and 91 years were surveyed across the four centres. Of these, 715 (96.4%) were adults aged 18 and above, 457 (61.6%) were female, 281 (37.9%) were males, and details of gender were missing in 4 (0.9%). Further details of demographic characteristics are provided in Table 1. Of the 742 PLWH surveyed, 594 (80.1%) were receiving ARVs.

Herbal use was reported in a total of 310 individuals (41.8%). Of these, 119 (38.4%) took herbals prior to starting ARVs while 191 (61.6%) started taking herbals after starting ARVs (Table 2). Time from diagnosis of HIV (P = 0.73) and whether individuals were receiving ARVs (P = 0.53) were not significantly associated with herbal medication use. PLWH who use herbals did so for a variety of reasons: to cure HIV (46.8%), or following the advice of family (67.4%) or friends (31.6%). Altogether, 40.3% said they felt herbals were ineffective for HIV while 4.5% believed themselves cured (Table 2). Ingestion of herbal medications while on ARVs was more likely in the elderly (OR 2.31; 95% CI 1.34, 3.99) and the employed (OR 1.23; CI 0.89, 1.70) compared to the unemployed (Table 3).

Table 3.

Association of surveyed variables and herbal medication use among PLWH.

	Univariate analysis			Multivariate analysis
Variable	β	Odds ratio (OR) (95% confidence interval)	P	β	Odds ratio (OR) (95% confidence interval)	P
Age	0.688	1.990 (1.183, 3.347)	0.009	0.839	2.314 (1.343,3.987)	0.003
Gender	–0.039	0.797 (0.712, 1.298)	0.797
Level of education	0.248	1.282 (0.930, 1.766)	0.130	0.190	1.209 (0.868, 1.686)	0.262
Employment status	0.192	1.228 (0.887, 1.696)	0.228
Months since HIV diagnosis	–0.688	0.502 (0.370, 0.681)	<0.001	–0.724	0.485 (0.355, 0.663)	<0.001
Commenced ARVs	0.154	1.167 (0.080, 1.696)	0.418

HIV: human immunodeficiency virus; ARV: antiretroviral.

As an extension to this study, 138 herbal samples were sourced from herbal vendors in diverse locations across Nigeria to assay for the presence of ARVs. Of the 138 samples collected and analysed, three (2%) contained detectable ARVs. One sample from Jos contained tenofovir and emtricitabine (estimated as 0.02 ng/mg powder and ≤0.01 ng/mg powder, respectively), while two samples from Ibadan contained tenofovir (estimated as <0.01 and 0.13 ng/mg powder) and emtricitabine (estimated as <0.01 ng/mg powder), with one of these also containing lamivudine (estimated as 0.02 ng/mg powder). Other ARV classes were not detected.

Dosing recommendations provided by the herbal vendors are often not precise. We found a typical dose recommendation was ‘3 fingers’ or scoops of medicinal powder in the palm of the hand, conservatively estimated as 1–2 teaspoons (1 teaspoon estimated as 5 g). Based on these recommendations, a single dose of 2 teaspoons (approximately 10 g) of contaminated herbal powder could potentially deliver up to 1.3 µg of tenofovir, 0.1 µg of emtricitabine and 0.2 µg of lamivudine. Although amount of drug detected is small, repeated exposure, or exposure to higher doses with different batches or preparations, could promote drug resistance.

In Nigeria, tenofovir and emtricitabine are available in fixed-dose combination as TRUVADA®. We wanted to examine if the discrepancy in the amount of tenofovir and emtricitabine observed could have been explained by differential degradation when crushed or dissolved, or recovery during the extraction process. Recovery from dissolved TRUVADA® tablets in water at room temperature carried out after 12 weeks and 9 months, respectively, was 63.2% and 1.47% for emtricitabine, compared with 0.8% and 1.47% for tenofovir. There were also considerable differences in drug solubility, recovery (extraction efficiency) and matrix effects (ion suppression) between different herbal preparations, which more likely explained the differences in measured quantity between both drugs.

Discussion

We observed widespread use of herbal medicines in Nigeria (Table 1) regardless of age, gender, educational or employment status. Our data are consistent with previous studies conducted in this region.^9,25 A total of 594 (80%) of PLWH were receiving ARVs and herbal medicine use was highly prevalent in patients receiving HIV treatment (259/594 [43.6%] of those receiving ARVs use herbal or traditional medicines). Among the herbal users, 38.4% were using these remedies prior to initiation of ARVs, while 61.2% started using them after HIV diagnosis (Tables 1 and 2).

