Impact of Efavirenz Metabolism on Loss to Care in Older HIV+ Africans
- 71 Downloads
Background and Objective
Efavirenz is commonly used in Africa and is frequently associated with neurocognitive toxicity, which may compromise clinical outcomes. Older individuals are at increased risk for drug toxicity and clinical outcomes may be worse in older age, particularly among those individuals with cytochrome P450 (CYP) 2B6 polymorphisms associated with slower efavirenz metabolism. The aim of this study was to determine if the CYP2B6 polymorphisms differentially impacts loss to care in older people.
We conducted a prospective cohort study of 914 treatment-naïve HIV+ adults initiating efavirenz-based antiretroviral treatment at public HIV clinics in Gaborone, Botswana between 2009 and 2013. Older age, defined as age ≥ 50 years, was the primary exposure and loss to care at 6 months was the primary outcome. Interaction between age and CYP2B6 516G>T and 983T>C polymorphisms, defined as extensive, intermediate, and slow metabolism, was assessed. Neurocognitive toxicity was measured using a symptom questionnaire. Age-stratified logistic regression was performed to identify factors associated with loss to care.
Older age was associated with loss to care (OR 1.95, 95% CI 1.30–2.92). Age modified the effect of CYP2B6 genotype on loss to care with older, slow metabolizers at over four-fold higher risk when compared to older, intermediate metabolizers (OR 4.06 95% CI 1.38–11.89); neurocognitive toxicity did not mediate this risk. CYP2B6 metabolism genotype did not increase risk of loss to care in younger participants.
Older age was associated with loss to care, especially among those with slow efavirenz metabolism. Understanding the relationship between older age and CYP2B6 genotype will be important to improving outcomes in an aging population initiating efavirenz-based ART in similar settings.
We would like to thank the patients who participated in this study and medical staff at the Bontleng, Broadhurst 3, Broadhurst Traditional Area, Morwa, Nkoyaphiri, Phase II, and Village Infectious Diseases Care Clinics for their assistance with this endeavor. We are grateful to the Ministry of Health of Botswana for supporting this project.
Compliance with Ethical Standards
Conflict of Interest
The authors declare there is no conflict of interest.
United States National Institute of Mental Health (R01 MH080701) and Penn Center for AIDS Research (P30 MH097488) and Penn Mental Health AIDS Research Center (P30 AI 045008) both NIH-funded programs.
The parent study was approved by the Institutional Review Board at the University of Pennsylvania and by the Botswana Ministry of Health. Informed consent was obtained from all participants included in this study. Funding agencies had no involvement in the analysis, interpretation of results, or development of this manuscript.
- 1.Guideline On When To Start Antiretroviral Therapy And On Pre-exposure Prophylaxis For HIV. Geneva: World Health Organization. 2015. http://apps.who.int/iris/bitstream/10665/186275/1/9789241509565_eng.pdf?ua=1. Accessed 25 Aug 2016.
- 2.Munoz-Moreno JA, Fumaz CR, Ferrer MJ, et al. Neuropsychiatric symptoms associated with efavirenz: prevalence, correlates and management. A neurobehavioral review. AIDS Rev. 2009;11:103–9.Google Scholar
- 3.Marzolini C, Telenti A, Decosterd LA, et al. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS. 2001;15:71–5.Google Scholar
- 4.Ward BA, Gorski JC, Jones DR, et al. The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J Pharmacol Exp Ther. 2003;306:287–300.Google Scholar
- 5.Klein K, Lang T, Saussele T, et al. Genetic variability of CYP2B6 in populations of African and Asian origin: allele frequencies, novel functional metabolizers, and possible implications for anti-HIV therapy with efavirenz. Pharmacogenet Genom. 2005;15:861–73.Google Scholar
- 6.Sustiva (efavirenz) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company. 2017. http://packageinserts.bms.com/pi/pi_sustiva.pdf. Accessed 6 Aug 2018.
