**2. Main body**

*Nutrition and HIV/AIDS - Implication for Treatment, Prevention and Cure*

commonest cause for pediatric hospital admission [3].

life and survival of children [7, 8].

important.

drugs [10].

2016, over 3100 children died due to AIDS-related illness [5].

Acquired immune deficiency syndrome (AIDS) is a disease caused by a retrovirus known as human immunodeficiency virus (HIV) [1]. HIV/AIDS remains one of the world's most significant public health challenges, particularly in low- and middle-income countries [2]. Children constitute a segment of the population affected by the virus. HIV contributes to illness and death of children and is the

Of the total 1.8 million children living with HIV, an estimated 110,000 die of AIDS-related illnesses each year which means 290 children die of AIDS-related illnesses every day. Nearly 90% of HIV-infected children live in sub-Saharan Africa (SSA) [4]. In Ethiopia it is estimated that 65,088 children are living with HIV. In

The introduction of antiretroviral therapy (ART) presented an enormous opportunity in terms of reducing morbidity and mortality due to AIDS, worldwide. Ethiopia has been engaged in the scale-up of ART access to its people since 2005 [6]. It has been shown that the improvement in access to ART improves the quality of

Studies show that early access to ART could prevent 25% of HIV-related deaths [7–9]. Therefore, to reduce child mortality attributed to HIV/AIDS, the provision of comprehensive treatment, care, and support for HIV-infected children is very

Ethiopia has adopted the World Health Organization's (WHO) recommendations for ART where "regardless of their CD4 cell count, all HIV-infected individuals should start treatment to reduce morbidity and mortality associated with HIV infection" [3]. The number of sites providing ART service in Ethiopia, including both public and private facilities, has increased from 3 to over 1000, and persons initiated on treatment has increased from 24,000 to 308,000 during the period 2006–2016 with more than 23,400 children under the age of 15 taking antiretroviral

Survival of HIV-positive children in Ethiopia and other similar settings has improved as a result of increased access to ART; however, it is still low in the first 6 months after initiation of ART [11]. Reports from Kenya, Zambia, and Malawi show that death among HIV-positive children following ART initiation remains high, ranging from 7.5 to 15% [12–14]. This contrasts the substantially higher survival probability among HIV-positive children initiated on ART in developed countries [15]. Findings from other studies elsewhere in Africa and other low-income countries show that ART programs have resulted in decreased mortality among children on ART [16–18]. Available evidences also depicted that the survival of the children is not only affected by the care delivered by ART programs but also more fundamentally influenced by low CD4 count, advanced disease according to WHO staging, low hemoglobin (Hgb) level, and opportunistic infections (OIs) like bacterial pneumonia and tuberculosis [19–21]. However, as far as our search of the available literature has revealed, little is known about the effect of factors like viral load, nutritional status, cotrimoxazole (CTZ) preventive therapy (CPT), and isoniazid (INH) preventive therapy (IPT) on survival status of children below 15 years of age. Therefore, this study intended to estimate the survival time and identify associated factors by including viral load, nutritional status, CPT, and IPT among HIV-infected children initiated on ART in public health facilities in Arba Minch town,

**1. Introduction**

**2**

Southern Ethiopia.

### **2.1 Patients and methods**

*Study area and period*: We conducted the study in Arba Minch town from March 20, 2017 to April 10, 2017. Arba Minch town is located about 495 km southwest of the capital city Addis Ababa and about 275 km from Hawassa, the capital of the Southern Nations, Nationalities, and Peoples' Region (SNNPR). Arba Minch town has one general hospital and one public health center, which provide ART service. Arba Minch Hospital was among the first few public hospitals to start ART in Ethiopia in August 2003. Arba Minch Health Center started ART service at the end of 2007. According to the Gamo Gofa Zone Health Department (ZHD) report, the Arba Minch Hospital and Arba Minch Health Center provide HIV/AIDS interventions, including free diagnostic, treatment, and monitoring services. Since August 2003, ART has been provided to children living with HIV regardless of CD4 count and WHO clinical stage, with financial support from the Norwegian Lutheran Mission. Data from ZHD show that a total of 664 children with HIV/AIDS were enrolled on chronic HIV care at the hospital and the health center since January 2009, but only 608 started ART (460 children at Arba Minch General Hospital and 148 children at Arba Minch Health Center) [22].

