Determinants of first-line antiretroviral treatment failure among adult patients on treatment in Mettu Karl Specialized Hospital, South West Ethiopia; a case control study.

BACKGROUND: Antiretroviral therapy has dramatically reduced Human Immunodeficiency Virus related morbidity and mortality. It has also transformed HIV infection into a manageable chronic condition. However, first-line antiretroviral treatment failure continues to grow especially in resource limited settings. Despite this, determinants of first-line antiretroviral treatment failure are not well studied in Ethiopia.
OBJECTIVE: To identify determinants of first-line antiretroviral treatment failure among adult patients on antiretroviral therapy in Mettu Karl Specialized Hospital, South West Ethiopia, in 2020.
METHODS: A hospital based case-control study was conducted from October to November 2020. Simple random sampling technique was used to select participants. Interviewer administered questionnaire and record review were used for data collection. Data were entered into epi data version 3.1 and exported to SPSS version 20 for analysis. Bivariable and multivariable logistic regression analysis were used. At the end, variables with P-value < 0.05 at 95% confidence intervals for adjusted odds ratio were considered statistically significant determinants of first line treatment failure. RESULT: A total of 113 cases and 339 controls were included in the study with response rate of 98.6%. Sixty-four (56.6%) of cases and 183 (54.0%) of controls were females. Baseline WHO clinical stage III and IV (AOR = 1.909, 95% CI: (1.103, 3.305), baseline body mass index<18.5kg/m2(AOR = 2.208,95% CI:(1.257,3.877),baseline CD4 cell count <100cells/mm3 (AOR = 3.016, 95% CI: (1.734, 5.246), having history of TB co-infection (AOR = 1.855, 95% CI: (1.027, 3.353), having history of lost to follow up (AOR = 3.235, 95% CI: (1.096, 9.551), poor adherence to medication (AOR = 7.597, 95% CI: (4.059, 14.219) and initiation of treatment after two years of diagnosis with HIV (AOR = 4.979, 95% CI: (2.039, 12.158) were determinants of first-line antiretroviral treatment failure.
CONCLUSION: In this study several variables were found to be determinants of first-line antiretroviral treatment failure. Concerned bodies should give more attention to early diagnosis of HIV, early enrollment in chronic HIV care and early initiation of ART before patients develop advanced WHO clinical stages. In addition, focus has to be given for patients with low CD4 count. Regular screening for TB, counseling on optimal adherence to medication and enhancing nutritional status of patients with low body mass index are also crucial to prevent first-line antiretroviral treatment failure.

Introduction

Human Immunodeficiency Virus (HIV) and its clinical outcome, Acquired Immune Deficiency Syndrome(AIDS), has become one of the world’s major public health problems and development challenges [1]. According to the Joint United Nations Program on HIV/AIDS (UNAIDS) report, an estimated 37.7 million people were living with HIV/AIDS in 2020. In the same year, 1.5 million people became newly infected with HIV and over 680,000 people died of the disease. From the total people living with HIV, 27.5 million were accessing Anti-Retroviral Therapy (ART). From the total of over 79.3 million infections since the start of the pandemic, 36.3 million people have died so far [2].

ART has dramatically reduced HIV related morbidity and mortality and has transformed HIV infection into a manageable chronic condition. The treatment is also highly effective at reducing sexual transmission of HIV in patients who have adequately suppressed viral loads [3]. The ART treatment goals are suppression of HIV replication, restoration and preservation of immune function, reduction in HIV related morbidity and mortality that improves the quality of life of People Living With HIV/AIDS (PLWHA) [4]. On the other hand, when first-line antiretroviral treatment failure develops, all benefits of ART are affected [5].

Virological suppression, clinical recovery and immunological improvement are expected from PLWHA after initiation of ART [3]. First-line ART failure occurs when a combination of the antiretroviral regimen fails to control HIV infection. This could be virologic, immunologic and/or clinical failure [6]. Virologic failure occurs when plasma viral load remains above 1000 copies/ml based on two consecutive viral load measurements in three-month interval, with adherence support following the first-viral load test. Immunological failure occurs when CD4 count is at or below 250 cells/mm3 following clinical failure or persistent CD4 levels below 100cells/mm3. Clinical failure occurs when new or recurrent clinical event indicating severe immunodeficiency (World Health Organization(WHO) clinical stage IV condition) occurs after six months of effective treatment [4].

Frequent assessment of treatment response is important while the patient is on ART. Monitoring the response to ART and diagnosis of treatment failure for patients on antiretroviral therapy is important to achieve treatment goals. First-line antiretroviral treatment failure can be assessed virologically, immunologically and or clinically. The WHO recommends viral load monitoring as a backbone for detection of treatment failure [5].

The WHO recommended viral load testing as a preferred monitoring approach to diagnose and confirm antiretroviral treatment failure in 2013. However, in low- and middle-income countries, where the majority of individuals living with HIV live, viral load testing is scarce (7). When compared to clinical and immunological surveillance, viral load testing provides an earlier and more accurate indication of therapy failure (4).

