Cutaneous adverse drug reactions among people living with human immunodeficiency virus in a tertiary care hospital in Johor,Malaysia

Abstract

Background

Cutaneous adverse drug reactions (cADRs) among people living with HIV (PLWH) are common. Data on drug eruptions among PLWH in Malaysia are limited. Thus, our study aimed to determine the clinical patterns of cADRs among PLWH and the risk factors associated with severe cutaneous adverse reactions (SCAR).

Methods

A cross-sectional study was conducted among PLWH who developed cADRs presenting to our dermatology clinic from June 2020 to December 2020. The Naranjo scale was used for drug causality assessment.

Results

A total of 78 PLWH were recruited with a male-to-female ratio of 12:1. The maculopapular eruption was the commonest type of cADRs (75.6%), followed by drug reaction with eosinophilia and systemic symptoms (DRESS) (15.4%). SCAR is defined as a potentially life-threatening, immunologically mediated, drug-induced disease, accounting for 17.9% of the cases. Most of the patients were on antiretroviral therapy (ART) (85.9%), with efavirenz + tenofovir/emtricitabine being the most common combination (80.6%). Efavirenz (51.3%) was the main culprit drug implicated, followed by trimethoprim/sulfamethoxazole (23.1%) and nevirapine (11.5%). CD4 T-cell count <100 cells/μL (p = 0.006) was the independent risk factor for SCAR. Most cases had probable causal relationships with the culprit drugs (84.6%) and were not preventable (93.6%).

Conclusions

The commonest cADR seen in PLWH was maculopapular eruption, while efavirenz, trimethoprim/sulfamethoxazole, and nevirapine were the three main implicated drugs. Most of the cases had probable drug causality and were not preventable. PLWH with CD4 count <100 cells/μL were particularly at risk of developing SCAR. Overall, this study showed that immune suppression and polypharmacy as a consequence of opportunistic infection prophylaxis are important factors contributing to the increased risk of ADRs among PLWH.

Keywords

Cutaneous adverse drug reactions human immunodeficiency virus antiretroviral therapy,severe cutaneous adverse reactions

Introduction

In Malaysia, it was estimated that there were 87,000 people living with human immunodeficiency virus (PLWH) in 2019.¹ Notably, about 56% of PLWH were on antiretroviral therapy (ART) in 2019.¹ According to our national guidelines, the preferred first-line ART treatment regimen is the combination of tenofovir, emtricitabine and efavirenz.² Other alternative regimens include the combination of tenofovir, emtricitabine and nevirapine, and the combination of either zidovudine or abacavir with lamivudine and either efavirenz or nevirapine.²

The use of ART has significantly impacted the progression of the disease, reducing mortality and morbidity among PLWH and improving their quality of life.³ However, all these advantages have been accompanied by a tremendous increase in the number of adverse drug reactions (ADRs) among PLWH, who have a higher risk of developing cutaneous ADRs (cADRs) compared to the general population.^4-6 Previous studies have shown that ADRs have significantly contributed to the non-compliance to ART, discontinuation of the medication, and eventually led to treatment failure.⁷

There are very few studies that attempted to identify the types and frequency of cADRs among PLWH. To date, limited data are available locally on drug reactions among PLWH. Thus, this study aimed to determine the clinical patterns of cADRs, drug causality and preventability, as well as the risk factors associated with severe cutaneous adverse reaction (SCAR) among PLWH.

Materials and methods

The current study was a cross-sectional study conducted in the dermatology clinic of Hospital Sultanah Aminah Johor Bahru, a tertiary referral centre for the state of Johor in Malaysia. The study was conducted from 1 June 2020 till 31 December 2020.

The estimated sample size was based on a study by KJ Smith et al.⁸ A minimum sample size of 76 samples is required based on the population proportion formulae⁹ with a population size of 4000. The inclusion criteria were PLWH aged 18 years old and above who developed cADRs to systemic drugs, both in and outpatient, including those referred from other departments and healthcare facilities. All the patients who fulfilled the inclusion criteria during the study period were recruited with written informed consent. Patients who did not consent to participate in this study were excluded. This study was registered and approved by the Malaysian National Medical Research Register (NMRR-20-1323-55588). Ethical approval for this study was obtained from the Medical Research and Ethics Committee (MREC), Ministry of Health Malaysia.

