Introduction
Globally, there are 19.7 million women living with HIV, accounting for 54% of adults living with HIV.1 Each year, over 1 million women living with HIV experience pregnancy, with an increasing proportion receiving antiretroviral therapy in pregnancy, from 49% in 2010 to 82% in 2022.2 In the USA, over 265 000 women are living with HIV, comprising 22% of adults living with HIV.3 However, the physical, behavioural and mental health outcomes of young women living with HIV of reproductive age in the USA and individual and social determinants of these outcomes have not been well-studied.
Despite advances in HIV treatment and care, a suboptimal proportion of women living with HIV in the USA engage in HIV care, adhere to antiretrovirals and achieve viral suppression, which are all crucial to promoting health and reducing the risk of HIV transmission.4 In 2021 about 25% of all US adult women living with HIV were not receiving HIV care, and only 64% were virally suppressed at the time of their most recent clinical visit.5 Over 60% of postpartum women living with HIV are not virally suppressed 6–24 months after giving birth.6–10 Women with perinatally-acquired HIV (PHIV) have even lower rates of viral suppression, with 70–85% not virally suppressed at 12 months post partum.11 12
Women living with HIV are disproportionately black and/or Latina, reflecting the influence of structural racism in driving disparities in access to prevention and care, antiretroviral medication adherence, mental health, comorbidities and overall well-being.13 14 ‘Weathering’ induced by chronic exposure to racism and forms of social and economic disadvantage, has the potential to accelerate ageing and declines in health among minoritised women and is a possible mechanism linking structural racism to adverse health outcomes.15–17 Structural racism shapes racialised residential segregation, disproportionate exposures to environmental hazards, less access to quality healthcare, discrimination during medical encounters and increased negative experiences with the criminal legal system.18–21 Yet little is known about the specific effects of structural racism and other associated harmful social policies (eg, living in states with more laws criminalising HIV) on the health of women living with HIV.
Additionally, women experiencing HIV-related stigma may also experience higher levels of social isolation and depression, which could contribute to suboptimal adherence.22 The intersection of HIV-related stigma and racism, classism, sexism, disability and heterosexism, have been associated with suboptimal HIV care, posing additional threats to positive health outcomes.23 24 However, few studies to date have examined the impact of racism, and intersectional stigma and discrimination on the health of marginalised women living with HIV of childbearing age, despite the fact that HIV disproportionately impacts women who identify as black and Latina in the USA.
Although there has been extensive research examining the health of older women living with HIV in the USA,25–27 less is known about the health of women living with HIV currently of reproductive age in the USA. Investigating the complex milieu of biological, social, environmental and structural events influencing the health and well-being of women living with HIV across their reproductive life course, including those who are nulliparous, pregnant, post partum or parous and women who have never been or will not become pregnant is imperative for achieving health equity and informing interventions to optimise long-term health of women living with HIV.
There is an opioid crisis in the USA, with opioid use driven largely by use of prescription opioids.28 Additionally, cannabis legalisation in many US states for both medical and recreational use may affect substance use trends across the reproductive life course among women living with HIV.29 Substance use has been linked to food insecurity, suboptimal adherence and challenges in retention in HIV care among older women living with HIV in the USA,30 however, less is known about alcohol and other substance use and its treatment among younger women living with HIV.
Due to improvements in HIV treatment and medical advances which dramatically reduce the risk of perinatal HIV transmission, more women living with HIV are now choosing to have children.31–35 In the USA, approximately 3500 women living with HIV give birth annually.36 Pregnancy rates for women living with HIV are comparable to women without HIV.31 However, about 80% of pregnancies among women living with HIV in the USA are reported to be unintended, compared with 40–50% in the general population.12 37–39 This disparity highlights a need to better understand and support the reproductive intentions, concerns about HIV transmission and health of women living with HIV, as well as the environmental, psychosocial, economic and sociopolitical conditions in which they live. Women living with PHIV represent a unique subset of individuals, and there is a dearth of information on the potential impact of lifelong HIV and antiretrovirals on their long-term health and pregnancies.
