Closing the pediatric gap in the first 90: is caregiver sex associated with HIV status of orphans and vulnerable children? Learning from the USAID Kizazi Kipya Project in Tanzania

Background Tanzania has met only 50.1% of the 90% target for diagnosing HIV in children. Context-specific strategies are necessary to find the hidden children for HIV testing. This study assesses the association between caregiver sex and HIV status of orphans and vulnerable children (OVC). Methods Data originate from the community-based, USAID-funded Kizazi Kipya Project, which works towards increasing OVC’s and their caregivers’ uptake of HIV/AIDS and other social services in Tanzania. Included in this study are 39,578 OVC ages 0–19 years who the project served during January-March 2017 in 18 regions of Tanzania and who voluntarily reported their HIV status. Data analysis involved multi-level logistic regression, with OVC HIV status as the outcome and caregiver’s sex the main independent variable. Results Three-quarters (74.3%) of the OVC included in the study had female caregivers, and their overall HIV prevalence was 7.1%. The prevalence was significantly higher (p<0.001) among OVC with male caregivers (7.8%) than among OVC with female caregivers (6.8%), and indeed, multivariate analysis showed that OVC with male caregivers were significantly 40% more likely to be HIV-positive than those with female caregivers (OR=1.40, 95% CI 1.08–1.83). This effect was the strongest among 0–4 year-olds (OR=4.02, 95% CI 1.61–10.03), declined to 1.72 among 5–9 year-olds (OR=1.72, 95% CI 1.02–2.93), and lost significance for children over age 9 years. This effect was adjusted for OVC sex and nutritional status; caregiver marital status, education level, and HIV status; family’s place of residence, size, wealth quintile, and health insurance ownership; and co-residence of multiple OVC. Conclusion OVC in Tanzania with male caregivers have a 40% higher likelihood of being HIVpositive than those with female caregivers. HIV risk assessment activities should target OVC with male caregivers, as well as OVC who have malnutrition,


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The human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS) (1,2) remains a global threat (3,4). It is still incurable and in spite of prevention and treatment efforts, AIDS continues claiming lives. The UNAIDS estimates that 37 million people are living with HIV/AIDS worldwide, with 1.8 million new infections, and 940,000 AIDS-related deaths recorded each year (5). A majority of people living with HIV (PLHIV) are in developing countries, and more than 50% are women and 5.7% are children under 15 years of age (5). Sub-Saharan Africa bears the largest share of the global HIV/AIDS burden, having recorded about two-thirds of new infections and threequarters of AIDS-related deaths in 2016 (5). Tanzania has seen a general decline in prevalence of HIV/AIDS among 15-49 year-olds, from 7.0% in 2005 (6) to 4.7% in 2017 (7). In 2016, UNAIDS put Tanzania's overall HIV prevalence among adults at 4.7% (8), and in 2018, UNICEF estimated an HIV prevalence of 0.4% among children (9), defined as those under age 15 years (10).

Methods of and factors leading to transmission of HIV in children
Vertical transmission, commonly known as mother-to-child transmission of HIV (MTCT) is the predominant mode through which children acquire HIV (11,12). Other routes include blood transfusions and the use of contaminated sharp objects (13). In communities affected by AIDS, children who have lost parents and family members become more vulnerable to HIV infection from the lack of caregivers, lack of access to school and inability to stand for their rights; in these cases, children can be infected through sexual abuse or rape (14). Prevention of mother-to-child transmission of HIV (PMTCT) services during pregnancy, delivery and breastfeeding can stop MTCT (15), but relying primarily on this approach does not address the challenge of maternal seroconversion during late pregnancy and breastfeeding (16,17) and creates coverage gaps (18).
In the areas hardest hit by the HIV/AIDS epidemic, such as sub-Saharan Africa, the association of orphanhood and AIDS is well established (19)(20)(21). Orphanhood, which occurs when a child under 18 years of age loses one or both parents (11), fuels HIV risk in children, is increasing, and is becoming a serious social and public health threat in Tanzania and elsewhere in the world. For example, orphans are two to three times more likely than their non-orphaned counterparts to have acquired HIV by the time they reach adolescence (22,23). In 2016, Tanzania had 2.6 million orphans from all causes, 810,000 of whom were orphaned by AIDS (24). The magnitude of orphanhood in the country increases with age, from as low as 1% in children under age 2 years to high as 18% in children aged 15-17 years (25). Orphanhood also varies by geographical location, with the highest rate in Iringa region (13%), followed by Ruvuma (12%) and Mara (12%) (25). However, it is important to note that widespread access to antiretroviral therapy (ART) has led to increased survival among HIV-positive caregivers, meaning fewer new cases of children orphaned due to HIV (26).