Study procedure

After obtaining the consent, a complete history and physical examination were performed and available medical records were reviewed. All the study participants were assessed by a dermatologist. Relevant laboratory tests and skin biopsies, if needed, were also performed. The diagnosis of cADRs was made based on the history, morphology, and distribution of the rashes, as well as the investigation results. Any other diseases that could trigger the eruptions were excluded. All the findings including the demographic data, medical history, drug history, physical examination, and laboratory results were documented in a standard clinical report form.

Culprit drug was determined based on the chronology from the initial drug intake to the onset of reaction, the notoriety of the drug in causing the reaction, improvement of the lesions on withdrawal of the drug and recurrence of the lesions on rechallenge. Previous exposure to the drug without reaction renders it unlikely to be the culprit drug. If more than one drug was thought to be responsible, then the most likely offending agent was withdrawn and the impression was confirmed by the subsidence of the rash following the withdrawal of the drug.

Drug causality assessment was performed using the Naranjo scale.¹⁰ The Naranjo scale comprises of 10 questions that are answered as “Yes”, “No”, or “Do not know”. Different point values (−1, 0, +1 or +2) are assigned to each answer with the total scores ranging from −4 to +13. The ADRs were categorized into “definite” if the score is >8, “probable” if the score is between 5 to 8, “possible” if the score is between 1 to 4, and “doubtful” if the score is <1.

Drug preventability was assessed using the Schumock and Thornton preventability scale.¹¹ The modified form of this scale has three sections named definitely preventable, probably preventable and not preventable. The first section comprises of five questions while the second section has four questions. All the answers are categorized as “Yes” or “No”. The ADRs were classified as “definitely preventable” if the answer was “Yes” to one or more questions in the first section. If all the answers were “No” then we proceeded to the second section. The reactions were “probably preventable” if the answer was “Yes” to one or more questions in the second section. If all the criteria were not fulfilled, we proceeded to the third section and the reactions were classified as “not preventable”.

Statistical analysis

Descriptive statistics were presented as counts and percentages for categorical variables. Mean with standard deviation (SD) was used for the analysis on the normally distributed data, while median with interquartile range (IQR) was used for data that were not normally distributed. SCAR is defined as a potentially life-threatening, immunologically mediated, drug-induced disease which includes Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis and generalized bullous fixed drug eruptions.^12,13 Risk factors for developing SCAR were analysed using logistic regression models. Factors for which a p-value < 0.25 for the interaction with SCAR being observed were included in the multivariable logistic regression model. The odds ratio (OR) was presented for every risk factor, followed by a 95% confidence interval (CI). Statistical significance was set at p < 0.05. Statistical analysis was carried out with the Statistical Package for the Social Sciences (SPSS) (version 22; SPSS Inc., Chicago, IL. USA).

Results

Demographic characteristics

A total of 78 PLWH were recruited in the study. Their demographic and clinical characteristics are shown in Table 1. Overall, male gender predominance was seen with a male-to-female ratio of 12:1. The mean age was 35.8 years (SD = 9.84). Men who have sex with men (MSM) was the most typical risk factor for HIV acquisition (52.6%). Most of the patients were on ART (85.9%) with efavirenz + tenofovir/emtricitabine being the commonest regimen (69.2%). The median CD4 T-cell count was 164.50 cells/μL (IQR = 319).

Table 1.

Demographic and clinical characteristics of 78 PLWH with cutaneous ADRs.

