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Early mortality among children and adults in antiretroviral therapy programs in Southwest Ethiopia, 2003–15

  • Hailay Abrha Gesesew ,

    Roles Conceptualization, Formal analysis, Methodology, Validation, Writing – original draft, Writing – review & editing

    hailushepi@gmail.com

    Affiliations Public Health, Flinders University, Adelaide, Australia, Epidemiology, Jimma University, Jimma, Ethiopia

  • Paul Ward,

    Roles Conceptualization, Methodology, Validation, Writing – review & editing

    Affiliation Public Health, Flinders University, Adelaide, Australia

  • Kifle Woldemichael,

    Roles Conceptualization, Methodology, Validation, Writing – review & editing

    Affiliation Epidemiology, Jimma University, Jimma, Ethiopia

  • Lillian Mwanri

    Roles Conceptualization, Methodology, Validation, Writing – review & editing

    Affiliation Public Health, Flinders University, Adelaide, Australia

Early mortality among children and adults in antiretroviral therapy programs in Southwest Ethiopia, 2003–15

  • Hailay Abrha Gesesew, 
  • Paul Ward, 
  • Kifle Woldemichael, 
  • Lillian Mwanri
PLOS
x

Abstract

Background

Several studies reported that the majority of deaths in HIV-infected people are documented in their early antiretroviral therapy (ART) follow-ups. Early mortality refers to death of people on ART for follow up period of below 24 months due to any cause. The current study assessed predictors of early HIV mortality in Southwest Ethiopia.

Methods

We have conducted a retrospective analysis of 5299 patient records dating from June 2003- March 2015. To estimate survival time and compare the time to event among the different groups of patients, we used a Kaplan Meir curve and log-rank test. To identify mortality predictors, we used a cox regression analysis. We used SPSS-20 for all analyses.

Results

A total of 326 patients died in the 12 years follow-up period contributing to 6.2% cumulative incidence and 21.7 deaths per 1000 person-year observations incidence rate. Eighty-nine percent of the total deaths were documented in the first two years follow up—an early-term ART follow up. Early HIV mortality rates among adults were 50% less in separated, divorced or widowed patients compared with never married patients, 1.6 times higher in patients with baseline CD4 count <200 cells/μL compared to baseline CD4 count ≥200 cells/μL, 1.5 times higher in patients with baseline WHO clinical stage 3 or 4 compared to baseline WHO clinical stage 1 or 2, 2.1 times higher in patients with immunologic failure compared with no immunologic failure, 60% less in patients with fair or poor compared with good adherence, 2.9 times higher in patients with bedridden functional status compared to working functional status, and 2.7 times higher with patients who had no history of HIV testing before diagnosis compared to those who had history of HIV testing. Most predictors of early mortality remained the same to the predictors of an overall HIV mortality. When discontinuation was assumed as an event, the predictors of an overall HIV mortality included age between 25–50 years, base line CD4 count, developing immunologic failure, bedridden functional status, and no history of HIV testing before diagnosis.

Conclusions

The great majority of deaths were documented in the first two years of ART, and several predictors of early HIV mortality were also for the overall mortality when discontinuation was assumed as event or censored. Considering the above population, interventions to improve HIV program in the first two years of ART follow up should be improved.

Introduction

Worldwide in 2015, 38.8 million people were living with human immunodeficiency virus (HIV), 2.5 million new HIV infections, and 1.2 million HIV/AIDS (acquired immunodeficiency syndrome) deaths were estimated, and sub-Saharan Africa (SSA) accounted for 76% of the global morbidity and 75% of the global mortality [1]. Ethiopia, one of the countries in SSA, had an estimate of 39,140 newly HIV-infected people, 768,040 people living with HIV, and 28,650 HIV/AIDS deaths in 2015 [1]. Ethiopia contributed 3% each to the global death and number of HIV-infected people in SSA respectively [2]. Antiretroviral therapy (ART) program in Ethiopia was commenced in 2003 in 12 hospitals at cost to the patients [3], and then since 2005, it was provided free of charge in 22 hospitals with the help of the international donors such as Global Fund, World Bank, and President's Emergency Plan for AIDS Relief (PEPFAR) [3, 4]. A total of 270,460 people were on ART in 913 health facilities in 2012–13 [3, 5] and the coverage rose to 339,043 adults and 22,955 children in 2014 [6].

The effectiveness of a country’s ART program depends on the HIV treatment cascade or HIV care continuum. HIV care continuum is a series of steps in which a person with HIV takes from initial diagnosis through their successful treatment with HIV medication [7, 8] that includes HIV diagnosis, assessment for ART eligibility, retention, and virological suppression. The success of The Joint United Nations Program on HIV and AIDS (UNAIDS) treatment targets—diagnosing 90% of people living with HIV, providing 90% of those diagnosed antiretroviral therapy (ART), and achieving viral suppression for 90% of patients receiving treatment—is affected by several factors [811]. Particularly, in order to meet the second and third 90s of the UNAIDS treatment targets, patient retention is a key program. However, attrition has been a routine impediment and remains monotonous in the thirty years of targeted HIV diagnosis and 20 years since ART rollout. Mortality from HIV, death of HIV-infected patients in the period of ART due to any cause, is one of the major contributors to attrition.

