Objective: This retrospective cohort study is aimed to assess reasons and predictors of regimen change from initial highly active antiretroviral therapy among 1533 Human Immunodeficiency virus-infected adult patients at the Jimma University Tertiary Hospital. Results: One in two (47.7%) adults changed their antiretroviral therapy regimen. Patients who were above the primary level of education [Hazard ratio (HR) 1.241 (95% CI 1.070–1.440)] and with human immunodeficiency virus/ tuberculosis co-infection [HR 1.405 (95% CI 1.156–1.708)] had the higher risk of regimen change than their compara- tor. Individuals on Efavirenz [HR 0.675 (95% CI 0.553–0.825)] and non-stavudine [HR 0.494 (95% CI 0.406–0.601)] based regimens had lower risk of regimen change. Keywords: Regimen change, Risk factors, Initial highly active antiretroviral therapy, Ethiopia in Ethiopia, it was between 9.8 and 31.4% in 2012 and Introduction 2014 . Beyond access to HAART, the long-term suc- Globally, the number of people living with human immu- cesses of treatment programs in resource-limited settings nodeficiency virus (HIV) reached 38.8 million in 2015 depend on patient retention on therapy. . In Ethiopia, there were 786,040 HIV-infected people, The reasons and risk factors for HAART regimen 39,140 new HIV infections and 28,650 human immuno- changes have been assessed by studies from resource- deficiency virus/acquired immunodeficiency syndrome rich and resource-limited settings [13–17]. Similarly, in (HIV/AIDS) related deaths in 2015 . Ethiopia, some studies determined factors contributed Highly active antiretroviral therapy (HAART) has led to ART regimen change [12, 18]. However, the previous to a major reduction of HIV related morbidity and mor- studies that assessed either the prevalence [12, 18] or fac- tality [2–4]. These optimum clinical and public health tors [12, 18–22] for regimen change were all from the achievements of antiretroviral therapy (ART) require northern part of the country. In this study, we assessed consistent long-term adherence . Currently, ART regi- reasons and risk factors for the initial HAART regimen men changes become a big challenge and cause diminish- changed among patients who started HAART as part of ing the clinical and immunological benefit of treatment routine clinical care at Jimma University Tertiary Hospi- [6, 7], failing virological suppression, increase drug resist- tal [JUTH]. ance  and increase mortality and morbidity due to HIV/AIDS [8, 9]. Main text In Africa, the magnitude of regimen change in Methods 2009–2012 was between 13.7 and 57.4% [10, 11] and Study design, settings, and participants A retrospective data from 1533 treatment-naïve adult *Correspondence: email@example.com patients who first received HAART from 2006 to June Department of Medicine, College of Medicine and Health Science, 2014 at ART clinic of JUTH, Southwest Ethiopia, Jigjiga University, Jigjiga, Ethiopia was analyzed. The treatment protocol for Ethiopia is Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Mekonnen et al. BMC Res Notes (2018) 11:351 Page 2 of 6 implemented using World Health Organization (WHO) HAART regimen changes was estimated using Kaplan– ART treatment guideline for HIV infection in adults and Meier survival analysis. We applied Cox-proportional adolescents  and national guidelines for HIV preven- hazards regression to identify risk factors associated with tion, care, and treatment: Federal Democratic Republic of outcome variable (time of regimen change). Variables Ethiopia . According to the current treatment guide- found to be associated with the outcome in the univariate lines, HIV-infected adults are eligible to start ART if their analysis assuming a significance threshold of 20% were Cluster of differentiation 4 cell (CD4cell) count is ≤ 500 included in the multivariate analysis. The multivariate cells/mm irrespective of the CD4 cell count and WHO analysis results showed a significant effect on the out - clinical stage. Breastfeeding women, pregnant women, come considering the significance thresholds of 5% were and serodiscordant couples can start ART irrespective of described. WHO clinical stages and CD4 cell count. Ethical consideration Data collection techniques and data quality control Ethical clearance was obtained from Ethical clearance A standard checklist containing study variables were board of Jimma University and data access permission developed from the patient registry card which was was obtained from the medical director of JUTH. We developed by the Ethiopian