Variables		n = 78	%
Age	Age group
	<20	1	1.3
	20–29	23	29.5
	30–39	30	38.5
	40–49	14	17.9
	50–59	9	11.5
	≥60	1	1.3
Gender	Male	72	92.3
Gender	Female	6	7.7
Ethnicity	Malay	45	57.7
	Chinese	23	29.5
	Indian	5	6.4
	Others	5	6.4
BMI	<18.5	10	12.8
	18.5–24.9	51	65.4
	25.0–30.0	10	12.8
	>30.0	7	9
Duration of diagnosis	<1 year	41	52.6
	1–5 years	25	32.1
	>5 years	12	15.4
Risk factor for HIV acquisition	MSM	41	52.6
	Heterosexual	24	30.8
	Bisexual	6	7.7
	PWID	7	9.0
ART	No	11	14.1
ART	Yes	67	85.9
ART regimen	Efavirenz + tenofovir/emtricitabine	54	69.2
	Nevirapine + tenofovir/emtricitabine	10	12.8
	Lamivudine/zidovudine + efavirenz	1	1.3
	Lamivudine/zidovudine + Lopinavir/ritonavir	1	1.3
	Lamivudine/zidovudine+ atazanavir/ritonavir	1	1.3
CD4 count (cell/mm³)	<100	29	37.2
	100–199	13	16.7
	200–299	8	10.2
	300–399	9	11.5
	400–499	8	10.2
	≥500	11	14.1
Medical history	Syphilis (treated)	30	38.5
	Chronic hepatitis B	8	10.3
	Chronic hepatitis C	7	9
	Hypertension	7	9
	Diabetes	6	7.7
	Tuberculosis	6	7.7
	• Treated TB (2)
	• Latent TB (2)
	• TB lymphadenitis (2)

BMI: Body mass index; MSM: Men who have sex with men; PWID: People Who Inject Drugs; TB: Tuberculosis.

Clinical patterns

Most of the cutaneous ADRs were maculopapular eruptions (59 cases, 75.6%), followed by drug reaction with eosinophilia and systemic symptoms (DRESS) (12 cases, 15.4%), Steven-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) (2 cases, 2.6%), urticaria/angioedema (2 cases, 2.6%) and photodermatitis (2 cases, 2.6%) (Figure 1). Maculopapular eruptions were mainly due to ART (43 cases, 72.9%) and antibiotics (14 cases, 23.7%), while DRESS was mainly because of antibiotics (7 cases, 58.3%). 14 cases (17.9%) of SCAR were seen in this study, namely SJS, TEN and DRESS (Figure 2).

Figure 1.

Distribution of cutaneous ADRs among PLWH. DRESS: Drug reaction with eosinophilia and systemic symptoms; SJS: Steven-Johnson Syndrome; TEN: Toxic epidermal necrolysis.

Figure 2.

(a) & (b) Morbilliform rash in a patient with DRESS secondary to Trimethoprim/sulfamethoxazole.

Following drug exposure, the median time to the development of cADRs was 9 days (range 1–58 days). The median time to onset of cARDs after drug initiation was 8 days (range 3–30 days) for maculopapular eruptions and 27.5 days (range 8–58 days) for DRESS. Overall, most patients (67 cases, 85.9%) were treated in an outpatient setting, while 11 patients (14.1%) required hospitalization.

Culprit drugs

Antiretroviral agents were the most commonly implicated drug group (50 cases, 64.1%), followed by antibiotics (23 cases, 29.5%) and antituberculous drugs (4 cases, 5.1%). Overall, most of the cutaneous drug eruptions in this study were due to efavirenz (40 cases, 51.3%), followed by trimethoprim/sulfamethoxazole (18 cases, 23.1%) and nevirapine (9 cases, 11.5%) (Table 2). Efavirenz was responsible for most of the maculopapular eruptions (36 cases, 61%), while trimethoprim/sulfamethoxazole was the main culprit drug for DRESS (5 cases, 41.7%) (Table 3). In this study, three out of seven patients with a history of hypersensitivity to trimethoprim/sulfamethoxazole have developed cADRs with dapsone.

Table 2.

Drugs implicated in cutaneous ADRs.

Culprit drugs	No of patients	%
Antiretroviral drug
Efavirenz	40	51.3
Nevirapine	9	11.5
Lopinavir-ritonavir	1	1.3
Antibiotic
Trimethoprim/sulfamethoxazole	18	23.1
Clindamycin	2	2.6
Dapsone	3	3.8
Antituberculous drug
Isoniazid	2	2.6
Isoniazid/rifampicin	2	2.6
NSAIDs
Etoricoxib	1	1.3

NSAIDs: Nonsteroidal anti-inflammatory drugs.

Table 3.

Frequency of drugs implicated by cutaneous ADRs.

