ORIGINAL RESEARCH PAPER Volume - 9 | Issue - 7 | July - 2020 | PRINT ISSN No. 2277 - 8179 | DOI : 10.

36106/ijsr

INTERNATIONAL JOURNAL OF SCIENTIFIC RESEARCH

ADVERSE EVENT MONITORING OF ANTIRETROVIRAL DRUGS AT A TERTIARY

CARE HOSPITAL OF NORTH INDIA

Pharma
Neena Bhatti PG Resident Department Of Pharmacology CMC Ludhiana.
Girish Joseph* PG Resident Department Of Pharmacology CMC Ludhiana. *Corresponding Author
Jatinder Singh Senior resident department of pharmacology GMCH Patiala.
Manhardeep Kaur PG resident Department of SPM GMCH Patiala.
ABSTRACT
Background Adverse event is major problem worldwide. ADR incidence is likely to be high in India and constitute an enormous burden for
society, due to malpractice by unqualied practitioners and easy availability of drugs. Pharmacovigilance reporting is still poor in India. As ART
regimen is to be continued for whole life of patients, we tried to identify ADRs after long term use which are missed in clinical trials.
Material And Methods A prospective cross-sectional observational study was conducted in a tertiary care hospital in north India. Only those
patients with adverse events and who gave written informed consent of any gender/ age were enrolled from all HIV infected patients on ART
therapy between Jan. 2017 to Dec. 2018. The reported ADRs were assessed for causality by using WHO UMC scale.
ResultsIn this study, 245 patients experienced a total of 415 ADRs.In these 245 patients, 104 (42.44%) were men, and 141 (57.55%) were women.
The most common drugs leading to Adverse Drug Reaction was combination of TLE followed by combination of ZLN, ZAT. The most common
ADR noted was itching (50), dizziness (34) and Rash (33). ADR incidence was found to be 1.73 per patient. Incidence of Serious ADRs was 0.5%.
Causality assessment of 80.7% ADRs were possible, 2.8% were probable and 16.4% were unlikely.
ConclusionFrom this study, we can say antiretroviral drugs are not entirely safe and there is pressing need for monitoring these drugs. Physicians
should be aware of these ADRs so that these can be prevented/treated at an early stage. This will enhance the safety ofantiretroviral drugs.
KEYWORDS
Adverse Drug Reactions, Human Immune Deciency Virus, Acquired Immunodeciency Syndrome
INTRODUCTION there was number of ADRs due treatment, such as fat redistribution,
Adverse event is dened as any untoward medical occurrence that dyslipidemia, and sexual dysfunction. These reactions were severe
may occur due to treatment with a pharmaceutical product, but in some patients to cause have non-compliance or discontinuation of
which does not necessarily have a causal relationship with ART.17,18For example, non-nucleoside reverse transcriptase inhibitors
1
treatment. When a causal relationship is established between drug (NNRTI's) are associated with rash and hepatotoxicity 19. Nucleoside
and adverse event, it becomes adverse drug reaction (ADR) or reverse transcriptase inhibitors (NRTI's) are associated with
adverse drug effect. Adverse event is major problem worldwide, hypersensitivity reactions, anemia, and neutropenia. 20Protease
even developed countries like US, where drugs use is monitored inhibitors are known to be associated with hyperlipidemia,
very cautiously, ADRs are 4th cause of death and reason for 6.7% of hyperglycemia, and gastrointestinal symptoms 21. Furthermore,
hospitalization.2 In India, due to malpractice by unqualied increasingly complex drug therapies for HIV-infected patients
practitioners and easy availability of drugs, ADR incidence is likely resulted in more ADRs.22 As ART regimen is to be continued for
3
to be high and constitute an enormous burden for society . whole life of patients, we tried to identify ADRs after long term use
which are missed in clinical trials.
ADRs result in morbidity, prolonged hospital stays, increased health
expenditure and mortality, so its need of situation to prescribe drugs To our knowledge, there has been no published data regarding ADRs
rationally and for constant observation of ADRs. In clinical trials, associated with ART among North Indian HIV/AIDS patients. The
drugs are tested on a relatively small population, in highly selected objective of this study was to explore the occurrence of ADRs
patients excluding pregnant, lactating women and patients of among HIV/AIDS patients receiving ART.
extreme age groups, with multiple co morbid conditions and patients
on multiple drug therapy for only short period (maximum 3-5 MATERIALS AND METHODS
years)4-6. Therefore, rare adverse reactions having frequency less A prospective cross-sectional observational study was conducted at
than 0.5 to 1%, delayed reactions and ADRs occurring due to long antiretroviral center of a tertiary care hospital in north India. This
term use are missed in clinical trials7,8. After marketing of drug, it is study was conducted as a part of spontaneous monitoring of adverse
administered to lakhs of patients with many comorbidities and events for reporting to PvPI. All HIV infected patients on
9
patients with multiple drug therapies in all age groups. Therefore, antiretroviral therapy with adverse events between Jan. 2017 to Dec.
ADR monitoring must be started along with administration of drug 2018 of any gender/ age were included in the study after taking
and continued throughout life of the drug. 10After the Thalidomide written informed consent. Patients not giving consent were excluded
disaster in 1962, Pharmacovigilance programs were established in from study. Patient' records were thoroughly reviewed and relevant
many countries like UK, Australia, New Zealand, Canada and data was noted on a validated data collection form. Demographic
Sweden for adverse event monitoring.11Standard Control and clinical characteristics of patients that were susceptible to ADRs
Organization (CDSCO) has initiated a well-organized and highly were recorded and observed during the study period. The reported
participative Pharmacovigilance Programme of India (PvPI). In spite ADRs were assessed for causality by using WHO UMC scale.
of all effort, pharmacovigilance reporting is still poor in India. India Categorical data was reported numerically as numbers and
rates below 1% in pharmacovigilance as against the world rate of percentages of the total, while continuous data was reported using
12
5%. mean and standard deviations.

