Highly Active Antiretroviral Therapy Induced Hematological and Dermatological Adverse Drug Reactions in People Living with HIV in India

Rajesh Radhakrishnan

Abstract

Abstract

Background:  In India, People living with Human immunodeficiency virus (PLW-HIV) are at higher risk for developing hematological and dermatological adverse drug Reactions (ADRs) to Highly Active Antiretroviral Therapy (HAART) compared general population, leading to prolonged hospitalization causing financial burden and treatment failure.

Objective: The study was to characterize the pattern of hematological and dermatological ADRs associated to HAART in PLW-HIV with regards to causality outcomes, demographics, predictability, and preventability of reported ADRs to HAART.

Methods: A prospective observational study was conducted at medicine department for reporting hematological and dermatological ADRs to HAART in PLW-HIV with Institutional Ethics Committee approval. HIV Seropositive patients (HIV-SPP) were monitored for hematological and dermatological ADRs to HAART during their hospital stay. The World Health Organization (WHO) definition of ADRs was used to assess the causality. Predictability of ADRs was assessed based on Micromedex data base. Preventability of ADRs was assessed by using Schumock and Thornton criteria.

Results: A total of 174 HIV-SPP were enrolled with 133(76.4%) males and 41 (23.6%) females. Out of which 99 ADRs were reported. ADRs to HAART were highest 70(70.7%) in males compared to 29(29.3%) in females. The CD4 T-cell count (cells/µl) at the time of reported ADRs ranges ≤ 350 cells/µl in 79(79.8%). Sixty seven hematological and Thirty two dermatological ADRs to HAART was reported. Greater number of hematological 40(59.6%) and dermatological ADRs 15(46.8) were reported with Zidovudine + Lamivudine + Navirapine based HAART regimen. In most of the reported ADRs suspected drug was withdrawn. WHO causality assessment was Probable. Severity of ADRs were moderate to mild with one Fatal ADRs. Hematological ADRs reorted are 1) Anemia with zidovudine, 35(52.2%) 2) Pancytopenia with zidovudine 20(29.9%) 3) Neutropenia with Lamivudine, 4) Leucopenia, bictyopenia, eosinophilia with zidovudine. Dermatological ADRs of maculopapular rash 7(21.8%) with Nevirapine, Tenofovir + Emtricitabine + Efavirenz and Lamivudine based HAART regimen followed by hyper pigmentation 7(21.8%) with Zidovudine, Nevirapine, lamivudine + Emtricitabine.

Conclusion: In India, with increasing use of newer and older HAART combinations, physician must focus attention in PLW-HIV for routine monitoring of all possible risk factors for early prevention of hematological and dermatological ADRs with HAART.

Keywords

Human immunodeficiency virus; highly active antiretroviral therapy; adverse drug reactions; Dermatological and hematological adverse drug reactions

References

Mukherjee S, Era N, Saha B, Tripathi SK. Adverse drug reaction monitoring in patients on antiretroviral therapy in a tertiary care hospital in Eastern India. Indian J Pharmacol. 2017; 49(3):223-28.

Rajesh R, Sudha V, Varma D, Sonika S. Association between medication adherence outcomes and adverse drug reactions to highly active antiretroviral therapy in Indian immunodeficiency virus-positive patients. J Young Pharm. 2012 ;( 4):250-60.

Rajesh R, Vidyasagar S, Varma DM, Mohiuddin S, Noorunnisa. Evaluation of incidence of zidovudine induced anemia in Indian human immunodeficiency virus positive patients in comparison with stavudine based highly active antiretroviral therapy. Int J Risk Saf Med 2011; 23(3):171-80.

Masuka JT, Chipangura P, Nyambayo PP, Stergachis A, Khoza S. A comparison of Adverse drug Reaction Profiles in Patients on Antiretroviral and Antitubercular Treatment in Zimbabwe. Clin Drug Investig 2018; 38(1): 9-17.

Koochak HE, Babaii A, Pourdast A, Golrokhy R, Rasoolinejad m, Khodaei S, Moghadam SR, Taheri RR, Seyed Alinaghi SA. Prevalence of Adverse drug Reaction to Highly Active Antiretroviral Therapy (HAART) among HIV Positive Patients in Imam Khomeini Hospital of Tehran, Iran. Infect Disord Drug Targets 2017; 17(2):116-19.

Cheung CP, Lai WH, Shuter J. Zidovudine-versus Tenofovir- Based Antiretroviral Therapy for the Initial Treatment of HIV Infection in the Ethnic Minority Region of Liangahan Prefecture, Sichuan Province, China. J Int Assoc Provid Provid AIDS Care. 2017; 16(2); 189-93.

Tetteh RA, Nartey ET, Lartey M, Mantel-Teeuwisse AK, Leufikens HG, Yankey BA, Dodoo AN. Association between the Occurrence of Adverse drug events and modification of First-Line Highly Active Antiretroviral Therapy in Ghanaian HIV Patients. Drug Saf. 2016; 39(11):1139-149.