Reaction pattern	Culprit drugs	No of patients
Maculopapular eruption (n = 59)	Efavirenz	36
	Trimethoprim/sulfamethoxazole	11
	Nevirapine	7
	Clindamycin	2
	Dapsone	1
	Lopinavir-ritonavir	1
	Isoniazid	1
DRESS (n = 12)	Trimethoprim/sulfamethoxazole	5
	Dapsone	2
	Efavirenz	2
	Isoniazid/rifampicin	2
	Nevirapine	1
SJS/TEN (n = 2)	Nevirapine	1
SJS/TEN (n = 2)	Isoniazid	1
Photodermatitis (n = 2)	Trimethoprim/sulfamethoxazole	1
Photodermatitis (n = 2)	Efavirenz	1
Urticaria/angioedema (n = 2)	Trimethoprim/sulfamethoxazole	1
Urticaria/angioedema (n = 2)	Efavirenz	1
Cutaneous vasculitis (n = 1)	Etoricoxib	1

DRESS: Drug reaction with eosinophilia and systemic symptoms; SJS: Steven-Johnson Syndrome; TEN: Toxic epidermal necrolysis

The median number of total medications taken by the patients was three (range 2–12). A total of six patients had features of polypharmacy (intake of more than five drugs) and they were mainly patients with CD4 count < 200 cells/μL (5 cases, 83.3%).

Risk factors

Logistic regression was conducted to identify the risk factors associated with SCAR. Several factors such as age, gender, ethnicity, comorbidity, and previous drug allergy were evaluated but they did not significantly correlate with SCAR.

Univariate analysis showed that factors such as CD4 T-cell count <100 cells/μL and the number of drugs had a p-value <0.25 for the interaction with SCAR and these factors were included in the multivariable logistic regression model. Multivariate analysis showed that CD4 T-cell count <100 cells/μL was the only independent predictor of SCAR. Patients who presented with CD4 T-cell count <100 cells/μL were six times more likely to develop SCAR (adjusted OR = 5.92; 95% CI 1.65 to 21.24; p = 0.006) (Table 4).

Table 4.

Risk factors associated with SCARs.

Risk factors	n (%)		Univariate analysis		Multivariate analysis^a
	Non-SCAR	SCAR	Crude OR^b	p-value	Adjusted OR^b	p-value
	(n = 64)	(n = 14)	(95% CI)^c	p-value	(95% CI)^c	p-value
Age (years)
<40	43 (67.2)	11 (78.6)	1	—	—	—
≥40	21 (32.8)	3 (21.4)	0.42	0.382	—	—
			(0.06, 2.92)
Gender
Female	5 (7.8)	1 (7.1)	1	—	—	—
Male	59 (92.2)	13 (92.9)	0.55	0.705	—	—
			(0.02,11.29)
Ethnicity
Malay	36 (56.3)	9 (64.3)	1	—	—	—
Chinese	20 (31.3)	3 (21.4)	0.62	0.575	—	—
Chinese			(0.12, 3.26)
Indian	4 (6.3)	1 (7.1)	0.34	0.447	—	—
Indian			(0.02, 5.59)
Others	4 (6.3)	1 (7.1)	0.68	0.773	—	—
Others			(0.05, 9.48)
Comorbidity
No	23 (35.9)	4 (28.6)	1	—	—	—
Yes	41 (64.1)	10 (71.4)	2.03	0.474	—	—
			(0.29, 14.22)
Syphilis
No	40 (62.5)	8 (57.1)	1	—	—	—
Yes	24 (37.5)	6 (42.9)	0.91	0.921	—	—
			(0.13, 6.15)
Previous drug allergy
No	52 (81.3)	9 (64.3)	1	—	—	—
Yes	12 (18.7)	5 (35.7)	1.80	0.521	—	—
			(0.30, 10.73)
CD4 count (cells/μL)
≥100	45 (70.3)	4 (28.6)	1	—	1	—
<100	19 (29.7)	10 (71.4)	5.69	0.021	5.92	0.006
			(1.31, 24.79)		(1.65, 21.24)
Number of drugs
<5	56 (87.5)	9 (64.3)	1	—	1	—
≥5	8 (12.5)	5 (35.7)	4.31	0.079	3.21	0.105
			(0.85, 21.93)		(0.78, 13.21)

^aBackward Stepwise Likelihood Ratio was applied for multivariate analysis.

^bOdds Ratio.

^cConfidence Interval.

SCAR: Severe cutaneous adverse reactions.

Drug causality and preventability

Based on the Naranjo scale, most of the cases in this study were classified as probable drug causality (66 cases, 84.6%). The remaining 12 cases were classified as definite (6 cases, 7.7%) and possible drug causality (6 cases, 7.7%).

