Advance Publication by J-STAGE Japanese Journal of Infectious Diseases
Adverse drug reactions in HIV/AIDS patients at a tertiary care hospital penang, Malaysia
Kashifullah Khan, Amer Hayat Khan, Syed Azhar Sulaiman, Chow Ting Soo, and Ali Akhtar
Received: June 7, 2014. Accepted: April 8, 2015 Published online: June 12, 2015 DOI: 10.7883/yoken.JJID.2014.246
Advance Publication articles have been accepted by JJID but have not been copyedited or formatted for publication.
ADVERSE DRUG REACTIONS IN HIV/AIDS PATIENTS AT A TERTIARY CARE HOSPITAL PENANG, MALAYSIA
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Kashifullah Khan 1, Amer Hayat Khan 1, Syed Azhar Sulaiman 1, Chow Ting Soo2, Ali Akhtar1
Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia, Penang 11800, Malaysia
Infectious Disease Department, General Hospital Pulau Pinang, Penang, Malaysia
Corresponding author:
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KashifUllah Khan. Address: Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia Tel: 006-011-26293299; Fax: 00604 657 0017 Email:
[email protected]
Key Words: ADRs, Lipodystrophy, HAART, HIV/AIDS
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Running Title: ADRs during HAART Therapy In Malaysia
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Words Count: 1730, (excluding title page, abstract, references, figures and tables).
Abstract (Summary) Current study is aimed to explore and observe adverse drug reactions occurrence of antiretroviral
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therapy among HIV/AIDS patients.
An observational retrospective study of all patients on HAART therapy diagnosed with HIV infection from Jan 2007 to Dec 2012 was conducted at Hospital Pulau Pinang, Malaysia. Patient socio-demographic details along with clinical features and susceptible ADRs were observed
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during the study period.
Out of 743 patients 571 (76.8%) were male and 172 (23.1%) were female. Overall 314 (42.2%) patients had experienced adverse drug reactions. A total number of 425 (57.2%) adverse drug reactions were reported among which 311 (73.1%) occurred in males and 114 (26.8%) in female
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patients, with a significant statistical relationship (p=0.02, OR=1.21). Overall 239 (56.2%) ADRs were recorded among Chinese, 94 (22.1%) in Malay, and 71 (16.7%) in Indian, which had a statistical significant association with ADRs (p-value=0.05, OR=1.50). Out of total 425 (57.2%)
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ADR’s, Lipodystrophy was recorded 151 (35.5%) followed by Skin rashes 80 (18.8%), Anaemia
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74 (17.4%) and Peripheral Neuropathy 27 (6.3%). The findings of present study suggest that there is a need of intensive monitoring for ADRs in HIV treatment centres of Malaysia.
Introduction:
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Human Immune deficiency virus (HIV) infection leads to Acquired immune deficiency syndrome (AIDS), transmitted from person to person through sexual fluids, blood, and breast milk while mostly through injecting drug users, sex workers, and men who sex with men(1). According to the survey conducted by World Health Organization in 2012, 31.4 to 35.9 million people were affected with HIV Aids globally, ,of which about 0.8% were adults aged 15-49
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years, More over survey also reports that new cases of HIV and deaths reported were 2.5 million and 1.7 million respectively till the end of 2011(2). The Asian region which is also a home to the world most populous nations i.e. China and India, has also an estimated 4.8 million people living with HIV(3). In Malaysia, 79,855 cases of HIV were reported, 71 %of which were found in
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Malay, 15% in Chinese, 8% in Indian and 6% in all other ethnic population by the end of 2011(4). An estimated 33.3 million people are living with HIV globally and around 3 million people have accessed to the highly active antiretroviral therapy (HAART) as on 2009(5). In
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Malaysia, the number of HIV/AIDS patients receiving HAART has increased from 1,710 people
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in 2003 to 6,207 people in 2007(6). In 1996-1997 when antiretroviral treatment (ART) was first introduced, approximately 50% of mortality reduction was shown among people living with HIV/AIDS who were compliance with the ART regimen(7). The initial HAART therapy with three antiretroviral (ARV) drugs has led to significant reduction in AIDS morbidity and mortality(8). However, now the initial HAART regimen contain a complex set of ART drugs hence in spite of benefits associated with the use of
ART, the issues of adverse drug reactions such as fat redistribution, dyslipidaemia, and sexual dysfunction have remained a great concern which may lead to the non-compliance and discontinuation of ART(9,10). For instance the use of non-nucleoside reverse transcriptase inhibitors (NNRTI’s) has been associated with rash and hepatotoxicity(11). Nucleoside reverse
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transcriptase inhibitors (NRTI’s) have been linked with hypersensitivity reactions, anemia and neutropenia(12). Protease inhibitors have also been associated with hyperlipidaemia, hyperglycaemia amd gastrointestinal symptoms(13, 14). Furthermore, an increasingly complex drug therapy for HIV-infected patients increases the chances of adverse drug reaction(15).
