|Year : 2013 | Volume
| Issue : 2 | Page : 145-148
Evaluation of the adverse reactions of antiretroviral drug regimens in a tertiary care hospital
Zahoor A Rather, Mukta N Chowta, G. J. K Prakash Raju, Faheem Mubeen
Department of Pharmacology, Kasturba Medical College, Manipal University, Mangalore, Karnataka, India
|Date of Submission||11-Apr-2012|
|Date of Decision||12-Jun-2012|
|Date of Acceptance||31-Dec-2012|
|Date of Web Publication||11-Mar-2013|
Mukta N Chowta
Department of Pharmacology, Kasturba Medical College, Manipal University, Mangalore, Karnataka
Source of Support: None, Conflict of Interest: None
Objectives: Antiretroviral toxicity is an increasingly important issue in the management of HIV-infected patients. The objective of our study was to evaluate the toxicity profile of currently used antiretroviral regimens and to compare these toxicities among males and females.
Materials and Methods: A retrospective analysis with a one year follow-up was done at a tertiary care hospital by reviewing the record. Patients who were >18 years of age attending the hospital and were initiated an antiretroviral drug regimen were included in the analysis. Data regarding demographic details, medical history, details of human immunodeficiency virus (HIV) infection including most recent CD4 count, details of antiretroviral therapy (ART) collected from patient's records. Adverse drug reactions were recorded by reviewing patient records.
Result: A total of 99 patients were included in study. Among them, 71 (71.7%) were males and 28(28.3%) were females. Common adverse effects observed included anemia (58.6%), pruritus(23.2%), skin rash(18.2%), hypertriglyceridemia(15.2%), and hepatitis (60.6%), peripheral neuropathy (14.1%). Prevalence of skin rash was more in females than males, the difference being statistically significant. Pruritus was also commonly seen in females than males though the difference observed in our study is statistically insignificant. Hypertriglyceridemia was more in males compared to females, the difference is statistically significant.
Conclusion: The most common adverse effects associated with currently used ART regimens are anemia, hepatic toxicity, itching, skin rash, elevated triglycerides, and peripheral neuropathy. Gender differences were seen mainly with skin rash, which was significantly more in females.
Keywords: Adverse effects, antiretroviral therapy, HIV
|How to cite this article:|
Rather ZA, Chowta MN, Prakash Raju G, Mubeen F. Evaluation of the adverse reactions of antiretroviral drug regimens in a tertiary care hospital. Indian J Pharmacol 2013;45:145-8
|How to cite this URL:|
Rather ZA, Chowta MN, Prakash Raju G, Mubeen F. Evaluation of the adverse reactions of antiretroviral drug regimens in a tertiary care hospital. Indian J Pharmacol [serial online] 2013 [cited 2021 Feb 25];45:145-8. Available from: https://www.ijp-online.com/text.asp?2013/45/2/145/108294
| » Introduction|| |
Antiretroviral toxicity is an increasingly important issue in the management of HIV-infected patients. Drug-related toxicity is being increasingly recognized because of the declining incidence of human immunodeficiency virus (HIV)-1- associated opportunistic disease.The principal toxicities of the antiretroviral drugs include mitochondrial toxicity, hypersensitivity, dyslipidemia, insulin resistance, cardiovascular risks, birth defects and lipodystrophy, as well as other drug-specific adverse effects. 
The incidence of HIV infection among women is increasing. Since relatively small number of female subjects is included in earlier HIV clinical trials, little is known about the influence of sex on the incidence and characteristics of adverse drug reactions (ADRs) in females. Data from several studies suggest that sex differences may exist in several aspects of HIV infection and its management, including differences in the tolerability of some antiretroviral drugs. ,,,, Objective of this study was to evaluate the toxicity profile of currently used antiretroviral regimens in Indian patients and to compare these toxicities among males and females.