Understanding individual, biological and social determinants of health of women living with HIV of reproductive age before, during and after pregnancy is of clinical and public health importance both to improve short-term pregnancy outcomes and to mitigate long-term chronic disease risk. Although pregnancy is a time of increased risk for physical and mental health complications, the contribution of pregnancy to long-term health of women living with HIV has not been sufficiently examined. For example, hypertensive disorders of pregnancy are potent signals for elevated risk of long-term cardiovascular (CVD) and metabolic disease40–43 and antiretroviral medications may influence CVD risk.44 Additionally, mental health conditions are prevalent among women living with HIV who are parenting,45 yet the influence of parenting on the physical and mental health of women living with HIV, and on their ability to engage in their own HIV care and maintain adherence to antiretrovirals, particularly if children have acute or chronic health needs, has not been well-studied. Finally, although neighbourhood deprivation has been linked to viral load, little is known about the relationship of other social and physical environmental factors (eg, air pollution and extreme temperature) to pregnancy and the overall well-being of women living with HIV.46–48
To address these scientific gaps, the Health Outcomes around Pregnancy and Exposure to HIV/Antiretrovirals (ARVs) (HOPE) longitudinal study, funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, will enrol and follow a large US-based cohort of women living with HIV of reproductive age, including those with PHIV, to understand their health and well-being outcomes over time. In this paper we present the HOPE study protocol, including the conceptual framework, aims, design, methods and characteristics of the first 437 participants enrolled as of 1 January 2024. Due to its focus on the reproductive life course, HOPE enrols only individuals assigned female sex at birth. For simplicity, the terms ‘woman’ and ‘women’ are used throughout this paper. However, the HOPE study population includes cisgender women, transgender men, non-binary individuals and gender-diverse people.
Methods and analysis
HOPE study objectives
The HOPE study has four primary aims: (1) Establish the HOPE cohort to evaluate the health and well-being of women living with HIV of reproductive age using innovative epidemiological study designs and cost-effective methods for enrolment, follow-up and data collection; (2) assess HIV-related outcomes in multiple domains (defined below) and overall health of women living with HIV over their reproductive life course, including reproductive health, coinfections, long-term non-communicable diseases, as well as potential inflammatory and epigenetic processes associated with these outcomes; and psychosocial determinants of health including mental health diagnoses, stigma, racism, inequity, disclosure of HIV and opioid and other substance use/misuse; (3) determine the association of HIV disease-related factors, including timing of acquisition, treatment, disease course and engagement in care, with the overall physical, mental and behavioural health of women living with HIV during their reproductive years; (4) assess the relationship of adverse infant or child health outcomes to the health of women living with HIV.
In addition to four overall study aims, the HOPE study is designed to address aims examining multilevel dynamic determinants of health within specific domains: Mental health, reproductive health, cardiometabolic health, coinfections, HIV outcomes, HIV care continuum, substance use and stigma, racism and social determinants of health. The domain-specific aims and selected hypotheses are summarised in online supplemental table 1. Key exposures include ARV regimens received over the life course, comorbidities and social and structural determinants of health, including HIV-related stigma, poverty, racism and discrimination. Many variables of interest in the HOPE study can be evaluated as exposures and as outcomes, depending on the research question.
Supplemental material
Conceptual framework
The HOPE study conceptual framework is informed by the socioecological model, which recognises that factors operating at multiple levels including individual, interpersonal and family, community and institutional and structural/societal, may affect individuals’ health and risk of adverse outcomes.49–51 The HOPE framework also incorporates a life course perspective and Developmental Origins of Health and Disease framework, which acknowledge that biological and social factors across generations, at early stages of development and across the reproductive life span, are critical determinants of reproductive health, which in turn, influence later chronic health conditions52–55 (figure 1). Changes in exposure to these factors, in HIV disease, as well as pregnancy and postpartum events, may affect health. Infections other than HIV, the mode of HIV acquisition and timing of HIV diagnosis, type and timing of ARV treatment and adherence can influence engagement in care, HIV outcomes and overall health of women living with HIV.56 57 The needs and health of children in turn may affect women’s health. This cyclical and dynamic relationship, occurring in the context of structural factors including HIV-related stigma, violence, racism, inequity and poverty as well as trauma and depression may negatively influence HIV outcomes through direct or indirect pathways, including toxic stress, potentiating health outcome disparities among women living with HIV.50 58–63 Conversely, resilience resources including individual, family and interpersonal resources, social support and availability and access to community resources may mitigate potential adverse effects on health and well-being and support positive outcomes.64–68
Health Outcomes around Pregnancy and Exposure to HIV/Antiretrovirals conceptual model. ART, antiretroviral therapy; VL, viral load.