Recent global, regional and national estimates for mortality reported that 0.03 million deaths in high-income countries, 0.1 million deaths in middle-income countries, and 0.4 million deaths in low-income countries were recorded [1]. Similarly, several studies [1219] that assessed the magnitude and predictors of mortality in Ethiopia are growing. Accordingly, the incidence of mortality has been reported between 2 and 25.9%, and the factors affecting for mortality of Ethiopian patients included but are not limited to male, primary level of education, single marital status, weight loss, bed-ridden functional status, low baseline cluster of differentiation 4 (CD4) count, advanced World Health Organization (WHO) clinical staging, tuberculosis (Tb)/HIV co-infection, severe anemia and substance abuse. In addition, the majority of the previous studies from Ethiopia reported high mortality is recorded in < 24 months since ART starting [1315, 17, 20].

However, firstly, none of these studies assessed what predictors determined for the mortality in the early follow up periods. Secondly, none of the studies were also carried out in the southwestern part of the nation. Southwest Ethiopia has different cultural and socioeconomic characteristics, and according to the 2011 Ethiopian census, the regional state has the highest HIV prevalence (6.5%) in the nation than the other parts of the country (<2%) where the previous studies have been carried out. Therefore, the predictors that determine mortality may be different and need to be understood contextually to design interventions tailored to the individual regional states. Thirdly, all studies that assessed the predictors of mortality considered LTFU as censored, and none of them assumed the outcome of discontinued patients could be a death. Previous tracing studies from Ethiopia and Kenya reported that 40–86% of LTFU cases failed to re-engage to the care [21], and 50% of LTFU patients were found dead [22, 23]. Such failing to assume LTFU patients as deceased would lead to a biased estimate and spuriously low risk or odds ratio calculation. Fourthly, the great majority of the retrospective cohort studies from Ethiopia reported from a short-term durability of ART follow up periods or relatively low sample size.

The current study assessed the incidence and predictors of mortality in the early follow up periods using a 12-years data from the ART clinic at Jimma University Teaching Hospital (JUTH) in Southwest Ethiopia. The study also compared the predictors of early mortality with the cumulative mortality, and added another model assuming a worst-case scenario whereby all discontinued patients were assumed dead.

Methods

Study design, setting and participants

We used retrospective cohort study in ART clinic at JUTH in Southwest Ethiopia using patient records from June 2003 to March 2015. Details of the study setting has been described elsewhere [2426]. All HIV-infected children and adults enrolled for ART care in JUTH were the target population. The details of the treatment protocol for Ethiopia is described elsewhere [27].

Data source and procedures

We extracted the data from JUTH electronic medical records (EMR) system designed since 2007. Clinicians record clinical and non-clinical information of patients on paper form, and then data clerks entered into the EMR system. Two data clerks undertake the data entry process to warrant completeness. The International Center for AIDS Care and Support (ICAP) at Colombia University has been delivering technical assistance on the electronic patient level data management, and carrying out check up of data completeness. This ensures the accuracy and reliability of the EMR data. If outcome status of a patient were not recorded or transferred out, records would be excluded from the analysis. Fig 1 demonstrates the schematic presentation of data extraction HIV infected children and adult enrolled in the period 2003–2015 in Jimma University Teaching Hospital, Southwest Ethiopia.

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Fig 1. Schematic presentation of data extraction of HIV infected patients on ART in 2003–15 in Jimma University Teaching Hospital, Southwest Ethiopia—This figure shows the data extraction flowchart.

https://doi.org/10.1371/journal.pone.0198815.g001

Study variables and measurements

The response variables were the survival time in months and events related to HIV. ART patients were followed until the date of the event, discontinuation or the end of the study. We defined mortality as the death of people on ART in the reporting period due to any cause [22]. Patients who are alive and on ART until March 2015, and discontinued from ART—LTFU, defaulting and stopping medication—were considered as a censored i.e. they were assumed to be alive for the time period they had been under follow up. ART outcomes—mortality, discontinuation or alive and on ART—were the outcomes that were recorded in the final date of the data collection. ART duration was dichotomized as early and short. Short-term follow up period was defined if the ART follow-up period was below 24 months [22]. The independent variables included age, sex, marital status, educational status, religion, ART adherence, Cotrimoxazole adherence, late presentation for HIV care (LP), clinical failure, immunological failure, treatment failure, Tb/HIV co-infection, baseline functional status, history of HIV testing and ART shift. History of HIV testing refers to testing (one or more times) for HIV before HIV diagnosis. ART shift is switching of first line to second line ART regimen. Attrition refers to a condition where HIV-infected patients fail to retain in care i.e. mortality, lost to follow up from ART, defaulting from ART or stopping ART. Table 1 reports the operational definitions for variables related to attrition (mortality and discontinuation). Table 2 reports the measurements of LP, adherence, clinical, immunological and treatment failures.