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To our knowledge, there has been no published data regarding adverse drug reactions associated with HAART in Malaysian HIV/AIDS patients. Thus, the objective of this study was to explore the occurrence of ADR’s among HIV/AIDS patients receiving HAART.
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Materials and Methods:
A retrospective cross-sectional observational study was conducted at infectious disease
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department of general hospital pulau Pinang, Malaysia. All the HIV infected patients on HAART therapy from Jan 2007 to Dec 2012 were included for the study. Pregnant women and children
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diagnosed with HIV were excluded from the study. The patient’s record forms were thoroughly reviewed and relevant data was noted on a validated data collection form. Demographic and clinical characteristics of patients that were susceptible to ADRs were recorded and observed during the study period. The reported ADRs were assessed for causality by using Noranjo’s algorithm scale(16). Categorical data was reported numerically as numbers and percentage of the total while continuous data was reported using mean and standard deviations (SD). Chi- square
and Fischer’s exact tests were used to detect significance between categorical variables. Univariate analyses were also used for estimating further correlation between the ADRs and different variables. A p-value of .05 or below was considered statistically significant.
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All statistical calculations were performed using SPSS statistical package (Version 20).
Results
A total of 997 patients were diagnosed as HIV infection between Jan 2007 and Dec 2012, of
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whcih743 fulfilled our inclusion criteria. Out of 743 patients 571 (76.8%) were male and 172 (23.1%) were female. Overall 314 (42.2%) patients had experienced adverse drug reactions. A total number of 425 (57.2%) adverse drug reactions were reported among which 311 (73.1%) occurred in males and 114 (26.8%) in female patients. A statistical significant relationship was
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observed between the gender and the occurrence of adverse drug reactions (p=0.002) (Table 1). In multiethnic population of Malaysia, 239(56.2%) ADRs were recorded in Chinese people, 94(22.1%) in Malay, 71(16.7%) in Indian while 21(5%) in all other ethnicity with a significant
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statistical relation (p=0.05) (Table 1). Moreover on univariate analysis a significant relation was
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observed in Indian race only (p= 0.05, OR=1.50) (Table 2). Among different age groups, 112 (35.66%) patients had experienced ADRs that belong to age group 41-50 years while 107 (34.07%) patients were having ages between 31 to 40, followed by 66 (21%) patients that were aged 50 years and above, however there was no statistically significant relation of ADRs occurrence among different age groups (p-value = 0.51) (Table 1). However On further analysis, patients with age group less than 30 years (p=0.02, OR=0.59) had
a statistical significant association with ADR’s as compared to other age groups (Table 2). Among the enrolled 743 patients, 512(68.9%) patients were smokers and 340(45.8%) were alcoholic, both of which had a significant association with ADR’s (p= 0.01, p= 0.009 respectively) (table 1). Univariate analysis indicate that smokers (OR=1.52 p= 0.009) and non
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alcoholics (OR=1.48, p= 0.008) had significant association with ADR’s (table 2).
In 314 patients, 425 suspected ADRs, 225 (71.65%) patients developed one ADR, 67 (21.3%) patients developed two ADRs, and 22 (7%) patients suffered from three ADRs.
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The most common HAART regimen used were AZT+3TC+EFV (41.8%), TDF+FTC+EFV (34.2%), D4T+3TC+NVP (22.3%), AZT+3TC+NVP (21.2%) of First line HAART therapy, while AZT+3TC+LOP-RITO (6.1%) and TDF+FTC+LOP-RITO (5.9%) were of second line of the therapy. Lipodystrophy (35.5%) was mostly Stavudine associated however was also found in
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patients receiving Zidovudine containing regimes. Rash (18.8%) was commonly associated in patients with Nevirapine and Efavirenz containing regimes while anemia (17.4%) was found in
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patients who were on Zidovudine containing regimes. The common ADRs observed out of total 425 (57.2%) were Lipodystrophy 151 (35.5%)
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followed by Skin rashes 80 (18.8%), Anaemia 74 (17.4%), Peripheral Neuropathy 27 (6.3%), and Dizziness 24 (5.6%) (table3). Once complete data of patient was taken, ADRs were classified as “definite”, “probable”, “possible” and “doubtful” based on Naranjo causality assessment scale for ADRs. Naranjo’s causality assessment scale criteria are based on score ranging from +2 to -1 given for each
criteria. The probability scale is based on the total score; ≤0 doubtful, 1 to 4 possible, 5 to 8 probable and ≥9 definite. According to Naranjo causality assessment scale, 210(49.4%) ADRs were found to be probable,
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177(41.6%) possible, 34(8%) definite and 04(0.9%) doubtful (Table 4).