Globally, about 10–20% of adult patients on first-line antiretroviral treatment are reported to have developed treatment failure with higher figures (15–25%) being reported in Sub-Saharan Africa [7]. In Sub-Saharan Africa, many patients who experience treatment failure do not switch to potent second-line regimens due to resource limitation, yet those who remain on failing first-line regimen experience disproportionately higher morbidity and mortality compared to those who switch [8]. In Ethiopia, prevalence of first-line antiretroviral treatment failure was 15.3% by using the three WHO treatment failure criteria (virological, immunological and clinical) [9].

Despite the scaling up of antiretroviral treatment in resource limited settings, development of first-line antiretroviral treatment failure remained a big challenge [10]. Treatment failure among population taking ART in Ethiopia is a public health concern because patients experiencing treatment failure will have an increased risk of morbidity, mortality and increased transmission as well as accumulation of drug resistant mutations [11].

According to a study conducted in the United States(US) in 2014, the cost of treating a patient with a second-line ART drug increases by 24% as compared to the first-line treatment [12]. Currently, in Ethiopia where medication is fully funded by the government, treatment failure and frequent substitution of medications are becoming major challenges in control of the disease [13].

Different studies identified that age <35 years, being male, higher educational level, urban residence, unemployment, advanced clinical stage III/IV, having history of TB co-infection, baseline CD4< 100cell/mm3, baseline BMI <18.5 kg/mm2, poor adherence, lost to follow up, baseline ART regimen, high frequency of alcohol use and smoking as determinant factors of first-line antiretroviral treatment failure [14-18].

Investigating and managing determinant factors of first-line antiretroviral treatment failure is very important to achieve treatment targets, decrease morbidity and mortality, decrease HIV transmission and sustain the quality of life of PLWHA.

The need of undertaking the study is that there is limited evidence on determinants of first-line antiretroviral treatment failure in Ethiopia and no known research has been done in the study area to identify determinant factors of first-line ART failure among adult patients on treatment. Even though viral load test is the gold standard technique for early detection of first-line antiretroviral treatment failure, most of the previous studies in Ethiopia, did not consider virological failure because of the absence of the test service in primary care settings. Many studies considered only immunological and clinical failure as criteria of first-line antiretroviral treatment failure. But in this study virological failure, which is one of the decision criteria of first-line antiretroviral treatment failure was considered in addition to immunological and clinical failure. Therefore, this study aimed to identify determinants of first-line antiretroviral treatment failure among adult patients on antiretroviral therapy in Mettu Karl Specialized Hospital, South West Ethiopia.

Materials and methods

Study design, area and period

A hospital based unmatched case-control study was conducted. The study was conducted at Mettu Karl Specialized Hospital which is the only specialized hospital in the area serving a population of more than 1.4 million with different services including HIV prevention, care and treatment. The hospital is located in Mettu town, on a distance of 600 Kilometers from Ethiopian capital Addis Ababa. It provides specialized health care for peoples in three neighboring regions of Ethiopia; Oromia, Gambella and South Nations Nationalities and Peoples Regions. The Gambella Region is one of Ethiopia’s nine regions with the highest HIV prevalence and incidence. In this hospital, ART service started in 2005. Currently total of 1600 people are receiving ART at the facility. The hospital has laboratory services to determine CD4 count and viral load to monitor ART patients. The study was conducted from October 25 to November 24/2020.

Source and study populations

Source populations

The source populations for cases in the study were all adult PLWHA documented to have first-line antiretroviral treatment failure and enrolled to the second-line antiretroviral treatment at the hospital. The source populations for controls were all adult PLWHA who did not develop first-line antiretroviral treatment failure and on first-line antiretroviral treatment the hospital.

Study populations

Study populations for cases in the study were adult HIV Patients on ART, aged ≥ 18 years, documented to have first-line antiretroviral treatment failure and eligible for the study during study period. Study population for controls were adult HIV patients on ART, aged ≥18 years, who did not fail first-line antiretroviral treatment and who were on first-line ART for six or more months.

Sample size determination and sampling technique

Sample size was calculated using Epi Info version 7 for unmatched case control study design by considering the significant determinant factor of first-line antiretroviral treatment failure such as baseline BMI< 18.5kg/m2, having history of lost to follow up, baseline CD4 cell<50 cell/mm3, poor adherence, smoking, history of TB co-infection(Table 1).

Table 1

Sample size calculation for the study on determinants of first-line antiretroviral treatment failure among adult patients on antiretroviral therapy in Mettu Karl Specialized Hospital, South West Ethiopia, 2020.

Variables	The ratio of cases to controls	% of Controls exposed	AOR	% of Cases exposed	Sample size
Baseline BMI< 18.5 kg/m2 [19]	1:3	44.5	2.75	68.8	194(49, 145)
Having history of lost to follow up [20]	1:3	6.01	3.66	19.0	282(71, 211)
Baseline CD4 < 50 cells/ mm3 [21]	1:3	10.1	3.96	30.5	167(42, 125)
Poor adherence [17]	1:3	6.08	2.986	16.2	416(104, 312)
Smoking [22]	1:3	18	5.9	56.4	72 (18, 54)
History of TB co-infection [22]	1:3	26.7	3.9	58.7	110(28, 82)

From the above table, poor adherence was found to result in the largest sample size; it was used to determine sample size as independent variable. By using 95% Confidence Interval(CI), 80% power, a case to control ratio of 1:3 and using a two population proportion formula, the calculated sample size was 416 (104 cases and 312 controls). Then by adding 10% for non-response, the final sample size was 458 (115 cases and 343 controls).