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In this context, pediatric HIV testing, care and treatment must receive the same attention and resources as PMTCT (27). However, pediatric HIV care has lagged behind as a result of weak and fragmented systems for pediatric case finding. Consequently, many children die of HIV, often undiagnosed (27).
The 90-90-90 targets In 2014, at the 20th International AIDS Conference in Melbourne, Australia, UNAIDS launched the 90-90-90 targets for HIV/AIDS programming, which state that by 2020, 90% of all PLHIV will know their status, 90% of people diagnosed with HIV will be on ART, and 90% of people on ART will achieve viral suppression (28). Essentially, early identification, prompt and sustained treatment, and viral suppression can prevent the transmission of HIV, thus impacting HIV incidence at a population level (29). UNAIDS' call also applied to children and adolescents, not just adults.
While the first 90 is the parent of the subsequent 90s in the cascade, its performance gap is largest (30), with only 75% of people worldwide knowing their status in 2017 (31). Tanzania's progress towards achieving the 90-90-90 targets mirrors the global trend at 61-94-87 among adults (7). Progress in the pediatric population also lags behind, with only 50.1% of Tanzanian children living with HIV (CLHIV) diagnosed (7). Therefore, a critical priority for the country is identifying and linking to care all individuals who could be infected but are unaware of their HIV status (7).

Gaps in testing coverage and efficacy for orphans and vulnerable children (OVC)
Most HIV-positive children are diagnosed late and at an advanced stage of diseases progression (32). Further, evidence shows that without ART, 53% of CLHIV die before their second birthday (33). Most of these children were born to women who did not access or who only partially accessed PMTCT services (34). A substantial proportion of these deaths could have been prevented if the children were identified, diagnosed, and initiated on treatment. But, pediatric HIV case-finding remains challenging (34,35), particularly access to HIV testing services (HTS) for children.
Factors associated with HIV status in children have been identified in previous studies and can demonstrate heightened risk for acquiring HIV, thus an increased need to focus HTS on specific groups. For example, maternal CD4 count during pregnancy, mixed feeding, and being hospitalized since birth were noted among children born to mothers in PMTCT programs in Zimbabwe (36). A study among HIV exposed children in Uganda observed that infants who did not receive ART prophylaxis at birth and children delivered outside the health facility were more likely to be HIV-positive than their counterparts (37). Significant association between malnutrition and HIV status in children has been observed in many countries, including Burkina Faso, Ghana, Rwanda, and India (38)(39)(40)(41)(42). Other studies have noted a higher likelihood of HIV infection in children living with HIV infected caregivers (43). 5 However, the literature lacks adequate evidence of HIV prevalence among OVC and corresponding risk factors. The association between caregiver sex and OVC HIV status is missing. Given the links between orphanhood and HIV, knowing them is crucial for informing pediatric case-finding strategies to ultimately close the pediatric gap in the first 90.
Tanzania offers index testing services to children if the biological mother is HIV-positive or if the father is HIV-positive and reports that the child's mother is HIV-positive, deceased, or of unknown status and/or that a biological sibling under age 15 years is HIV-positive (44). However, if the father comes for HTS and tests HIV-negative, nothing else is enquired under the current index testing algorithm. While children with female caregivers are further covered by HTS under the current index testing algorithm, children under the direct care of these fathers will be missed. The problem is compounded by a lower prevalence for health-seeking behavior, including HIV testing, among men than among women (45,46). This highlighted a need for a critical analysis of whether caregiver sex is associated with HIV infection in children, especially OVC, in order to inform further targeted efforts toward diagnosis targets and to further improvement pediatric case-finding modalities for universal coverage of HTS for children.

Data source
Data are from Pact's community-based, USAID-funded Kizazi Kipya Project in Tanzania household meets one or more of the 14 enrollment criteria that cover household vulnerabilities related to HIV: household is headed by a child (under age 18 years), household is headed by an elderly caregiver (age 60 years or older), household cares for at least one single or double orphan, caregiver is chronically ill and unable to meet his/her children's basic needs, caregiver is a drug user, caregiver or an adolescent age 10-19 years in the household is a sex worker, at least one adolescent girl age 10-19 years in the household is sexually active, adolescent girl age 10-19 years in the household is pregnant or has a child of her own, at least one household member is HIV-positive, at least one child in the household has tuberculosis, at least one child in the household is severely malnourished, at least one child in the household has been or is being abused or at risk of abuse, at least one child in the household is living and/or working on the streets, and at least one child in the household is working in mines. These criteria are equally applied for all implementation areas and age groups. Njombe has the highest in the country (11.4%) according to the recent Tanzania HIV Impact Survey (7). A total of 67 district councils (48 rural and 19 urban) from the 18 regions considered high HIV burden were included in this study.