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Table 1. Measurements for variable related to death and ART attrition (mortality and discontinuation).

https://doi.org/10.1371/journal.pone.0198815.t001

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Table 2. Measurements for late presentation for HIV care, ART or cotrimoxazole adherence, and immunological, clinical & treatment failures.

https://doi.org/10.1371/journal.pone.0198815.t002

Statistical analyses

We edited and cleaned up the data, to summarize the characteristics of cohort, we used descriptive statistics that included median and range values for continuous data; percentage, frequency tables, and graphs for categorical data. The calculation for cumulative incidence (CI) and incidence rate (IR) of mortality is presented in Table 1. For children, the event (death) was occurred only in 26 participants, and this small event occurrence does not allow us to conduct further inferential statistics—the cox regression analysis. For adults, we used Kaplan Meir curve to estimate survival time and compare the time to event among the different groups of patients. The log-rank test was used to check any significant differences in survival among different levels of the categorical variables measured in the study. We calculated the estimated survival time in months using the time between date of treatment initiation and date of death or censoring.

We applied bivariate cox regression analysis to see the existence of crude association and select candidate variables (with P value below 0.25) to multiple cox regression. We carried out a multiple cox regression analysis to identify independent predictors of mortality using a stepwise variable selection. We assessed the assumption for proportional hazard graphically. We checked the goodness of fit of the final model using Hosmer and Lemeshow test and was found fit. We also checked the collinearity diagnosis between selected independent variables. P-value of <5% was considered significant in the final model. Three models were constructed. Model I shows the predictors of early mortality among HIV-infected patients attending short-term (<24 months) ART follow-ups. Model II—real case assumption—shows the predictors of an overall mortality (cumulative) among HIV-infected patients attending ART assuming discontinuation as censored. Model III—worst case assumption or intention-to-treat analysis—shows the predictors of an overall mortality (cumulative) among HIV-infected patients attending ART assuming discontinuation as event(death) in addition to the real event. We used Statistical Package for the Social Sciences (SPSS) version 22.0 for all data analyses.

Ethical approval

The ethical clearance was obtained from the Social and Behavioral Research Ethics Committee (SBREC) at Flinders University (Project number: 7086) and Institutional Review Board (IRB) of College of Health Sciences at Jimma University (Ref No: RPGC/386/2016). A de-identified data was extracted from the database, and its access permission was obtained from JUTH board.

Results

The study included 8,172 ART patients enrolled from 21 June 2003 to 15 March 2015, with a median follow up times of 49 months. Of total, 5,299 (64.8%) patients were on ART of whom 4,900 (92.5%) were adults and 399 (7.5%) were children. Table 3 presents the clinical and non-clinical characteristics of HIV-infected adults and children on ART. Of the children, the majority (58.1%) were age 5-<15 years, half (52.4%) were males, and three-quarter (73.9%) were Christians. Four out of five children (79.4%) had moderate or severe immunosuppression, and half (50.5%) of the children had baseline WHO clinical stage 3 or 4. The prevalence of Tb/HIV co-infection among children was 28.6%.

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Table 3. Clinical & non-clinical characteristics of HIV infected people enrolled in ART care in Southwest Ethiopia from 2003–15.

https://doi.org/10.1371/journal.pone.0198815.t003

The median time on ART was 40 months where as the estimated survival time was 104.2 (99.8–108.5) months. Of the adults, 59.8% were females, 48.7% were married and 39% had primary school education. Three quarters (73.6%) of HIV-infected adults had baseline CD4 count below 200 cells/mm3, and 54.3% had WHO clinical stage 3 or 4. Tb/HIV co-infection was diagnosed in about a quarter of adults (27.9%). In addition, 29(0.9%) HIV-infected adults were switched to second line ART drugs.

Cumulative incidence (CI) and incidence rate (IR) of mortality in HIV-infected patients

Of the 5299 ART patients, 2763 (52.5%) patients were alive and on ART, 1154 (21.9%) patients discontinued from the treatment, and 1015 (19.3%) patients transferred to other sites by the end of march 2015(Table 4). The remaining 326 (6.2%) patients died contributing to a CI of 6.5% (26/399) in children and 6.1% (300/4900) in adults. Of the total deaths, 220 deaths (67.5%) occurred in the first six months of ART follow up, 37 (11.3%) occurred in between 6-<12 months, 32 (9.8%) occurred in between 12-<24 months and the remaining 37 (11.3%) deaths occurred ≥24 months.

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Table 4. Annual number of patients enrolled in ART care and their outcomes.

https://doi.org/10.1371/journal.pone.0198815.t004

The total follow-up period encompassed 15, 051 person-years observations, and an estimated survival time of 121.9 (95%CI: 120.3–123.5) months. The overall IR was 21.7 deaths (22.2 deaths for children and 21.6 deaths for adults) per 1000 person-years observations. The magnitude of mortality had peaked in 2006 but reduced significantly and remained low in subsequent years of follow-up (Table 4). Fig 2A–2D respectively show mortality status of study participants by baseline CD4 count, immunologic failure, history of Tb/HIV co-infection and functional status using Kaplan-Meier graphs. Accordingly, the hazard distribution of ART clients for sex, baseline CD4 count and history of Tb/HIV co-infection was statistically significant.

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Fig 2.