Infection with the human immune deciency virus (HIV) RESULTS

causesAcquired Immunodeciency Syndrome (AIDS) 13. According A total of 51,234 patients diagnosed with HIV infection visited ART
to a survey conducted in 2012 by the World Health Organization, center between Jan. 2017 and Dec. 2018 in tertiary care hospital in
31.4 to 35.9 million people worldwide were infected with HIV, of north India. Out of 50,000, only 245 patients fullled our inclusion
which about 0.8% were adults aged 15–49 years.14 About 4.8 million criteria. In these 245 patients, 104 (42.44%) were men, and 141
people are living with HIV infection in Asia.15 (57.55%) were women. Overall, 245 patients experienced a total of
415 ADRs. A statistically signicant relationship was observed
In 1996–1997, after introduction of antiretroviral treatment (ART), between patient sex and the occurrence of ADR (P < 0.005).
approximately 50 % mortality was reduced among people living
with HIV/AIDS.16 Regardless of the efcacy of the ART regimen, The most common drugs leading to Adverse Drug Reaction was
56 International Journal of Scientific Research
Volume - 9 | Issue - 7 | July - 2020 PRINT ISSN No. 2277 - 8179 | DOI : 10.36106/ijsr

combination of Tenofovir, Lamivudine and Efavirenz followed by antiretroviral drugs was reported to PvPI in Vigibase through
combination of Zidovudine, Nevirapine and Lamivudine, vigiow software in regional ADR monitoring center.
Zidovudine, abacavirand Tenofovir as shown in Table 1. The most
common ADR noted was itching (50), dizziness (34) and Rash (33).
Patients suffering from ADRs due to Tenofovir, Lamivudine and
Efavirenz shown in gure 1. Patients suffering from ADRs due to
Zidovudine, Nevirapine and Lamivudine are shown in gure 2.
ADR incidence was found to be 1.73 per patient. The average
number of drugs prescribed was 1.64 per patient. Incidence of
Serious ADRs was 0.5%. A difference in adverse drug reactions
according to age was also seen. Mean age of patients was 41.65 ±
13.48 years. Maximum patients having adverse events due to
antiretroviral treatment were from adolescent age group and very
less patients from extremes of age were having ADRs.