- 7.Ogburn ET, Jones DR, Masters AR, et al. Efavirenz primary and secondary metabolism in vitro and in vivo: identification of novel metabolic pathways and cytochrome P450 2A6 as the principal catalyst of efavirenz 7-hydroxylation. Drug Metab Dispos. 2010;38(7):1218–29.Google Scholar
- 8.Rotger M, Colombo S, Furrer H, et al. Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients. Pharmacogenet Genom. 2005;15(1):1–5.Google Scholar
- 9.Gounden V, van Niekerk C, Syma T, et al. Presence of the CYP 2B6 516G>T polymorphism, increased plasma efavirenz concentrations and early neuropsychatric side effects in South Africa HIV-infected patients. AIDS Res Ther. 2010;7:32.Google Scholar
- 10.Cummins NW, Neuhaus J, Chu H, et al. Investigation of efavirenz discontinuation in multi-ethnic populations of HIV-positive individuals by genetic analysis. EBioMedicine. 2015;12:706–12.Google Scholar
- 11.Nwogu JN, Ma Q, Babalola CP, et al. Pharmacokinetic, pharmacogenetic, and other factors influencing CNS penetration of antiretrovirals. AIDS Res Treat. 2016;2016:2587094.Google Scholar
- 12.Wyen C, Hendra H, Vogel M, et al. Impact of CYP2B6 983T>C polymorphism on non-nucleoside reverse transcriptase inhibitor plasma concentrations in HIV infected patients. J Antimicrob Chemother. 2008;61(4):914–8.Google Scholar
- 13.Ribaudo HJ, Liu H, Schwab M, et al. Effect of CYP2B6, ABCB1, and CYP3A5 polymorphisms on efavirenz pharmacokinetics and treatment response: an AIDS clinical trials group study. J Infect Dis. 2010;202(5):717–22.Google Scholar
- 14.Mehlotra RK, Bockarie MJ, Zimmerman PA. CYP2B6 983T>C polymorphism is prevalent in West Africa but absent in Papua New Guinea: implications for HIV/AIDS treatment. Br J Clin Pharmacol. 2007;64(3):391–5.Google Scholar
- 15.Schoen JC, Erlandson KM, Anderson PL. Clinical pharmacokinetics of antiretroviral drugs in older persons. Expert Opin Drug Metab Toxicol. 2013;9(5):573–88.Google Scholar
- 16.Klotz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metabol Rev. 2009;41:67–76.Google Scholar
- 17.Moore AR, O’Keeffe ST. Drug-induced cognitive impairment in the elderly. Drugs Aging. 1999;15(1):15–28.Google Scholar
- 18.von Moltke LL, Greenblatt DJ, Romach MK, et al. Cognitive toxicity of drugs used in the elderly. Dialogues Clin Neurosci. 2001;3(3):181–90.Google Scholar
- 19.Gross R, Bellamy SL, Ratshaa B, et al. CYP2B6 genotypes and early efavirenz-based HIV treatment outcomes in Botswana. AIDS. 2017;31(15):2107–13.Google Scholar
- 20.Farmer KC. Methods for measuring and monitoring medication regimen adherence in clinical trials and clinical practice. Clin Ther. 1999;21(6):1074–90.Google Scholar
- 21.Clifford DB, Evans S, Yang Y, Acosta EP, Goodkin K, Tashima K, et al. Impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals. Ann Intern Med. 2005;143:714–21.Google Scholar
- 22.Nogueras M, Navarro G, Anton E, et al. Epidemiological and clinical features, response to HAART, and survival in HIV-infected patients diagnosed at the age of 50 or more. BMC Infect Dis. 2006;6:159.Google Scholar
- 23.Sotaniemi EA, Arranto AJ, Pelkonen O, Pasanen M. Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions. Clin Pharmacol Ther. 1997;61(3):331–9.Google Scholar
- 24.Ryscavage P, Kelly S, Li JZ, et al. Significance and clinical management of persistent low-level viremia and very-low-level viremia in HIV-1-infected patients. Antimicrob Agents Chemother. 2014;58(7):3585–98.Google Scholar
- 25.Botswana National HIV & AIDS Treatment Guidelines. Gabarone: Ministry of Health. 2012. https://aidsfree.usaid.gov/sites/default/files/tx_botswana_2012.pdf. Accessed 8 Aug 2018.
- 26.Joska JA, Westgarth-Taylor J, Hoare J, et al. Neuropsychological outcomes in adults commencing highly active anti-retroviral treatment in South Africa: a prospective study. Br J Clin Pharmacol. 2013;75(4):997–1006.Google Scholar
- 27.Beckham SW, Beyrer C, Luckow P, et al. Marked sex differences in all-cause mortality on antiretroviral therapy in low- and middle-income countries: a systematic review and meta-analysis. J Int AIDS Soc. 2016;19(1):21106.Google Scholar
- 28.Baron RM, Kenny DA. The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol. 1986;51(6):1173–82.Google Scholar
- 29.StataCorp. Stata Statistical Software: Release 13. College Station: StataCorp LP; 2013.Google Scholar
- 30.Vinikoor MJ, Joseph J, Mwale J, et al. Age at antiretroviral therapy initiation predicts immune recovery, death, and loss to follow-up among HIV-infected adults in urban Zambia. AIDS Res Hum Retroviruses. 2014;30(10):949–55.Google Scholar
