Malnutrition as predictor of survival from anti-retroviral treatment among children living with HIV/AIDS in Southwest Ethiopia: survival analysis

Background Approximately 70% of HIV positive people live in Africa where food insecurity and under nutrition are endemic. However the impact of malnutrition on treatment outcome is not clear. This study assessed the effect of under nutrition on Anti-Retroviral Therapy treatment outcome among pediatric age group living with HIV/AIDS in Public Hospitals, Southwest Ethiopia. Method A retrospective cohort study was conducted on records of 242 pediatric children in Guraghe zone Public Hospitals. Also median, mean, standard deviation and interquartile range were calculated. Life table, hazard function and survival function were plotted. Log rank test with 95% confidence interval of mean survival time was done. The nutritional status data were managed via WHO Anthros plus and BMI for age Z score was calculated. To assess effects of nutritional status on mortality, both Bivariate and multivariate cox proportional hazard regression was conducted with crude (CHR) and adjusted hazard ratio (AHR) (95% confidence interval and p value). P value of less than 0.05 was used as cut off point to declare statistical significance. Results A total of 243 records of pediatric ART records with mean age of 11.6 (± 3.8 years) were reviewed. About 178 (73.3%) have got therapeutic feeding on the course of ART treatment. Whereas significant number of children, 163 (67.1%) reported to had eating problems. A total of 13 (5.3%) children were dead with incidence density of 11.2 deaths per 1000 person years. There is significantly higher survival time among well nourished (11.1 years with 95% CI: 10.8 to 11.4) as compared to underweight children (9.76 with 95% CI: 9.19 to 10.32 years). Underweight children had almost three fold increase incidence of death (AHR = 3.01; 95% CI: 0.80–11.4). Similarly children with anemia had higher incidence of death than children without anemia (AHR = 1.55; 95% CI: 0.49–4.84). Conclusions Low nutritional status at the start of ART evidenced by underweight and anemia were found to be predictors of survival among HIV positive children. There should be improved, sustained and focused nutritional screening, care and treatment for children on ART follow up.


Introduction
Background Nutrition is a critical component of treatment, care, and support, for chronic Human Immune Virus (HIV) care especially among children [1]. Human Immune Virus (HIV) and acquired immune deficiency syndrome (AIDS) and under nutrition interact in a vicious cycle: HIV-induced immune impairment and increased risk of infection can worsen malnutrition, lead to nutritional deficiencies through decreased food intake, malabsorption syndromes, and increased need and higher nutrient loss [2]. Children with HIV/AIDS have reduced appetite and ability to consume food, as well as a higher incidence of diarrhea resulting in malabsorption and nutrient losses [2,3], which makes malnutrition common phenomena [4]. In addition nutritional status has an impact on the adherence of ART drug intake which is important for good treatment outcome and increased expectancy [5].
Nutritional status modulates the immunological response to HIV infection, affecting the overall clinical outcomes [6,7]. Weight loss is an important predictor of death from AIDS. The links between nutrition and HIV/AIDS increase the negative effects of HIV infection on human development at individual, household, community and national levels [8].
Early mortality with advanced disease of HIV is common features of individuals who are already enrolled on ART drugs [9]. Those people living with HIV (PLWHA) and co-infected with tuberculosis (TB), leads to even greater metabolic stress and risk of malnutrition [10].
Approximately 36.9 million people globally live with HIV and AIDS, out of these 3.2 million were children under 15 years, including 220,000 new cases of pediatric age group. Sub Saharan Africa harbors 70% of global burden where food insecurity and under nutrition are endemic [1].
Under nutrition is a significant factor affecting human immune deficiency virus (HIV) care and treatment in resource limited settings [11]. Poor nutritional status and its intersection with food insecurity, poverty, and coinfections also pose a serious threat to efforts to combat HIV/AIDS mainly through hindering favorable treatment outcomes [5,12]. Undernourished children with PLWHA at start ART had 2-6 times increased risks of death in the first 6 months of ART [3,13].
In addition, untreated HIV infection increases energy needs by as much as 10% in asymptomatic adults, 20-30% in symptomatic adults, and 50-100% in children with weight loss [14]. Study from Northwest Ethiopia showed overall prevalence of malnutrition, underweight, stunting and wasting was 42.9, 41.7, 65 and 5.8% respectively [15].
Various level of ART treatment outcome, incidence rate of 16.9 deaths per 1000 child-years. With death rate of 4.81% [16], while another study [17] showed cumulative probabilities of survival at 3, 6, 12, and 24 months of ART were 0.96, 0.94, 0.93, and 0.92 respectively. Majority (90.2%) of the deaths occurred within the first year of treatment.
Generally previous studies have been conducted in Ethiopia addressing the predictors of mortality among ART clients, yet there are a limited number of studies with this specific age group and proper assessment of nutritional status was not used. Furthermore there is no sufficient evidence in the specific area regarding the effects of malnutrition (using BMI for age for children) on Survival of children from HIV/AIDS in the study area. Thus, this particular study aimed to address the magnitude of malnutrition and more specifically its effects on the survival status of children from HIV/AIDS in this particular area which will be an important input to the area and the region Country as well.

