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      Magnitude and causes of first-line antiretroviral therapy regimen changes among HIV patients in Ethiopia: a systematic review and meta-analysis

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          Abstract

          Background

          Antiretroviral therapy (ART) has markedly decreased the morbidity and mortality due to HIV/AIDS. ART regimen change is a major challenge for the sustainability of human immunodeficiency virus (HIV) treatment program. This is found to be a major concern among HIV/AIDS patients in a resource-limited setting, where treatment options are limited.

          Objectives

          The aim of this review is to generate the best available evidence regarding the magnitude of first-line antiretroviral therapy regimen change and the causes for regimen change among HIV patients on ART in Ethiopia.

          Methods

          The reviewed studies were accessed through electronic web-based search strategy from PubMed Medline, EMBASE, Hinari, Springer link and Google Scholar. Data were extracted using Microsoft Excel and exported to Stata software version 13 for analyses. The overall pooled estimation of outcomes was calculated using a random-effect model of DerSimonian–Laird method at 95% confidence level. Heterogeneity of studies was determined using I 2 statistics. For the magnitude of regimen change, the presence of publication bias was evaluated using the Begg’s and Egger’s tests. The protocol of this systematic review and meta-analysis was registered in the Prospero database with reference number ID: CRD42018099742. The published methodology is available from: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=99742.

          Results

          A total of 22 studies published between the years 2012 and 2018 were included. Out of 22 articles, 14 articles reported the magnitude of regimen change and consisted of 13,668 HIV patients. The estimated national pooled magnitude of regimen change was 37% (95% CI: 34, 44%; Range: 15.1–63.8%) with degree of heterogeneity (I 2), 98.7%; p-value < 0.001. Seventeen articles were used to identify the causes for first-line antiretroviral therapy regimen change. The major causes identified were toxicity, 58% (95% CI: 46, 69%; Range: 14.4–88.5%); TB co-morbidity, 12% (95% CI: 8, 16%; Range: 0.8–31.7%); treatment failure, 7% (95% CI: 5, 9%; Range: 0.4–24.4%); and pregnancy, 5% (95% CI: 4, 7%; Range: 0.6–11.9%).

          Conclusions

          The original first-line regimen was changed in one-third of HIV patients on ART in Ethiopia. Toxicity of the drugs, TB co-morbidity, treatment failure, and pregnancy were the main causes for the change of the first-line regimen among HIV patients on antiretroviral therapy.

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          Most cited references41

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          Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naïve patients. I.CO.N.A. Study Group. Italian Cohort of Antiretroviral-Naïve Patients.

          To evaluate the frequency of discontinuation of the first highly active antiretroviral regimen (HAART) and the factors predictive of discontinuing for toxicity and failure in a population-based cohort of HIV-positive individuals in Italy, naïve from antiretrovirals at enrolment. The study population consisted of individuals who initiated HAART and had at least one follow-up visit. The primary end-points were discontinuation of any component of HAART for drug toxicity and discontinuation for failure. Survival analyses were performed to identify predictive factors for reaching the two end-points. Eight hundred and sixty-two individuals initiated HAART; in 727 of them (84.3%) this consisted of two nucleoside reverse transcriptase inhibitors (NRTI) and one protease inhibitor (PI). Over a median follow-up of 45 weeks, 312 patients (36.2%) discontinued therapy: 182 (21.1%) discontinued due to toxicity, 44 (5.1%) due to failure. The probability of discontinuing HAART at 1 year was 25.5% [95% confidence interval (CI), 21.9-28.9] due to toxicity and 7.6% (95% CI, 4.9-1 0.3) due to failure. Independent factors associated with discontinuation for toxicity were: gender [relative hazard (RH) = 0.51; 95% CI, 0.32-0.80 for men versus women], type of treatment (indinavir-containing regimens, RH = 1.94; 95% CI, 1.10-3.41 and ritonavir-containing regimens, RH = 3.83; 95% CI, 2.09-7.03 versus hard-gell saquinavir) and time spent on treatment (RH = 0.89; 95% CI, 0.80-0.98 for each additional month). Discontinuation due to failure was independently associated with the most recent HIV-RNA (RH = 3.20; 95% CI, 1.74-5.88 for log10 copies/ml higher), and with type of treatment (indinavir-containing regimens, RH = 0.21; 95% CI, 0.06-0.78 and ritonavir-containing regimens, RH = 0.23; 95% CI, 0.04-1.26 versus hard-gell saquinavir). If the current HAART regimen caused no toxicity, less than 10% of naïve patients discontinue their first HAART regimen because of failure after 1 year from starting therapy.
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            Treatment modification in human immunodeficiency virus-infected individuals starting combination antiretroviral therapy between 2005 and 2008.

