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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 8  |  Issue : 1  |  Page : 4-10

Descriptive analysis of adverse drug reactions to antiretroviral therapy: Causality, severity, and preventability assessment at a tertiary care teaching hospital


1 Department of Pharmacology, SMS Medical College, Jaipur, Rajasthan, India
2 Department of Medicine, ART Center, SMS Medical College, Jaipur, Rajasthan, India
3 National Center for Disease Informatics and Research, Bengaluru, Karnataka, India
4 Department of Medicine, RUHS College of Medical Sciences, Jaipur, Rajasthan, India

Date of Submission04-Jan-2021
Date of Acceptance26-Mar-2021
Date of Web Publication30-Mar-2022

Correspondence Address:
Dr. Munesh Kumar
A-2, New Heera Bagh Flats, Near Kalyan Dharamshala, Jaipur, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJAM.IJAM_1_21

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  Abstract 


Introduction: Antiretroviral therapy (ART) is highly toxic, may cause various adverse drug reactions (ADRs). Hence, regular monitoring and reporting of ADRs to ART are essential to ensure the maximum benefit from these medications. The aim/objective of this study is to evaluate the pattern, causality, severity, and preventability of ADRs due to antiretroviral drugs.
Materials and Methods: A descriptive observational study was carried out on people living with human immunodeficiency virus (HIV), at ART center of SMS Medical College and attached group of hospitals, Jaipur, after due approval from the Institutional Ethics Committee. ADRs due to various ART regimens were studied over a period of 12 months. Clinical information of ADRs and other relevant details was collected on predesigned pro forma and causality, severity, and preventability of reported ADRs were duly assessed.
Results: Five hundred and twenty-four HIV patients taking ART presented with a total of 996 ADRs. Maximum ADRs were implicated by tenofovir + lamivudine + efavirenz and were related to the central nervous system (35.3%) and gastrointestinal system (19.6%). Other ART caused ADRs of anemia, rashes, renal impairment, hepatobiliary impairment, and rare ADR of Steven–Johnson Syndrome (S-J Syndrome) and gynecomastia. Among encountered ADRs, 73.8% were preventable, whereas 26.2% were not preventable. Causality assessment was found to be possible, probable, and certain in 72.7%, 24.9%, and 2.4% of ADRs, respectively.
Conclusion: ART is associated with a broad range of ADRs, ranging from mild to life-threatening adverse reactions. The activities of pharmacovigilance, ADR monitoring, and reporting are mandatory to improve the drug safety.
The following core competencies are addressed in this article: Medical knowledge, Patient care, Practice-based learning and improvement, and Systems-based practice.

Keywords: Adverse drug reactions, antiretroviral therapy, causality, preventability, severity


How to cite this article:
Jain C, Sharma L, Sharma N, Agrawal A, Tak A, Kumar M. Descriptive analysis of adverse drug reactions to antiretroviral therapy: Causality, severity, and preventability assessment at a tertiary care teaching hospital. Int J Acad Med 2022;8:4-10

How to cite this URL:
Jain C, Sharma L, Sharma N, Agrawal A, Tak A, Kumar M. Descriptive analysis of adverse drug reactions to antiretroviral therapy: Causality, severity, and preventability assessment at a tertiary care teaching hospital. Int J Acad Med [serial online] 2022 [cited 2022 Jul 4];8:4-10. Available from: https://www.ijam-web.org/text.asp?2022/8/1/4/341180




  Introduction Top


Acquired immunodeficiency syndrome (AIDS) is a fatal illness caused by human immunodeficiency virus (HIV). It breaks down the body's immune system, leaving the victim vulnerable to a host of life-threatening opportunistic infections, neurological disorders, or unusual malignancies. It is probable that a person will be infected for life.

India has the third highest burden of HIV in the world with national adult HIV prevalence of 0.22% (0.16%–0.30%) with range of 0.25% among males and 0.19% among females. According to the annual report 2018–2019 published by the Department of Health and Family Welfare, the total number of people living with HIV (PLHIV) in India are 21.40 lakhs with an estimated 87 thousand new HIV infections and 69.11 thousand people died of AIDS-related causes nationally in 2017.[1]