Of concern, 45 (14.5%) of herbal users were yet to initiate ARVs which could be detrimental to their treatment in the future if exposed to low levels of ARV in herbal remedies (Table 1). Previous reports of low-level ARV exposure to neonates during PMTCT suggest that continuous low-level exposure to ARVs could drive resistance.²⁵^,²⁶ Our finding of contamination of herbals with ARVs is a concern, though concentration was very small and may not be sufficient to drive resistance, finding contamination in herbals is detrimental to treatment and HIV programme success. Around half of the subjects perceived use of herbal medicines to either moderately or completely relieve symptoms such as headaches, fever and generalised body weakness.

We found 2% of herbal medicines contained small, but detectable quantities of ARVs, yielding an estimated dose of 0.1–1.3 µg ingested per dosing occasion. The clinical relevance of this is unclear. However, continuous low-level exposure to drug can lead to resistance, provided sufficient drug is present to drive selection pressure for resistant mutants. Furthermore, potential drug–drug interaction of herbals and ARVs as well as safety^8,17 was difficult to ascertain since constituents of the herbal medicines were unknown.²⁷ Although the concentrations detected were very low, actual concentrations may have been higher given the different efficiencies of extraction and degradation over time that were observed.

The finding that traditional or herbal remedies may contain pharmaceutic agents is not new. Previously, herbal medicines have been found to contain antipyretics, anti-inflammatory agents or steroids, diuretics, antidiabetics, sedatives, antihistamines and vasodilators through accidental or deliberate contamination.²⁸ Accidental contamination may result from carryover of drug during local manufacture of medicines; however, this is less likely here as HIV drugs are not locally co-manufactured with herbals to our knowledge. It is difficult to ascertain whether contamination was deliberate or accidental in this case. HIV drugs are dispensed free of charge through the National Treatment Programme; their use and belief that they are beneficial for the treatment of HIV disease may provide both the opportunity and the motive for any deliberate contamination. Herbalists and their medicines can play an important role in supplementing and supporting HIV treatment in treatment settings^18,29 where weak health systems and complex cultural beliefs around symptom management³⁰ promote widespread herbal use. Enforcing the regulation of herbal medicine practices³ and re-evaluating policies guiding herbal practitioners in Nigeria is urgently required to avoid harmful practices that put the general public at risk.

Limitations

We were not able to ascertain how herbal use influenced engagement with HIV services, or adherence to ARVs although these are important questions to address in future research. Moreover, we were only able to assess PLWH already engaged with treatment services. There is currently no clear understanding of positive or negative effects of traditional medicines as adjunctive treatment in PLWH. However, the lack of regulation and standardisation in these preparations argues strongly for further work to confirm our findings in other countries where herbal medicine use is prevalent and to understand whether ARV contamination of herbal medicines has a negative impact on ARV programmes through the generation of drug resistance. Surveys were only conducted in a small population from northern Nigeria, which may vary from other regions of the country. Therefore, a larger study that aims at ensuring fair representation of all the regions of Nigeria is required.

Conclusion

Herbal medicine use was widespread and mostly utilised concomitantly with ARVs. Although a fairly large proportion utilised herbals prior to ARV initiation, co-administration of herbal medicines with ARVs is concerning, since the constituents and safety profiles of the herbal medicines are unknown. Toxicity and herbal–ARV interactions are uncharacterised which favours urgent evaluation of policies by authorities to regulate their practices. Erroneous perception of herbals to relieve HIV symptoms or cure disease is a problem and herbals need to be further evaluated for their medicinal benefits. Finally, further evaluation of our findings by researchers to establish the best approach to monitor and enforce safe practices of herbalists for public safety of herbal products as well as collaborative research of medicinal herbs is required.

Footnotes

Acknowledgements

We are grateful to the State Specialist Hospital, Gombe, Faith Alive Foundation Hospital and PMTCT Centre, Dalhatu Araf Specialist Hospital, Lafia, Nasarawa State, and Rural Hospital, Idong, Kaduna State, for allowing us to conduct surveys in their HIV clinics.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Nigerian Government via the National Universities Commission (NUC) and Tertiary Education Trust Fund (TETFund) as part of funding for PhD programme to a beneficiary of 2011 Presidents Honours Award scholarship from Federal Ministry of Health Nigeria. The authors acknowledge infrastructural support from the Liverpool Biomedical Research Centre funded by Liverpool Health Partners. The Liverpool Drug Interactions website has received funding from Gilead Sciences, ViiV Healthcare, Janssen and Merck.

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