Modified Schumock and Thornton scale revealed that most of the reactions were not preventable (73 cases, 93.6%). The remaining five cases (6.4%) were classified as definitely preventable. Four out of the five definitely preventable cases had a previous history of cutaneous adverse reactions to the same culprit drugs, namely efavirenz (2 cases), nevirapine (1 case) and antituberculous drug (1 case). Among the four cases, one patient developed DRESS, while the other three patients had maculopapular eruptions.

Discussion

The current study examined the clinical patterns of cADRs among PLWH in Hospital Sultanah Aminah, Malaysia. Most of the study participants were aged between 20 to 39 years old (68%) with male predominance (92.3%). These findings were consistent with our national data¹ and another study by Smith et al.⁸ According to our national data, most of the PLWH are male and more than 70% are aged between 20 to 39 years old.¹ In the past 10 years, the trend of the HIV epidemic in Malaysia shifted from a predominance of cases in people who inject drugs (PWID) to more cases of sexual transmission with more than 90% reported cases in 2019.¹ Similarly, most of the participants in this study contracted HIV via sexual transmission, predominantly MSM.

Our data confirmed that maculopapular eruption was the most common type of cADRs among PLWH, similar to studies from the United Kingdom,⁴ United States,⁸ Central Africa¹⁴ and India.¹⁵ A total of 14 cases (17.9%) of SCAR were seen in this study. Our results have concurred with a Cameroonian study by Koutou et al.¹⁴ who reported 16.7% SCAR among ART-taking PLWH. In contrast, a Nigerian study by Salami et al. conducted during the pre-ART era reported the prevalence of SCAR among PLWH as high as 60 percent.¹⁶ The discrepancies between the two African studies were due to the development of safer regimens for the treatment of HIV and associated opportunistic infections (OIs).¹⁷ Early initiation of ART in recent years has led to a reduction in HIV-associated OIs and a decrease in the use of prophylactic drugs.¹⁸ This effort has also considerably reduced the exposure of PLWH to antimicrobials, the commonest group of drugs causing cADRs among PLWH.¹⁸

The three main drugs implicated in this study were efavirenz (51.3%), trimethoprim/sulfamethoxazole (23.1%) and nevirapine (11.5%). The findings of culprit drugs varied among different studies. Two previous studies^4,8 had reported trimethoprim/sulfamethoxazole and penicillin to be responsible for most of the drug eruptions. The variability of the culprit drugs could be influenced by the availability of the ART and the differences in prescribing habits across different regions. A study by Kouotou et al.¹⁴ showed that nevirapine and trimethoprim/sulfamethoxazole were the main causative agents for 41 drug eruptions among PLWH. This study from Cameroon mainly included people of African ancestry. Therefore, the different ethnic backgrounds of the study participants could explain the discrepancies of the culprit drugs in view that the pharmacogenetics of cADRs is population specific.⁶

The reported incidence of efavirenz-induced drug reactions has been reported to vary between 4.8% and 20% in previous studies.^14,19–20 In this study, efavirenz was the commonest culprit drug likely due to the widespread use of efavirenz containing ART in our centre, considering that efavirenz containing regimen is the preferred first-line ART according to our national guidelines.² Most of the drug eruptions induced by efavirenz were maculopapular eruptions consistent with the previous literature.¹⁹ Photodistributed eruptions had been reported as a unique manifestation of efavirenz hypersensitivity by Isaacs et al.²¹ In this study, one case of photodermatitis caused by efavirenz was recorded.

Previous literature had reported the incidence of trimethoprim/sulfamethoxazole-induced cADRs in patients with HIV ranged between 30% to 80%.^19,22–24 The data in this study showed that trimethoprim/sulfamethoxazole had induced 23.1% of the drug eruptions, comparable to the 26.8% reported by Kouotou et al.¹⁴

Interestingly, in this study, three out of seven patients with hypersensitivity to trimethoprim/sulfamethoxazole (42.8%) developed cADRs with dapsone. Cross-reactivity to dapsone among patients with trimethoprim/sulfamethoxazole hypersensitivity could be explained by the underlying genetic predisposition. Studies from China^25,26 and Thailand²⁷ had reported the association of HLA B*13:01 in dapsone-induced hypersensitivity. A multi-country study involving Taiwan, Thailand and Malaysia also showed a strong association between HLA B*13:01 and trimethoprim/sulfamethoxazole-induced SCAR among Asians, especially with DRESS.²⁸ Overall, the findings of this study highlight the need for higher vigilance when prescribing dapsone in trimethoprim/sulfamethoxazole-intolerant patients and to consider other safer alternatives.