Table 1 Fig4
Drugs Patients suffering from
ADRs DISCUSSION
Tenofovir, Lamivudine and Efavirenz 336 A wide range of adverse drug reactions are caused by anti-retroviral
Zidovudine, Nevirapine and Lamivudine 57 drugs. This study was conducted in patients attending the Attending
antiretroviral center of a Medical College and Hospital of North
Zidovudine 12
India. The ADRs reported with anti-retroviral drugs were recorded
Abacavir 5 over a period of two years. The frequency and distribution of
Tenofovir 5 adverse drug reactions and antiretroviral drugs implicated in these
Total 415 reactions were studied.

The most common drug leading to Serious Adverse Drug Reaction

was Tenofovir, Lamivudine and Efavirenz followed by Zidovudine,
Nevirapine and Lamivudine. In a prospective study conducted by
Sharma et. al. from 2004-06 in Department of Skin and V.D
Medical College and SSG Hospital, Vadodara concluded the
maximal frequency of ADRs was seen with zidovudine (AZT)
(50%) followed by stavudine (d4T) (47.9%), efavirenz (EFV)
(45.4%) and nally, Nevirapine (NVP) (18.4%). 23

The most common ADR in ours study, was itching (50), dizziness
(34) and Rash (33). In an observational retrospective study by khan
Fig.1 et al on patients on HAART therapy diagnosed with HIV infection
conducted at Hospital Pulau Pinang, Malaysia from Jan 2007 to Dec
2012 was Lipodystrophy was recorded 151 (35.5%) followed by
Skin rashes 80 (18.8%), Anaemia, 74 (17.4%) and Peripheral
Neuropathy 27 (6.3%).24
In this study 245 patients were enrolled, in which preponderance of
ADRs was more than women. In a prospective observational study
conducted by Modayil et al. has found high prevalence of ADRs in
females, when compared to males. The reason for differences in
prevalence of ADRs among gender might be due to difference in
body mass index and fat composition or hormonal effects on drug
metabolism.25
A difference in adverse drug reactions according to age was also
Fig 2
seen. Mean age of patients was 41.65± 13.48 years. Maximum
patients having adverse events due to antiretroviral treatment were
from adolescent age group and very less patients from extremes of
age were having ADRs. In observational retrospective study by khan
et al on patients on HAART therapy, most of the patients were
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. An
ADRs observed in adults was similar to Mehta et al.,however,
Melmon KL has reported large percentages of ADRs in geriatric and
pediatric populations. 26,27
Dechallenge (discontinuation of the suspected drug) was done in 22
% cases, whereas in 78 % of the cases initial drug therapy was
Fig.3 continued. In a prospective observational study conducted by Rajesh
et al from August 2009 to May 2012 to characterize the pattern of
Causality Assessment: ADRs to cART at Kasturba Hospital, Manipal in South India
A causal relationship between the drug and the reaction was elaborated 63.5% of the reports after “dechallenge” of the suspected
established on the basis of lag period between the start of the drug antiretroviral medication, denite improvement was documented. In
and appearance of the reaction, response to dechallenge, laboratory 94% of the reports “No rechallenge” was instituted. After
tests and the data available regarding the drug using the WHO UMC “rechallenge of the suspected antiretroviral medication” recurrence
causality assessment scale. Dechallenge (discontinuation of the of symptoms positive was observed in 1.3% of the reports and no
suspected drug) was done in 22 % cases, whereas in 78 % of the occurrence of symptoms negative with “rechallenge of the suspected
cases initial drug therapy was continued. Causality assessment was antiretroviral medication” was seen in 1.7%.28
done according to WHO UMC causality assessment in gure 4.
Causality assessment of 80.7% ADRs were possible, 2.8% were In our study, Causality assessment of 80.7% ADRs was possible,
probable and 16.4% were unlikely. All data of ADRs due to 2.8% was probable and 16.4% was unlikely. In a prospective
International Journal of Scientific Research 57
Volume - 9 | Issue - 7 | July - 2020 PRINT ISSN No. 2277 - 8179 | DOI : 10.36106/ijsr