*Study design*: A health facility-based retrospective cohort study.

**Source populations**: All children living with HIV who were enrolled on firstline ART at the center.

**Study populations**: All children living with HIV who were enrolled on first-line ART at the center and who fulfill the inclusion criteria.

**Inclusion criteria**: Those who were aged <18 years and enrolled on first-line ART and have follow-up at Arba Minch General Hospital and Health Center.

*Sample size determination*: The sample size was calculated by applying a two-population proportion formula using Epi-Info version 7. Co-trimoxazole preventive therapy, tuberculosis (TB) co-infection at baseline, and anemia were considered, and taking the most significant predictors of the three variables, anemia was used [17] with the following assumptions: 95% CI, power 80%, ratio of unexposed to exposed 1:1, parameter outcome in exposed hemoglobin (Hgb) < 10 gm/dl = 14.7%, outcome in unexposed Hgb ≥ 10 gm/dl = 5.8%, and hazard ratio (HR) = 2.5. This resulted in sample size of 412 children. As there were a total of 421 children in the study area who fulfilled the inclusion criteria, we included all 421 in this study.

*Sampling procedure and sampling technique*: A total of 608 children who started ART during the study period were identified in the two ART clinics. Charts were organized according to the hospital card number, in a chronological order, with each chart representing one child. As some of the charts in the hospital were not arranged in numerical order, the investigator assigned new numbers for all those registered between 2009 and 2016, starting from 1 to 608. Of these, the investigator drew 421 samples which fulfilled the inclusion criteria after reviewing the information transcribed to the pre-structured data abstraction form; 187 individuals did not fulfill the inclusion criteria; therefore, those charts were excluded from the study. Children ≤14 years of age and on ART registered for chronic care at public health institutions of Arba Minch town from 1 January 2009 to 30 December 2016 were included in the study. Those whose cards were incomplete with information on baseline CD4 count, WHICH staging and date of ART start and current status were excluded from the study.

#### **2.2 Variables in the study**

*Dependent variable*: The response (outcome) variable in this study was "survival time" of HIV-infected children after starting ART.

*Independent variables*: The predictor variables included five continuous covariates (age, hemoglobin level, weight, height, and CD4 count) and nine categorical variables (gender, co-trimoxazole prophylaxis, TB co-infection status, isoniazid prophylaxis, functional status, clinical stage of the disease according to WHO scaling, type of ART drug, adherence to ART, and year of ART initiation).

#### **2.3 Operational definition of terms**

*Censored*: includes lost to follow-up, transfer out, and live beyond the study time. *Adherence to ART*: assessed by counting the number of tablets the children miss within the first 3 months after starting ART.

*Survival*: absence of experience of death.

*Survival time*: the length of time in months a child was followed up from the time the child started ART until death, was lost to follow-up, or was still on follow-up.

#### **3. Data collection procedure and data quality control**

A structured interviewer-administered questionnaire was used to collect the data [23–25]. The questionnaire was primarily developed in English and then translated into Amharic language for simplicity of data collection. Then Amharic version was also back-translated to English language for its consistency by two different language experts. The data collection tool has four sections. Pretesting of the data collection tool was done on 17 individuals who were selected from Berber Health Center that were not included in the actual study. Based on the pretest, a data collection tool was corrected to ensure logical sequence, clarity, and skipping patterns. Data was collected by eight trained health professionals and supervised by two bachelor degree health professionals. All data collectors and supervisors were trained for 2 days and performed practical exercises to be familiar with the questionnaire. Exit interview was done. The participants' weight was measured in kilograms with 0.2 kg increments using standard beam balance, and the scale was checked at zero during measurement. The study participant was removing their heavy outer clothes and shoes. The participant height was measured using the standard measuring scale to the nearest 0.5 cm. The participants were asked to take off their shoes, stand erect, and look straight in vertical plain. The data collectors were regularly supervised for proper data collection as well as checked for completeness and consistency throughout data collection period.

