Antiretroviral Therapy-associated Adverse Drug Reactions and their Effects on Virologic Failure- A Retrospective Cohort Study in Nigeria

Author(s): Isaac O. Abah*, Nondumiso B.Q. Ncube, Hazel A. Bradley, Oche O. AgbaJi, Phyllis Kanki.

Journal Name: Current HIV Research

Volume 16 , Issue 6 , 2018

Become EABM
Become Reviewer

Graphical Abstract:


Background: Adverse drug reactions (ADRs) associated with antiretroviral therapy (ART) can rapidly reverse the gains of ART resulting in poor health outcomes. We need an improved understanding of specific ART-related ADRs that influence virologic outcomes.

Objective: To investigate the frequency of clinical ADRs and assess their effect on virologic failure in patients on ART.

Method: We described the prevalence of major clinical ADRs, and the association between specific ADRs and virologic failure in a clinic cohort of HIV-1 infected Nigerians aged ≥18 years, on firstline ART between June 2004 and February 2012. Multivariable logistic regression was run to identify predictors of virologic failure at 24 and 72 weeks of ART.

Results: Data of 12,115 patients with a median age of 34 (interquartile range: 29-41) years, and predominantly females (67%) were evaluated. Overall, 957 (7.9%) patients experienced at least one ADR during a median follow-up period of 4 years (interquartile range: 1-7). The three most prevalent ADRs were lipodystrophy (2.6%), anemia (1.9%), and skin rash (0.7%). Virologic failure rate was 36% and 34% at 24 and 72 weeks of ART, respectively. Anemia independently predicted the odds of virologic failure at 72 weeks of ART (adjusted odds ratio, 1.74; 95% CI: 1.2-2.51); adjusted for sex, age, pre-treatment CD4+ cell count, antiretroviral regimen, and medication refill adherence.

Conclusion: Antiretroviral therapy-associated anemia increases the likelihood of late virologic failure. We recommend routine monitoring of hemoglobin levels and prompt management of anemia in all patients on ART as a strategy to improve virologic success rates.

Keywords: Adverse drug reaction, antiretroviral therapy, anemia, toxicity, treatment failure, viral suppression.