The Government of India has launched a free antiretroviral therapy (ART) initiative on the April 1, 2004 in eight tertiary level hospitals across six high prevalent states and the national capital territory of Delhi. Since then, there has been a rapid decline in the HIV-related mortality and morbidity due to the wider availability of affordable, more efficacious and less toxic antiretroviral (ARV) drugs.[2] Nevertheless, drug-related toxicities may be a global issue. Some studies have accounted major individual toxicities such as neuropsychiatric adverse effects of ART mainly due to Efavirenz, bone marrow suppression and anemia mostly associated with zidovudine, hepatobiliary disorders associated with nevirapine and to a lesser extent with efavirenz, pancreatitis with didanosine, hypersensitivity with abacavir and lipodystrophy associated primarily with stavudine. Among ART list of medications, recently stavudine is removed as it attributes to most serious adverse drug reactions (ADRs) of peripheral neuropathy and lipodystrophy. This emphasizes the importance of ADR monitoring.[3],[4]

Realizing the implication of monitoring ADRs to improve public health, Pharmacovigilance Programme of India was started in 2010, according to this program ADR monitoring centers (AMC) have been set up in many medical institutions all over the country.[5] There are 8 AMCs in Rajasthan including SMS Medical College, Jaipur, which started its AMC on January 2011. AMCs are responsible for collecting the adverse event information from the patients, performing follow-up with them, to check the completeness of the ADR reports as per standard operating procedures, entering information in the prescribed software (Vigiflow) and sending them to National Coordinating Center through the same software. Before entering the data into Vigiflow, the data are analyzed for causality, severity, and preventability of ADRs.[6],[7]

There are few data from our country on ADRs due to ART. Keeping this in view, we are conducting a study with the objectives to assess the three mentioned scales of ADR due to ART with emphasis on the pattern of ADR in our setup. The study could be helpful to revise the therapeutic protocols.


  Materials and Methods Top


A descriptive observational study was conducted for the period of 1 year (January 2019–December 2019) in PLHIV receiving ART, at ART center of Sawai Man Singh Medical College and attached group of hospitals Jaipur, India, after getting approval from the Institutional Ethics Committee (IEC 4122/MC/EC/2018, dated 9/10/18). All the spontaneous ADRs due to ART in subjects of either sex and all ages were included in the study. ADRs due to the medications used for treating the opportunistic infections and co-morbid conditions with potential to cause renal and hepatic toxicity or drug interaction to highly active antiretroviral therapy (HAART) were excluded. Demographic details, clinical information of ADRs, and required laboratory investigations were collected on predesigned pro forma. Collected information was reviewed in consultation with treating physicians at ART center and was further assessed for their causality, severity, and preventability as per the standard algorithms. ADR reporting form provided by Indian Pharmacopoeia Commission was also filled and documented into Vigiflow through AMC of our Department. Circumspection of information assumed was ensured, and all the appraises to assert prudence were undertaken. Descriptive statistical analysis was performed and following three algorithms were used as the study tool.

WHO-UMC system for causality assessment

Causality assessment is the method by which the extent of relationship between a drug and a suspected reaction is established and based on the four basic principles: Temporal eligibility, dechallenge and outcome, rechallenge and outcome, and confounding factors.[8]

Hartwig's Assessment Scale severity assessment

Criteria for severity assessment are a questionnaire which includes seven levels. Levels 1 and 2 depict the ADR is mild type; levels 3 and 4 depict moderate type; and levels 5 and 6 depict severe type of ADR.[9]

Schumock and Thornton scale for preventability assessment

Criteria for preventability assessment are also a questionnaire. Any answer of “yes” to any question suggests that the ADR might have been preventable.[10]


  Results Top


Five hundred and twenty-four HIV patients taking HAART were presented with a total of 996 ADRs. Age group analysis revealed that HIV patients presented with maximum ADRs were from reproductive age group, i.e. 21–40 years (51%) followed by that 41–60 years (33.4%). Out of the total population, 310 males (59.16%), 211 females (40.25%), and 3 were intersex (0.57%) presented with one or more ADRs. The total number of ADRs was greater than the total number of patients affected with a reaction. Sociodemographic characteristics are depicted in [Table 1].
Table 1: Frequency distribution of demographic and epidemiological characteristics of human immunodeficiency virus/acquired immunodeficiency syndrome patients

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Maximum ADRs (90.7%) were accounted by the drug combination of tenofovir (TDF 300 mg) + lamivudine (3TC 300 mg) + efavirenz (EFV 600 mg) (TLE), followed by zidovudine (AZT 300 mg BD) + lamivudine (3TC 300 mg) + efavirenz (EFV 600 mg)/nevirapine (NVP 200 mg BD) accounted for 8% and abacavir (ABC 300 mg BD) + lamivudine (3TC 300 mg) + efavirenz (EFV 600 mg) accounted for 0.30% (three patients of pediatric age group) of ADRs. Among second-line regimens, Ritonavir boosted atazanavir (ATV/r 300 mg + 100 mg) and lopinavir (LPV/r 400 + 100 mg) accounted for 1% and raltegravir (RAL 400 mg) darunavir/ritonavir (DRV/r 600 mg + 100 mg) combinations accounted for 0.80% of ADRs out of the various ARV drug combinations.