(a-d) Kaplan-Meier plot of hazard function stratified according to baseline CD4 count, immunologic failure, Tb/HIV co-infection and functional status among a cohort of ART clients respectively; JUTH hospital, Southwest Ethiopia; 2016—This figure presents the association between baseline CD4 count immunologic failure, Tb/HIV co-infection and functional status, and HIV mortality.

https://doi.org/10.1371/journal.pone.0198815.g002

Predictors for mortality among adult HIV patients on ART

Table 5 demonstrates the findings from three models of the cox regression analysis. Model I presents results of the bivariate and multivariable cox regression analysis of predictors for early mortality among adult HIV patients attending short-term ART follow-ups. Predictors of early mortality included being separated/divorced/ widowed, having a baseline CD4 count below 200 cells/μL, baseline WHO clinical staging, developing immunologic failure, fair or poor ART adherence, bedridden functional status and no history of HIV testing. HIV patients who were separated, divorced, or widowed were 50% less likely (AHR = 0.5, 95%CI: 0.3–0.8) to die compared to those who never married. Compared to patients with baseline CD4 count 200 cells/μL and above, the hazard of death was higher (AHR = 1.6, 95%CI: 1.05–2.5) among patients with baseline CD4 count <200 cells/μL. In addition, compared to patients with baseline WHO clinical stage 3 or 4, the hazard of death was higher (AHR = 1.5, 95%CI: 1.05–2.5) among patients with baseline WHO stage 1 or 2. Patients who developed immunologic failure were two times (AHR = 2.1, 95%CI: 1.4–3.01) at risk to die than those who did not develop immunologic failure. The hazard of death was 40% less among patients with poor or fair ART adherence compared to those with good adherence. Patients with bedridden functional status were more likely (AOR = 2.9, 95%CI: 2.02–4.07) to die than their comparator. Patients with no history of HIV testing before diagnosis had also a higher risk of mortality (AHR = 2.7, 95%CI: 1.9–3.8) than those who had history of HIV testing.

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Table 5. Factors related to HIV-associated mortality among HIV-infected adults in 2003–2015, JUTH, Southwest Ethiopia.

https://doi.org/10.1371/journal.pone.0198815.t005

Model II—real case assumption—reports results of the bivariate and multiple cox regression analysis of predictors for overall mortality (cumulative) among HIV patients attending ART assuming discontinuation and alive as censored. Predictors of mortality included being separated/widowed/divorced, having baseline CD4<200cells/μL, short ART duration, bedridden functional status and no history of HIV testing. Females had 40% lesser probability (AHR = 0.5, 95%CI: 0.3–0.8) to die than males. HIV-infected patients who were separated, divorced or widowed were less likely (AHR = 0.5, 95%CI: 0.2–0.9) to die than those who never married. Patients with baseline CD4 count <200 cells/μL had an elevated risk of death (AOR = 2.01, 95%CI: 1.5–3.5) than those with baseline CD4 count 200 cells/μL and above. HIV patients with longer ART duration has less likely (AHR = 0.08, 95%CI: 0.05–0.1) to die than those who were on short ART duration. Having bedridden functional status (AHR = 2.2, 95%CI: 1.4–3.9) and no history of HIV testing (AHR = 2.7, 95%CI: 1.9–3.8) were also another risk factors for the overall mortality.

Model III—worst case assumption or intention-to-treat approach—presents results of the bivariate and multiple cox regression analysis of predictors for overall mortality among HIV-infected patients attending ART assuming discontinuation as event. In addition to baseline CD4 count, functional status and history of HIV testing—predictors of mortality in the real case assumption—, age and immunological failure had statistically significant association when discontinuation is assumed as an event.

Discussion

In this study, the cumulative incidence mortality for HIV-infected patients on ART was found to be 6%, which is lower than was reported in studies carried out in another parts of Ethiopia such as Tigray [15], Southern Nations, Nationalities and Peoples Region (SNNPR)[19] and Amhara [34], where the CI were 9%, 10% and 41% respectively. Despite that, participants of the current study setting are diversified (i.e. from high HIV prevalence rate settings, low HIV prevalence rate settings, and refugee camps), the magnitude of death was not higher than from the other settings. This may be attributed to several reasons. First, the magnitude of death may be attributed to the level of late HIV care presentation. For example, 65% of the participants in the present study were late presenters as compared to 69% in Tigray [35]. Second, the magnitude of death may be attributed to the level of adherence to ART. For example, 20% of the participants in the present study were non-adherent as compared to 26% in the SNNPR [36].Third, the magnitude of death may be attributed to the magnitude of Tb/HIV co-infection. For example, 28% of the participants in the present study had Tb/HIV co-infection as compared to 44% in Amhara [37].