Simple random sampling technique was used to recruit study participants for cases and controls. Adult patients who developed first-line antiretroviral treatment failure and those who did not develop first-line antiretroviral treatment failure were identified and their Medical Record Numbers (MRN) was listed as cases and controls. Accordingly, register of 1353 patients who did not develop first-line antiretroviral treatment failure and on first-line was developed. Then to select study subjects for controls simple random sampling technique was used by computer generated random numbers based on MRN of patients.

For cases, register of 194 adult patients who developed first-line antiretroviral treatment failure and enrolled to the second-line antiretroviral therapy at the hospital was prepared. Cases were then selected by simple random sampling technique using computer generated random numbers based on MRN of patients.

Data collection tools and procedures

Data was collected from patients and medical records using structured interviewer administered questionnaire and structured checklists respectively. The questionnaire was developed from WHO ART guideline, ART follow up guideline of Federal Ministry of Health of Ethiopia and Ethiopian Demographic and Health Survey(EDHS) 2016 [4,5,23]. In addition, other tools were adopted from previously conducted studies [19,21,24,25]. The questionnaire comprised four parts; socio-demographic factors, clinical factors, antiretroviral treatment related factors and behavioral factors. Questions related with behavioral factors and socio-demographic factors were included in structured interviewer administered questionnaires and collected from patients. Questions related to clinical and antiretroviral treatment related factors were included in the checklist and collected from record review. In the hospital, CD4 T- cell count measurement was done by using the Pima™ CD4 Analyzer (Abbott Molecular Inc., Chicago, Illinois, United States, formerly and Alere). The Viral load measurement was conducted by using the Roche (COBAS® AmpliPrep/COBAS® TaqMan® HIV-1 Test, Roche Diagnostics, Indianapolis, Indiana, United States). All laboratory procedures were conducted according to the Ethiopian national protocol for laboratory tests for ART patients [26].

Operational definitions

Adults: In this study, participants aged 18–64 years are considered as adults [23].

Poor adherence: Less than 85% adherence, which is defined as missing greater than or equal to five doses out of 30 doses or greater than 10 doses from 60 doses.

Fair adherence: 85%-94% adherence, which is defined as missing two to four doses out of 30 doses or four to nine doses from 60 doses.

Good adherence: Greater than or equal to 95% adherence i.e. missing less than or equal to one out of 30 doses or missing less than or equal to two from the 60 prescribed doses [5,27].

Data analysis procedures

The collected data was coded and entered into epi data version 3.1 and exported to statistical package for social sciences (SPSS) version 20 for analysis. Checking and cleaning of data was done before analysis. Frequencies and proportions were used to describe the data. Cross tabulation was used to summarize descriptive statistics in each group. Bivariable and multivariable logistic regression were used to identify determinants of first-line antiretroviral treatment failure. Variables with P-value <0.25 at bivariable analysis were taken to multivariable logistic regression analysis. The multivariable model was fitted to identify the independent determinants of first-line antiretroviral treatment failure using backward stepwise removal method. The model fitness was checked by Hosmer and Lemeshow goodness of fit test by considering p-value >0.05. Finally, variables that have significant association with first-line antiretroviral treatment failure were identified and reported based on the adjusted odds ratio (AOR) with corresponding 95% CI at P-value <0.05.

Ethics statement

This research is undertaken in full compliance to the ethics requirements of the Declaration of Helsinki. The proposal of the research work was reviewed and approved by Ethics Review Committee of College of Health Sciences, Mettu University (Ref. No RCS/050/2020). Written informed consent was taken from individual participants after detailed explanation of the research procedures. Confidentiality of the research participant’s information was kept and no identifying information was included in the data collection tool.

Result

Socio-demographic characteristics of participants

A total of 452(113 cases and 339 controls) HIV patients on ART were involved in the study with response rate of 98.6%. Sixty-four (56.6%) of cases and 183 (54.0%) of controls were females. Regarding marital status, 42 (37.2%) of cases and 193 (56.9%) of controls were married; while 30 (26.5%) of cases and 33 (9.7%) of controls were single. Forty-one (36.3%) of cases and 92 (27.1%) of controls were living in rural areas (Table 2).

Table 2

Socio-demographic characteristics of HIV patients on ART at Mettu Karl Referral Hospital, South West Ethiopia, 2020.