Study setting
Guraghe zone is one of the administrative zones in southern nations and nationalities region. It has 13 districts and two town administrations. Wolkite town is the capital of Guraghe zone which is found 425 km and 158 km from Hawassa and Addis Ababa respectively on the way to Jimma. There are five hospitals with four governmental and one private (Non-governmental) hospital. There were 758 pediatric children who were HIV positive from August 2013-September 2017 (during the past 5 years), in those public hospitals. This study was conducted from June 1 to 20/ 2018.

Study design
A retrospective cohort study design was conducted using records from August, 2013 to September, 2017. All pediatrics patients under the age of 18 years on ART in Guraghe zone, SNNPR, Ethiopia were source population.

Eligibility criteria
All randomly selected records of pediatrics patients (6 months -18 years) on ART from the selected Hospitals in Guraghe zone, SNNPR, Ethiopia were study population. Records with incomplete data on nutritional status (weight, height), age, and/or ART treatment outcome were excluded from the study. Records in which the intake form, register or follow up form lacks the aforementioned variables were excluded. Cases which transferred to other facilities (transfer outs) and those cases of death with confirmed accidental death due to injury (unrelated competing causes of death) were excluded.

Sample size determination
The sample size for the first objective was calculated based on single population proportion formula. Using incidence of mortality among ART clients (P = 2.3%) from study done in Zewditu hospital [19] and margin of error, 5% at 95% confidence interval as follows.
The sample size became 35. For the second specific objective the sample size was calculated using specific software version 13.0 (Stata corps Ltd), using 80% power, 5% type I error and estimates of outcome, the sample size was 347. But as the available records of pediatric ART clients is below the calculated sample size (243), all records of eligible children were included in the study.

Sampling procedures
Since, in Guraghe zone there are five hospitals first we stratify the hospitals and from the lists of hospitals we selected two governmental hospitals out of four which have higher case load. Using the average 5 year case load of each hospitals, we proportionally allocated the sample size to each hospitals. And records were selected using simple random sampling by computer random number generator. Then using unique ART number or medical record number (MRN) the clients' card were retrieved. However, the total number of eligible study participants were below the calculated sample size, all records of children (243) from the selected Hospitals were included in the study.

Data collection methods
Quantitative data were collected using structured and cross checked checklist. The check list included information on weight, socio-demographic characteristics, treatment related issues, ART treatment outcome (as death or survival from the card or register). The data were collected by trained data collectors. Data were collected by 30 health professional (BSc nurses and health officers), who have good knowledge on ART therapy. The number of data collectors assigned to each hospital was based on their previous case load. .

Variables of the study
The dependent variable of this study is ART treatment Outcome (time to death) while age at enrollment, sex, parents survival status, nutritional status (BMI for age score), functional status, ART adherence, CD4 at the start, WHO stage at the start, cotrimoxazole prophylaxis, INH prophylaxis, co morbidities, ART regimen, eligibility criteria (CD4 or WHO staging) were independent variables.

Operational definitions
Death: when the child had approved records of death in his medical record where it is not due to accidental unrelated causes. Censored: those records or ART clients who did not develop the outcome (death) at the ends of the study. Malnutrition is when the enrollment BMI for age z score of the child is below − 2 SD. Under nutrition for children was defined as BMI for age zscore of < − 2 SD (thinness or underweight), using World Health Organization (WHO) 2006 and 2007 reference standards. .