The majority of deaths happened during the first 6 months after treatment initiation, but reduced substantially in the first year of treatment, and remained low in subsequent years of follow-up as reported elsewhere [19, 22, 3840]. This has an implication with the criteria for ART initiation. The treatment protocol for Ethiopia is implemented using WHO ART treatment guideline [41] and National Guidelines for Comprehensive HIV Prevention, Care and Treatment: Federal Democratic Republic of Ethiopia, Ministry of Health [42]. These protocols consider baseline CD4 count and/or WHO clinical staging. According to these protocols, patients were used to wait until their CD4 count and/or WHO clinical staging dropped down to the criteria. Recently, since the end of 2016, the initiation of test and treat strategy in the country will have an impact on reducing early HIV mortality. This program should be strengthened throughout the nation. The HIV mortality had peaked in 2005–07, and this could possibly be: i) the free introduction of ART in 2005–6 in Ethiopia was without intensive preparation [22]; ii) high rate of late HIV diagnosis (70–74%) was recorded in the period in the current study; iii) there was poor awareness about the modern medicine, and to the contrary, traditional medicine was more well-known and accessible in Ethiopia[43]; iv) negative belief about ART treatment could be another reason [44]; and v) there was a scarcity of ART supply and the referral linkage was very poor since the system was at an early stage. Since 2008, the HIV mortality has markedly declined as reported by the previous studies [4547]. Since the scale up of ART in 2005, the overall mortality rate decreased by 40%, 85% and 100%, respectively, in 2007, 2011 and 2014. The Government of Ethiopia that has made a significant improvement in health infrastructure—health-care institutions, laboratories, and capacity building of health professionals—has contributed to the significant reduction of HIV mortality [3, 5]. The remarkable reduction of death could also be attributed to the introduction of effective combination of ART [4850],early initiation of ART due to lowering the CD4 based ART initiation criteria [51], and the expansion of ART programs to primary health care facilities [52].

Findings of the current study, as consistent as other findings, revealed that predictors of early mortality included no history of HIV testing [53], low baseline CD4 count[19, 54, 55], advanced WHO clinical stage [22, 55], immunologic failure[56] and bedridden functional status [14, 19, 22]. Such patients with low CD4 count, advanced WHO clinical stage, immunologic failure and bedridden functional status are vulnerable to advanced stage of disease and subsequently death [22]. Additionally, patients who had no history of HIV testing could be diagnosed late, and rapidly progress to advanced stage of the HIV/AIDS[53]. This particularly calls for earlier HIV diagnosis and timely initiation of ART, and generally cues consolidation of the HIV care continuum to diminish early HIV-related mortality[19]. In the present study, it is very surprising that patients with fair or good adherence has less probability of dying than those HIV patients with good adherence, and this needs further study. Despite the development of significant immunological or clinical failure, only 29 (0.9%) patients were switched to second line ART drugs, as explained in a previous study[54] that reported 6 (0.2%) patients were switched to second line ART drugs.

The study should be interpreted in light of the following strengths and limitations. The study included all age groups, very large sample and long follow up times (since the commencement of ART history), and these increase the power to detect differences in mortality by the study variables. In addition, the study participants involved in the current study area were from different socio-demographic characteristics. There are a number of HIV-infected people from Gambella, a regional state where the highest prevalence of HIV (6.5%) was recorded. On the other hand, majority of people were from Oromiya regional state, where the prevalence of HIV is similar (1.2–2%) to the other regional states of the nation. A considerable number of people were also attending the HIV clinic from a refugee camp located near Jimma.

However, the following limitations should be taken in to consideration: (1) being a single reference center may not reflect the situation of a whole country; (2) the CI of mortality might slightly be affected, as outcome status of 32 patients (2 children and 30 adults) was not recorded; (3) there might be a misclassification bias of deaths among discontinued patients; (4) the intention-to-treat analysis may underestimate survival functions since all discontinued patients were assumed dead; (5) The data for analysis used date back to 2015, and this did not include data after the ‘test and treat’ strategy has been initiated; and (6) the association of some important variables such HIV-related stigma that has significant impact in the cascade of HIV care [57] was not assessed due to retrospective nature of the study design.

Conclusions

The magnitude of mortality was considerable (21.7 deaths per 1000 person-years), and majority of deaths (89%) occurred within 24 months of ART follow-up; however, the annual rate of mortality has been decreasing significantly. Thus, to retain patients long with a favourable quality of life, a thoughtful consideration should be given to the early HIV care services targeting to the above-mentioned predictors. Predictors of early mortality were also predictors of the overall mortality even in the intention-to-treat analysis. This suggests that applying interventions focusing on these predictors will reduce not only the death of patients attending ART care but also those who had discontinued.

Acknowledgments

We acknowledge Jimma University Teaching Hospital for providing access to the data. This study was conducted for the partial fulfilment of a PhD in Public Health at Faculty of Medicine, Nursing and Health Sciences, Flinders University. We acknowledge Australian Government Research Training Program Scholarship for supporting the PhD program. The scholarship provider had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors did not receive any specific grant for this research.