Discussion
Current study is the retrospective study on the incidence of ADRs in HIV-positive patients using
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HAART therapy in Malaysia. The study observed the significant ADRs associated with the use of HAART therapy in the population of Pulau Pinang, Malaysia. In the present study, the prevalence of ADRs was high in males as compared to female patients, same as the findings in Lihite et al.(17). In contrast to our finding, Rajesh et al.(18) has found
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high prevalence of ADRs in females, when compared to males. The reason for differences in prevelance of ADRs among gender might be due to difference in body mass index and fat composition or hormonal effects on drug metabolism. In our study most of the patients were
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belonged to the age group of 31-40 years and 41-50 years i.e.257(34.5%) and 254(34.1%) respectively ; therefore we might have detected majority of ADRs from this group of patients.
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An ADRs observed in adults was similar to Mehta et al.(19), however Melmon KL(20) has reported large percentages of ADRs in geriatric and pediatric populations. The prevalence of adverse drug reactions to HAART therapy was 57.2% in the current study. This rate (57.2%) was lower than the rates reported among HIV infected population in India (71.1%)(21), somehow similar to Nigeria (54%)(22), but is higher than the rate reported in Brazil
(34.5%)(23) And as reported in a large cohort study of HIV infected adults in Switzerland(24). This suggests that the spectrum of ADRs to HAART therapy vary from one country to another and between developed and developing countries. The variation in the rates may be explained by the differences in the methodology of the studies, HAART regimens prescribed and population
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of the study. The variations may be because of the concurrent medications used for treating opportunistic infections and other co-morbid conditions. This may also be because of lack of all necessary materials and equipments which may use as to easily identify the adverse drug reaction occurred and to control when compared to the developed countries.
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Among the various ADRs observed, Lipodystrophy (35.5%) and Skin rashes (18.8%) were the most predominant, followed by anemia (17.4%). Similar findings of 34.2% were reported regarding Lipodystrophy in Rwandan population of 409 adults in 2007(25) and was greater than Botswana study(26) where reported 16%. Kumarasamy N et al in india reported 42% incidence
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of skin rashes, higher than our study which reported 18.8%. In the same study anemia were reported 5.4%(27) which is lower as compare to findings of the current study that are 18.8% , moreover high incident rate was showed in Lihite et al. (23.7%)(17) and Singh et al. 15.8%(28). In our study rashes were found in 6.25% of patients. Sharma et al(21) reported rashes in 10% of
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their study population while Matcha et al (29) reported that 26% of females and 22% of males on
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NVP developed rash. The incidence of skin rash was reported higher in Matcha et al. (2001), the reason of which includes their selection of specific drug, nevirapine. Moreover, Peripheral neuropathy was observed in 6.3% of patients in the current study population which is more than reported by B. Divakar et al(30) in only 1% of subjects, while it was present in 22.2% of patients in the study conducted by Sharma et al(21). Peripheral neuropathy is a long term adverse effect of stavudine and some other antiretroviral drugs. It develops only after 6 months of treatment. As
the current study was retrospective that may be we observed higher cases of peripheral
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neuropathy than a study conducted by B. Divakar et al which duration was only 6 months.
Causality assessment of ADRs by Naranjo scale showed that most of the ADRs were probable (49.4%) and possible (41.6%), however 8% were also reported definite and 0.9% doubtful ADRs. This study results in contrast with Lihite et al where majority (63.7%) was possible, while
probable.
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somehow same as the study conducted by Rajesh et al. where most of the ADRs (63.5%) were
The study was conducted in only one ART center of Government General Hospital of Penang, Malaysia. These may exclude the actual number of HIV infected patients who were on HAART
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and experienced ADRs.
In conclusion, the current study was an attempt to identify the most commonly reported HAART therapy induced ADRs in Malaysia. Multiple Patient variables that include ethnicity, age group
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and smoking had a significant association of ADR’s. The information obtained of the present study suggest that treating physician must focus on early detection and prevention of ADRs in
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HIV infected patients which will be useful in optimization of treatment in HIV patients.
