Is caregiver sex associated with HIV infection among orphans and vulnerable children in Tanzania? Learning from the USAID Kizazi Kipya Project

Background Tanzania has met only 50.1% of the 90% target for diagnosing HIV in children. Context-specic strategies are necessary to nd 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 signicantly 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 signicantly 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 signicance 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


Background
The human immunode ciency virus (HIV) that causes acquired immunode ciency syndrome (AIDS) (1,2) remains a global threat (3,4). The UNAIDS estimates that there are 37 million people living with HIV/AIDS (PLHIV) worldwide, a majority of whom are in developing countries, more than half are women, and 5.7% are children under 15 years of age (5). In 2016, UNAIDS estimated Tanzania's overall HIV prevalence among adults at 4.7% (6), and in 2018, UNICEF estimated an HIV prevalence of 0.4% among children (7) under age 15 years in Tanzania (8). This prevalence was also reported by the 2016-2017 Tanzania HIV Impact Survey (9). Further estimates by the UNAIDS show that in 2018, there were 92,000 (72,000-110,000) children living with HIV, 8,600 (6,500-13,000) children newly infected with HIV, and 5,400 (3,900) child deaths due to AIDS in Tanzania (10). Page 3/22 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).

Methods of and factors leading to transmission of HIV in children
In the areas heavily affected by HIV/AIDS, 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), increases HIV risk in children. 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 as high as 18% in children aged 15-17 years (25). Orphanhood also varies by geographical location, with the highest rates in Iringa (13%), Ruvuma (12%), and Mara (12%) regions (25). However, widespread access to antiretroviral therapy (ART) has led to increased survival among HIV-positive caregivers, reducing cases of children orphaned due to HIV (26).
In this context, pediatric HIV testing, care and treatment must receive the same attention and resources as PMTCT (27). Pediatric HIV care has lagged as a result of weak and fragmented systems for pediatric case nding. 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 identi cation, prompt and sustained treatment, and viral suppression can prevent the transmission of HIV, thus reducing HIV incidence at a population level (29).
While the rst 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 (9). Progress in the pediatric population also lags behind, with only 50.1% of Tanzanian children living with HIV (CLHIV) diagnosed (9). Therefore, a priority for the country is identifying and linking to care all individuals, and particularly children, who could be infected but are unaware of their HIV status (9).
Gaps in testing coverage and e cacy for orphans and vulnerable children (OVC) Most HIV-positive children are diagnosed late and at an advanced stage of disease progression (32). Further, evidence shows that without ART, 53% of CLHIV die before their second birthday (33). Most of these children are born to women who do not access or who only partially access PMTCT services (34). A substantial proportion of these deaths could have been prevented if the children were identi ed, diagnosed, and initiated on treatment. But, pediatric HIV case-nding remains challenging (34,35), particularly access to HIV testing services (HTS) for children.
Factors associated with HIV status in children have been identi ed in previous studies and can demonstrate heightened risk for acquiring HIV, thus an increased need to focus HTS for speci c 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). Signi cant association between malnutrition and HIV status in children has been observed in many countries, including Burkina of these fathers will be missed. The problem is compounded by a lower predilection for health-seeking behavior, including HIV testing, among men than among women (45,46). This highlights a need for a critical analysis of whether caregiver sex is associated with HIV infection in children, especially OVC. This will inform further targeted efforts toward diagnosis targets and to further improvement in pediatric case-nding modalities for universal coverage of HTS for children.

Data source
Data are from Pact's community-based, USAID-funded Kizazi Kipya Project in Tanzania (2016-2021). The project aims to increase the uptake of HIV and other health and social services by OVC and their household members. Community Case Workers (CCWs) collected the data from caregivers' self-reports during bene ciary enrollment using the project's Screening and Enrollment, and Family and Child Asset Assessment (FCAA) tools. Bene ciaries are enrolled into the project if their 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. Of these regions, Mjini Magharibi has very low adult HIV prevalence (0.6%), while Njombe has the highest in the country (11.4%) according to the recent Tanzania HIV Impact Survey (9). A total of 67 district councils (48 rural and 19 urban) considered high HIV burden from the 18 regions were included in this study.

Study population
The study population encompassed 39,578 OVC who were enrolled in the USAID Kizazi Kipya Project from January to March 2017, and had complete information on their HIV status and their caregivers' characteristics. In the context of the U.S. President's Emergency Plan for AIDS Relief (PEPFAR), an OVC is a child, ages 0-17 years, who is either orphaned (i.e. lost one or both parents to HIV/AIDS) or made more vulnerable because of HIV/AIDS (47). For programming purposes, the USAID Kizazi Kipya Project extends the OVC age to 19 to include all adolescents (48). Therefore, OVC included in this study were aged 0-19 years.
The majority of the OVC were under age 15 years (n = 27,935, 70.6%). USAID Kizazi Kipya de nes 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 identi ed 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 bene ciary 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: (see Formula 1 in th Supplementary Files) 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 (in years), OVC nutritional status, caregiver age (in years), 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 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.
This was based on an explorative analysis of OVC HIV prevalence by family size as a discrete variable.
Families with similar prevalence were grouped together, thus the categories. The smallest household had two occupants -the OVC and his/her caregiver.
Nutritional status was assessed using mid-upper arm circumference (MUAC) measuring tapes. MUAC is recommended for community-based screening of acute malnutrition (49). Interpretation of the readings was Wealth quintile was constructed using principal component analysis (PCA) of household assets to determine household socio-economic status (51). 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 (52). The usual assumption of independence of the observations did not hold because two or more 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 (53). 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 in uence in their social life and health outcomes.
Five multivariate models were constructed. The rst model encompassed the entire study 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 fth model was for 11,643 OVC in the age group 15-19 years. The strati cation 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 the conventional signi cance level of 5% (α = 0.05), whereby any association corresponding with a p-value less than 0.05 was considered statistically signi cant.