Variable	Category	Cases (%) (n = 113)	Control (%) (n = 339)	Total (%)
Age at initiation of ART	< 35 years	49 (43.4%)	119 (35.1%)	168 (37.2%)
	> = 35 years	64(56.6%)	220 (64.9%)	284 (62.8%)
Sex	Male	49 (43.4%)	156 (46.0%)	205 (45.4%)
	Female	64 (56.6%)	183 (54.0%)	247 (54.6%)
Marital status	Married	42 (37.2%)	193 (56.9%)	235 (52%)
	Single	30 (26.5%)	33 (9.7%)	63 (13.9%)
	Divorced	25 (22.1%)	63 (18.6%)	88 (19.5%)
	Widowed	16 (14.2%)	50 (14.7%)	66 (14.6%)
Place of residence	Urban	72 (63.7%)	247 (72.9%)	319 (70.6%)
	Rural	41 (36.3%)	92 (27.1%)	133 (29.4%)
Occupational status	Government employee	13 (11.5%)	37 (10.9)	50 (11.1%)
	Farmer	20 (17.7%)	45 (13.3%)	65 (14.4%)
	Daily laborer	21 (18.6%)	57 (16.8%)	78 (17.3%)
	Merchant	21 (18.6%)	79 (23.3%)	100 (22.1%)
	House wife	22 (19.5%)	95 (28%)	117 (25.9%)
	Others*	16 (14.2%)	26 (7.7%)	26 (5.8%)
Educational status	No formal education	21 (18.6%)	60 (17.7%)	81 (17.9%)
	Primary school (1–8)	41 (36.3%)	169 (49.9%)	210 (46.5%)
	Secondary school (9–12)	33 (29.2%)	67 (19.8%)	100 (22.1%)
	College and above	18 (15.9%)	43 (12.7%)	61 (13.5%)
Criteria used to diagnose treatment failure	Virological	24 (21.2%)
	Clinical/immunological	39 (34.5%)
	Clinical/virological	8 (7.1%)
	Immunological/virological	7 (6.2%)
	All criteria	35 (31.0%)

*Students, driver, self and private business, Non-Governmental Organization workers.

Bivariable logistic regression analysis of first-line antiretroviral treatment failure

Bivariable logistic regression analysis was carried out to assess the association of variables with first-line treatment failure. Among these variables, smoking, khat chewing, baseline WHO clinical stage, baseline BMI, baseline CD4 count, history of TB co-infection, history of lost to follow up, adherence status to antiretroviral drugs, disclosure status, time lag to initiate ART after diagnosis with HIV were candidates for multivariable logistic regression analysis at P-value <0.25 in bivariable logistic regression model (Table 3).

Table 3

Bivariate logistic regression analysis of first-line antiretroviral treatment failure of HIV patients on ART at Mettu Karl Specialized Hospital, South West Ethiopia, 2020.

Variable	Category	Case (N = 113)	Control (N = 339)	COR (95% CI)	P-value
Smoking status	Yes	28 (24.8%)	57 (16.8%)	1.630 (0.975, 2.723)	.062
	No	85 (75.2%)	282 (83.2%)	1
Khat chewing	Yes	30 (26.5%)	67 (19.8%)	1.462 (0.890, 2.400)	.133
	No	83 (73.5%)	271 (80.2%)	1
Baseline WHO stage	Stage I and II	53 (46.9%)	234 (69.0%)	1
	Stage III and IV	60 (53.1%)	105 (31.0%)	2.523 (1.632, 3.899)	< .01
Baseline BMI	<18.5kg/m2	63 (55.8%)	89 (26.3%)	3.539 (2.272, 5.513)	< .01
	> = 18.5kg/m2	250 (73.7%)	50 (44.2%)	1
Baseline CD4 cell count	<100cells/mm3	59(52.2%)	69 (20.4%)	4.275 (2.715, 6.732)	< .01
	> = 100cells/mm3	54 (47.8%)	270 (79.6%)	1
TB co-infection	Yes	46 (40.7%)	65 (19.2%)	2.894 (1.822, 4.596)	< .01
	No	67 (59.3%)	274 (80.8%)	1
History of lost to follow up	Yes	15 (13.3%)	8 (2.4%)	6.333 (2.608, 15.378)	< .01
	No	98 (86.7%)	331 (97.6%)	1
Adherence status	Good	37 (32.7%)	240 (70.8%)	1
	Fair	18 (15.9%)	65 (19.2%)	1.796 (0.960, 3.360)	.067
	Poor	58 (51.3%)	34 (10.0%)	11.065 (6.404, 19.118)	< .01
Disclosure status	Yes	105(92.9%)	334 (98.5%)	1
	No	8 (7.1%)	5 (1.5%)	5.090 (1.630, 15.893)	.005
Time lag to initiate ART after diagnosis with HIV	Within the same month	30 (26.5%)	158 (46.6%)	1
	One to twenty four months	65 (57.5%)	157 (46.3%)	2.180 (1.342, 3.544)	.002
	After twenty four months	18 (15.9%)	24 (7.1%)	3.950 (1.913, 8.157)	< .01

COR: Crude odds ratio; CI: Confidence interval; 1: Reference category.

Determinants of first-line antiretroviral treatment failure

In multivariable logistic regression analysis, baseline WHO clinical stage III and IV, baseline body mass index < 18.5kg/m2, baseline CD4 count <100 cells/mm3, having history of TB co-infection, having history of lost to follow up, poor adherence to antiretroviral drugs, initiation of ART after two years of diagnosis with HIV were significantly associated with first-line antiretroviral treatment failure.

The finding of this study showed that, HIV positive patients on ART with stages III and IV baseline WHO clinical stage were almost two times more likely to fail first-line antiretroviral treatment when compared with stage I and II baseline WHO clinical stage [AOR = 1.909, 95% CI: 1.103, 3.305].

Patients on ART with baseline Body Mass Index of <18.5kg/m2 were two times more likely to develop first-line antiretroviral treatment failure than patients with baseline BMI of > = 18.5kg/m2 [AOR = 2.208, 95% CI: 1.257, 3.877].

Patients on ART withCD4 count of <100cells/mm3 at the time of initiation of ART had three times more likelihood to fail first-line antiretroviral treatment when compared with those who had CD4 count of > = 100cells/mm3 at the time of initiation of ART [AOR = 3.016, 95% CI: 1.734, 5.246].