| » Material and Methods|| |
A retrospective analysis with one year follow-up was done at a tertiary care hospital by reviewing the record. Patients who were >18 years of age attending the hospital and were initiated an antiretroviral therapy (ART) were included in the analysis. All HIV positive patients who were on antiretroviral therapy were included in the study. The study was conducted after approval from the Institutional Ethics Committee.Demographic details, medical history, details of HIV infection including most recent CD4 count, details of ART as well as other concomitant medication were recorded. Adverse drug reactions were recorded by reviewing patient records. Results of laboratory investigations done were also noted. The details of suspected ADRs including drugs involved, treatment given for ADRs, and the outcome were also documented. Wherever appropriate, suspected ADRs were discussed with the clinicians. Naranjo'salgorithm was used for causality assessment.  Adverse drug reactions were coded using Common Terminology Criteria for Adverse Events v3.0 (CTCAE). 
Descriptive data was expressed as percentages. Chi square test was used to analyze categorical data and continuous data was analysed by using Student t-tests for comparison among different genders.
| » Result|| |
A total of 99 patients were included in study. Differences in mean age and mean weight between males and females were statistically significant, being lower in females [Table 1].
|Table 1: Comparison of demographic data among males and females on antiretroviral regimen|
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[Table 2] shows the distribution of various adverse effects among male and female patients. Most common adverse effect was anemia which was seen in 58.6% of patients. Causality assessment of adverse effects was'possible' in majority of the adverse effects as per the Naranjo's algorithm. Prevalence of skin rash was more in females than males, the difference being statistically significant. Pruritus was also commonly seen in females than males though the difference observed in our study is statistically insignificant. Hypertriglyceridemia was more in males compared to females.
|Table 2: Comparison of adverse effects to antiretroviral regimen among males and females|
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[Table 3] shows the regimen-wise comparison of adverse events. There was no statistically significant difference in the incidence of adverse events between Lamivudine+Nevirapine +Zidovudine and Lamivudine+Nevirapine+Stavudine regimen.
|Table 3: Comparison of adverse events to different antiretroviral regimen|
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| » Discussion|| |
Since adverse drug reactions are one of the common causes for poor adherence to treatment, evaluation of ADRs may help clinicians to optimize the drug regimens. Observational studies conducted in the developed world have documented possible virological, immunological, and clinical differences between men and women receiving ART, which may account for differences in ADRs among male and female patients. ,
Increased prevalence of anemia was seen in our patients, though zidovudine was administered to only 20% of the patient population. An increased prevalence of anemia was seen in the regimen devoid of zidovudine, though the difference was statistically in significant. Concomitant opportunistic infection and poor quality of life could have increased the prevalence of anemia in our patients. Zidovudine causes bone marrow suppression leading to anemia and thrombocytopenia. Agarwal et al., reported high incidence of zidovudine-induced anemia in HIV-infected patients in eastern India. 
Lactic acidosis and pancreatitis also were seen in our patients. These are considered to be significant adverse effects in view of their seriousness, though it was seen in less number of patients. Lactic acidosis appears to be more common in females.  However, we could not observe such findings may be because of smaller sample size of female patients in the present study. Lactic acidosis is one of the most serious presentations of nucleoside analogue reverse transcriptase inhibitor(NRTI)-associated mitochondrial toxicity. Although this complication is rare, the associated mortality rate may be high. Lactic acidosis was caused by stavudine, which was used in significant number of patients. Lactic acidosis is one of the established adverse effects of this drug. Michele et al., reported incidence of lactic acidosis in HIV-infected patients receiving stavudineas a single agent.
Peripheral neuropathy was observed in 18.8% of patients. The main anti-retroviral drug causing peripheral neuropathy is stavudine, didanosine, and zalcitabine. Didanosine and zalcitabine were not used. Hence, stavudine could be responsible for the peripheral neuropathy observed in the patients. Sacktor et al., reported in their study that peripheral neurotoxicity occurred in patients, presumably because of stavudine-based ART, suggesting the need for less toxic therapy. 