*Data processing and analysis*: The completeness and consistency of the data was checked, coded, and double entered into Epi-info version 7 and exported to Statistical Package for Social Sciences (SPSS) version 20 for analysis. Exploratory data analysis was carried out to check the levels of missing values and presence of influential outliers. Descriptive statistics such as mean (standard deviation), frequencies, and proportions were used to describe the characteristics of the cohort. Kaplan-Meier survival curve together with log-rank test was used to assess survival experience of an individual at specific times and to compare survival between different independent variables.

The analysis was conducted in several steps. First, univariate Cox proportional hazard regression model was performed for each independent variable

**5**

*Nutritional Status and Its Effect on Treatment Outcome among HIV-Infected Children Receiving…*

and outcome of interest to identify potentially significant variables for consideration in the multivariable Cox proportional hazards regression model. Based on the univariate analysis, variables were selected for the multivariable analysis. Variables whose univariate significance test results were below p-value <0.25 were included in the multivariable regression model. In addition, context and findings of previous studies were considered in the identification of candidate

Multivariable analysis was started with a model containing all of the selected variables. The model was built through a stepwise regression procedure, which added variables successively (the most significant at each step) until no variable added significant information and compared by likelihood ratio test and Harrell's concordance statistic test. Interactions and confounders were tested and the cutoff point of beta change greater than 20% was used. The results of the final model were expressed in terms of hazard ratio with 95% confidence intervals (CI) and interpreted accordingly. Kaplan-Meier survival curve together with log-rank test was used to check for the existence of any significant differences in survival between the various categories of variables considered in this study. Statistical significance was

*Ethical considerations*: Ethical approval was obtained from the ethical review committee of Arba Minch University, College of Medicine and Health Sciences, with reference number CMHS/4268/09. Following the approval, an official letter of cooperation was written to concerned bodies by the Department of Public Health of Arba Minch University. Permission was granted from the Hospital and Health Center Administration as per the recommendation letter from the department. Personal identifiers were excluded during data extraction; rather codes were used. Considering the study was being conducted on secondary data, obtaining informed consents from the participants was not possible. However, the confidentiality of information was maintained by not recording their name from the chart, and the recorded data were not accessed by a third person except by the

*Baseline characteristics of the study participant*: A total of 421 study participants (children under 15 years old) were included in the study. The sample is comprised of 241 (57.2%) males and 180 (42.8%) females. The ages of the cohort at ART initiation ranged from 3 to 168 months with a median age of 72 (IQR = 33–108) months. Based on WHO clinical staging, 196 (47%) children initiated ART at an advanced stage of the disease, i.e., WHO clinical stage III or IV. During the ART initiation, 139 (33%) children were affected by one or more opportunistic illness, of which 41 children were found to have died at the end of the study. Sixty (14.3%) had history of TB at the start of ART, and 36 died during the follow-up time. At the initiation of ART, mean (SD) value for weight of children was 18.6 (±9.65) kg, and mean (SD) value for height of the cohort was 110.8 (±32.19) cm. The baseline median value for Hgb was 10.9 (IQR = 8.8–12.3) g/dl, and 181 (43.1%) of the children had absolute CD4 count below threshold for immune

Among the reviewed participants, 410(97.4%) were on first-line ART regimen, while the rest were started on second line. Concerning the type of ART regimens, around 61% of children were taking D4T-based drug regimens when they started

*DOI: http://dx.doi.org/10.5772/intechopen.85851*

variables for multivariable analysis.

declared if the p-value was less than 0.05.

principal investigator.

deficiency at initiation of ART.

the treatment (**Table 1**).