Data quality control
Two days training was given to the data collectors before the actual data collection. Principal investigators and supervisors monitored and check the daily progress of the data collection. The information collected were cross checked with different sources (intake forms, ART register and ART chronic follow up form). The data were entered in to EpiData software and was restricted by legal values and other parameters to minimize errors. The data were also be entered by two independent data entry clerks and then cross checked for possible errors of data entry. Mismatched data were cross checked with the hard copy and corrected accordingly.

Data processing and analysis
The raw data were entered in to Epi-Data software version 3.1 and exported to SPSS version 20 for analysis. Data were presented in frequency, percentages, tables, and graphs. To analyze time to death among ART clients from the day of enrolment, survival analysis was done. Also median, mean, standard deviation and interquartile range were calculated. Life table, hazard function and survival function were plotted. To compare average survival time among different characteristics, log rank test with 95% confidence interval of mean survival time and P of log rank test was done. Patients were followed retrospectively from the day of enrolment to ART till they develop the outcome or being censored. The nutritional status data (age, weight, height) were entered in to WHO Anthros software and BMI for age Z score was calculated automatically. Then it was exported to SPSS version 20. Nutritional status was categorized in to Malnourished (BMI for Age Z score below − 2) while, the others as normal nutritional status (BMI for Age > = − 2, including obese and overweight) as over nutrition is rare among RVI clients.
To assess effects of nutritional status on mortality, both Bivariate and multivariate cox proportional hazard regression were conducted with crude (CHR) and adjusted hazard ratio (AHR) (95% confidence interval and p value). P value of less than 0.05 was used as cut off point to declare statistical significance.

Ethical consideration
The study was approved by Wolkite University Institutional and Health Ethical Review committee. Letter of cooperation was taken from the university to the zonal health office and to the respective hospitals sequentially. Before data collection Informed consent was obtained from the respective hospital managers after full explanations of the study procedure. Then during the actual data collection all hard copy and softcopy data were under full protection in the hands of the investigators. The collected data will not be used for other purpose than the study primary objectives. Written informed consent was obtained from hospital administrator on the behalf of the ART data in their hospital. No tissue sample or human experiment was done.

Socio demographic characteristics
A total of 243 records of pediatric ART records with mean age of 11.6 (± 3.8 years) were reviewed and included in the study. More than half children (55.1%), came from rural areas. Only about 41% of children parents live together while 10.7% and 30.5% lost their mother and father at some period% of time. About 209 (86%) of children live with their parents, while others with their relatives or lonely. Almost all, 240 (98.8%) had a care giver who can take care of them, of whom 86% of them were parents either father or mother of the child (   (Fig. 1). Concerning the ART adherence at the time of last ART visit, 202 (83.3%) had good adherence while 2.9% had poor ART adherence which need adherence support. In addition, 88.5% and 90.5% of children had taken INH and cotrimoxazole prophylaxis respectively. A total of 33 children (13.6%) reported to have anemia and 25 (10.3%) had virological failure, persistent increase in viral count above 1000 cells/mm 3 . Accordingly, 13 (5.3%) of clients got shift of ART regimen from first line to second line, which was mainly due to clinical and immunologic failure ( Table 3) (Fig. 2).

ART treatment outcome
A total of 200 (82.3%) of children were active on ART follow up while, 13 (5.3%) were dead during the course of their chronic HIV care with incidence density of 11.2   Table 4). Majority of death among children were observed during the early period of ART start, in which 12 out of 13 deaths occurred during the first 2 years of ART start (Fig. 4). Even if the patter of death were similar, higher number of deaths (9 deaths) were observed among malnourished than well nourished (4 deaths) children.
Under Kaplan Meir test for comparison of mean survival time by nutritional status, there is significantly higher survival time among well nourished (11.1 years with 95% CI: 10.8 to 11.4) as compared to underweight children (9.76 with 95% CI: 9.19 to 10.32 years) ( Table 5).