Previous literature had reported the incidence of nevirapine-induced rash ranged between 15% to 32%.¹⁹ In our study, nevirapine was the third most common implicated drug, contributing 11.5% of the drug euptions. However, the study by Kouotou et al. reported a higher prevalence of nevirapine-induced drug eruptions (43.1%) among PLWH.¹⁴ Another study of 101 PLWH treated with ART in France had identified 14 cases of cutaneous drug eruptions attributable to nevirapine (13.86%).²⁹

Previous studies have reported older age,⁸ ethnicity,⁸ female gender^20,30 and history of drug allerg^30,31 as the risk factors for cADRs among PLWH. However, this result was not demonstrated in our study possibly due to the different ethnic backgrounds of the study participants and different eras in the HIV epidemic. Logistic regression analysis showed that CD4 T-cell count <100 cells/μL was the independent predictor for SCAR among PLWH. Previous literature consistently reported the deterioration of the immune system with a decrease in CD4 T-cell count was significantly associated with an increased risk of cutaneous adverse reactions.^4,8,19,32 Similar findings had been observed among PLWH with adverse reactions to trimethoprim/sulfamethoxazole prophylaxis.³³ However, the study by Boonyagars et al. among HIV-TB co-infected patients who received antituberculous treatment failed to demonstrate the association between CD4 T-cell count and cutaneous adverse reactions.³¹ The findings of this study regarding risk factors for severe cutaneous adverse reactions are important as higher vigilance and close monitoring could be implemented when initiating medications in patients with CD4 count <100 cells/μL.

Regarding the drug preventability, our study showed a lower rate of preventable cases (5 cases, 6.4%) compared to a study by Bezabhe et al. (8 cases, 12.1%).³⁰ The preventable cases were mainly a result of repeated administration of the same causative drugs. To address this, it is important to educate patients and healthcare workers on the risks of drug reactions in PLWH. Before medication initiation, potential adverse events should be explained to the patients, and patients should be instructed to stop the medication immediately if any adverse events arise. To avoid re-exposure, patients should always carry the allergic card or medic alert bracelet given to them. Documentation of previous adverse reactions could be improved via the digital medical record systems and computerized medication entry.

There were some potential limitations in this study. First, the study was conducted in a single centre over a 7 month period with a relatively small sample size. Therefore, it may not be easy to extrapolate our findings to the whole country. The study was conducted at a Dermatology clinic in a tertiary referral centre. This may skew the number of ADRs which might result in a higher prevalence of observed ADRs compared to the primary care setting. Besides, it was challenging to identify the culprit drugs in patients taking multiple drugs as drug challenge tests were not performed most of the time.

Conclusions

The commonest cutaneous drug eruption seen in PLWH was the maculopapular eruption, similar to other countries. Efavirenz, trimethoprim/sulfamethoxazole and nevirapine were the three main culprit drugs. Most cases had probable drug causality and were not preventable. PLWH with CD4 count <100 cells/μL were particularly at risk of developing SCAR. Overall, this study showed that immune suppression and polypharmacy as a consequence of opportunistic infection prophylaxis are important factors contributing to the increased risk of ADRs in PLWH. In the future, a larger study population is required to establish the real-world pictures of cADRs among PLWH.

Supplemental Material

Supplemental Material - Cutaneous adverse drug reactions among people living with human immunodeficiency virus in a tertiary care hospital in Johor, Malaysia

Supplemental Material for Cutaneous adverse drug reactions among people living with human immunodeficiency virus in a tertiary care hospital in Johor, Malaysia by Keow Yin Chua and Kwee Eng Tey in International Journal of STD & AIDS

Acknowledgement

The authors would like to thank the Director General of Health Malaysia for the permission to publish this paper.

Footnotes

Declaration of conflicting interests

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

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Keow Yin Chua

Supplemental material

Supplement material for this article is available in online.

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