Nevirapine was commonly used in our patients, thereby, explaining the increased dermatological adverse drug effects, like skin rashes and itching seen in our patients.The common adverse effects of NNRTIs are rash and hepatitis. Gangar et al., were the first to suggest a trend toward a higher frequency of rash among women taking nevirapine than among men. Three additional studies provide further support of this sex difference.  Similar trend was observed in two of our patients Chen et al., have induced skin rashes by the use of nevirapine in rats and determined that the 12-hydroxylation metabolic pathway is responsible for the rashes. 
Another adverse effect of NRTIs is hepatitis, a complication that is more likely to occur among women taking nevirapine than among men,  but our study has failed to show such a tendency. In fact, our study has shown higher prevalence of hepatitis in males.
Dyslipidemias were seen in a small number of patients in the present study. This could be due to the fact that none of our patients received protease inhibitor (PI)-based regimen. In contrast to the earlier reports,  number of patients who had hypertriglyceridemia were more in males compared to females. The number of females in this study was small as compared to males, which could have been responsible for the observed discrepancy.
Cardiovascular disease has emerged as a major cause of morbidity and mortality in HIV following initial reports of dyslipidemia, probably as a result of the combination of the pro-inflammatory effects of HIV infection, an increased prevalence of traditional risk factors, and the effects of ART.  One of the principle drivers behind the well-documented increase in the risk of cardiovascular disease in HIV-infected patients is dyslipidemia. 
Gender-dependent differences in susceptibility to adverse events are common. NRTI-related lactic acidosis is a severe, life threatening complication of NRTI treatment, which appears to be more frequent in women, especially if obese. The non-nucleoside reverse transcriptase inhibitor, nevirapine is also responsible for more frequent side effects in women than in men. Nevirapine related rash has been observed in 9.5% of women but only in 1.1% of men, and nevirapine-associated hepatotoxicity is also more common in women, especially if they have high CD4 cell count. Hypersensitivity reactions to other, non nevirapine-based, regimens are also more frequent in women. Body fat redistribution, a commonly occurring side effect of treatment in patients on long-term antiretroviral therapy, also follows a sex-specific pattern and females are more susceptible to lipodystrophy and metabolic abnormalities.
The exact reasons for sex differences in adverse reactions to antiretroviral drugs cannot be explored. Although several studies in human pharmacology have described differences in pharmacokinetics, in drug response toxicity between males and females, sex differences are difficult to ascribe to simple distinct mechanisms, Differences in drug levels or in drug response depend on sociocultural, psychoperceptual and behavioral factors, body size and composition, genetic, molecular or biochemical factors, and hormonal/reproductive influences.  Differences in weight and body mass index between men and women may be playing an important role. Some drugs have metabolic pathways in which significant differences between male and female subjects have been demonstrated. Sex differences in fat composition and the impact on drug distribution may also play a role, as may the genomic constitutional difference that exists between men and women and the way in which this difference affects the levels of various enzymes involved in drug metabolism. ,
The possible limitations of the present study include its retrospective nature and relatively smaller number of patients.Further studies are needed to understand the gender differences in the toxicity of antiretroviral drugs. The exact mechanisms behind the role of gender in antiretroviral toxicity need to be evaluated.
To conclude the most common adverse effects associated with currently used anti retroviral therapy regimens are anemia, hepatic toxicity, itching, skin rash, elevated triglycerides, peripheral neuropathy, thrombocytopenia, and pancreatitis. Prevalence of pruritus, skin rash were more in female patients, whereas hypertriglyceridemia was more in males. Individualized gender-based dose regimens may be an option to reduce the severity of adverse effects and, thereby, improve quality of life in these patients.These data will help develop better treatment strategies for HIV.