Montaner JSG, Reiss P, Cooper D, et al. A Randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients. JAMA 1998; 279: 930-7.
Dieffenbach CW, Fauci AS. Thirty years of HIV and AIDS: future challenges and opportunities. Ann Intern Med 2011; 154: 766-71.
Cambiano V, Lampe FC, Rodger AJ, et al. Long-term trends in adherence to antiretroviral therapy from start of HAART. AIDS 2010; 24: 1153-62.
Tanser F, Bärnighausen T, Grapsa E, Zaidi J, Newell M-L. High coverage of ART associated with decline in risk of HIV acquisition in rural KwaZulu-Natal, South Africa. Science 2013; 339: 966-71.
Deeks S, Lewin S, Havlir D. The end of AIDS: HIV infection as a chronic disease. Lancet 2013; 382: 1525-33.
Murphy RA, Sunpath H, Kuritzkes DR, Venter F, Gandhi RT. Antiretroviral therapy-associated toxicities in the resource-poor world: the challenge of a limited formulary. J Infect Dis 2007; 196(3): S449-56.
CHMP. Emea Guideline on Conduct of Pharmacovigilance for Medicines Used By the Paediatric Population 2007. pp. 1-13
Khan K, Khan AH, Sulaiman SAS, Soo CT. P17.34 Survival trend and impact of adverse drug reactions during haart on survival function in HIV/AIDS patients. Sex Transm Infect 2015; 91: A236.
Keiser O, Fellay J, Opravil M, et al. Adverse events to antiretrovirals in the Swiss HIV Cohort Study: Effect on mortality and treatment modification. Antivir Ther 2007; 12: 1157-64.
Mouton JP, Mehta U, Parrish AG, et al. Mortality from adverse drug reactions in adult medical inpatients at four hospitals in South Africa: a cross-sectional survey. Br J Clin Pharmacol 2015; 80: 818-26.
Bartlett JA, Chen S-S, Quinn JB. Comparative efficacy of nucleoside/nucleotide reverse transcriptase inhibitors in combination with efavirenz: results of a systematic overview. HIV Clin Trials 2007; 8: 221-6.
Spire B, Carrieri P, Garzot M, L’henaff M, Obadia Y. Factors associated with efavirenz discontinuation in a large community-based sample of patients. AIDS Care 2004; 16: 558-64.
Prosperi MCF, Fabbiani M, Fanti I, et al. Predictors of first-line antiretroviral therapy discontinuation due to drug-related adverse events in HIV-infected patients: a retrospective cohort study. BMC Infect Dis 2012; 12: 296.
Katz IT, Kaplan R, Fitzmaurice G, et al. Treatment guidelines and early loss from care for people living with HIV in Cape Town, South Africa: A retrospective cohort study. PLoS Med 2017; 14: 1-12.
Renaud-Théry F, Nguimfack BD, Vitoria M, et al. Use of antiretroviral therapy in resource-limited countries in 2006: distribution and uptake of first- and second-line regimens. AIDS 2007; 21(Suppl. 4): S89-95.
UNAIDS. Ending AIDS: Progress towards the 90–90–90 targets.. 2017.
Nachega JB, Sam-Agudu NA, Mofenson LM, Schechter M, Mellors JW. Achieving viral suppression in 90% of people living with human immunodeficiency virus on antiretroviral therapy in low- and middle-income countries: Progress, challenges, and opportunities. Clin Infect Dis 2018; 66: 1487-91.
Margolis AM, Heverling H, Pham PA, Stolbach A. A review of the toxicity of HIV medications. J Med Toxicol 2014; 10: 26-39.
Trickey A, May MT, Vehreschild JJ, Obel N, Gill MJ, Crane HM, et al. Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies. Lancet HIV 2017; 4: e349-56.
McMahon JH, Elliott JH, Bertagnolio S, Kubiak R, Jordan MR. Viral suppression after 12 months of antiretroviral therapy in low- and middle-income countries: A systematic review. Bull World Health Organ 2013; 91: 377-85.
Boender TS, Sigaloff KCE, McMahon JH, et al. Long-term virological outcomes of first-line antiretroviral therapy for HIV-1 in low- and middle-income countries: A systematic review and meta-analysis. Clin Infect Dis 2015; 61: 1453-61.
Taiwo BO, Idoko JA, Welty LJ, et al. Assessing the viorologic and adherence benefits of patient-selected HIV treatment partners in a resource-limited setting. JAIDS J Acquir Immune Defic Syndr 2010; 54: 85-92.
Abah IO, Darin MK, Ebonyi AO, et al. Patterns and predictors of first-line antiretroviral therapy modification in HIV-1-infected adults in a large urban outpatient cohort in Nigeria. J Int Assoc Provid AIDS Care 2015; 14(4): 348-54.
Agbaji OO, Abah IO, Falang KD, et al. Treatment discontinuation in adult HIV-infected patients on first-line antiretroviral therapy in Nigeria. Curr HIV Res 2015; 13: 184-92.
National Agency for the Control of AIDS (NACA). GLOBAL AIDS RESPONSE Country Progress Report Nigeria GARPR 2014.http: // NGA narrative_report_2014.pdf (accessed August 15, 2015)
Federal Ministry of Health (FMoH) Nigeria; National Guidelines for HIV and AIDS Treatment and Care in Adolescents and Adults 2010.: pp. 1-67.. http: // art.pdf (accessed August 15, 2015)
Federal Ministry of Health (FMoH) Nigeria; National Guidelines for HIV and AIDS Treatment and Care in Adolescents and Adults 2007.pp. 1-67. http: // adult_ 2007. pdf (accessed August 15, 2015)