Federal Ministry of Health simply extracted anonymized data from the patient’s (FMOH). During data collection, the most recent labora- medical registry and no participant was involved in the tory results before starting ART were generally used as study. baseline values. Pregnant women initiated ART for pre- vention of mother to child transmission (PMCT) and Results transfer-in patients were excluded from the study. Death, Characteristics of study participants transferred out and unrecorded outcome variables would A total of 1533 naive patients who started ART with at be excluded from complete case analysis. least one follow-up visit were included for complete case analysis, of which 963 (62.8%) were females. Socio-demo- Study variables and measurements graphics, clinical and laboratory characteristics of the Survival time was measured from the start of ART and patients are shown in Table 1. ended at the time of regimen changed or when patients were censored. Regimen change refers to both medica- Prevalence and trends of ART regimen change tion modification (i.e. Patients who had modified one or Patients were followed for a total of 4546.85 PY with two ART from the three ART regimens) and discontinu- a median follow up of 54.20 (95% CI 51.012–57.388) ation (i.e. Patients who had stopped all regimens at once). months. In total, 731 (47.7%) had regimen changed cor- Lost to follow up (LTFU) (i.e. Patients who had missed at responding to an overall incidence rate of 16.08 (95% least three appointments, but had not yet been classified CI 14.94–17.27) per 100 PY. The number of default - as dead or transferred), and defaulters (i.e. Patients who ers and LTFU adult patients were 239 (15.60%) and 107 had missed less than three clinical appointments, but (6.98%), respectively. Of the 731 adults who had regi- had not yet been classified as dead or transferred) were men changed, 640 (87.55%) were modifications and 91 censored. (12.45%) were discontinuations. The median time from The independent variables include: age, sex, marital ART initiation to regimen change was 24.37 (95% CI status, past opportunistic infection, tuberculosis (Tb) 21.463–27.204) months. status, baseline functional status, educational status, ini- Kaplan–Meier estimates of the overall probabilities of tial CD4 count, and WHO clinical stages. Educational regimen change at 3-month and 1-year for the cohort status was categorized into below (1–8 grade) and above were 8.1% (7.4–8.8%) and 16.6% (15.6–17.6%), respec- (> 9 grade) primary level education. Functional status was tively. The next 2- and 3-year probabilities of regimen classified into the following categories: working (i.e. the changes were 24.2% (95% CI 23.1–25.3%) and 31.2% (95% ability to perform usual work in and out of the house), CI 30–32.4%), respectively. ambulatory (i.e. the ability to perform activities of daily Drug toxicities were the predominant reasons [n = 431 living), and bedridden (i.e. not able to perform activities (58.96%)] for ART regimens changed. Among docu- of daily living). mented toxicities: 82 (61.19%) were fat changes, 30 (22.38%) were peripheral neuropathies, 14 (10.45%) were Statistical analyses anemic, 5 (3.73%) were central nervous system (CNS) The collected data were cleaned, categorized, coded, toxicities and one hepatotoxicity. entered and analyzed by using statistical package for A new TB treatment [n = 120 (16.42%)], planning preg- social sciences (SPSS) version 16. The probability of nancy or being pregnant [n = 29 (3.96%)] and treatment Mekonnen et al. BMC Res Notes (2018) 11:351 Page 3 of 6 Table 1 Baseline socio-demographic and clinical charac- Table 2 Hazard ratios (95% CI) for ART regimens change teristics of patients on ART at JUTH, Ethiopia 2015 among HIV infected adult patients at JUTH, Ethiopia, 2015 Baseline characteristics N (%) Variables Unadjusted HR (95% Adjusted HR (95% CI) CI) Age (years), [interquartile range (IQR)] 30 (26–38) Educational status Sex Female 963 (62.8) Below primary level 1 1 education Male 570 (37.2) Above primary level 1.209 (1.046–1.398) 1.241 (1.070–1.440) Marital status education In relationship 733 (47.8) TB status Not in relationship 798 (52.0) Negative 1 1 Missing values 2 Positive 1.356 (1.126–1.633) 1.405 (1.156–1.708) Educational status Functional status < primary level education 835 (54.5) ≥ primary level education 698 (45.5) Working 1 1 Functional status Ambulatory 1.196 (1.017–1.408) 1.169 (0.987–1.385) Working 1058 (69.0) Bedridden 1.428 (1.020–1.998) 1.369 (0.972–1.929) Ambulatory 394 (25.7) Initial