| » References|| |
|1.||Montessori V, Press N, Harris M, Akagi L, Montaner JS. Adverse effects of antiretroviral therapy for HIV infection. CMAJ 2004;170:229-38. |
|2.||Hawkins C, Chalamilla G, Okuma J, Spiegelman D, Hertzmark E, Aris E, et al. Sex differences in antiretroviral treatment outcomes among HIV-infected adults in an urban Tanzanian setting AIDS 2011;25:1189-97. |
|3.||Mocroft A, Gill MJ, Davidson W, Phillips AN. Are there gender differences in starting protease inhibitors, HAART, and disease progression despite equal access to care? J Acquir Immune Defic Syndr 2000;24:475-82. |
|4.||Sterling TR, Vlahov D, Astemborski J, Hoover DR, Margolick JB, Quinn TC. Initial plasma HIV-1 RNA levels and progression to AIDS in women and men. N Engl J Med 2001;344:720-5. |
|5.||Moore AL, Kirk O, Johnson AM, Katlama C, Blaxhult A, Dietrich M, et al. Virologic, immunologic, and clinical response to highly active antiretroviral therapy: The gender issue revisited. J Acquir Immune Defic Syndr 2003;32:452-61. |
|6.||Kumarasamy N, Venkatesh KK, Cecelia AJ, Devaleenol B, Saghayam S, Yepthomi T, et al. Gender-based differences in treatment and outcome among HIV patients in South India. J Womens Health (Larchmt) 2008;17:1471-5. |
|7.||Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45. |
|8.||National Cancer Institute. Common Terminology Criteria for Adverse Events v3.0 (CTCAE) Publish Date: August 9, 2006. Available from: http://www.eortc.be/services/doc/ctc/ctcaev3.pdf. [Last accessed 2012 Jan 5]. |
|9.||Gandhi M, Aweeka F, Greenblatt RM, Blaschke TF. Sex differences in pharmacokinetics and pharmacodynamics. Annu Rev Pharmacol Toxicol 2004;44:499-523. |
|10.||Agarwal D, Chakravarty J, Chaube L, Rai M, Agrawal NR, Sundar S. High incidence of zidone induced anaemia in HIV infected patients in eastern India. Indian J Med Res 2010;132:386-9. |
|11.||Floridia M, Giuliano M, Palmisano L, Vella S. Gender differences in the treatment of HIV infection. Pharmacol Res 2008;58:173-82. |
|12.||Mokrzycki MH, Harris C, May H, Laut J, Palmisano J. Lactic acidosis associated with stavudine administration: A report of five cases. Clin Infect Dis 2000;30:198-200. |
|13.||Sacktor N, Nakasujja N, Skolasky RL, Robertson K, Musisi S, Ronald A, et al. Benefits and risks of stavudine therapy for HIV-associated neurologic complications in Uganda. Neurology 2009;72:165-70. |
|14.||Gangar M, Arias G, O'Brien JG, Kemper CA. Frequency of cutaneous reactions on rechallenge with nevirapine and delavirdine. Ann Pharmacother 2000;34:839-42. |
|15.||Ofotokun I, Pomeroy C. Sex differences in adverse reactions to antiretroviral drugs. Top HIV Med 2003;11:55-9. |
|16.||Chen X, Tharmanathan T, Mannargudi B, Gou H, Uetrecht JP. A study of the specificity of lymphocytes in nevirapine-induced skin rash. J Pharmacol Exp Ther 2009;331:836-41. |
|17.||Feeney ER, Mallon PW. HIV and HAART-Associated Dyslipidemia. Open Cardiovasc Med J 2011;5:49-63. |
|18.||Aboud M, Elgalib A, Pomeroy L, Panayiotakopoulos G, Skopelitis E, Kulasegaram R, et al. Cardiovascular risk evaluation and antiretroviral therapy effects in an HIV cohort: Implications for clinical management: The CREATE 1 study. Int J Clin Pract 2010;64:1252-9. |
|19.||Miller MA. Gender-based differences in the toxicity of pharmaceuticals-the Food and Drug Administration's perspective. Int J Toxicol 2001;20:149-152. |
[Table 1], [Table 2], [Table 3]