Factors Associated with Poor Viral Suppression Among Children and Adolescents Accessing Antiretroviral Therapy in Selected Health Facilities in Lagos, Nigeria


 IntroductionNigeria has the second largest HIV burden in Sub-Saharan Africa, with high burden amongst children and adolescents. In 2017, it was estimated that 160,000 children (0-9 years) and 230,000 adolescents (10-19 years) are living with HIV globally, with death in 21,000 children and 5400 adolescents resulting from AIDS-related illnesses. The main objective of the study was to determine the factors associated with poor viral suppression in children and adolescents accessing antiretroviral therapy in secondary health facilities in Lagos State.MethodsA descriptive retrospective study of children and adolescents living with HIV accessing care and support in 7 Global Fund supported ART treatment facilities in Lagos between January 2013 and June 2020. Data extraction was done between July 2020 and August 2020. The sociodemographic, clinical and laboratory data were extracted from patients’ folders. Binary logistic regression model was done to identify the determinants of viral non-suppression among children and adolescents age groups. ResultsThe study population consisted of 363 children (age 0-9 years) and 275 adolescents (age 10-19 years). The mean age of children was 5.8±2.2 years and that of adolescent was 13.21±2.8years. About 256(70 %) of children were virally unsuppressed and 118(43 %) had non-suppressed viral load status among adolescents. Binary logistic regression showed that children with WHO stage IV of HIV disease had greater odds (OR=7.984, 95% CI=1.042-61.163) of having suppressed viral load and children who live with their non-biological caregiver had greater odds of having a suppressed viral load compared to the biological caregiver group (OR=2.0421, 95% CI=1.083-10.965). Among adolescents, binary logistic regression showed location of abode and drug pick-up pattern as independent predictors of poor viral suppression. Adolescent patients living in rural setting had greater odds of being virally unsuppressed compared to those living in urban settlement (OR=1.755, 95% CI=1.001-3.083) while patients who have regular drug pick-up pattern from their ART health centres had lesser odds (OR=0.585, 95% CI=0.591-0.912) of viral non-suppression.CONCLUSIONThe findings highlight the need for a renewed focus on developing and strengthening HIV programmes in rural areas where children and adolescents living with HIV are more likely to be virally unsuppressed. More emphasis and resources should be channelled to Public health intervention such as health education, social support group programmes to improve drug pick up and adherence in adolescents living with HIV.


Introduction
Human Immunode ciency Virus (HIV) is one of the leading causes of morbidity and mortality due to infectious diseases globally, with the highest impact felt in sub-Saharan Africa [1].
In Sub-Saharan Africa, Nigeria has the second largest HIV burden. The recently concluded national AIDS indicator and impact survey puts the national prevalence at 1.4%, with a prevalence of 0.2% in children aged 0-14 years. Globally, the annual number of new infections among children (0-14 years) has almost halved since 2010 with a 47% reduction in new HIV cases, despite this signi cant progress, the number of children becoming newly infected with HIV remains unacceptably high, [2], [3], [4] While accurate health-related data for children and adolescents remain scarce and are not readily available in Nigeria [5] there is emerging evidence indicating that this age groups have been facing challenges in accessing focused HIV services [6]. Due to the peculiar challenges of both age groups, which include various socio-economic barriers and a tendency towards high-risk sexual behaviours among adolescents, it is important that children and adolescents achieve protracted viral suppression during lifelong ART to mitigate the exceptionally high mortality associated with unsuccessful HIV treatment, and to achieve the epidemiological goal of HIV control [7] [8] The President's Emergency Plan for AIDS Relief (PEPFAR) program in Nigeria de nes Virologic suppression as a viral load (measured in RNA copies) of less than 1000copies/ml and is the most effective measure of treatment response for patients on ART [9].
Several studies have demonstrated suboptimal viral suppression in children and adolescents in high and lowresource settings. A study conducted in Nigeria, observed that the viral load suppression rates through adolescence and post-transition were only 55.6-64.0% [10]. Another study in Cambodia showed a relatively low viral suppression rate amongst adolescents compared to the adult population groups, with the viral suppression rate at 76.8% and 90% respectively [11]. In Kenya, children were more likely to be virally unsuppressed if their caregivers were not suppressed in comparison to children with caregivers that were virally suppressed [12]. Other associated factors with child viral non-suppression in children as stated in the study include younger child age at ART initiation and child tuberculosis treatment at the time of the viral load assay [13] Treatment for children and adolescents also presents several challenges including the complexity in ART dosing and the need to adjust doses as the child grows, which may be a problem especially for providers who are not skilled enough with children care or too busy to track the suppression status, which is not an uncommon scenario in low-resource settings where the paucity of healthcare workers is very signi cant [14].The associated factors of poor viral suppression in these patient group have not been well explored in secondary health care setting in Nigeria and it is important to elicit them with a view to utilizing the ndings to mitigate this. This study was conducted to identify factors associated with poor viral suppression among children and adolescents accessing antiretroviral therapy.