References

  1. 1. Wang H, Wolock TM, Carter A, Nguyen G, Kyu HH, Gakidou E, et al. Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980–2015: the Global Burden of Disease Study 2015. Lancet HIV. 2016;3(8):e361–87. Epub 2016/07/30. pmid:27470028.
  2. 2. UNAIDS. The gap report. Geneva, Switzerland: 2014.
  3. 3. Mekonnen Yared, Rachel Sanders, Senait Tibebu, Emmart P. Equity and Access to ART in Ethiopia. USA: USAID, Initiative HP; 2010 2010. Report No.: 1.
  4. 4. Mitiku H, Abdosh T, Teklemariam Z. Factors affecting adherence to antiretroviral treatment in harari national regional state, eastern ethiopia. Isrn aids. 2013;2013:960954. Epub 2013/09/21. pmid:24052892; PubMed Central PMCID: PMCPmc3773384.
  5. 5. Assefa Y, Alebachew A, Lera M, Lynen L, Wouters E, Van Damme W. Scaling up antiretroviral treatment and improving patient retention in care: lessons from Ethiopia, 2005–2013. Globalization and Health. 2014;10:43–. PubMed PMID: PMC4046386. pmid:24886686
  6. 6. CDC. HIV/AIDS progress in 2014 (update): Ethiopia. Addis Ababa, Ethiopia: WHO, 2015.
  7. 7. Gardner EM, McLees MP, Steiner JF, del Rio C, Burman WJ. The Spectrum of Engagement in HIV Care and its Relevance to Test-and-Treat Strategies for Prevention of HIV Infection. Clinical Infectious Diseases. 2011;52(6):793–800. pmid:21367734
  8. 8. Kranzer K, Govindasamy D, Ford N, Johnston V, Lawn SD. Quantifying and addressing losses along the continuum of care for people living with HIV infection in sub-Saharan Africa: a systematic review. Journal of the International AIDS Society. 2012;15(2):17383. Epub 2012/12/04. pmid:23199799; PubMed Central PMCID: PMCPmc3503237.
  9. 9. Bennett Russell, Goodwyn Alison, Griffin Amy, Pittenger Katie, Shubert V. HIV Care Continuum: The Connection Between Housing And Improved Outcomes Along The HIV Care Continuum. USA: CDC, Development HaUDsOoCPa; 2013.
  10. 10. Campbell C, Cornish F. Towards a "fourth generation" of approaches to HIV/AIDS management: creating contexts for effective community mobilisation. AIDS care. 2010;22 Suppl 2:1569–79. Epub 2011/01/05. pmid:21161761.
  11. 11. Hull MW, Wu Z, Montaner JS. Optimizing the engagement of care cascade: a critical step to maximize the impact of HIV treatment as prevention. Curr Opin HIV AIDS. 2012;7(6):579–86. Epub 2012/10/19. pmid:23076123.
  12. 12. Biressaw S, Abegaz WE, Abebe M, Taye WA, Belay M. Adherence to Antiretroviral Therapy and associated factors among HIV infected children in Ethiopia: unannounced home-based pill count versus caregivers' report. BMC Pediatrics. 2013;13:132. http://dx.doi.org/10.1186/1471-2431-13-132. pmid:24229394.
  13. 13. Setegn T, Takele A, Gizaw T, Nigatu D, Haile D. Predictors of Mortality among Adult Antiretroviral Therapy Users in Southeastern Ethiopia: Retrospective Cohort Study. 2015;2015:148769. pmid:25821596.
  14. 14. Damtew B, Mengistie B, Alemayehu T. Survival and determinants of mortality in adult HIV/Aids patients initiating antiretroviral therapy in Somali Region, Eastern Ethiopia. Pan African Medical Journal. 2015;22. pmid:26889319
  15. 15. Tadesse K, Haile F, Hiruy N. Predictors of mortality among patients enrolled on antiretroviral therapy in Aksum hospital, Northern Ethiopia: A retrospective cohort study. PloS one. 2014;9(1). pmid:24498093
  16. 16. Mulissa Z, Jerene D, Lindtjorn B. Patients Present Earlier and Survival Has Improved, but Pre-ART Attrition Is High in a Six-Year HIV Cohort Data from Ethiopia. PloS one. 2010;5(10). PubMed PMID: WOS:000282748100015. pmid:20949010
  17. 17. Alemu AW, Sebastian MS. Determinants of survival in adult HIV patients on antiretroviral therapy in Oromiyaa, Ethiopia. Global health action. 2010;3. Epub 2010/11/03. pmid:21042435; PubMed Central PMCID: PMCPmc2967337.
  18. 18. Tadele A, Shumey A, Hiruy N. Survival and predictors of mortality among adult patients on highly active antiretroviral therapy at debre-markos referral hospital, North West Ethiopia; a retrospective cohort study. Journal of AIDS and Clinical Research. 2014;5(2).
  19. 19. Tachbele E, Ameni G. Survival and predictors of mortality among human immunodeficiency virus patients on anti-retroviral treatment at Jinka Hospital, South Omo, Ethiopia: a six years retrospective cohort study. Epidemiol Health [Internet]. 2016 2016; 38:[e2016049 p.]. Available from: http://europepmc.org/abstract/MED/27820957 http://dx.doi.org/10.4178/epih.e2016049.
  20. 20. Biadgilign S, Reda AA, Digaffe T. Predictors of mortality among HIV infected patients taking antiretroviral treatment in Ethiopia: a retrospective cohort study. AIDS Research and Therapy. 2012;9:15–. PubMed PMID: PMC3403909. pmid:22606951