Patients with history of TB co-infection were almost twice more likely to develop first-line treatment failure than those patients without TB co-infection [AOR = 1.855, 95% CI: 1.027, 3.353].

Patients with history of lost to follow up had three times more likely to fail first-line antiretroviral treatment when compared with patients did not have lost to follow up history [AOR = 3.235, 95% CI: 1.096, 9.551].

HIV positive patients on ART with poor adherence to antiretroviral drugs were more than seven times more likely to fail first-line antiretroviral treatment when compared to patients with good adherence to antiretroviral drugs [AOR = 7.597, 95% CI: 4.059, 14.219].

Patients who initiated ART after two years of being HIV positive had around five times more probability to fail first-line antiretroviral treatment when compared to patients initiated ART within the same month of being HIV positive [AOR = 4.979, 95% CI: 2.039, 12.158] (Table 4).

Table 4

Multivariable logistic regression analysis on determinants of first-line antiretroviral treatment failure among HIV Patients on ART at Mettu Karl Specialized Hospital, South West Ethiopia, 2020.

Variable	Category	Case (N = 113)	Control (N = 339)	COR (95% CI)	AOR (95% CI)
Baseline WHO clinical stage	Stage I and II	53 (46.9%)	234 (69.0%)	1	1
	Stage III and IV	60 (53.1%)	105 (31.0%)	2.523 (1.632, 3.899)	1.909 (1.103, 3.305) *
Baseline BMI	<18.5kg/m2	63 (55.8%)	89 (26.3%)	3.539 (2.272, 5.513)	2.208 (1.257, 3.877) *
	> = 18.5kg/m2	250 (73.7%)	50 (44.2%)	1	1
Baseline CD4	<100 Cells/mm3	59(52.2%)	69 (20.4%)	4.275 (2.715, 6.732)	3.016 (1.734, 5.246) *
	> = 100Cells/mm3	54 (47.8%)	270 (79.6%)	1	1
TB co-infection	Yes	46 (40.7%)	65 (19.2%)	2.894 (1.822, 4.596)	1.855 (1.027, 3.353) *
	No	67 (59.3%)	274 (80.8%)	1	1
History of lost to follow up	Yes	15 (13.3%)	8 (2.4%)	6.333(2.608, 15.378)	3.235(1.096, 9.551) *
	No	98 (86.7%)	331 (97.6%)	1	1
Adherence status	Good	37 (32.7%)	240 (70.8%)	1	1
	Fair	18 (15.9%)	65 (19.2%)	1.796 (0.960, 3.360)	1.322 (0.643, 2.716)
	Poor	58 (51.3%)	34 (10.0%)	11.065(6.404, 19.118)	7.597 (4.059, 14.219) *
Disclosure status	Yes	105 (92.9%)	334 (98.5%)	1	1
	No	8 (7.1%)	5 (1.5%)	5.090 (1.630, 15.893)	1.663 (0.460, 6.013)
Time lag to initiate ART after diagnosis	Within the same month	30 (26.5%)	158 (46.6%)	1	1
	One to twenty four months	65 (57.5%)	157 (46.3%)	2.180 (1.342, 3.544)	1.702 (0.928, 3.121)
	After twenty four months	18 (15.9%)	24 (7.1%)	3.950 (1.913, 8.157)	4.979 (2.039, 12.158) *

*Statistically significant at p-value<0.05;

COR: Crude odds ratio; AOR: Adjusted odds ratio; CI: Confidence interval; 1: Reference category.

Discussion

The identification and management of first-line ART failure is a key challenge for HIV programs in resource limited settings. Staying on a failing first-line antiretroviral therapy is associated with an increased risk of mortality. In addition to this, development of drug resistance limits the ability to construct new, potent and tolerable regimens in the future. This study was aimed to identify determinants of first-line antiretroviral treatment failure.

In this study first-line antiretroviral treatment failure was found to be significantly associated with stage III and IV baseline WHO clinical stage of HIV, low baseline Body Mass Index (<18.5 kg/m2), baseline CD4 count <100cells/mm3, having history of TB co-infection, having history of lost to follow up, poor adherence to antiretroviral drugs and initiation of ART after two years of diagnosis with HIV positive.

The current study has identified that patients with advanced WHO clinical stage III and IV at the time of initiation of ART were almost two times more likely to fail first-line antiretroviral treatment when compared with stage I and II baseline WHO clinical stage. This finding has similarity with the studies conducted in Sanglah Hospital, Bali Indonesia [15], Senegal [28], and in Harar public hospitals, Eastern Ethiopia [24]. This might be due the fact that advanced WHO clinical stage of HIV disease is associated with high viral load and low CD4 cell count that compromise immunity and may negatively affect response to first-line antiretroviral treatment [29].

In this study, patients with low baseline Body Mass Index (BMI) of <18.5kg/m2 were two times more likely to develop first-line antiretroviral treatment failure than patients with baseline BMI of > = 18.5kg/m2. This finding is consistent with report from studies conducted in Woldia Hospital, North East Ethiopia, by 2017 [19], University of Gonder Specialized Hospital, Ethiopia, in 2019 [30]. This might be due to the fact that patients with low BMI have low nutritional status that leads to weakened immunity, blunted immune response and increased likelihood of first-line antiretroviral treatment failure [31].