Predictors of survival among ART children
Using both categorical and numerical covariates, cox proportional hazard regression model was done. The cox proportional hazard assumptions were fulfilled and checked using global test (p value of above 0.05).
Younger children had shown to have higher hazards of death, which is per each year increase in age of child the hazards of death decrease by 14% (CHR = 0.86 95% CI: 0.75-0.99). Children from rural area had two fold increased hazards of death (CHR = 1.90; 95% CI: 0.58-6.12). Those children who were underweight (defines as low BMI for age z score below − 2 as compared to the WHO growth reference) shown to have almost four fold increased risk of early death as compared to wellnourished ones (CHR = 3.36; 95% CI: 1.03-10.9). Children with fair (CHR = 4.73; 95% CI: 1.4-14.9) and poor ART adherence (CHR = 4.73; 95% CI: 1.4-14.9) had more than four times increased hazards of death as compared to well adhered clients. In addition, those clients who were not supplemented with therapeutic foods had two times higher hazards of death (CHR = 2.18; 95% CI: 0.48-9.84) ( Table 6).
Clients who started ART immediately with the same days of HIV confirmation had lower hazards of early   (Table  6). After adjusting for confounder variables, multivariate cox proportional hazard regression was fitted. As a result, advanced WHO stage, nutritional status, duration of pre ART follow up and presence of anemia were significantly associated with increased hazards of death. Underweight children had almost three fold increase in hazard of death (AHR = 3.01; 95% CI: 0.80-11.4). Similarly children with anemia had higher hazards of death than children without anemia (AHR = 1.55; 95% CI: 0.49-4.84) ( Table 6).

Discussions
The findings from this study showed that a total of 13 (5.3%) children were dead during the course of their chronic HIV care with incidence density of 11.2 deaths per 1000 person years of follow up. Additionally, majority of deaths occurred during the first 2 years after the start of ART. Similarly review data on national level showed mortality rate of 5 to 8% at 6 month and 24 months of ART start [19]. Mortality rate (hazards of death was higher among males than females which is comparable to study in Iran which showed lower cumulative proportion surviving among males than in females (P = 0.0001) [20]. In addition study in Addis Ababa also showed about 8.8% mortality rate among children in which majority of death occurs during early periods of ART follow-up [21]. Study from Northern Ethiopia also showed mortality rate of about 8% [17].
Thus, as the prevalence of malnutrition among children contributed to almost half of under-five mortality and affects up to 40% of children, maintaining good nutritional status of children is one of the primary proxy indicator for good treatment outcome [23]. This in turn  will aggravate the bad cycles of HIV and malnutrition in that it will leads to advanced diseases and poor adherence to HIV chronic care [23,24]. Significantly, higher number of HIV infected children had higher prevalence of underweight (77% versus 35%), stunting (65 and 61%) and wasting (63 and 26%) respectively [7]. Despite having nutritional rehabilitation, a fourfold increase in mortality is observed among HIV positives indicating the need for improved and focused nutritional care for children for improved treatment outcomes. In addition there should be high energy and micronutrient foods locally prepared in the community or some preparations like ready to use therapeutic foods or others should be readily available to the ART clients.
It estimated that about 3.2 million children living with HIV/AIDS, almost 90% cases were found in sub Saharan African countries in which malnutrition is common problem facing children [23]. This will interact with each other creating double burden among children in that malnutrition will reduce HAART effectiveness, response to drugs while increasing the risks of early death.
In addition, majority of children would not start ART before 6 months. Thus, children usually starts care later where children develop advanced stage disease including advanced WHO stage defining illnesses leading to lower survival [6]. Early initiation of ART usually improve the clinical outcomes of children. On the other side, in areas where ART coverage is about 54% [19,25], late detection and initiation of treatment will deteriorate the nutritional status of children causing early mortality and immunological failure.
Despite its impressive methods and findings, as of any study the findings of this study should be seen in the light of some limitations. As the number of children on ART were smaller, the sample size was somewhat lower which might affect the power of the study. In addition, the secondary nature of the data makes, the availability of some factors like iron status and other nutritional indices unavailable.

Conclusion and recommendations
Low nutritional status at the start of ART evidenced by underweight and anemia were found to be predictors of survival among HIV positive children. There should be improved, sustained and focused nutritional screening, care and treatment for children on ART follow up. In addition strong adherence support for chronic HIV care should be emphasized, so that it will be a significant input for improved nutritional status and ultimately improved treatment survival. The Health extension workers and the HIV support groups in collaboration with ART care givers should educate and promote care givers to enhance better nutritional support and care for children in addition to adherence to HAART therapy.