Prabhakaran N, Jaisankar TJ, Hamide A, Malathi M, Kumari R, Thappa DM. Effect of antiretroviral therapy on mucocutaneous manifestations among Human Immunodeficiency virus-infected patients in a tertiary care center in South India. Indian J Sex Transm Dis. 2015; 36(2):166-73.

Modayil RR, Harugeri A, Parthasarathi G, Ramesh M, Prasad R, Naik V, Giriyapura V.Adverse drug reactions to antiretroviral therapy (ART): an experience of spontaneous reporting and intensive monitoring from ART center in India. Pharmacoepidemiol Drug Saf 2010; 19(3):247-55.

Khaloli H, Dashti-Khavidaki S, Mograz M, Etghani A, Almasi F. Antiretroviral induced adverse drug reactions in Iranian human immunodeficiency virus positive patients. Pharmacoepidemiol Drug Saf 2009; 18(9):848-57.

National AIDS Control Organization ministry of health and family welfare, government of India. [Online] Available from: http://www.nacoonline.org/ [Accessed 1st April 2018].

Heath KV, Singer J, O’Shaughnessy MV, Montaner JS, Hogg RS. Intentional nonadherence due to adverse symptoms associated with antiretroviral therapy. J Acquir Immune Defic Syndr 2002; 31(2):211–7.

Hawkins T. Understanding and managing the adverse effects of antiretroviral therapy. Antiviral Res 2010; 85(1):201-9.

Tamir Z, Alemu J, Tsegaye A. Anemia among HIV Infected Individuals Taking ART with and without Zidovudine at Addis Ababa, Ethiopia. Ethiop J Health Sci. 2018; 28(1):73-82.

Guidelines for national Roll-out of second line ART; National AIDS Control Organization, Ministry of health and family welfare, Govt of India. [Homepage on the internet].[Updated 2018 April] Available from: http://www.mcf.org.in/MCF/pdf/NACO%20guidelines%20for%20second%20line%20ART_draft_Nov%20%202008.pdf.

National Accreditation Board for Hospitals & Healthcare Providers. [Homepage on the internet]. [Updated 2018 April 2nd ] Available from: http://nabh.co/main/howtoxs.asp

World Health Organization. Uppsala Monitoring Center (1996) Safety monitoring of medicinal products, guidelines for setting up and running phamacovigilance center, Geneva. Available at: URL: http://www.who.int/en/ (accessed 14 March 2018).

Naranjo CA, Busto U, Sellers EM. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther.1981; 30(2):239-45.

Schumock GT, Thornton JP. Focusing on the preventability of adverse drug reactions. Hosp Pharm 1992; 27(6):538.

A practical handbook on the pharmacovigilance of antiretroviral medicines. Publication of the World Health Organization, Geneva, Switzerland 2009:43-63.

Tadesse WT, Mekonnen AB, Tesfaye WH, Tadesse YT. Self-reported adverse drug reactions and their influence on highly active antiretroviral therapy in HIV infected patients: a cross sectional study. BMC Pharmacol Toxicol. 2014 June 23; 15:32 doi: 10.1186/2050-6511-15-32.

Anwikar SR, Bandekar MS, Smrati B, Pazare AP, Tatke PA, Kshirsagar NA. HAART induced adverse drug reactions: a retrospective analysis at a tertiary referral health care center in India. Int J Risk Saf Med. 2011; 23(3):163-9.

Masenyetse LJ, Manda SO, Mwambi HG. An assessment of adverse drug reactions among HIV positive patients receiving antiretroviral treatment in South Africa. AIDS Res Ther 2015; Mar 5:12-6 doi: 10.1186/s12981-015-0044-0. eCollection 2015

Ighovwerha O, Claire P. Sex difference in adverse reactions to antiretroviral drugs. Top HIV Med. 2003; 11:55-59.

Bersoff-Matcha SJ, Miller WC, Aberg JA. Sex differences in nevirapine rash. Clin Infect Dis. 2001;32(1):124-129.

Moore AL, Mocroft A, Madge S. Gender differences in virologic response to treatment in an HIV-positive population: a cohort study. J Acquir Immune Defic Syndr. 2001;26:159-163.

Fagot JP, Mockenhaupt M, Bouwes-Bavinck JN, for the EuroSCAR study group. Nevirapine and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. AIDS. 2001; 15(14):1843-1848.

Currier JS, Spino C, Grimes J. Differences between women and men in adverse events and CD4+ responses to nucleoside analogue therapy for HIV infection. The AIDS Clinical Trials Group 175 Team. J Acquir Immune Defic Syndr. 2000; 24:316-324.

Korsnes JS, Goodwin BB, Murray M, Candrilli SD. Antiretroviral Treatment Switching and its association with Economic outcomes and Adverse Treatment Effects among Commercially Insured and Medicaid- Enrolled patients with HIV in the United States. Ann Pharmacother 2016; 50(12):989-1000.

Mehta U, Durrheim DN, Blockman M, Kredo T, Gounden R, Barnes KI. Adverse drug reactions in adult medical 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.