The finding of this study indicated that patients with low baseline CD4 count of <100cells/mm3 were three times more likely to fail first-line antiretroviral treatment than patients with baseline CD4 count of > = 100cells/mm3. This finding is comparable with studies done in India by 2016 [32], in Northwestern Tanzania by 2019 [10], in Dire Dawa, Eastern Ethiopia by 2019 [33]. This finding might be due the reason that patient with low baseline CD4 cell count have a lesser immunity that may favor the occurrence of opportunistic infection and lead to clinical failure. In addition, low CD4 cell count is difficult to be replaced enough in HIV patients on ART and may lead to first-line antiretroviral treatment failure [29,34]

Having history of TB co-infection is found to be an independent determinant of first-line antiretroviral treatment failure. Patients who had history of HIV-TB co-infection were around two times more likely to fail first-line antiretroviral treatment when compared to patients who had no history of TB co-infection. Similarly studies conducted in India in 2016 [32], Gutu District, Zimbabwe by 2017 [14], Debre Markos Referral Hospital, North West Ethiopia in 2018 [35], showed that HIV-TB co-infection was independent determinant factors of treatment failure among adult patients on ART. The occurrence of tuberculosis during antiretroviral treatment has multiple effects including pills burden and drug-drug interaction which may lead to first-line treatment failure [36].

Having history of lost to follow up was associated with first-line treatment failure. Patients with history of lost to follow up were three times more likely to develop first-line treatment failure than patients without history of lost to follow up. This finding is similar with studies conducted in Harare Central Hospital, Zimbabwe by 2014 [7], in Nigerian Teaching Hospital, Nigeria by 2019 [37], in Central Ethiopia St. Luke Referral Hospital and Tulu bolo General Hospital by 2019 [20]. This might be due to the result of on-going viral replication in the absence of ART, which results in decrease of CD4 cell count and increase viral load that leads to first-line antiretroviral treatment failure [38].

Patients with poor adherence to antiretroviral drugs have more than seven times higher probability of developing first-line treatment failure than patients with good adherence to antiretroviral drugs. The finding is consistent with studies conducted in Nigerian Teaching Hospitals by 2019 [37], in Cameroon by 2016 [39], University of Gondar Teaching Hospital by 2016 [25], in Sekota, Northeast Ethiopia by 2019 [40]. This might be due to the fact that adherence issue is the pillar for patients on ART. Patients with poor adherence to antiretroviral drugs are associated with loss of sustained viral suppression, higher risk of drug resistance that leads to first-line antiretroviral treatment failure [41].

Patients who were enrolled to ART after two years of diagnosis with HIV were nearly five times more likely to develop first-line antiretroviral treatment failure when compared with patients who were enrolled to ART within the same month of being diagnosed with HIV. This finding was in line with those studies conducted in Zimbabwe [7], in Central Ethiopia St. Luke Referral Hospital and Tulu bolo General Hospital [20]. This might be due to the possibility that patients who stay long time without initiation of ART after diagnosis face an increase in viral load and develop other opportunistic infections. This might also be due to the difficulty of viral suppression and increase CD4 cell count when the patients delay to start ART [42].

Contrary to findings from several studies [15-17,19,39], some important socio demographic variables like age, sex and educational status were not found to be significant determinants of first line ART failure in the current study. This may be due to difference in socio demographic characteristics of study participants and socio economic differences between the study settings. Most of the studies that reported the association were conducted in Asian and West African countries. Differences in the study design and sample size may have also played roles in the observed variation. Studies outside Ethiopia used cross sectional design while some studies used huge case-control ratio which may have diluted the association.

In addition, behavioral characteristics like smoking, alcohol consumption, and chat chewing were not found to be significant determinants of ART failure. This may be due to significant reduction of these detrimental behaviors as a result of continuous counseling for HIV patients as per the national guideline in Ethiopia and the study setting [5].

Limitation

The case-control nature of this study may have resulted in difficulties in recalling of some exposures.

Conclusion

This study showed that baseline stage III and IV WHO clinical stage of HIV, low baseline Body Mass Index (<18.5 kg/m2), baseline CD4 count <100cells/mm3, having history of TB co-infection, having history of lost to follow up, poor adherence to antiretroviral drugs and initiation of ART after two years of diagnosis with HIV positive were factors associated with first-line antiretroviral treatment failure. Concerned bodies should give attention to early diagnosis of HIV, early enrollment in chronic HIV care and timely initiation of ART before patients develop advanced disease condition. In addition, focus has to be given for patients with low CD4 count. Regular screening for tuberculosis, counseling on optimal adherence to medication and enhancing nutritional status of patients with low body mass index are also crucial to prevent first-line antiretroviral treatment failure.

(SAV)

Click here for additional data file.

26 Aug 2021

PONE-D-21-13362

Determinants of first-line antiretroviral treatment failure among adult patients on antiretroviral therapy in a Specialized Hospital, South West Ethiopia; A case control Study

PLOS ONE

Dear Dr. Siraj,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Two experts in the field handled your manuscript, and we are appreciative of their time and contributions. Although interest was found in your study, several major concerns arose that require your attention. Notably, the novelty of this study needs to be stated in the rationale. Also, it was indicated that the scope of this work is a bit narrow to a region of Ethiopia and should be expanded to engage the broad audience of this Journal and how these findings could relate to international health outcomes.