Conflict of Interest: There is completely no potential conflict of interest of any other
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relationships, conditions or circumstances regarding the manuscript.
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References 1.
Averting HIV and AIDS 2011. Available from: http://www.avert.org.
2.
UNAIDS (2012). Report on global aids epidemic, Geneva UN aids. Available from:
http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2012/gr2012/201
3.
M an
21120_UNAIDS_Global_Report_2012_with_annexes_en.pdf.
Core Slides: Global Summary of the AIDS Epidemic; 2013 2013. Available from:
http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2013/gr2013/201 309_epi_core_en.pdf.
World Health Organization 2008 2008. Available from: http://www.who.int/en/.
5.
World Health Organization 2008. Available from: http://www.who.int/en/.
6.
Goh E, Tan L, Chow S, et al. Use of complementary medicine in systemic lupus
pt ed
4.
7.
ce
erythematosus patients in Malaysia. APLAR J Rheumato. 2003;6(1):21-5. Palella Jr FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality
Ac
among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998;338(13):853-60. 8.
Jensen-Fangel S. The effectiveness of highly active antiretroviral therapy in HIV-infected
patients. Dan Med Bull 2004;51(4):371-92. 9.
Organization WH. Antiretroviral therapy for HIV infection in adults and adolescents:
recommendations for a public health approach-2010 revision. 2010.
10.
Minzi O, Irunde H, Moshiro C. HIV patients presenting common adverse drug events
caused by highly active antiretroviral therapy in Tanzania. Tanzan J Health Res 2009;11(1). 11.
Knobel H, Guelar A, Montero M, et al. Risk of side effects associated with the use of
nevirapine in treatment‐naïve patients, with respect to gender and CD4 cell count. HIV Med
us cr ip
12.
t
2008;9(1):14-8.
Taha TE, Kumwenda N, Kafulafula G, et al. Haematological changes in African children
who received short-term prophylaxis with nevirapine and zidovudine at birth. Ann Trop Paediatr 2004;24(4):301-9. 13.
Vigouroux C, Gharakhanian S, Salhi Y, et al. Adverse metabolic disorders during highly
14.
M an
active antiretroviral treatments (HAART) of HIV disease. Diabetes Metab 1999;25(5):383-92. Nuesch R, Srasuebkul P, Ananworanich J, et al. Monitoring the toxicity of antiretroviral
therapy in resource limited settings: a prospective clinical trial cohort in Thailand. J Antimicrob Chemother 2006;58(3):637-44.
Miller CD, El‐Kholi R, Faragon JJ, et al. Prevalence and risk factors for clinically
pt ed
15.
significant drug interactions with antiretroviral therapy. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 2007;27(10):1379-86. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of
ce
16.
Ac
adverse drug reactions. Clin Pharmacol Ther 1981;30(2):239-45. 17.
Reddy AK, Lihite RJ, Lahkar M, et al. A study on adverse drug reactions in HIV infected
patients at a ART centre of tertiary care hospital in Guwahati, India. Asian J Pharm Clin Res 2013;6:102-104.
18.
Rajesh R, Vidyasagar S, Nandakumar K. Highly active antiretroviral therapy induced
adverse drug reactions in Indian human immunodeficiency virus positive patients. Pharmacy Practice 2011;9(1). 19.
Mehta U, Durrheim DN, Blockman M, et al. Adverse drug reactions in adult medical
us cr ip
t
inpatients in a South African hospital serving a community with a high HIV/AIDS prevalence: prospective observational study. Br J Clin Pharmacol 2008;65(3):396-406. 20.
Gholami K, Shalviri G. Factors associated with preventability, predictability, and severity
of adverse drug reactions. Annals of pharmacotherapy 1999;33(2):236-40. 21.
Sharma A, Vora R, Modi M, et al. Adverse effects of antiretroviral treatment. Indian J
22.
M an
Dermatol Venereol Leprol 2008;74(3).
Eluwa GI, Badru T, Akpoigbe KJ. Adverse drug reactions to antiretroviral therapy
(ARVs): incidence, type and risk factors in Nigeria. BMC Clin Pharmacol 2012;12(1):7. 23.
de Pádua CM, Cesar C, Bonolo P, et al. High incidence of adverse reactions to initial
24.
pt ed
antiretroviral therapy in Brazil. Braz J Med Biol Res 2006;39(4):495. Keiser O, Fellay J, Opravil M, et al. Adverse events to antiretrovirals in the Swiss HIV
Cohort Study: effect on mortality and treatment modification. Antivir Ther 2007;12(8):1157. van Griensven J, De Naeyer L, Mushi T, et al. High prevalence of lipoatrophy among
ce
25.