Steinman MA, Hanlon JT. Managing medications in clinically complex elders: There's got to be a happy medium. JAMA 2010; 304(14):1592-1601.

Tchetnya X, Ngwasiri CA, Munge T, Aminde LN. Severe eye complications from toxic epidermal necrolysis following initiation of Nevirapine based HAART regimen in a child with HIV infection: a case from Cameroon. BMC Pediatr. 2018; 18(1):108. doi: 10.1186/s12887-018-1088-9.

Sabin CA, Smith CJ, d'Arminio Monforte A. Response to combination antiretroviral therapy: variation by age. AIDS 2008; 22(12):1463-1473.

Syed IA, Sulaiman SA, Hassali MA, Syed SH, Shan LH, Lee CK. Factors associated with poor CD4 and Viral load outcomes in patients with HIV/AIDS. J Med Virol. 2016; 88(5):790-7.

Sachdeva RK, Sharma A, De D, Malhi J, Rewari BB, Singh S, Varma S. Lamivudine-Induced skin rash Remains an Underdiagnosed Entity in HIV: A Case Series from a Single Center. J Int Assoc Provid AIDS Care. 2016; 15(2):153-8.

Stewart A, Lehloenya R, Boulle A, de Waal R, Maartens G, Cohen K. Severe antiretroviral-associated skin reactions in south African patients: a case series and case-control analysis. Pharmacoepidemiol Drug Saf. 2016; 25(11):1313-9.

Jean PF, Maja M, Jan-Nico BB, Luigi N, Cecile V, Jean CR, et al. Nevirapine and the risk of Stevens –Johnson Syndrome or toxic epidermal necrolysis. AIDS 2001; 15:1843–1848.

Blitz M, Spivack E, Kerpel S, Freedman P. Stevens-Johnson syndrome in an HIV infected patient. AIDS. 1999;9:184–5,190.

Carr DF, Chaponda M, Comejo Castro EM, Jorgensen AL, Khoo S, Van Oosterhout JJ, Dandara C, Kampira E, Ssali F, Munderi P, Lalloo DG, Heyderman RS, Pirmohamed M. CYP2B6 c.983T>C polymorphism is associated with nevirapine hypersensitivity in Malawian and Ugandan HIV populations. J Antimicrob Chemother.2014; 69(12):3329

Zhang JC, Sun YT. Efavirenz-induced exofoliative dermatitis. Scand J Infect Dis 2013: 70-72.doi:10.3109/00365548.2012.693198. [Epub ahead of print]

Munyao TM, Abinya NA, Ndele JK, Kitili PN, Maimba JM, Kamurai EN, Wanyika HW. Exfoliative erythroderma at Kenyatta National Hospital, Nairobi. East Afr Med J. 2007; 84(12):566-70.

Salami TA, Enahoro Ozieqbe O, Omeife H. Exfoliative dermatitis: patterns of clinical presentation in a tropical rural and suburban dermatology practice in Nigeria. Int J Dermatol.2012; 51(9):1086-9.

Eyer-Silva WA, Freire MAL, Silva GARD. Drug-induced hypersensitivity syndrome after initiation of darunavir and raltegravir. Rev Soc Bras Med Trop. 2017; 50(4):575-6.

Clay PG. The abacavir hypersensitivity reaction: A review. Clin Ther 2002; 24:1502-1512.

Hervey PS, Perry CM. Abacavir: A review of its clinical potential in patients with HIV infection. Drugs 2000; 60:447-479.

Krucke GW, Benjamin L, Cooper, Deanna EG, Richard M, Grimes. Characteristics of HIV Infected Patients with Biopsy Diagnosed Spongiotic Dermatitis. World J AIDS; 2011(1); 146-8.

Hassan A, Babadoko AA, Mamman AI, Ahmed SA. Zidovudine induced pure red cell aplasia: a case report. Nigerian J Med 2012; 18(3):332-33.

Sakorn P, Pakhaporn S, Suchart K, Virat K, Prattana L, Chanat P. Evolution of hematological parameters in HIV-1-infected patients with and without Thalassemia carriges during highly active antiretroviral therapy. HIV Clin Trials 2009; 10(2):88-93.

Melanie-Anne AJ, Yasin AR, Colin NM, Martin PG. Lamivudine-induced red cell aplasia. J Med Microbiology 2008; 57:1032-1035.

Woldeamanuel GG, Wondimu DH. Prevalence of anemia before and after initiation of antiretroviral therapy among HIV infected patients at Black Lion Specialized Hospital, Addis Ababa, Ethiopia: a cross sectional study. BMC Hematol. 2018, March 15:18-7.

Shah I. Adverse effects of antiretroviral therapy in HIV-1infected children. J Trop Pediatr 2006; 52:244-248.

Sharma A, Vora R, Modi M, Sharma A, Marfatia Y. Adverse effects of antiretroviral treatment. Indian J Dermatol Venereol Leprol 2008; 74:234-37.

Sreenivasan S, Dasegowda V. Adverse effects after HAART Initiation in resource-limited settings: a prospective study from Mysore, India. J Infect Dev Ctries 2010 ;( 11):750-3.

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