  21. 21. Hickey MD, Omollo D, Salmen CR, Mattah B, Blat C, Ouma GB, et al. Movement between facilities for HIV care among a mobile population in Kenya: transfer, loss to follow-up, and reengagement. AIDS care. 2016:1–8. Epub 2016/05/05. pmid:27145451.
  22. 22. Assefa Y, Lynen L, Kloos H, Hill P, Rasschaert F, Hailemariam D, et al. Long-term Outcomes and Their Determinants in Patients on Antiretroviral Treatment in Ethiopia, 2005/6-2011/12: A Retrospective Cohort Study. Jaids-Journal of Acquired Immune Deficiency Syndromes. 2015;70(4):414–9. PubMed PMID: WOS:000364316300012.
  23. 23. Wubshet M, Berhane Y, Worku A, Kebede Y. Death and seeking alternative therapy largely accounted for lost to follow-up of patients on ART in northwest Ethiopia: a community tracking survey. PLoS ONE [Electronic Resource]. 2013;8(3):e59197. pmid:23527132.
  24. 24. Gesesew H, Tsehaineh B, Massa D, Tesfay A, Kahsay H, Mwanri L. The role of social determinants on tuberculosis/HIV co-infection mortality in southwest Ethiopia: A retrospective cohort study. BMC Research Notes. 2016;9(1). pmid:26868489
  25. 25. Gesesew H, Tsehaineh B, Massa D, Tesfay A, Kahsay H, Mwanri L. The prevalence and associated factors for delayed presentation for HIV care among tuberculosis/HIV co-infected patients in Southwest Ethiopia: a retrospective observational cohort. Infect Dis Poverty. 2016;5(1):96. Epub 2016/11/03. pmid:27802839.
  26. 26. Gesesew H, Tsehayneh B, Massa D, Gebremedhin A, Kahsay H, Mwanri L. Predictors of mortality in a cohort of tuberculosis/HIV co-infected patients in Southwest Ethiopia. Infectious Diseases of Poverty. 2016;5(1):109. pmid:27915999
  27. 27. Gesesew HA, Ward P, Woldemichael K, Mwanri L. Prevalence, trend and risk factors for antiretroviral therapy discontinuation among HIV-infected adults in Ethiopia in 2003–2015. PloS one. 2017;12(6):e0179533. pmid:28622361
  28. 28. CDC. From the Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Jama. 1993;269(6):729–30. Epub 1993/02/10. pmid:8093740.
  29. 29. Gesesew HA, Fessehaye A T, Birtukan T A. Factors Affecting Late Presentation for HIV/AIDS Care in Southwest Ethiopia: A Case Control Study. Public Health Research. 2013;3(4):98–107.
  30. 30. Abaynew Y, Deribew A, Deribe K. Factors associated with late presentation to HIV/AIDS care in South Wollo ZoneEthiopia: a case-control study. AIDS Res Ther. 2011;8:8. Epub 2011/03/02. pmid:21356115; PubMed Central PMCID: PMCPmc3058009.
  31. 31. Blake C, Margaret JO, Robert JS, Mary LL, Martha FR. 1994 Revised Classification System for Human Immunodeficiency Virus Infection in Children Less Than 13 Years of Age. MMWR. 1994;43(RR-12):1–10.
  32. 32. Tadios Y, Davey G. Retroviral drug adherence & its correlates in Addis Ababa, Ethiopia. Ethiopian medical journal. 2006;44.
  33. 33. WHO. WHO definitions of clinical, immunological and virological failure for the decision to switch ART regimens: WHO; 2013 [cited 2015 September 2]. Available from: http://www.who.int/hiv/pub/guidelines/arv2013/art/WHO_CG_table_7.15.pdf.
  34. 34. Abebe N, Alemu K, Asfaw T, Abajobir AA. Survival status of hiv positive adults on antiretroviral treatment in Debre Markos Referral Hospital, Northwest Ethiopia: Retrospective cohort study. Pan African Medical Journal. 2014;17. pmid:25452834
  35. 35. Assen A, Molla F, Wondimu A, Abrha S, Melkam W, Tadesse E, et al. Late presentation for diagnosis of HIV infection among HIV positive patients in South Tigray Zone, Ethiopia. BMC public health. 2016;16:558. Epub 2016/07/14. pmid:27405542; PubMed Central PMCID: PMCPmc4942918.
  36. 36. Endrias M, Alemayehu W, Gail D. Adherence to ART in PLWHA and Yirgalem Hospital, South Ethiopia. Ethiopian Journal of Health Development. 2008;22(2):174–9.
  37. 37. Ahmed E, Girma T, Moges W, Mengistu E. Tuberculosis and Human Immune Deficiency Virus Co-infection in Debre Markos Referral Hospital in Northwest Ethiopia: A Five Years Retrospective Study. Journal of AIDS & Clinical Research. 2013;4(263).
  38. 38. Bachani D, Garg R, Rewari BB, Hegg L, Rajasekaran S, Deshpande A, et al. Two-year treatment outcomes of patients enrolled in India's national first-line antiretroviral therapy programme. The National medical journal of India. 2010;23(1):7–12. Epub 2010/09/16. pmid:20839585.
  39. 39. Morineau G, Vun MC, Barennes H, Wolf RC, Song N, Prybylski D, et al. Survival and quality of life among HIV-positive people on antiretroviral therapy in Cambodia. AIDS patient care and STDs. 2009;23(8):669–77. Epub 2009/07/14. pmid:19591600.