Ac
patients on stavudine-containing first-line antiretroviral therapy regimens in Rwanda. Transactions of the Royal Society of Tropical Medicine and Hygiene 2007;101(8):793-8. 26.
Wester CW, Okezie OA, Thomas AM, et al. Higher-than-expected rates of lactic acidosis
among highly active antiretroviral therapy-treated women in Botswana: preliminary results from a large randomized clinical trial. JAIDS Journal of Acquired Immune Deficiency Syndromes 2007;46(3):318-22.
27.
Kumarasamy N, Venkatesh KK, Cecelia AJ, et al. Spectrum of adverse events after
generic HAART in southern Indian HIV-infected patients. AIDS patient care and STDs 2008;22(4):337-44. 28.
Singh H, Dulhani N, Tiwari P, et al. A prospective, observational cohort study to elicit
Chhattisgarh. Indian J Pharmacol 2009;41(5):224. 29.
Bersoff-Matcha SJ, Miller WC, Aberg JA, et al. Sex differences in nevirapine rash. Clin
Infect Dis 2001;32(1):124-9. 30.
us cr ip
t
adverse effects of antiretroviral agents in a remote resource-restricted tribal population of
Divakar B, Mistry S, ND Kantharia M. The study of adverse drug reactions (ADR’S) in
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ce
pt ed
Med Pharm Sci 2012;3(2):09-18.
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HIV patients taking highly active antiretroviral therapy in ART centre, NCH, surat, India. Int J
p*-Value
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0.002
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Table 1: Characteristics of HIV patients in Pulau Penang (n=743) Characters Patients with ADRs Total ADRs N (%) N (%) Gender Male 235 (74.8) 311 (73.1) Female 79 (25.1) 114 (26.8) Age Groups (Years) 50 66 (21) 92 (21.6) Ethnicity Malay 65 (20.7) 94 (22.1) Chinese 179 (57) 239 (56.2) Indian 51 (16.2) 71 (16.7) Others 19 (6) 21 (5) Smoking Status Smoker 200 (63.6) 269 (63.2) Non-smoker 114 (36.3) 156 (36.7) Alcohol Use Alcoholic 126 (40.1) 162 (38.1) Non-alcoholic 188 (59.8) 263 (61.8) Drug abuse Drug abuse 18 (5.7) 26(6.11) Non-drug abuse 296 (94.2) 399(93.8)
0.51
0.05
0.01 0.009 0.39
p*-Value .26
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.02 .80 .46 .19
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Table 2: Univariate analysis of Patient demographics with ADRs Patient variable Total ADRs OR 95% CI N (%) Gender Male 311 (73.1) 1.21 .86 - 1.71 Female 114 (26.8) Age group 50 92 (21.6) 1.27 .88 – 1.48 Ethnicity Malay 94 (22.1) .94 .66 – 1.34 Chinese 239 (56.2) .78 .58 – 1.05 Indian 71 (16.7) 1.50 .98 – 2.29 Others 21 (5) 1.56 .79 – 3.05 Smoking Status Smoker 269 (63.2) 1.52 1.11 – 2.07 Non-smoker 156 (36.7) Alcohol Use Non-alcoholic 263 (61.8) 1.48 1.10 – 1.99 Alcoholic 162 (38.1) Drug abuse Non-drug abuse 399(93.8) 1.59 .89 – 2.85 Drug abuse 26(6.11)
.74 .10 .05 .19
0.009 0.008
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Vomiting Diarrhea Sleep Disorder Dizziness Rash Lipodystrophy Anemia Peripheral Neuropathy Itching Pancreatitis Weight loss Lactic acidosis Hepatotoxicity Hepatic Steotasis Blurred vision Lethargy Total Number of ADRs
Number of ADRs N=425 (%) 03 (0.7) 06 (1.4) 04 (0.9) 24 (5.6) 80 (18.8) 151 (35.5) 74 (17.4) 27 (6.3) 13 (3.05) 13 (3.05) 06 (1.4) 08 (1.8) 07 (1.6) 02 (0.4) 05 (1.1) 02 (0.4) 425(57.2%)
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Table 3: ADRs Distribution Adverse Drug Reactions
Definite/ Certain Probable Possible
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Table 4: Causality assessment of ADRs by Naranjo assessment scale Causality Score No. OF ADRs (%)
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Unlikely/ Doubtful
9
34 (8%)
4 to 8
210 (49.4%)
1 to 4
177 (41.6%)
0
04(0.9%)