Gilks CF, Crowley S, Ekpini R, Gove S, Perriens J, Souteyrand Y, et al. The WHO public-health approach to antiretroviral treatment against HIV in resource-limited settings. Lancet 2006; 368: 505-10.
World Health Organization (WHO). WHO | Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. 2013.http: // guidelines/arv2013/download/en/ (accessed August 18, 2015)
World Health Organization (WHO). Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. 2nd ed. France: World Health Organization 2016.
World Health Organization (WHO). AntiretrovirAl therApy for hiv infection in Adults And Adolescents: Recommendations for a public health approach. vol. 4911.. 2010.
Nigeria Federal Ministry of Health (FMH) National Guidelines for Prevention of Mother to Child Transmission of HIV. PMTCT 2010.
Hohl CM, Karpov A, Reddekopp L, Stausberg J. ICD-10 codes used to identify adverse drug events in administrative data: a systematic review. J Am Med Inform Assoc 2014; 21: 547-57.
Beutler E, Waalen J. The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration? Blood 2006; 107: 1747-50.
Abah IO, Ojeh VB, Musa J, et al. Clinical utility of pharmacy-based adherence measurement in predicting virologic outcomes in an adult HIV-infected cohort in jos, north central Nigeria. J Int Assoc Provid AIDS Care 2016; 15: 77-83.
El-Khatib Z, Ekstrom AM, Coovadia A, et al. Adherence and virologic suppression during the first 24 weeks on antiretroviral therapy among women in Johannesburg, South Africa - a prospective cohort study. BMC Public Health 2011; 11: 88.
World Health Organization (WHO). Consolidated Guideline on the use of antiretroviral drugs for treating and preventing HIV infection. 2nd ed. Geneva: World Health Organization 2016.
Cescon A, Patterson S, Chan K, et al. Gender differences in clinical outcomes among HIV-positive individuals on antiretroviral therapy in Canada: A multisite cohort study. PLoS One 2013; 8: 6-13.
Chen M, Dou Z, Wang L, Wu Y, Zhao D, Gan X, et al. Gender Differences in Outcomes of Antiretroviral Treatment Among HIV-Infected Patients in China. JAIDS J Acquir Immune Defic Syndr 2017; 76: 281-8.
Reginald OO, Haruna MM, et al. Adverse reactions associated with antiretroviral regimens in adult patients of a university teaching hospital HIV program in Zaria, Northern Nigeria: An observational cohort study. J Antivirals Antiretrovir 2012; 4: 006-013
Bassi P, Gashau W, Olaf K, Dodoo A, Okonkwo P, Kanki P. Prevalence of adverse drug reactions among HIV/AIDS patients on HAART in University of Maiduguri Teaching Hospital (UMTH), Nigeria: A four-year retrospective study. BMJ Glob Heal 2017; 2: A39.2-A39
Balogun SH, Adeleye OA. Patient reporting practices of suspected adverse drug reactions to antiretroviral drugs in a tertiary health facility in Nigeria. Niger Postgrad Med J 2014; 21: 331-7.
Nemaura T, Dhoro M, Nhachi C, Kadzirange G, Chonzi P, Masimirembwa C. Evaluation of the prevalence, progression and severity of common adverse reactions (Lipodystrophy, CNS, peripheral neuropathy, and hypersensitivity reactions) associated with Anti-Retroviral Therapy (ART) and anti-tuberculosis treatment in outpatients in. J AIDS Clin Res 2012; 4.
Lartey M, Essel A, Asante-Quarshie A, Kenu E, Ganu V, Neequaye A. Adverse drug reactions to antiretroviral therapy during the early art period at a tertiary hospital in Ghana. Pan Afr Med J 2014; 18: 25.
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; 12: 6.
Kityo C, Gibb DM, Gilks CF, et al. High level of viral suppression and low switch rate to second-line antiretroviral therapy among HIV-infected adult patients followed over five years: Retrospective analysis of the DART trial. PLoS One 2014; 9.
Fox MP, Van Cutsem G, Giddy J, et al. Rates and predictors of failure of first-line antiretroviral therapy and switch to second-line ART in South Africa. JAIDS J Acquir Immune Defic Syndr 2012; 60: 428-37.
Sanne IM, Westreich D, Macphail AP, Rubel D, Majuba P, Van Rie A. Long term outcomes of antiretroviral therapy in a large HIV/AIDS care clinic in urban South Africa: a prospective cohort study. J Int AIDS Soc 2009; 12: 38.
Hammond R, Harry TC. Efficacy of Antiretroviral Therapy in Africa: Effect on Immunological and Virological Outcome Measures – A Meta-Analysis. Int J STD AIDS 2008; 19: 291-6.
Patterson S, Cescon A, Samji H, et al. Cohort Profile: HAART Observational Medical Evaluation and Research (HOMER) cohort. Int J Epidemiol 2014; 58-67.
Scarsi KK, Eisen G, Darin KM, et al. Superior Effectiveness of Zidovudine Compared with Tenofovir When Combined with Nevirapine-based Antiretroviral Therapy in a Large Nigerian Cohort. Clin Infect Dis 2015; 62: 512-8.
Meloni ST, Chang CA, Eisen G, et al. Long-term outcomes on antiretroviral therapy in a large scale-up program in Nigeria. PLoS One 2016; 11: e0164030.