CD4 Bedridden 63 (4.1) ≤ 200 1 1 Missing values 18 (1.2) > 200 0.850 (0.719–1.005) 0.923 (0.777–1.097) Initial CD4 NNRTIs-based Median (IQR) in cells/mm 144 (IQR 79–210) NVP based 1 1 ≤ 200 1102 (71.8) EFV based 0.736 (0.605–0.895) 0.675 (0.553–0.825) > 200 429 (28) NRTIs-based Missing values 2 D4T based 1 1 WHO clinical stages Non-D4T based 0.507 (0.418–0.615) 0.494 (0.406–0.601) Stage I 290 (18.9) Stage II 436 (28.4) Stage III 648 (42.3) failure [n = 24 (3.28%)] were the other reasons for regi- Stage IV 159 (10.4) mens changed. Others (n = 127) had no documented rea- Past opportunistic infections son for regimen changed. Yes 1183 (77.2) No 342 (22.3) Missing values 8 Predictors for ART regimen change TB status The results from the multivariable Cox-proportional haz - Negative 1207 (78.7) ards regression analysis found patients who were above Positive 281 (18.3) the primary level of education [HR 1.241 (1.070–1.440)] Missing values 45 (2.9) and with HIV/TB co-infection [HR 1.405 (1.156–1.708)] NNRTIs had a higher risk of regimen change than their compara- NVP-based 1056 (68.9) tor as shown in Table 2. Patients on EFV-based regi- EFV-based 477 (31.1) mens [HR 0.675 (95% CI 0.553–0.825)] and non-D4T NRTIs based regimens [HR 0.494 (0.406–0.601)] had the lower D4T-based 942 (61.4) hazard of change than NVP and D4T based regimens, TDF-based 338 (22.0) respectively. ZDV-based 253 (16.5) Discussion WHO clinical stage I indicates asymptomatic and persistent generalized lymphadenopathy; WHO clinical Stage 3 was defined if one of the following Regimen change affects the success of the treatments is present: weight loss of > 10% body weight, chronic diarrhea for > 1 month, to achieve United Nations Program on HIV and AIDS fever for > 1 month, oral candidiasis, or pulmonary Tb within the previous (UNAIDs) goals . Near to one in two (47.7%), indi- year, or severe bacterial infections; WHO clinical Stage 4 was defined if one of the following is present in an HIV diagnosed patient: HIV wasting syndrome, viduals changed their regimen in this present study. The (Pneumocystcarini pneumonia)PCP, toxoplasmosis of the brain, cryptosporidiosis regimen change rate found in the current study is higher with diarrhea for > 1 month, cytomegalovirus disease, herpes simplex virus infection, progressive multifocal leukoencephalopathy, candidiasis, extra- than findings elsewhere in Ethiopia [12, 26]. It is also pulmonary Tb, lymphoma, kaposi’s sarcoma higher when compared to other cohort studies in Uganda NNRTIs non-nucleoside reverse transcriptase inhibitors, NRTIs nucleoside reverse (39.21%)  and Nigeria (28%) . However, cohort transcriptase inhibitors, NVP Nevirapine, EFV Efavirenz, D4T Stavudine, TDF Tenofovir, ZDV Zidovudine studies from resource-rich countries like UK, Italy, and Mekonnen et al. BMC Res Notes (2018) 11:351 Page 4 of 6 Brazil showed higher incidence rates of regimen changes benchmarking programs such as a linkage-case-manage- (28.3–41.5 per 100 PY) [17, 29, 30]. This is expected as ment to enhance ART linkage and retention, which have viral load measurement and availability of subsequent demonstrated to be effective in similar settings [46, 47]. antiretroviral treatment options are limited when com- pared with resource-rich settings . Limitation of the study Toxicities were the predominant reasons for ART We acknowledge the limitations of the current study regimens changed. This is consistent with other studies including: [29, 30, 32–34]. Like other studies, [17, 27, 35] our study found that fat changes and peripheral neuropathy were • Reasons for regimen change were documented only the most frequent toxicities. Unlike our setting and other if they were incidental to regimen change, therefore, sub-Saharan countries, hematological toxicities were the their frequency cannot be used to estimate their most common toxicities reported in Latin Americans actual occurrence. [16, 31, 36, 37]. • The outcome status of regimen changed patients was New TB drug treatment was also a major reason for the not known. initial ART regimen change, especially for NVP-based • Some variables such as mental illness and stigma regimens. This was due to an interaction of NVP with the were not assessed as our data source lacked this anti-TB drugs such as Rifampin [38, 39]. In order to avoid information. this drug interaction, clinicians replace the NVP with Abbreviations EFV [23, 24]. Being infected with HIV virus may also ART : antiretroviral therapy; D4T: stavudine; EFV: efavirenz; FMOH: Ethiopian expose patients