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Academic Editor

PLOS ONE

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3. We noted several instances in the manuscript where the P value equals zero; please correct and clarify.

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6. Thank you for submitting the above manuscript to PLOS ONE. During our internal evaluation of the manuscript, we found significant text overlap between your submission and the following previously published works, some of which you are an author.

https://www.dovepress.com/virological-treatment-failure-among-adult-hivaids-patients-from-select-peer-reviewed-fulltext-article-IDR

https://www.researchsquare.com/article/rs-2178/v2

https://www.dovepress.com/first-line-antiretroviral-treatment-failure-and-associated-factors-in--peer-reviewed-fulltext-article-HIV

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Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is a well-written paper with a sound analysis, providing some interesting findings. The major contribution of this submission is that it is the first study in Ethiopia using viral load tests to confirm the correlates of non-adherence. Thus, while this study in Ethiopia identifies the barriers of adherence to first-line ART, there is not much new in the paper that has not been identified before. The method is sound and the study appears to have been nicely conducted. The results section is well-presented. I think this paper could be a publishable paper of some new insights within the Ethiopian context. However, I don't believe that PLOS one is the most appropriate venue as the journal includes pieces with broader focus and this paper may be a bit narrow. I would suggest that it should be published in a regional journal within Africa.

Reviewer #2: Ethical approval is not mentioned in the manuscript.

Detailed comments is as follows:

Comments to the paper: PONE-D-21-13362

General

The comments are described in the main manuscript with high-lighted texts and accessible to the author for possible amendments.

The paper is well articulated and relevant in addressing the current global health issue still imposing challenges to the globe even though showing promised changes.

Specifically to mention some,

Title

o Make it shorten if possible and to include hospital’s name

Introduction

o Abbreviated words/phrases should be explained fully at first appearance in the sentence, like ART, WHO, and the like.

o Distance of the study area from Addis Ababa, capital city of Ethiopia, not mentioned

o CD4 and viral load variables, how are they collected and analyzed, machine used never explained under data collection procedure

Methodology

o Study area is not fully described, distance/location from capital city not known.

o Sample size calculation not elaborated

o Ethical clearance and consent sub-section not included including approval board and number.

o Terms are not defined like adult, adherence (good, fair and poor), and the like

Result

o Table 1; others should be rechecked as it is greater than others; or else all mentioned variables should be listed out.

o Table2: p-value should be different from zero.

o Table 3: smoking and khat variables should be removed from that table. And also look for punctuation correction beneath the table

Discussion

o It becomes only one-sided discussion, only issue of similarity/consistency. Sometimes, disagreement is expected.

o Very recently published data/article (2021) not included in the study.

Conclusion

o It lacks recommendation

Limitation

o Not included as if the study is without limitation.

References

o Even though few, recent published data /online statistics for HIV-AIDS epidemiology not used/included.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Submitted filename: PONE-D-21-13362 commented.docx

Click here for additional data file.

Submitted filename: PONE-D-21-13362 track changes.pdf

Click here for additional data file.

14 Sep 2021

Date 14/09/2021

To: PLOS ONE

Issue: Rebuttal Letter

Dear all at the PLOS ONE and esteemed reviewers, we are very grateful to your academic inputs. We found all your comments and editorial recommendations very important for betterment of our paper. In regard to this, we prepared a rebuttal letter responding to all your comments separately for journal requirement and for the two reviewers. The specific editorial and review comments are fully accepted and changes are made in the manuscript accordingly. The responses are placed next to the provided comments for all in the next pages of this letter. We are ready to further refine our manuscript if you found some of your comments are insufficiently accommodated.

Regards

Sabit Zenu Siraj

Corresponding Author of the Manuscript

Response to Journal Editorial Comments

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

Response: The document is revised to fulfil PLOS ONE’s style and file naming requirements.

2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information.

Response: The required Ethics Statement is added to the manuscript file and to the online system. Manuscript, Page 9, Line 214-220.

3. We noted several instances in the manuscript where the P value equals zero; please correct and clarify.

Response: The P-Value in the table is corrected as P0.01. Manuscript, Page 11, Table 3

4. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly.

Response: The data availability statement is changed and the data is currently supplemented as supplementary file.

5. Please include your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well.

Response: The required Ethics Statement is added to the manuscript file and to the online system. Manuscript, Page 9, Line 214-220.

6. During our internal evaluation of the manuscript, we found significant text overlap between your submission and the following previously published works, some of which you are an author.

Response: The observed similarity with the said online sources is accidental. The observed similarity is currently paraphrased. Manuscript, Page 4, Line 84-88

Response to Reviewer 1

Reviewer Comments

This is a well-written paper with a sound analysis, providing some interesting findings. The major contribution of this submission is that it is the first study in Ethiopia using viral load tests to confirm the correlates of non-adherence. Thus, while this study in Ethiopia identifies the barriers of adherence to first-line ART, there is not much new in the paper that has not been identified before. The method is sound and the study appears to have been nicely conducted. The results section is well-presented. I think this paper could be a publishable paper of some new insights within the Ethiopian context. However, I don't believe that PLOS one is the most appropriate venue as the journal includes pieces with broader focus and this paper may be a bit narrow. I would suggest that it should be published in a regional journal within Africa.

