STUDY OF ADVERSE DRUG REACTIONS IN ANTIRETROVIRAL
THERAPY
1
*C S Manju, 2Muhammed Shajeel P, 3Dr. Aquil Kalanad and 4B. Athira
1
Assistant Professor in Pharmacy, College of Pharmaceutical Sciences, Govt. Medical
College, Kozhikode, Kerala, India.
2
M. Pharm Student, College of Pharmaceutical Sciences, Govt. Medical College, Kozhikode,
Kerala, India.
3
Department of Medicine, Govt. Medical College, Kozhikode, Kerala, India
4
M.Pharm Student, College of Pharmaceutical Sciences, Govt. Medical College, Kozhikode,
Kerala, India.
ABSTRACT
Human immune deficiency virus infection is one of the most serious
challenges in health care. Highly Active Anti Retroviral Therapy
(HAART) is the name given to the aggressive treatment regimen. Anti
retro viral therapy exhibit greater level of efficacy with satisfactory
degree of toxicity. Adverse reactions to therapy lead to decrease in
patient compliance and adherence. The present work was a prospective
observational study used to evaluate the adverse drug reactions
associated with the use of antiretroviral drugs used in a tertiary care
hospital. The total incidence rate for Adverse Drug Reactions (ADRs)
was observed to be 40.50% in clinical settings of this study.
Tuberculosis was the most common Opportunistic Infection followed
by Candidiasis and skin infections. Incidence of ADRs was
significantly higher in Females. Gastrointestinal system involvement was the commonest
ADR encountered. Zidovudine + Lamivudine +Nevirapine were responsible for majority of
ADRs. Causality assessment between the ADR and suspected drug therapy were assessed
using the Naranjo probability scale. The severity of reaction was determined according to
modified Hartwig and Siegel scale and preventability by modified Schumock and Thornton
scale. Majority of the ADRs were probable, mild and preventable. The risk factors to ADRs
observed in this study are CD4 less than 200 cells/μL, female gender, tuberculosis,
Volume 5, Issue 01, 1226-1232. Research Article ISSN 2277– 7105
*Correspondence for
Author
C S Manju
Assistant Professor in
Pharmacy, College of
Pharmaceutical Sciences,
Govt. Medical College,
Kozhikode, Kerala, India. Article Received on 08 Nov 2015,
candidiasis and polypharmacy. In spite of high ADRs, HAART is the only answer to
HIV/AIDS; thus, management requires a highly precise balance between benefits of durable
HIV suppression and the risks of drug toxicity to achieve the therapeutic goals.
KEYWORDS : Adverse drug reactions, HAART therapy, opportunistic infections, poly pharmacy, causality, severity, preventability.
INTRODUCTION
One of the most formidable challenges in health sector is human immune deficiency virus
(HIV). Once infected the human body cannot clear out this virus. Highly active antiretroviral
therapy (HAART) is the name given to the treatment regimen to suppress HIV replication
and progression which has lead to a remarkable reduction in the morbidity and mortality.[1] Up to 25% of patients discontinue their HAART regimen because of treatment failure, toxic
effects and noncompliance with in the initial months of therapy. These medicines are
associated with significant safety concerns including serious Adverse Drug Reactions
(ADRs) with short and long term effects. Studies on incidence of ADRs reported that
incidence rate is 10 to 40%.[2] The pattern and incidence of ADRs may vary due to economic restrictions, co morbid conditions and opportunistic infections. In India adverse
drug reactions go unnoticed or are not reported.[3] Earlier antiretroviral drugs at their introduction stage are validated in white people but are now widely using in developing
countries.[4] So this study was aimed to determine the incidence of clinically significant adverse events after short term fixed dose regimen in terms of their causality, severity and
preventability.[5,6] Study also aimed to find out relationship between distribution of these ADRs with respect to age, sex, drug regimen, number of drugs and opportunistic infections.
MATERIALS AND METHODS Study settings
The study was designed to be a prospective observational study conducted in the Anti
Retroviral Therapy clinic, Department of Medicine, a tertiary care teaching hospital,
Kozhikode, Kerala, India over a period of 7 months from June 2013 to January 2014. Study
approved by the institutional ethics committee.
Data collection and study procedure
Total of 153 patients were enrolled in the study after signing the informed consent form. All
respective dosage, and route of administration with frequency, date of onset of reaction,
patient’s allergy status were noted. Data collected from patient’s case notes, treatment charts,
laboratory reports, consulting physicians and patient interview. Causality assessment between
the ADR and suspected drug therapy were assessed using the Naranjo probability scale. No
rechallenge was attempted in any patient. The severity of reaction was determined according
to modified Hartwig and Siegel scale and preventability by modified Schumock and Thornton
scale.
RESULTS
During the 7 months study period, 153 patients who were receiving antiretroviral therapy
were enrolled in the study. 85 were males and 68 were females. Tuberculosis was the most
common opportunistic infection with an incidence of 28% followed by candidiasis (16%) in
the study population. Out of 153 patients 62 patients experienced adverse drug reactions; of
them 46.8% were males and 53.2%were females. “Fig.1”
Prescribing Pattern of ART drugs in fixed combinations and Regimen wise distribution of ADR
Table 1
REGIMEN Total number of
patients on Regimen
Number of patients with ADR
Percentage of ADR Zidovudine, lamivudine, nevirapine
AZT+3TC+NVP 86 39 45.35
Zidovudine, lamivudine, efavirenz
AZT+3TC+EFV 49 19 38.77
Tenofavir,lamivudine,nevirapine
TDF+3TC+NVP 6 1 16.6
Tenofavir,lamivudine,efavirenz
TDF+3TC+EFV 6 1 16.6
Stavudine,lamivudine,nevirapine
D4T+3TC+NVP 6 2 33.3
Table 2
System wise distribution of ADRs
Increased risk of adverse drug reactions according to number of drugs used.