**4. Results**

#### *Nutritional Status and Its Effect on Treatment Outcome among HIV-Infected Children Receiving… DOI: http://dx.doi.org/10.5772/intechopen.85851*

and outcome of interest to identify potentially significant variables for consideration in the multivariable Cox proportional hazards regression model. Based on the univariate analysis, variables were selected for the multivariable analysis. Variables whose univariate significance test results were below p-value <0.25 were included in the multivariable regression model. In addition, context and findings of previous studies were considered in the identification of candidate variables for multivariable analysis.

Multivariable analysis was started with a model containing all of the selected variables. The model was built through a stepwise regression procedure, which added variables successively (the most significant at each step) until no variable added significant information and compared by likelihood ratio test and Harrell's concordance statistic test. Interactions and confounders were tested and the cutoff point of beta change greater than 20% was used. The results of the final model were expressed in terms of hazard ratio with 95% confidence intervals (CI) and interpreted accordingly. Kaplan-Meier survival curve together with log-rank test was used to check for the existence of any significant differences in survival between the various categories of variables considered in this study. Statistical significance was declared if the p-value was less than 0.05.

*Ethical considerations*: Ethical approval was obtained from the ethical review committee of Arba Minch University, College of Medicine and Health Sciences, with reference number CMHS/4268/09. Following the approval, an official letter of cooperation was written to concerned bodies by the Department of Public Health of Arba Minch University. Permission was granted from the Hospital and Health Center Administration as per the recommendation letter from the department. Personal identifiers were excluded during data extraction; rather codes were used. Considering the study was being conducted on secondary data, obtaining informed consents from the participants was not possible. However, the confidentiality of information was maintained by not recording their name from the chart, and the recorded data were not accessed by a third person except by the principal investigator.

### **4. Results**

*Nutrition and HIV/AIDS - Implication for Treatment, Prevention and Cure*

ing, type of ART drug, adherence to ART, and year of ART initiation).

**3. Data collection procedure and data quality control**

and consistency throughout data collection period.

ferent independent variables.

time" of HIV-infected children after starting ART.

**2.3 Operational definition of terms**

within the first 3 months after starting ART. *Survival*: absence of experience of death.

*Dependent variable*: The response (outcome) variable in this study was "survival

*Independent variables*: The predictor variables included five continuous covariates (age, hemoglobin level, weight, height, and CD4 count) and nine categorical variables (gender, co-trimoxazole prophylaxis, TB co-infection status, isoniazid prophylaxis, functional status, clinical stage of the disease according to WHO scal-

*Censored*: includes lost to follow-up, transfer out, and live beyond the study time. *Adherence to ART*: assessed by counting the number of tablets the children miss

*Survival time*: the length of time in months a child was followed up from the time the child started ART until death, was lost to follow-up, or was still on follow-up.

A structured interviewer-administered questionnaire was used to collect the data [23–25]. The questionnaire was primarily developed in English and then translated into Amharic language for simplicity of data collection. Then Amharic version was also back-translated to English language for its consistency by two different language experts. The data collection tool has four sections. Pretesting of the data collection tool was done on 17 individuals who were selected from Berber Health Center that were not included in the actual study. Based on the pretest, a data collection tool was corrected to ensure logical sequence, clarity, and skipping patterns. Data was collected by eight trained health professionals and supervised by two bachelor degree health professionals. All data collectors and supervisors were trained for 2 days and performed practical exercises to be familiar with the questionnaire. Exit interview was done. The participants' weight was measured in kilograms with 0.2 kg increments using standard beam balance, and the scale was checked at zero during measurement. The study participant was removing their heavy outer clothes and shoes. The participant height was measured using the standard measuring scale to the nearest 0.5 cm. The participants were asked to take off their shoes, stand erect, and look straight in vertical plain. The data collectors were regularly supervised for proper data collection as well as checked for completeness

*Data processing and analysis*: The completeness and consistency of the data was checked, coded, and double entered into Epi-info version 7 and exported to Statistical Package for Social Sciences (SPSS) version 20 for analysis. Exploratory data analysis was carried out to check the levels of missing values and presence of influential outliers. Descriptive statistics such as mean (standard deviation), frequencies, and proportions were used to describe the characteristics of the cohort. Kaplan-Meier survival curve together with log-rank test was used to assess survival experience of an individual at specific times and to compare survival between dif-