Law MG, Achhra A, Deeks SG, et al. Clinical and demographic factors associated with low viral load in early untreated HIV infection in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. HIV Med 2015; 16(Suppl. 1): 37-45.
Egger M, May M, Chêne G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: A collaborative analysis of prospective studies. Lancet 2002; 360: 119-29.
Agaba PA, Meloni ST, Sule HM, et al. Patients who present late to HIV care and associated risk factors in Nigeria. HIV Med 2014; 15: 396-405.
Federal Ministry of Health Abuja N. National guidelines for HIV prevention treatment and care, National AIDS and STI’s control programme. 2016
Chihana ML, Huerga H, Van Cutsem G, et al. Impact of “test and treat” recommendations on eligibility for antiretroviral treatment : Cross sectional population survey data from three high HIV prevalence countries. PLoS One 2018; 13(11): e0207656.
Walsh FJ, Bärnighausen T, Delva W, et al. Impact of early initiation versus national standard of care of antiretroviral therapy in Swaziland’s public sector health system: study protocol for a stepped-wedge randomized trial. Trials 2017; 18: 383.
Mwau M, Syeunda CA, Adhiambo M, et al. Scale-up of Kenya’s national HIV viral load program: Findings and lessons learned. PLoS One 2018; 13: 1-13.
Ssebunya R, Wanyenze RK, Lukolyo H, et al. Antiretroviral therapy initiation within seven days of enrolment: Outcomes and time to undetectable viral load among children at an urban HIV clinic in Uganda. BMC Infect Dis 2017; 17: 1-8.
Kedir MS, Gemeda DH, Suleman S. Treatment outcomes of nevirapine-versus efavirenz-based highly active antiretroviral therapy regimens among antiretroviral-naive adult patients in Ethiopia: A cohort study. Ther Innov Regul Sci 2015; 49: 443-9.
Mbuagbaw LC, Irlam JH, Spaulding A, Rutherford GW, Siegfried N. Efavirenz or nevirapine in three-drug combination therapy with two nucleoside-reverse transcriptase inhibitors for initial treatment of HIV infection in antiretroviral-naïve individuals. Cochrane Database Syst Rev 2010; CD004246.
Amoroso A, Etienne-Mesubi M, Edozien A, et al. Treatment outcomes of recommended first-line antiretroviral regimens in resource-limited clinics. JAIDS J Acquir Immune Defic Syndr 2012; 60: 314-20.
Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 2006; 354: 251-60.
El-Khatib Z, Katzenstein D, Marrone G, et al. Adherence to drug-refill is a useful early warning indicator of virologic and immunologic failure among HIV patients on first-line art in South Africa. PLoS One 2011; 6(3): e17518.
Bisson GP, Gross R, Bellamy S, et al. Pharmacy refill adherence compared with CD4 count changes for monitoring HIV-infected adults on antiretroviral therapy. PLoS Med 2008; 5: 777-88.
Syed IA, Sulaiman SAS, Hassali MA, Syed SH, Shan LH, Lee CKC. Factors associated with poor CD4 and viral load outcomes in patients with HIV/AIDS. J Med Virol 2016; 88: 790-7.
Njuguna C, Orrell C, Kaplan R, Bekker LG, Wood R, Lawn SD. Rates of Switching Antiretroviral Drugs in a Primary Care Service in South Africa before and after Introduction of Tenofovir. PLoS One 2013; 8(5): e63596.
Bezabhe WM, Bereznicki LR, Chalmers L, et al. Adverse drug reactions and clinical outcomes in patients initiated on antiretroviral therapy: A prospective cohort study from Ethiopia. Drug Saf 2015; 38: 629-39.
Shet A, Antony J, Arumugam K, Kumar Dodderi S, Rodrigues R, DeCosta A. Influence of adverse drug reactions on treatment success: Prospective cohort analysis of HIV-infected individuals initiating first-line antiretroviral therapy in India. PLoS One 2014; 9(3): e91028.
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; 15: 32.
Nachega JB, Hislop M, Nguyen H, et al. Antiretroviral therapy adherence, virologic and immunologic outcomes in adolescents compared with adults in southern Africa. J Acquir Immune Defic Syndr 2009; 51: 65-71.
Kapiamba G, Masango T, Mphuthi D. Antiretroviral adherence and virological outcomes in HIV-positive patients in Ugu district, KwaZulu-Natal province. Afr J AIDS Res 2016; 15: 195-201.
Ramadhani HO, Thielman NM, Landman KZ, et al. Predictors of incomplete adherence, virologic failure, and antiviral drug resistance among HIV-infected adults receiving antiretroviral therapy in Tanzania. Clin Infect Dis 2007; 45: 1492-8.
Cardoso SW, Grinsztejn B, Velasque L, et al. Incidence of Modifying or Discontinuing First HAART Regimen and Its Determinants in a Cohort of HIV-Infected Patients from Rio de Janeiro, Brazil. AIDS Res Hum Retroviruses 2010; 26: 865-74.
Shubber Z, Calmy A, Andrieux-Meyer I, et al. Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral therapy: a systematic review and meta-analysis. AIDS 2013; 27: 1403-12.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2018
Page: [436 - 446]
Pages: 11
DOI: 10.2174/1389450120666190214144609

Article Metrics

PDF: 43