  40. 40. Auld AF, Mbofana F, Shiraishi RW, Sanchez M, Alfredo C, Nelson LJ, et al. Four-year treatment outcomes of adult patients enrolled in Mozambique's rapidly expanding antiretroviral therapy program. PloS one. 2011;6(4):e18453. Epub 2011/04/13. pmid:21483703; PubMed Central PMCID: PMCPmc3070740.
  41. 41. WHO. Antiretroviral therapy for HIV infection in adults and adolescents. Geneva: WHO, 2010.
  42. 42. MoH. National Guidelines for Comprehensive HIV Prevention, Care and Treatment: Federal Democrtic Republic of Ethiopia, MoH. Addis Ababa: Minstry of Health, 2014.
  43. 43. Kebede DK, Alemayehu A, Binyam G, Yunis M. A historical overview of traditional medicine practices and policy in Ethiopia. EthiopJHealth Dev. 2006;20(2):127–34.
  44. 44. Amberbir A, Woldemichael K, Getachew S, Girma B, Deribe K. Predictors of adherence to antiretroviral therapy among HIV-infected persons: a prospective study in Southwest Ethiopia. BMC public health. 2008;8:265. Epub 2008/08/01. pmid:18667066; PubMed Central PMCID: PMCPmc2518153.
  45. 45. Pillay-van Wyk V, Msemburi W, Laubscher R, Dorrington RE, Groenewald P, Glass T, et al. Mortality trends and differentials in South Africa from 1997 to 2012: second National Burden of Disease Study. The Lancet Global Health. 2016;4(9):e642–e53. pmid:27539806
  46. 46. Larson E, O'Bra H, Brown JW, Mbengashe T, Klausner JD. Supporting the massive scale-up of antiretroviral therapy: the evolution of PEPFAR-supported treatment facilities in South Africa, 2005–2009. BMC public health. 2012;12:173. Epub 2012/03/13. pmid:22404862; PubMed Central PMCID: PMCPmc3323417.
  47. 47. Reniers G, Araya T, Davey G, Nagelkerke N, Berhane Y, Coutinho R, et al. Steep declines in population-level AIDS mortality following the introduction of antiretroviral therapy in Addis Ababa, Ethiopia. AIDS (London, England). 2010;23(4):511–8. pmid:19169138.
  48. 48. Montaner JSG, Lima VD, Harrigan PR, Lourenço L, Yip B, Nosyk B, et al. Expansion of HAART Coverage Is Associated with Sustained Decreases in HIV/AIDS Morbidity, Mortality and HIV Transmission: The “HIV Treatment as Prevention” Experience in a Canadian Setting. PloS one. 2014;9(2):e87872. PubMed PMID: PMC3922718. pmid:24533061
  49. 49. Yang CH, Huang YF, Hsiao CF, Yeh YL, Liou HR, Hung CC, et al. Trends of mortality and causes of death among HIV-infected patients in Taiwan, 1984–2005. HIV medicine. 2008;9(7):535–43. Epub 2008/06/17. pmid:18554309.
  50. 50. Granich R, Crowley S, Vitoria M, Smyth C, Kahn JG, Bennett R, et al. Highly active antiretroviral treatment as prevention of HIV transmission: review of scientific evidence and update. Curr Opin HIV AIDS. 2010;5(4):298–304. Epub 2010/06/15. pmid:20543604; PubMed Central PMCID: PMCPmc3501989.
  51. 51. WHO, CDC. HIV/AIDS progress in Ethiopia in 2014. Addis Ababa, Ethiopia: WHO Country Office for ETHIOPIA, 2014.
  52. 52. Reniers G, Blom S, Calvert C, Martin-Onraet A, Herbst AJ, Eaton JW, et al. Trends in the burden of HIV mortality after roll-out of antiretroviral therapy in KwaZulu-Natal, South Africa: an observational community cohort study. Lancet HIV. 2017;4(3):e113–e21. Epub 2016/12/14. pmid:27956187.
  53. 53. UNAIDS. World AIDS Day Report. 2012.
  54. 54. Mutasa-Apollo T, Shiraishi RW, Takarinda KC, Dzangare J, Mugurungi O, Murungu J, et al. Patient retention, clinical outcomes and attrition-associated factors of HIV-infected patients enrolled in Zimbabwe's National Antiretroviral Therapy Programme, 2007–2010. PloS one. 2014;9(1):e86305. Epub 2014/02/04. pmid:24489714; PubMed Central PMCID: PMCPmc3906052.
  55. 55. Tran DA, Ngo AD, Shakeshaft A, Wilson DP, Doran C, Zhang L. Trends in and Determinants of Loss to Follow Up and Early Mortality in a Rapid Expansion of the Antiretroviral Treatment Program in Vietnam: Findings from 13 Outpatient Clinics. PloS one. 2013;8(9):e73181. pmid:24066035
  56. 56. Ravimohan S, Tamuhla N, Steenhoff AP, Letlhogile R, Makutu DK, Nfanyana K, et al. Early immunologic failure is associated with early mortality among advanced HIV-infected adults initiating antiretroviral therapy with active tuberculosis. J Infect Dis. 2013;208(11):1784–93. Epub 2013/08/03. pmid:23908475; PubMed Central PMCID: PMCPMC3814836.
  57. 57. Gesesew HA, Tesfay Gebremedhin A, Demissie TD, Kerie MW, Sudhakar M, Mwanri L. Significant association between perceived HIV related stigma and late presentation for HIV/AIDS care in low and middle-income countries: A systematic review and meta-analysis. PloS one. 2017;12(3):e0173928. pmid:28358828