Type of ADR Frequency of ADR Percentage%
Nausea 20 19.04
Vomiting 10 9.5
Fatigue 2 1.9
Anemia 30 28.57
Lipodystrophy 2 1.9
Diarrhea 1 0.95
Jaundice 2 1.9
Skin rash 16 15.24
Decreased sleep 1 0.95
Neuropathy 4 3.8
Gastritis 3 2.85
Headache 1 0.95
Hair fall 2 1.9
Dyspepsia 4 3.8
Risk factors for adverse drug reactions to Anti retroviral drugs. table 3 Patient factors ADR occurrence in patients 1. Gender
Male female
29 33
2. Age 15-40 41-60 Above 60
37 23 2
3. CD4 count ˂ 200 cells/µL
˃200cells/µL
35 27
4. Number of drugs used 3-4
5-6 ˃6
11 23 28
5. Opportunistic infections Tuberculosis
candidiasis
16 8
Causality Assessment of ADRs
Causality assessment was done as per NARANJO’S ALGORITHM. Each questions in the
questionnaire is given a score (-1 to +2). Total score counted and ADR is scaled into the
[image:5.595.141.453.481.540.2]following categories.
Table 4
Severity assessment of ADRs by Hartwig Severity assessment Scale
Table 5
Preventability Assessment by Schumock and Thornton Scale
Table 6
Causality Score No. of ADRs Percentage of ADRs
Possible 1-4 46 43.8
Probable 5-8 59 56.2
Definite 9 0 0
Severity Score No. of ADRs Percentage of ADRs
Mild Level 1 & 2 70 66.6
Moderate Level 3 & 4 33 31.4
Severe Level 5, 6 & 7 2 2
Preventability Number of ADRs Percentage of ADRs
Definitely Preventable 73 69.5
Probably Preventable 22 20.95
DISCUSSION
The study observed significant morbidity with HAART therapy. Out of the 153 patients 55.5
% were males, “Fig 1”. But female patients had more ADRs.[7]
Tuberculosis was the most
common opportunistic infection (28%). Among those 43 TB infected HIV patients 16
individuals developed ADRs. Fixed dose combination of zidovudine, lamivudine and
nevirapine was the most prescribed regimen (table 1). It is a combination of two nucleoside
reverse transcriptase inhibitors and one non nucleoside reverse transcriptase inhibitor. 45.35
% of ADRs belongs to this regimen. Next prescribed regimen was zidovudine, lamivudine
and efavirenz.38.77% of ADRs occurred in this group. In both these regimen blood cell
complaints was the most reported ADR. Majority of cases anemia observed with in the first
four weeks of treatment. Another finding is improvement in hemoglobin level on
discontinuation of zidovudine. Majority of patients experienced vomiting within an hour
ingestion of zidovudine[8] (table 2). The organ system commonly affected by ADR was GIT,
“Fig. 2” which includes nausea, vomiting, diarrhea and gastritis in the first few weeks of
therapy and were self limiting. In this study we observed skin rashes in patients who were on
nevirapine containing regimen. Elevated liver enzymes were another problem with
nevirapine. Generally this was experienced by AZT+3TC+NVP regimen. In such situations
the regimen shifted to AZT+TC+EVZ. Majority of ADRs (45.16%) found in patients who
received more than 6 drugs comparing to patients who received 3 to 4 drugs which was
17.7%, “Fig.3”
HIV patients treated for opportunistic infections experience ADRs at higher rate than others.
The probability of occurrence of ADRs to antiretrovirals in patients with HIV and
tuberculosis was higher compared to HIV patients without any opportunistic infections. CD4
less than 200 cells/µL, female gender, tuberculosis and poly pharmacy were observed as risk
factors (table 3). In this study majority of ADRs, causality was “probable” (56.2%) and
“possible” `(43.8%) by using Naranjo’s algorithm. Causality assessment is the method by
which the extent of relationship between a drug suspected ADR is established. Majority of
ADRs were “preventable” (90.5%0 while 9.5% were “non preventable”.[9]
Most of the ADRs
were classified as “mild” (66.6%) where as 31.4% are moderate. Only 2 % were found to be
severe. In most of preventable ADRs, preventive measures for ADRs were advised to patients
like avoiding fatty foods and dairy products for prevention of nausea and vomiting in patients
receiving zidovudine. This study observed the most common cause of highly active
adverse effects like anaemia, eosinophilia, leucopenia, neutropenia, bicytopenia,
pancytopenia with zidovudine therapy.
CONCLUSIONS
ART exhibit greater level of efficacy with significant reduction in morbidity and mortality,
with satisfactory degree of toxicity. Combination treatment and presence of opportunistic
infections produces adverse events. So better understanding and close monitoring of adverse
drug reactions and its effective management is needed to support patients during their
treatment. There by we can improve the treatment outcome and quality of life of people
living with HIV/AIDS, with an added advantage of reduction in healthcare cost and drug
resistance
ACKNOWLEDGEMENTS: NIL
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