observational study conducted by Rajesh et al from August 2009 to Thailand. J AntimicrobChemother. 2006;58:637-44.
22. Miller CD, El-Kholi R, Faragon JJ, et al. Prevalence and risk factors for clinically
May 2012 to characterize the pattern of ADRs to cART at Kasturba signicant drug interactions with antiretroviral therapy. Pharmacotherapy.
Hospital, Manipal in South India elaborated Out of 230 suspected 2007;27:1379-86.
ADRs, WHO causality assessment was Probable in 132 (57.4%) of 23. Sharma A, Vora R, Modi M, Sharma A, Marfatia Y. Adverse effects of antiretroviral
treatment. Indian J DermatolVenereolLeprol 2008;74:234-7
ADRs. In 181 (78.7%) of the reports, the suspected drug was 24. Khan K1, Khan AH, Sulaiman SA, Soo CT, Akhtar A. Adverse Drug Reactions in
predictable. 28 HIV/AIDS Patients at a Tertiary Care Hospital in Penang, Malaysia. Jpn J Infect Dis.
2016;69(1):56-9.
25. Modayil RR, Harugeri A, Parthasarathi G, et al. Adverse drug reactions to
CONCLUSION antiretroviral therapy (ART): an experience of spontaneous reporting and intensive
In conclusion, the current study was an attempt to detect the most monitering from ART centre in India. Pharmacoepidemiol Drug Saf. 2010;19:247-55
commonly reported ART-induced ADRs during ART Therapy in a 26. Mehta U, Durrheim DN, Blockman M, et al. Adverse drug reactions in adult medical
inpatients in a South African hospital serving a community with a high HIV/AIDS
tertiary care hospital in northIndia. Drugs. From this study, we can prevalence: prospective observational study. Br J ClinPharmacol. 2008;65:396-406.
say antiretroviral drugs are not entirely safe and there is pressing 27. Gholami K, Shalviri G. Factors associated with preventability, predictability, and
need for monitoring these drugs. This can be done by post marketing severity of adverse drug reactions. Ann Pharmacother. 1999;33:236-40.
28. Rajesh R, Vidyasagar S, Varma DM, Guddattu V, Patel NR, Varghese M, Pulagam P.
surveillance at large number of centers over a long period of time. Evaluating the effects of combination antiretroviral therapy regimens and the
However, these results should be veried in multi-centric studies as development of adverse drug reactions in Indian human immunodeciency virus
sample size for some of them was small and hence cannot be positive patients. Saudi J Health Sci 2014;3:107-17
extrapolated to large population. Since all the adverse effects of the
drugs cannot be prevented, it is necessary to assess pattern of
adverse reactions and the common drugs causing these reactions.
Physicians should be aware of these ADRs so that these can be
prevented/treated at an early stage. This will enhance the safety
ofantiretroviral drugs.

Conflict Of Interest: Nil

Abbreviations:
ADR: adverse drug reactions, HIV: human immune deciency virus,
AIDS-Acquired Immunodeciency Syndrome, TLE: Tenofovir,
Lamivudine and Efavirenz, ZLN: Zidovudine, Nevirapine and
Lamivudine, ZAT: Zidovudine, abacavir and Tenofovir

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58 International Journal of Scientific Research