            Adverse effects of combination antiretroviral therapy (CART) commonly result in treatment modification and poor adherence. We investigated predictors of toxicity-related treatment modification during the first year of CART in 1318 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from the Swiss HIV Cohort Study who began treatment between January 1, 2005, and June 30, 2008. The total rate of treatment modification was 41.5 (95% confidence interval [CI], 37.6-45.8) per 100 person-years. Of these, switches or discontinuations because of drug toxicity occurred at a rate of 22.4 (95% CI, 19.5-25.6) per 100 person-years. The most frequent toxic effects were gastrointestinal tract intolerance (28.9%), hypersensitivity (18.3%), central nervous system adverse events (17.3%), and hepatic events (11.5%). In the multivariate analysis, combined zidovudine and lamivudine (hazard ratio [HR], 2.71 [95% CI, 1.95-3.83]; P < .001), nevirapine (1.95 [1.01-3.81]; P = .050), comedication for an opportunistic infection (2.24 [1.19-4.21]; P = .01), advanced age (1.21 [1.03-1.40] per 10-year increase; P = .02), female sex (1.68 [1.14-2.48]; P = .009), nonwhite ethnicity (1.71 [1.18-2.47]; P = .005), higher baseline CD4 cell count (1.19 [1.10-1.28] per 100/microL increase; P < .001), and HIV-RNA of more than 5.0 log(10) copies/mL (1.47 [1.10-1.97]; P = .009) were associated with higher rates of treatment modification. Almost 90% of individuals with treatment-limiting toxic effects were switched to a new regimen, and 85% achieved virologic suppression to less than 50 copies/mL at 12 months compared with 87% of those continuing CART (P = .56). Drug toxicity remains a frequent reason for treatment modification; however, it does not affect treatment success. Close monitoring and management of adverse effects and drug-drug interactions are crucial for the durability of CART.
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              Patterns and correlates of discontinuation of the initial HAART regimen in an urban outpatient cohort.

              To describe the patterns and correlates of discontinuation of the initial highly active antiretroviral therapy (HAART) regimen in an urban, outpatient cohort of antiretroviral-naive patients. Retrospective cohort of 345 randomly selected antiretroviral-naive patients who initiated HAART on 6 selected regimens between January 1997 and May 2001 in New Orleans, LA. An investigator reviewed medical records to collect information on concurrent medications, symptoms/diagnoses, staging indicators, and reasons for HAART discontinuation. Proportional hazards regression methods were used to identify predictors of discontinuation. After a median follow-up of 8.1 months, 61% of patients changed or discontinued their initial HAART regimen; 24% did so because of an adverse event. The events most commonly cited as the cause for discontinuation were nausea, vomiting, and diarrhea. A detectable viral load was associated with discontinuation at any time, while reporting nausea/vomiting or dizziness at the previous visit were associated with discontinuation during the first 3 months on HAART. Nausea/vomiting and not having AIDS at the time of HAART initiation were associated with discontinuation due to an adverse event at any time, while a high viral load, and dizziness or anorexia/weight loss at the previous visit were associated with discontinuation due to an adverse event in the first 3 months on HAART. Gastrointestinal adverse events of HAART are the most frequently cited reason for discontinuation of HAART. An effort should be made to educate patients about these events and to encourage continued adherence. Additionally, appropriate prophylaxes for these events are warranted.
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                Author and article information

                Contributors
                zerihunataro@yahoo.com
                dovehod@gmail.com
                fwmlab2000@gmail.com
                mekonnensisay27@gmail.com
                tewodrost1@gmail.com
                habtemit@gmail.com
                dmarami4@gamil.com
                zelalemtmariam@yahoo.com
                zeedshow@gmail.com
                Journal
                BMC Pharmacol Toxicol
                BMC Pharmacol Toxicol
                BMC Pharmacology & Toxicology
                BioMed Central (London )
                2050-6511
                1 November 2019
                1 November 2019
                2019
                : 20
                : 63
                Affiliations
                [1 ]ISNI 0000 0001 0108 7468, GRID grid.192267.9, Department of Medical Laboratory Sciences, College of Health and Medical Sciences, , Haramaya University, ; P.O.Box, 235 Harar, Ethiopia
                [2 ]ISNI 0000 0001 0108 7468, GRID grid.192267.9, Department of Pharmaceutical Chemistry, School of Pharmacy, College of Health and Medical Sciences, , Haramaya University, ; P.O. Box, 235 Harar, Ethiopia
                [3 ]ISNI 0000 0001 0108 7468, GRID grid.192267.9, Department of Pharmacology and Toxicology, School of Pharmacy, College of Health and Medical Sciences, , Haramaya University, ; P.O.Box, 235 Harar, Ethiopia
                [4 ]ISNI 0000 0000 9939 5719, GRID grid.1029.a, Western Sydney University, ; Sydney, Australia
                Author information
                http://orcid.org/0000-0002-6431-3511
                Article
                361
                10.1186/s40360-019-0361-3
                6824137
                31675986
                132a7b16-0575-4820-9d32-c2f598a493db
                © The Author(s). 2019

                Open AccessThis 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.

                History
                : 26 April 2019
                : 2 October 2019
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2019

                Toxicology
                Toxicology

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