- 31.Maskew M, Brennan AT, MacPhail AP, et al. Poorer ART outcomes with increasing age at a large public sector HIV clinic in Johannesburg, South Africa. J Int Assoc Physicians AIDS Care (Chic). 2012;11(1):57–65.Google Scholar
- 32.Mutevedzi PC, Lessells RJ, Rodger AJ, Newell M-L. Association of age with mortality and virological and immunological response to antiretroviral therapy in rural South African adults. PLoS One. 2011;6:e21795.Google Scholar
- 33.Semeere AS, Lwanga I, Sempa J, et al. Mortality and immunological recovery among older adults on antiretroviral therapy at a large urban HIV clinic in Kampala, Uganda. J Acquir Immune Defic Syndr. 2014;67:382–9.Google Scholar
- 34.Bakandaa C, Birungia J, Mwesigwa R, et al. Association of aging and survival in a large HIV-infected cohort on antiretroviral therapy. AIDS. 2011;25:701–5.Google Scholar
- 35.Eduardo E, Lamb MR, Kandula S, et al. Characteristics and outcomes among older HIV-Positive adults enrolled in HIV programs in four Sub-Saharan African countries. PLoS One. 2014;9(7):e103864.Google Scholar
- 36.Cornell M, Johnson LF, Schomaker M, et al. Age in antiretroviral therapy programmes in South Africa: a retrospective, multicentre, observational cohort study. Lancet HIV. 2015;2:e368–75.Google Scholar
- 37.Bisson GP, Gaolathe T, Gross R, et al. Overestimates of survival after HAART: implications for global scale-up efforts. PLoS One. 2008;3(3):e1725.Google Scholar
- 38.Ma Q, Vaida F, Wong J, et al. Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients. J Neurovirol. 2016;22:170–8.Google Scholar
- 39.Ciccarelli N, Fabbiani M, Di Giambenedetto S, et al. Efavirenz associated with cognitive disorders in otherwise asymptomatic HIV-infected patients. Neurology. 2011;76:1403–9.Google Scholar
- 40.Akinyemi JO, Ogunbosi BO, Fayemiwo AS, et al. Demographic and epidemiological characteristics of HIV opportunistic infections among older adults in Nigeria. Afr Health Sci. 2017;17(2):315–21.Google Scholar
- 41.Sani MU, Okeahialam BN. QTc interval prolongation in patients with HIV and AIDS. J Natl Med Assoc. 2005;97(12):1657–61.Google Scholar
- 42.Nachimuthu S, Assar MD, Schussler JM. Drug-induced QT interval prolongation: mechanisms and clinical management. Ther Adv Drug Saf. 2012;3(5):241–53.Google Scholar
- 43.Ogunmola OJ, Oladosu YO, Olamoyegun MA. QTc interval prolongation in HIV-negative versus HIV-positive subjects with or without antiretroviral drugs. Ann Afr Med. 2015;14(4):169–76.Google Scholar
- 44.Abdelhady AM, Shugg T, Thong N, et al. Efavirenz inhibits the human ether-A-Go-Go related current (hERG) and induces QT interval prolongation in CYP2B6*6*6 allele carriers. J Cardiovasc Electrophysiol. 2016;27(10):1206–13.Google Scholar
- 45.Lopez JA, Harold JG, Rosenthal MC, et al. QT prolongation and torsades de pointes after administration of trimethoprim-sulfamethoxazole. Am J Cardiol. 1987;59:376–7.Google Scholar
- 46.Thomford NE, Dzobo K, Chopera D, et al. Pharmacogenomics implications of using herbal medicinal plants on African populations in health transition. Pharmaceuticals (Basel). 2015;8(3):637–63.Google Scholar
- 47.Hughes GD, Puoane TR, Clark BL, et al. Prevalence and predictors of traditional medicine utilization among persons living with AIDS (PLWA) on antiretroviral (ARV) and prophylaxis treatment in both rural and urban areas in South Africa. Afr J Tradit Complement Altern Med. 2012;9(4):470–84.Google Scholar
- 48.Mills E, Foster BC, van Heeswijk R, et al. Impact of African herbal medicines on antiretroviral metabolism. AIDS. 2005;19(1):95–7.Google Scholar
- 49.Fasinu PS, Gutmann H, Schiller H, et al. The potential of Sutherlandia frutescens for herb-drug interaction. Drug Metab Dispos. 2013;41(2):488–97.Google Scholar
- 50.Africa LD, Smith C. Sutherlandia frutescens may exacerbate HIV-associated neuroinflammation. J Negat Results Biomed. 2015;14:14.Google Scholar
- 51.O’Brien D, Spelman T, Greig J, et al. Risk factors for mortality during antiretroviral therapy in older populations in resource-limited settings. J Int AIDS Soc. 2016;19(1):20665.Google Scholar
- 52.Greig J, Esther C, Casas EC, O’Brien DP, et al. Association between older age and adverse outcomes on antiretroviral therapy: a cohort analysis of programme data from nine countries. AIDS. 2012;26(Suppl 1):S31–7.Google Scholar
- 53.Pathai S, Gilbert C, Weiss HA, et al. Frailty in HIV-infected adults in South Africa. J Acquir Immune Defic Syndr. 2013;62(1):43–51.Google Scholar
- 54.Hontelez JA, de Vlas SJ, Baltussen R, et al. The impact of antiretroviral treatment on the age composition of the HIV epidemic in sub-Saharan Africa. AIDS. 2012;26(Suppl 1):S19–30.Google Scholar