The analysis was conducted in several steps. First, univariate Cox proportional hazard regression model was performed for each independent variable

**2.2 Variables in the study**

**4**

*Baseline characteristics of the study participant*: A total of 421 study participants (children under 15 years old) were included in the study. The sample is comprised of 241 (57.2%) males and 180 (42.8%) females. The ages of the cohort at ART initiation ranged from 3 to 168 months with a median age of 72 (IQR = 33–108) months. Based on WHO clinical staging, 196 (47%) children initiated ART at an advanced stage of the disease, i.e., WHO clinical stage III or IV. During the ART initiation, 139 (33%) children were affected by one or more opportunistic illness, of which 41 children were found to have died at the end of the study. Sixty (14.3%) had history of TB at the start of ART, and 36 died during the follow-up time. At the initiation of ART, mean (SD) value for weight of children was 18.6 (±9.65) kg, and mean (SD) value for height of the cohort was 110.8 (±32.19) cm. The baseline median value for Hgb was 10.9 (IQR = 8.8–12.3) g/dl, and 181 (43.1%) of the children had absolute CD4 count below threshold for immune deficiency at initiation of ART.

Among the reviewed participants, 410(97.4%) were on first-line ART regimen, while the rest were started on second line. Concerning the type of ART regimens, around 61% of children were taking D4T-based drug regimens when they started the treatment (**Table 1**).


#### *Nutrition and HIV/AIDS - Implication for Treatment, Prevention and Cure*

#### **Table 1.**

*Demographic and clinical characteristics and chemoprophylaxis status among children on antiretroviral treatment at Arba Minch Hospital and Health Center, Southern Ethiopia, 2017.*

## **5. Mean survival time after initiation of ART**

After initiation of ART, children were followed up for a minimum of 1 and maximum of 95 months with median follow-up period of 50 (IQR = 24–80) months. At the end of follow-up, 261 (62%) of the children were alive, 43 (10.2%) were lost to follow-up, 52 (12.4%) were transferred out to other facilities, and 65 (15.4%) were reported dead. The overall mean estimated survival time after ART initiation of children in the study was 82.3 (95% CI = 79.48–85.14) months.

There is a significantly different survival time between different factors considered in this study. Females have relatively lower survival time of 79.3 months than males with 84.6 months. Children 1–4 years of age had higher survival time of 86.8 months than those less than 1 and 5–14 years of age who had a mean survival time of 69.3 and 80.8 months, respectively.

**7**

**Figure 2.**

*Nutritional Status and Its Effect on Treatment Outcome among HIV-Infected Children Receiving…*

The overall Kaplan-Meier survivor function estimate showed that most of the deaths occurred in the earlier months of ART initiation, which declined in the later months of follow-up. Most of the graphs did not show differences between different categories. However, relatively larger gaps are observed in covariates such as WHO clinical stage, TB co-infection, low Hgb level (<10gm/dl), and CTZ and INH

*The plot of the overall estimate of Kaplan-Meier survivor function among children on ART at public health* 

**7. Results of the Cox proportional hazards regression model**

*on ART at public health facilities in Arba Minch town, 2017.*

One important predictor of low survival time in univariable Cox regression analysis was advanced WHO staging. The risk of low survival chance in individuals with advanced disease according to WHO staging at baseline was nearly 4 times

*Survival curves for children on ART by WHO clinical stage, hemoglobin level, and TB co-infection after start* 

*DOI: http://dx.doi.org/10.5772/intechopen.85851*

**6. Comparison of survival curves**

prophylaxes (**Figures 1** and **2**).

*facilities of Arba Minch town, Southern Ethiopia, 2017.*

**Figure 1.**

*Nutritional Status and Its Effect on Treatment Outcome among HIV-Infected Children Receiving… DOI: http://dx.doi.org/10.5772/intechopen.85851*