The analysis of pattern of ADRs [Figure 1] revealed that most commonly reported ADRs were of the central nervous system (CNS) (35.3%) followed by that of gastrointestinal system (19.6%) and nonspecific ADRs such as fever, headache, and fatigue were found associated with all treatment regimens. These ADRs occurred within the first 3 months of therapy, whereas hematological disorder (anemia), hypersensitivity reaction, hepatobiliary disorder, and renal impairment were observed after 1–2 years of starting ART. Among individual drug toxicities, zidovudine-based regimen (ZLE, ZLN) accounted for 8% ADRs including 68 cases of anemia and one case of pigmentation of nails. In 49 cases of anemia, ZLE was substituted by TLE and 6 ADRs with Grade IV anemia required blood transfusion. Tenofovir was found to be associated with 30 ADRs of renal impairment. Patients with creatinine clearance of 30–49 ml/min were managed by changing Tenofovir daily to alternate day therapy with supportive treatment. Five patients developed nephrotoxicity and had creatinine clearance-≤10 ml/min, in these patients tenofovir was substituted by abacavir.
Figure 1: Spectrum of adverse drug reactions to antiretroviral therapy among acquired immunodeficiency disease patients

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Apart from CNS and neuropsychiatric ADRs, Efavirenz was found to be associated with a variety of ADRs. Out of them, skin reactions were maximum in the form of itching and 108 cases of rashes. We also reported a rare ADR of Efavirenz-induced gynecomastia in two patients. One patient of gynecomastia presented with breast nodules and required surgical excision. When Efavirenz was replaced with an alternative ARV drug, gynecomastia was improved in both the patients.

Nevirapine was found to be associated with 11 cases of rash and one case of a severe type of mucocutaneous drug reaction known as Steven–Johnson Syndrome (S-J syndrome). Hospital admission and aggressive therapy was required in the management of S-J syndrome.

Out of 119 cases of rash, 80 cases demanded change of therapy; Nevirapine and Efavirenz were substituted by each other after the resolution of rash. Boosted Atazanavir and lopinavir regimen were notably colligated with dyslipidemia (1.4%). Nevirapine and second-line ART atazanavir-based regime and raltegravir + darunavir + ritonavir were attributed to hepatic impairment (3%) in the form of hyperbilirubinemia and increased liver enzymes. If ALT were found >5 times the baseline level, nevirapine was permanently discontinued. Nevirapine was substituted by efavirenz. Description of ADRs regarding onset, recovery, change in regimen, and causality is exhibited in [Table 2].
Table 2: Description of adverse drug reaction to antiretroviral drugs: Onset, recovery, and causality

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Out of 997 ADRs assessed for causality, using WHO-UMC causality assessment scale,[8] 725 ADR (72.5%) were found to be “possible” while 249 (24.9%) were found to be “probable and very few ADRs 24 (2.4%) could be assessed to be certain due to ethical constraints. Severity was assessed using Hartwig and Siegels Scale.[9] Majority (79%) of ADRs are assessed as mild, whereas 20% ADRs were moderate and 0.8% ADRs were severe and required hospital admission. Among total ADRs, 73.8% were preventable and 26.2% were nonpreventable, using Schumock and Thornton Scale[10] [Figure 2].
Figure 2: Assessment of causality, severity and preventability of adverse drug reactions to antiretroviral drugs

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  Discussion Top


Approach to ART has improved over the last few years due to execution and enforcement of versatile schemes by the National AIDS Control Organization. Anti-retroviral drugs (ARVs) are distributed free of cost to HIV patients at ART centers to increase the adherence to treatment.

The first-line ART essentially comprises of a nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) which is the backbone of the therapy, preferably nonthymidine (tenofovir plus lamivudine) and one nonnucleoside reverse transcriptase inhibitor, preferably EFV. National technical guidelines on ART have recommended now that all treatment naive patients with HIV infection, age >10 years, and body weight >30 kg to be initiated on a regimen consisting of tenofovir-lamivudine-efavirenz (TLE).[11] Fixed-dose combinations of ARVs are preferred in PLHIV as it facilitates desirable treatment adherence as the treatment is life-long and minimizes the chances of developing drug resistance and resultant treatment failure. Simultaneously, ARV drug toxicities may affect compliance to therapy, so it is essential to recognize drug toxicities and manage them efficiently.