Study population
The study population encompassed 39,578 OVC who were enrolled in the USAID Kizazi Kipya USAID Kizazi Kipya defines a caregiver as a guardian with the greatest responsibility for the daily care and rearing of one or more OVC in a single household. A caregiver is not necessarily a biological parent. Only one caregiver per OVC was included in this study: the person identified as having primary responsibility for caring for the child, i.e., the primary caregiver. References to caregiver in this manuscript denote each child's singular, primary caregiver

Study design
The study design constituted a cross-sectional secondary analysis of the existing FCAA data, as described above. The data were collected once during beneficiary screening and enrollment.

Variables
OVC HIV status as reported by the caregiver was the outcome or dependent variable and was measured through the two categories of negative and positive. For computational purposes, the variable was organized as follows: The main independent variable for this study was sex of the caregiver, measured through the two categories of male and female. Other independent variables included OVC sex, OVC age, OVC nutritional status, HIV status of the caregiver, education of the caregiver, family size, whether some or all the family members are covered by health insurance, whether the caregiver is physically or mentally disabled, household wealth quintile, and type of residence (rural or urban). Rural residence included all those living in district councils, whereas those living in township, municipal or city 7 councils were considered as urban residents.
Family size (i.e., number of people living in the same household) was divided into three categories: households with 2-3 members, households with 4-13 members, and households with 14 or more members.
Nutritional status was assessed using mid-upper arm circumference (MUAC) measuring tapes. MUAC is recommended for community-based screening of acute malnutrition (47).
Interpretation of the readings was guided by the standard definitions of the colors, whereby the person being assessed is nourished if the reading falls in the tape's green zone, the person being assessed is moderately undernourished if the reading falls in the yellow zone, the person being assessed is severely undernourished if the reading falls in the red zone (48).
Wealth quintile was constructed using principal component analysis (PCA) of household assets to determine household socio-economic status (49). Five wealth quintiles were formed, ranging from the lowest quintile (Q1) for the poorest households, to the highest quintile (Q5) for the most well-off households. Family-owned assets included in the PCA were dwelling materials (brick, concrete, cement, aluminium, other), livestock (chicken, goats, cows, other), transportation assets (bicycle, motorcycle/moped, tractor, motor vehicle, other), and productive assets (sewing machine, television, couch/sofa, cooking gas, hair dryer, radio, refrigerator, blender, oven, other).

Data analysis
Data analysis was conducted using Stata version 14.0 statistical software. Exploratory analysis was conducted through one-way tabulations to obtain distributional features of the respondents in each variable. Cross-tabulation of OVC HIV status by each of the independent variables was conducted to assess the variability of OVC HIV prevalence by levels of each of the independent variables. The Chi-Square (χ 2 ) test was used to assess the degree of association between OVC HIV status and each of the independent variables.
Multivariate analysis was conducted using a random-effects logistic regression model due to the hierarchical or clustered structure of the data (50). The usual assumption of independence of the observations did not hold because OVC who have the same caregiver, or who reside in the same household may be correlated. Thus, a multilevel model, which recognizes these data hierarchies and allows for residual components at each level in the hierarchy, was used (51). This choice was based on the assumptions that OVC from the same household and caregiver are dependent in their behavioral, physical, or mental characteristics because they share the same social, health, and economic resources available at the household level. This is likely to exert a related influence in their social life and health outcomes.
Five multivariate models were constructed. The first model encompassed the entire study 8 population of 39,578 OVC ages 0-19 years. The remaining models broke down the study population by age group: the second model was for 5,217 OVC in the age group 0-4 years, the third model was for 10,457 OVC in the age group 5-9 years, the fourth model was for 12,261 OVC in the age group 10-14 years, and the fifth model was for 11,643 OVC in the age group 15-19 years. The stratification of the multivariate analysis by OVC age offered a deeper examination, interpretation and comparisons of the patterns and concentration of the association between caregiver sex and OVC HIV status across different bands of the OVC age. All statistical inferences were made at a significance level of 5% (α = 0.05), whereby any association corresponding with a p-value less than 0.05 was considered statistically significant.

Limitations
Some key variables, such as whether the caregiver was the child's biological parent, were not available in the data. Recall bias was possible during data collection because all information (except for nutritional status, which was measured) was self-reported, though findings suggest that the effect may be minimal because results are comparable with existing biomedical and clinical studies. Since this study was cross-sectional in design, temporality cannot be established, which precludes drawing causal inferences from these findings.