Study design and population
This is a descriptive retrospective study of children and adolescents living with HIV accessing care and support in The Global Fund supported ART treatment facilities in Lagos from January 2013 to June 2020. The study was conducted in seven secondary health facilities supported by the Lagos State Ministry of Health and The Global Fund. The study population consisted of 638 patients, this represent all the active children and adolescent in care at the time period [363 children (0-9 years) and 275 adolescents (10-19 years)]. Data collection was done between July 2020 and August 2020.

A. Inclusion
The inclusion criteria is all HIV positive children (0-9years) and adolescents (10-19 years) who are currently on ART for at least 6 months and have had at least one viral load result at the time of the study.

B. Exclusion
The exclusion criteria is all HIV positive children (0-9 years) and adolescents (10-19 years) who currently have treatment interruption or loss to follow up and have not had at least one viral load result. Patients who were transferred out of the study facilities and those who were reported dead during the period were also excluded from the study.

Data collection
The study population consisted of 638 patients (363 children and 275 adolescents). The health facilities under study do not have an electronic medical record (EMR), therefore data were manually extracted from patient folders. A Microsoft Excel template was designed to extract patient-level data, containing participant's speci c index. The information extracted includes age at time of ART initiation, WHO clinical staging at diagnosis, current ART regimen, drug pick-up pattern (2 years prior till date), weight at baseline and at every 6 months interval until current weight, most recent viral load result, socio-demographic characteristics, and the disclosure status of the child.
Patient unique identi ers were excluded from the dataset to ensure anonymity and preserve patient con dentiality. Excel sheets used in the abstraction of study data were encrypted during transmission in line with standardized data safety protocols.
In this study, a regular drug pickup pattern is de ned as consistent drug pick-up on the scheduled dates as shown on the care card while an irregular drug pickup pattern is a drug pick up pattern that is not consistent with the scheduled dates and without proof of extra pills that accounted for the inconsistent pickup dates.
Drug pickup pattern is used as a proxy measurement for adherence, this is because it is considered an objective measure for adherence. Full disclosure is de ned in this study as patients (children and adolescents-10 years and above) who are aware of their HIV status and know they are taking medications because they have HIV while those with partial disclosure were patients who are not aware of their HIV status but understands that they need to be on medication to be healthy and those with no disclosure are patients who are not aware of their HIV status and do not know why they are on medication. The support group register was used to abstract data on disclosure. Good adherence in the study is de ned as patients with no missed drug pickup appointments while patients with poor adherence are patients with missed drug appointments greater than two weeks from the original drug pickup date.
Outcome variable which is viral load suppression is de ned as a viral load (measured in RNA copies) of less than 1000copies/ml.

Data analysis
Statistical analysis was done using SPSS version 23. Initial analyses were done by generating frequency tables and graphs. Appropriate bivariate analysis was carried out to assess statistical associations depending on the type of the variables and a binary logistic regression model was performed to identify factors determining viral non-suppression among children and adolescents age groups. The level of statistical signi cance was set at p value < 0.05. The adjusted odds ratio and 95% con dence interval were obtained to determine factors associated with viral suppression.

Study limitations
Patients' information was extracted manually and could have resulted in the unintentional omission of patients from the study. Furthermore, the method of data entry could have also resulted in transcription errors.