In the present study, maximum ADRs were related to CNS (35.3%) in form of confusion, abnormal dreams, dizziness, insomnia, and gastrointestinal system (19.6%) in the form of nausea, vomiting, diarrhea, and loss of appetite, attributed to all ART regimens and mainly by TLE. These ADRs were mild in severity and usually self-limiting. There was no need to discontinue ART. They were found preventable by advising the patient to take the pill of TLE at bed time, 2–3 h after dinner. Similar results were ascertained by a study done by Bhatti et al., where maximum ADRs were ascribed to TLE followed by the combination of zidovudine, nevirapine, and lamivudine.[12]

In conformity with the present study, ADRs related to the gastrointestinal system were similar to a study done by Era et al., while neuropsychotic ADRs were less in frequency in PLHIV receiving TLE as a first-line ART regimen.[13]

In our study, anemia was another common ADR (6.8%) and was associated with ZLE/ZLN. The blood picture of anemia was macrocytosis, neutropenia, and pancytopenia and probably the mechanisms involved are bone marrow suppression. Exchangeable results were ascertained in a study done by Divakar et al., in which out of different ADRs, 6.5% cases of anemia were reported.[14] While Kumar et al. documented that, anemia 29.10% (326) was the most commonly observed ADR due to ZLN/ZLE regimen and is a probably preventable reaction. Anemia observed in our study (hemoglobin <7 g/dl) has occurred within the first few months of initiation of therapy. In majority of the patients, improvement in hemoglobin level was observed once zidovudine containing regimen was withdrawn.[15]

Renal impairment was mainly due to Tenofovir. The ADR was reversible in majority of patients after dechallenge of the drug. In contradiction to the present study where frequency of ADRs related to renal impairment was higher, Kumar et al. reported 1.7% acute renal failure as an ADR in patients on TDF-based regimen and were probable in nature. The study also reported that TDF was substituted with other NRTI.[15]

Another study by Chowta et al. confirmed that, four patients developed nephrotoxicity with proteinuria as an ADR toward tenofovir-based regimen. Out of these, one was severe and the regimen was changed.[16]

Dermatological reactions were another common ADRs appeared in form of itching, rash, and hypersensitivity reactions, occurred mainly due to nevirapine and efavirenz. The rashes were erythematous, maculopapular, confluent, and most prominent on the body and arms associated with pruritus in some cases and with or without fever. We reported one severe ADR of nevirapine-induced SJ syndrome, presented with flu-like illness rash, sores on the skin and on mucus membranes with systemic involvement. The condition improved with stoppage of nevirapine-based therapy. Hospital admission and aggressive therapy were required in form of intravenous (i.v.) dexamethasone, i.v. fluids, prophylactic antibiotics, anti-allergic drugs, and treatment of local lesions.

Similar results were observed in a study done by Kumar et al., where rash and urticaria were seen in 10.62% of cases. They elaborated that skin and subcutaneous tissue disorders accounted for 7.88% of the total ADRs, which were majorly reported from nevirapine-based regimens. SJ syndrome was observed in four patients, three of them were in nevirapine-based regimens while one was in EFV-based regimen.[15] Another study by Mukherjee et al. reported various skin disorders as ADRs in 17 patients including rashes and nail pigmentation and four cases of SJ syndrome, two cases each from TLE and TLN regimen, required hospitalization.[17]

We also reported a rare ADR of Efavirenz-induced gynecomastia in two patients. Both the patients presented with bilateral gynecomastia, median time of appearance of symptoms were 2 years and regressed in median duration of 3 months after substitution of therapy. Similar findings were seen by Rukmangathen et al. in a case report on Efavirenz-induced gynecomastia.[18] Njuguna et al. received 51 reports of Efavirenz-induced gynecomastia. The median onset of gynecomastia was 15 months after efavirenz initiation.[19]

We found dyslipidemia and hepatobiliary disorder associated with nevirapine and second-line ART like ritonavir boosted atazanavir, lopinavir, and raltegravir darunavir regimens. Hepatic impairment in form of hyperbilirubinemia and increased liver enzymes. In accordance with our study, a study conducted by Bhuvana et al. reported that, hepatotoxicity (6.96%) was associated with NVP and EFV.[20]

Causality assessment done by WHO UMC algorithm found that the majority of ADR (72.4%) were “possible”, 24.9% of ADRs were “probable and required dechallenge of therapy while very few ADRs 24 (2.4%) could be assessed to be certain. Rechallenge of therapy was not done due to ethical constraints. Majority (79%) of ADRs are assessed as mild in severity. Among ADRs assessed, 73.8% were preventable and 26.2% including skin reactions, hypersensitivity reaction, SJ syndrome, and gynecomastia were not preventable as they belong to Type B (immunological reaction) ADR.