to develop TB early [38, 40] and thereby Federal Ministry of Health; HAART : highly active antiretroviral therapy; HIV/ AIDS: human immunodeficiency virus/acquired immunodeficiency syndrome; lead to modification of NVP to EFV. IQR: interquartile range; JUTH: Jimma University Tertiary Hospital; LTFU: lost In the current study, the hazard of regimen change was to follow up; NNRTIs: non-nucleoside reverse transcriptase inhibitors; NRTIs: higher in Tb/HIV co-infected patients than in patients nucleoside reverse transcriptase inhibitors; NVP: nevirapine; PCP: Pneumocystis jiroveci pneumonia; PMCT: prevention of mother to child transmission; TDF: with HIV infections alone. This is consistent with other tenofovir; UNAIDs: United Nations Program on HIV and AIDS; WHO: World studies [20, 41, 42]. Studies showed that co-morbidities Health Organization; ZDV: zidovudine. in patients with advanced disease and concurrent treat- Authors’ contributions ments for opportunistic diseases may affect antiretrovi - EM: conceived, designed and participated in data collection, conducted the ral tolerance and thereby disallow patients from regular data analysis and interpretation, developed the first draft and revised subse - treatment intake [40, 43, 44]. quent drafts. AW: advised on the conception of the study area, data analysis and interpretation. NH: reviewed and commented on successive drafts. TF: EFV-based regimens had the lower hazard of change commented on successive drafts. All authors read and approved the final than NVP-based regimens. This is similar to other stud - manuscript. ies [14, 16, 17, 45]. The increased hazard for NVP-based Author details regimens change might be due to the frequent use of Department of Medicine, College of Medicine and Health Science, Jigjiga fixed-dose combinations containing D4T and NVP as University, Jigjiga, Ethiopia. Department of Epidemiology, College of Health D4T was the drug most often modified. Early modifica - and Medical Sciences, Jimma University, Jimma, Ethiopia. School of Phar- macy, College of Health and Medical Sciences, Jimma University, Jimma, tion of NVP due to new TB treatment was also a possible Ethiopia. Department of Veterinary Clinical Studies, College of Veterinary reason for an increased hazard of NVP-based regimen Medicine, Jigjiga University, Jigjiga, Ethiopia. changes [38, 39]. Acknowledgements Patients who were above the primary level of edu- The authors acknowledge Jimma University, College of Health and Medical cation had the higher hazard of regimen change than Science for providing access to the data. We were also grateful for the data those below primary level education. Although we did collectors and supervisors for the carefully undertaking of their tasks. not assess their knowledge, this might be due to better Competing interests awareness of ART-associated toxicities and reasons for The authors declare that they have no competing interests. regimen change among the educated groups. Availability of data and materials All relevant data are within the paper. The SPSS data of individual patients Conclusion are not permitted to be provided to other bodies, as indicated on ethical One in two patients changed their ART, mainly due to clearance. However, researchers who need further clarification can obtain anonymized data from the corresponding author on reasonable request. drug toxicity. New TB drug treatment, being pregnant and treatment failure were other reasons for the regimen Consent to publish changed. Regimen changed patients were more likely Not applicable. to be HIV/TB co-infected, above primary level educa- Ethics approval and consent to participate tion, and on D4T or NVP based regimens. We recom- Ethical clearance board of Jimma University ethically approved all the study mended strengthening adherence level and adopting methods and protocols and responded with a letter reference number Mekonnen et al. BMC Res Notes (2018) 11:351 Page 5 of 6 RPGC/109/2013. Informed consent was not taken from the patients, as the antiretroviral therapeutic regimens among patients in southern India. J information was extracted from anonymized data. Acquir Immune Defic Syndr. 2006;41(1):53–8. 16. Cesar C, Shepherd BE, Krolewiecki AJ, Fink VI, Schechter M, Tuboi SH, Funding et al. Rates and reasons for early change of first HAART in HIV-1-infected Funding was obtained from Jimma University, College of health and medical patients in 7 sites throughout the Caribbean and Latin America. PLoS science. 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