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 ndings 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 ndings.

Results
Pro le of OVC Three-quarters of the OVC (74.3%) were living with a primary caregiver who was female. These OVC had  OVC HIV prevalence by each of the independent variables is presented in Figure 1. Overall 7.1% (n = 2,802) of OVC were reported HIV-positive. This proportion varied signi cantly by levels of several independent variables. With respect to caregiver sex, OVC HIV prevalence was signi cantly higher (p<0.001) among OVC with male caregivers than those with female caregivers (7.8% and 6.8%, respectively).
HIV prevalence was lowest (3.8%) among OVC living with HIV-negative caregivers and highest (14.1%) among OVC living with HIV-positive caregivers (p<0.001). OVC HIV status varied signi cantly by OVC nutritional status (p<0.001), whereby HIV prevalence among OVC who were severely and moderately undernourished was 21.5% and 17.0%, respectively, and 6.9% among OVC who were nourished. Caregiver's marital status was also associated with OVC HIV status (p<0.001), with OVC HIV prevalence being lowest (6.5%) among OVC with caregivers who were married or living together and highest (7.9%) among OVC living with caregivers who were never married.
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 signi cantly higher among OVC living in rural areas than in urban areas (8.2% and 5.7%, respectively) (p<0.001). As detailed in

Results from the multivariate analysis
Adjusted odds ratios (OR) and their corresponding 95% con dence 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 how caregiver sex and other individual and household characteristics are associated with HIV infection among OVC in Tanzania. Findings revealed that OVC with male caregivers were 40% more likely to be HIV-positive than those with female caregivers. This effect remained statistically signi cant 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 strati ed analysis by OVC age, the association was strongest among the 0-4 years age group and declined (but with statistical signi cance) 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 signi cance, although the direction of the association remained.
Given the Tanzanian cultural context, when a male is the primary caregiver, likely this is because the child's mother has died, possibly due to HIV, which increases the likelihood that the child is HIV-infected. The child may have acquired the HIV through MTCT. 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-nding 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. Speci cally, if an HTS client is a man and tests HIV-negative, the process stops (44). This leaves a service gap for children and other family members of the male HTS client who may be at risk or already infected with HIV. Therefore, in view of this association, the current pediatric case nding strategies may be expanded by considering caregiver sex an imperative dimension for targeted HTS among OVC.
Additionally, caregiving work has traditionally been viewed as the responsibility of women and girls (54-56), especially in African communities. These traditional gender norms have been reported to exclude men and boys from becoming caregivers, thus exacerbating the caregiving burden on women (54). 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, and possibly there is no female relative to care for the children etc.). In this context, men are likely to provide inadequate or suboptimal care for reasons such as lack of experience in child-rearing activities., This can result into less protection of the child from HIV risks and risk-seeking behaviors. Due to traditional occupational gender norms, men generally provide more economic support to the family than women (57), but not social or direct support in the caregiving process. Although the level of parental supervision has been acknowledged as an important factor in preventing and remediating HIV in children and youth (58), evidence of men's participation in the whole process of caregiving work is scant (59). There is a known link between HIV and child abuse and neglect (60) whereby child abuse by male caregivers puts children at a greater risk of HIV acquisition (61). While this study demonstrates a signi cant association between caregiver sex and OVC HIV status, further research is needed to uncover and explain the causal pathways of the relationship.

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 (43,62-66). Children primarily acquire HIV from their mothers in utero, during their delivery, or while being breastfed (12).This maybe a possible mechanism underlying the ndings of this study, wherein most of the OVC in this study had female caregivers, the majority of whom were possibly their biological mothers. Therefore, although it is important to address barriers against universal coverage of HIV services to prevent MTCT, HIV risk assessment and referral to HTS and other community case-nding activities should target OVC whose 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). The rural-urban gap in OVC HIV prevalence declined consistently with OVC age until prevalence among urban OVC exceeded that of rural OVC in the 15-19 years age category. This nding could have several interpretations. First, it could re ect cultural patterns of OVC mobility across extended family households due to vulnerability in a household, abandonment by the parent or caregiver, or death of one or more parents or caregivers (73). Younger OVC could be more likely to stay in or be relocated to caregivers in rural areas, while older OVC could be more likely to move to urban areas for education or economic opportunities. However, there is little published data on mobility of OVC in Tanzania  A such, more gender-sensitive programmatic activities targeting OVC with male caregivers are needed. For community-based programs such as the USAID Kizazi Kipya, which is built on a social welfare platform, households where the caregiver is male require additional attention during program service provision. For example, evidence-based HIV prevention approaches for adolescent OVC are often integrated into parenting classes that involve the adolescent and the caregiver together. Information on early infant diagnosis of HIV is integrated into early childhood development approaches. Prevention of sexual abuse is included in all parenting approaches. It is worth examining further the extent to which male caregivers are engaged in these parenting activities.
Other key dimensions that should be targeted and integrated in HIV programming efforts for improved OVC health outcomes are individual characteristics such as age and nutritional status; caregiver characteristics such as HIV status and marital status; household characteristics such as health insurance status, and family size; and rural versus urban residence. These factors should be considered when setting targets for community based OVC programs engaged in community-based pediatric case-nding activities. 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 Table 2 Page 21/22 Due to technical limitations Table 2 is available as a download in the supplementary section. Rural-urban differentials in HIV prevalence among OVC in Tanzania, by age group, 2017 (n = 39,578)

Supplementary Files
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