Profile of OVC
Three-quarters of the OVC (74.3%) were living with a primary caregiver who was female.  OVC HIV status by background characteristics OVC HIV prevalence by each of the independent variables is presented in Figure 1.  HIV prevalence also varied by family size; it was highest among OVC living in households with 14 or more and 1-3 household members (11.3% and 10.6% respectively) and lowest (6.0%) among OVC living in households with 4-13 members (p<0.001). With respect to location, HIV prevalence was significantly higher among OVC living in rural areas than urban areas (8.2% and 5.7%, respectively) (p<0.001). As detailed in Figure 2, HIV prevalence among OVC living in rural areas was highest in the youngest age group (0-4 years) and continued declining as OVC age advanced. After age 15 years, the OVC HIV prevalence in urban areas surpassed that in the rural areas. The proportion of OVC living with HIV varied by health insurance ownership, with the prevalence highest (10.8%) among OVC living in households with health insurance and lowest (6.5%) in households without health insurance. Results from the multivariate analysis Adjusted odds ratios (OR) and their corresponding 95% confidence intervals (CIs) for the association between caregiver's sex and OVC HIV status are presented in Table 2.

Linkages between caregiver sex and OVC HIV status
This study assessed the association between HIV status among OVC in Tanzania and the sex of their primary caregiver. Findings revealed a statistically significant association between the two.
OVC with male caregivers were 40% more likely to be HIV-positive than those with female caregivers.
This effect remained statistically significant even after adjusting for OVC sex, caregiver HIV status, OVC nutritional status, household family size, caregiver marital status, wealth quintile, place of residence, health insurance ownership, and household co-residence. In the stratified analysis by OVC age, the association was strongest among the 0-4 years age group and declined (but with statistical significance) among 5-9 year-olds. In the older OVC age groups of 10-14 and 15-19 years, the association declined further and lost statistical significance, although the direction of the association remained.
Given the cultural context, when a male is the primary caregiver, likely this is because the child's mother has died, perhaps due to HIV, which makes the child more likely to have HIV. The child may have acquired the HIV through MTCT, which can also explain the stronger association of HIV status among younger OVC compared to older OVC. This has important implications for risk assessment and referral to HIV testing services (HTS) for children. As noted earlier, orphaned children living with male caregivers are likely to miss HTS because the current case-finding modalities like index testing services are offered to individuals who are at risk of HIV exposure from the original client, who is often the mother. Specifically, if an HTS client is a man and tests HIV-negative, the process stops (44), thus leaving a service gap for children and other family members who may be at risk or already infected with HIV.
Additionally, caregiving work has traditionally been viewed as the responsibility of women and girls (52-54), especially in African communities. These traditional gender norms have been 13 reported to exclude men and boys from becoming caregivers, thus exacerbating the caregiving burden on women (52). This is corroborated by this study, in which about three-quarters of the OVC had female caregivers. Thus, men become caregivers not by choice, but because circumstances dictate (e.g., the child's mother has died). When this happens, men are likely to provide care that is inadequate or suboptimal, for example due to lack of experience in child-rearing activities, thus offering less protection from HIV risks and risk-seeking behaviors; due to traditional occupational gender norms, men generally provide more economic support to the family than women (55), but not social or direct support in the caregiving process. Level of parental supervision has been acknowledged as an important factor in preventing and remediating HIV in children and youth (56).
However, evidence of men's experience in the whole process of caregiving work is scant (57). There is a known link between HIV and child abuse and neglect (58) whereby child maltreatment, such as molestation by male caregivers, puts children at a greater risk of HIV acquisition (59). But, with this gap in the literature about the relationship between caregiver sex and OVC HIV status that led to this research, further research, especially qualitatively, is needed to uncover the causal pathways of the relationship demonstrated herein.

Additional risk factors for OVC HIV status
As expected, OVC with HIV-positive caregivers were more than 29 times more likely to be HIV-positive than OVC whose caregivers were HIV-negative, which is consistent with the literature (43,(60)(61)(62)(63)(64). Children primarily acquire HIV from their mothers in utero, during their delivery, or while being breastfed (12).This maybe a possible mechanism underlying the findings of this study, wherein 14 There was also a residence location aspect of the variability in HIV prevalence among OVC in the study area. The study population was almost evenly split between urban and rural locations, but urban residence was associated with a 29% lower odds of HIV infection than rural residence, implying that OVC who reside in rural areas may have higher burden of HIV infection. Rates of HIV prevalence due to location were highest among OVC ages 0-4 years who resided in rural areas compared to their urban counterparts in the same age group (9.6% vs. 3.7%; see Figure 2

Conclusions
The current study demonstrates that, OVC living with male caregivers are 40% more likely to be HIV-positive than those living with female caregivers. Further qualitative and quantitative research is needed to uncover the mechanism responsible for this trend. However, this study's findings can be used to reexamine pediatric case finding approaches to find more undiagnosed HIV-positive children from the OVC population. Other key dimensions that should be targeted and integrated in HIV programming efforts for Project was entirely voluntary. The FCAA tool was completed only after each caregiver had signed a statement of an informed consent. All information was voluntarily provided by the respective OVC's caregiver.

Consent for publication
Not applicable Availability of data and materials The datasets analyzed during the current study are not publicly available due confidentiality restrictions, but are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.  Table 2 Due to technical limitations Table 2 is available as a download in the supplementary section.