  Conclusion Top


ART enhances the survival and amends the quality of life of HIV patients by greatest possible sustained reduction in viral load and immune reconstitution; however, ADRs are the major hindrance. ARV drugs are consociated with a broad range of ADRs, ranging from low-grade intolerance, which may be self-limiting to life-threatening adverse reactions. The goal of ADR monitoring and pharmacovigilance is to ameliorate drug safety. This goal can be achieved by alleviating reporting of ADRs and educating the patients regarding ART-associated ADRs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Research quality and ethics statement

The authors declare that they followed applicable EQUATOR Network (http://www.equator-network.org/) research reporting guidelines. The authors also attest that this project work was determined require Institutional Review Board/Ethics Committee review, and the corresponding protocol/approval number is (IEC 4122/MC/EC/2018, dated 9/10/18).



 
  References Top

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National AIDS Control Organisation, Department of AIDS Control. Annual Report 2018-2019. New Delhi: Ministry of Health and Family Welfare; Sept 11/2019. Available from: https://main.mohfw.gov.in/sites/default/files/24%20 Chapter%20496AN2018-19.pdf. [Last accessed on 2020 Apr 24].  Back to cited text no. 1
    
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Hagos L, Fessehaye S, Anand IS. Nature and prevalence of adverse drug reaction of antiretroviral medications in Halibet National Referral Hospital: A retrospective study. BMC Pharmacology and Toxicology (2019) 20:24 https://doi.org/10.1186/s40360-019-0307-9  Back to cited text no. 3
    
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Amale PN, Deshpande SA, Nakhate YD, Arsod NA. Pharmacovigilance process in India: An overview. J Pharmacovigil 2018;6:1-7.  Back to cited text no. 5
    
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Protocol for National Pharmacovigilance Program CDSCO, Ministry of Health and Family Welfare, Government of India; 2004. Available from: https://www.researchgate.net/publication/7309414_Protocol_for_National_Pharmacovigilance_Program. [Last accessed on 2019 Dec 20].  Back to cited text no. 6
    
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Pharmacovigilance Program of India Guidance Document for Spontaneous Adverse Drug Reaction Reporting. Vol. 1; 2013. p. 1-69. Available from: https://www.rroij.com/open-access/pharmacovigilance-programme-in-india-current-status-and-its-per-spectives-.php?aid=68941 and view=mobile.[Last accessed on 2019 Dec 20].  Back to cited text no. 7
    
8.
The Use of the WHO-UMC System for Standardised Case Causality Assessment. Available from: http://www.who-umc.org/Graphics/24734.pdf. [Last accessed on 2020 May 21].  Back to cited text no. 8
    
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Schumock GT, Thornton JP. Focusing on the preventability of adverse drug reactions. Hosp Pharm 1992;27 (6):538.  Back to cited text no. 9
    
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Hartwig SC, Siegel J, Schneider PJ. Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm 1992;49 (9):2229-32.  Back to cited text no. 10
    
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Divakar B, Mistry SD, Kantharia ND, Mamtarani. The study of adverse drug reactions (ADR's) in HIV patients taking highly active antiretroviral therapy in ART Centre, NCH, Surat, India. Int J Med Pharm Sci 2012;03:9-18.  Back to cited text no. 14
    
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Rukmangathen R, Brahmanapalli VD, Devulapalli M, Thammisetty DP, Bondalapati A, Shaik SB, et al. A case report on efavirenz induced gynaecomastia. Indian J Pharm Pract 2017;10:223-6.  Back to cited text no. 18
    
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Njuguna C, Swart A, Blockman M, Maartens G, Chisholm B, Stewart A, et al. Cases of antiretroviral – Associated gynaecomastia reported to the National HIV and Tuberculosis Health Care Worker Hotline in South Africa. AIDS Res Ther 2016;13:1-5.  Back to cited text no. 19
    
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Bhuvana KB, Hema NG, Sangeetha. A prospective observational study of adverse drug reactions to antiretroviral therapy: Type and risk factors in a tertiary care teaching hospital. Int J Basic Clin Pharmacol 2014;3:380-4.  Back to cited text no. 20
    


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