Results
(a) Socio-demographics of respondents: A total of 638 patients were analysed [363 children (aged 0-9 years) and 275 adolescents (aged 10-19 years)]. Among the respondents, 53.3% (340) were females while 46.7% (298) were males. 206 (56.7%) of children were between 5-9 years with a mean age of 5.8±2.2 years, while majority of the adolescents were between the ages of 10-13 years with a mean age of 13.1±2.8years. About one third of the adolescent patients 90(32.7%) lives in a rural settlement while 106(29.9%) of children lived in rural settlements.      Findings from this study identi ed that 30% of children and 57% of adolescents were virally suppressed. The suppression rates are well below program achievements for viral suppression in adults (≈ 90% − 94%), and the set target of 95% for viral suppression according to the UNAIDS framework for HIV program target milestones.
A study conducted in Uganda highlighted a poor viral suppression in children and adolescents living with HIV that ranged between 27% -29%. Issues identi ed to be associated with viral non-suppression were fear of disclosure and sub-optimal disclosure of adolescents' HIV status, exhausting medications while traveling, lack of support, feelings of loneliness, lack of perceived improvement while on medication, poor linkage to care, attrition from care and treatment, poor transition from adolescent to adult services, economic hardship and AIDS-related stigma. [15], [16], [17], [18], [19], [20].
In this study, the factors that have a positive association with viral suppression in children are those who live with their biological caregiver / parents and those who commenced ART not later than when they are at WHO clinical stage IV. For adolescents living with HIV on ART, the study revealed a positive association between good adherence, proper disclosure of HIV status and an urban residence. Patients who reside with their biological caregivers are more likely to be virally suppressed than HIV-infected children who lived with nonbiological caregivers in children, but this did not appear to be so with the adolescent age group.
A biological caregiver may have a stronger emotional connection with the child and may be more motivated to promote good adherence compared with a non-biologic caregiver. Caregivers who are also on ART may draw from their own experiences to support their child's adherence. While this may be an important factor to their adherence to medication and viral suppression rate in children because of their dependence on their caregiver for administration of their medications, most adolescents living with (ALHIV) do not depend on their caregivers for the administration of their medications, and this might have provided explanation for the difference in the association between viral suppression and caregiver among ALHIV compared to the children group in our study [21] , [22] It is important to note that there are con icting evidence on the impact of caregivers' biological relationship to a child. While some studies agree that there are positive effects to the adherence to medications (adjudged in this study by drug pickup pattern) and viral suppression, other studies pointed otherwise. An Italian study found that younger children living with non-biologic caregivers had better adherence. Similar ndings were seen in a US study; however, the association did not maintain signi cance when controlling for other factors.
Conversely, a Romanian study of horizontally infected adolescents found that non-biologic caregivers were associated with worse adherence [23], [24], [25].This might re ect the impact of sociocultural backgrounds and household settings on children psychology and subsequently, drug adherence.
In this study, the WHO clinical staging of HIV disease at baseline was found to be signi cant in children but The process of disclosure is an important factor in ensuring adherence to medication and subsequently a reduction in the viral load of the client, therefore efforts to increase the availability and accessibility of treatment should be accompanied by disclosure initiatives. Disclosure is the rst step for children transitioning into adolescents and young adults who successfully manage their own HIV care. [27] The ideal disclosure age in this study was 10 years and above, and this supports a study conducted in Northern and southern Ghana where their preferred age was 10 years [28] .This study also revealed that most of the ALHIV either had partial disclosure or no disclosure of their HIV status, as only one tenth of the patients had being fully disclosed to. The disclosure status was found to be signi cantly associated with suppressed viral load which is similar with a study in Zambia where disclosure was found to have a strong association with undetectable viral load [29]. This is not unusual as the understanding of a disease state tends to help the patient have insight into why treatment is necessary, especially for chronic illnesses as in this case, HIV infection. Disclosure and awareness of the disease state also invariably tends to affect drug adherence.
Pertaining to the ndings of associations between type of living settlements (Rural vs Urban) and viral suppression in PLHIV, patients on ART living in rural areas experience substantial barriers to HIV care, including transportation and long distances to care, provider discrimination and stigma, concerns about con dentiality, lack of health care coverage, and limited healthcare options [30]. These barriers may contribute to delays in HIV testing among PLHIV living in rural areas and some evidence suggests that these categories of patients are less likely to be retained in care, adhere to antiretroviral medication, and reach viral suppression than patients living outside of rural areas. The former are also more likely to delay HIV testing and receive an HIV diagnosis at later disease stages than their non-rural counterparts. [31], [32], [33], [34], [35], [36] ART regimen are usually standardised according to national treatment guidelines and protocols. Optimised regimens and dosing are especially necessary in children, based on the need to achieve a rapid and sustained viral suppression and good clinical outcomes because of the tendency for a rapid and fulminant progression of HIV disease in this age group.

Conclusion
The identi cation of the factors that are most positively associated with poor viral suppression in children and adolescent patients living with HIV highlights the need for a renewed focus on developing and strengthening HIV programmes in rural areas where children and adolescents living with HIV are more likely to be virally unsuppressed. In addition, health education, psychosocial and sociocultural policies which focus on adherence challenges associated with this age groups should be incorporated into HIV programmes.

Declarations Ethical considerations
Ethical approval was obtained from APIN Institutional Review Board, a registered IRB under the National Health Research Ethics Committee. The study approval number is #IRB040-FR. In addition, patient unique identi ers were excluded from the dataset to ensure anonymity and preserve patient con dentiality. Excel sheets used in the abstraction of study data were encrypted during transmission in line with standardized data safety protocols.
Availability of data and material Data and material are available on request

Consent for Publication
Not applicable

Authors' contributions
The authors are involved in the conception and design of the work, data collection, data analysis and interpretation, drafting the article, while the corresponding author was involved in the critical revision of the article and all the authors approved the nal version to be published

Competing interest
We declare that there are no competing interest Duration on ART therapy for adolescents and children Drug pickup pattern for adolescents and children Pie chart showing the disclosure pattern in adolescents