Response: Dear Reviewer, we appreciate your encouragement and it will help us in our future endeavours. Regarding the suitability of PLOS ONE for this particular work, we submitted it to this journal because the journal is one of the most reputable. It publishes high-quality papers that have undergone extensive editorial and peer reviews. In Ethiopia, senior researchers actively encourage novice researchers like me to publish their works on PLOS ONE. In addition, the journal published high volume of academic researchers from Africa. According to the current data, the journal published over 5000 researches of different types conducted in or by Africans. Considering this, we would be happy if this paper is published on PLOS ONE.

Responses to Reviewer 2

Dear Reviewer, we are very grateful to your academic inputs. We amended the document as per your comments and specific responses are listed hereunder.

Title

1. Make it shorten if possible and to include hospital’s name

Response: The title is shortened and the name of the hospital is included as ‘Determinants of first-line antiretroviral treatment failure among adult patients on treatment in Mettu Karl Specialized Hospital, South West Ethiopia; a case control study’. Manuscript, Title, Page: line 1-3

Introduction:

2. Abbreviated words/phrases should be explained fully at first appearance in the

Response: All abbreviation issues are corrected. Manuscript, Introduction, Page 3-5, Line 52-126

3. Distance of the study area from Addis Ababa, capital city of Ethiopia, not mentioned

Response: The distance and some detail is added to the study area in Materials and Methods section. Manuscript, Materials and Methods, Page 6, Line 128-140.

4. CD4 and viral load variables, how are they collected and analysed, machine used never explained under data collection procedure

Response: The materials used in the hospital are added to the Materials and Methods sections under data collection tools and procedures. Manuscript; Materials and Methods, Data collection tools and procedures, Page 8, Line 189-195.

Methodology

5. Study area is not fully described, distance/location from capital city not known.

Response: The distance and other detail are added to the study area in Materials and Methods section. Manuscript; Materials and Methods, Page 6, Line 128-140.

6. Sample size calculation not elaborated

Response: The sample size was calculated by using Epi Info 7 using an option for Unmatched Case Control study. Power 80%, 95% CI and other parameters were used to calculate the sample size. Further detail is added to the document. Manuscript; Materials and Methods (sample size determination and sampling technique) Page 6-7, Line 154-178.

7. Ethical clearance and consent sub-section not included including approval board and number.

Response: The recommended Ethics Statement is added to the manuscript file and to the online system. Manuscript; Methods and Materials, Ethics Statement, Page 9, Line 214-220.

8. Terms are not defined like adult, adherence (good, fair and poor), and the like

Response: The terms are operationalized as recommended. Manuscript; Materials and Methods, Operational Definitions, Page 8, Line 197-203.

Result

9. Table 1; others should be rechecked as it is greater than others; or else all mentioned variables should be listed out.

Response: Corrected in the document. Manuscript; Result, Table 2, Page 9.

10. Table2: p-value should be different from zero

Response: The P-Value in the table is corrected as P0.01. Manuscript, Page 11, Table 3, the table is updated to table 3 as one more table is added to elaborate the sample size calculation procedures.

11. Table 3: smoking and khat variables should be removed from that table. And also look for punctuation correction beneath the table

Response: The variables are removed. The recommended changes are made to punctuations beneath the table. Manuscript; Result, Table 4, Page 13.

Discussion

12. It becomes only one-sided discussion, only issue of similarity/consistency. Sometimes, disagreement is expected.

Response: The recommended differences are added to the discussion. Manuscript; Discussion Page 26, line 358-369

13. Very recently published data/article (2021) not included in the study

Response: Recent UNAIDS 2021 report is added to the document and the information is updated accordingly.

Conclusion

14. It lacks recommendation

Response: Recommendation is added to the conclusion, Page 17, and Line 379-384

Limitation

15. Not included as if the study is without limitation.

Response: Limitation is added. Page 16, Line 370-372

References

16. Even though few, recent published data /online statistics for HIV-AIDS epidemiology not used/included.

Response: Updated epidemiological findings added to references. Page 18 and 19

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

11 Oct 2021

Determinants of first-line antiretroviral treatment failure among adult patients on treatment in Mettu Karl Specialized Hospital, South West Ethiopia; a case control study

PONE-D-21-13362R1

Dear Dr. Siraj,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Frank T. Spradley

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I can see that the reporting of the paper is improved and more clarity is provided. My original concern was with regards to the paper reaching the right audience and the fit to PLOS ONE, given that the findings are new and previously unstudied in the Ethiopian context, not the international context. Should the authors and editors of PLOS ONE both be happy about the fit and intended reach, I do believe that the research is well conducted and worthy of publishing.

Reviewer #2: First of all, I thank the journal editorial team to give me the opportunity of reviewing again. I have assessed the paper in that almost all comments were addressed by the author in-charge of the research paper.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

14 Oct 2021

PONE-D-21-13362R1

Determinants of first-line antiretroviral treatment failure among adult patients on treatment in Mettu Karl Specialized Hospital, South West Ethiopia; a case control study

Dear Dr. Zenu:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

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PLOS ONE Editorial Office Staff

on behalf of

Dr. Frank T. Spradley

Academic Editor

PLOS ONE