Leveraging the Pediatric HIV/AIDS Cohort Study infrastructure
The HOPE study is designed to address questions regarding the long-term health of women living with HIV of reproductive age during young adulthood, pregnancy and parenting (for those who have given birth to or are raising children as foster parents or through guardianship or adoption). HOPE is affiliated with the Pediatric HIV/AIDS Cohort Study (PHACS) network, a national multisite research network conducting longitudinal studies of long-term effects of HIV and ARV exposure on infants, children, adolescents and young adults with PHIV and those living with perinatal HIV exposure who are not living with HIV. The PHACS Surveillance Monitoring for ART Toxicities (SMARTT) study is an ongoing observational cohort study established in 2007 that follows children with perinatal HIV exposure who are not living with HIV from birth along with their biological mothers (women living with HIV) or other caregivers, to evaluate the safety of fetal exposure to ARVs.69 70 The PHACS Adolescent Master Protocols for Participants 18 Years of Age and Older (AMP Up Series) follow young adults living with PHIV and a comparison cohort of individuals with perinatal HIV exposure.71 Individuals in SMARTT and the AMP Up Series who meet HOPE eligibility criteria may co-enrol in HOPE, thus enriching the data collection for these individuals. The unique HOPE research platform fosters opportunities for multidisciplinary and cross-cutting research to inform public health policy for optimising the health of women living with HIV.
Patient and public involvement
The HOPE protocol, research focus and data collection instruments were designed in partnership with women living with HIV from the PHACS Community Advisory Board (CAB) and/or members of the PHACS Health Education and Community Core Community Task Force. A core principle of the HOPE study is to support research that reflects the perspectives and priorities of people living with HIV. Once all sites were open to accrual, we engaged HOPE participants to join a HOPE-specific CAB established to ensure representation of participants’ priorities in HOPE, drive the creation of health education materials and promote insights and opportunities to support participant retention. HOPE participants also serve on the PHACS Community Task Force, using the PHACS Health Education and Community Core infrastructure to work as paid consultants providing input and ensuring representation of HOPE participant priorities in all protocol activities. In collaboration with the HOPE protocol team, HOPE CAB members conduct reviews of research proposals using HOPE data, providing extensive written feedback. They also advise and assist with the development of resources supporting recruitment, retention and study conduct, coauthor publications and support the dissemination of study findings, aiming to use results to inform policy changes that promote health equity for women living with HIV. They have informed the creation of a video describing geocoding for participants and illustrated instructions to assist participants with vaginal and anal swab self-collection.
Study population and eligibility criteria
HOPE is a prospective observational cohort study enrolling women living with HIV who are 18–39 years of age at 12 clinical sites across 9 US states and Puerto Rico (figure 2). Individuals eligible to participate in HOPE are (1) woman, based on biological sex assignment at birth; (2) living with HIV as documented in their medical record; (3) 18 to <40 years of age if pregnant or parous and 18–30 years of age if nulliparous and non-pregnant; (4) at least 13 weeks of gestation at time of enrolment if pregnant; (5) willing to provide access to medical records and provide legal consent/assent and able to complete study assessments in English or Spanish. Individuals who are currently incarcerated and individuals concurrently enrolled in studies not approved by the HOPE protocol team are ineligible for HOPE.
Geographical locations of HOPE study sites across the USA and Puerto Rico. States in darker shade are locations of Pediatric HIV/AIDS Cohort Study sites. HOPE, Health Outcomes around Pregnancy and Exposure to HIV/Antiretrovirals.
Recruitment and retention
The study began enrolling participants in April 2022 with a goal of enrolling 1630 participants over 4 years from the following four groups:
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Nulliparous, non-pregnant participants 18–30 years of age (N~370).
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Participants who are pregnant or recently gave birth (≤3 days) and are 18 to <40 years of age (N~430).
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Postpartum (>3 days up to 12 months after delivery), non-pregnant participants 18 to <40 years of age (N~260).
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Parous, non-pregnant (>12 months after delivery) participants 18 to <40 years of age (N~570).
The study aims to recruit a population that includes at least 15% women living with PHIV in all of the above categories. The HOPE team is in the process of modifying the HOPE protocol eligibility criteria to accelerate accrual. This includes increasing the maximum eligible age to 45 years of age, removing the minimum weeks of gestation in pregnancy and expanding eligibility to women whose preferred language for completing assessments is Haitian Creole.
In addition to co-enrolling eligible PHACS participants, each site enrols qualifying participants who are not part of the PHACS network through outreach to local CABs and to clinicians who provide care to women living with HIV. Recruitment strategies were informed by CAB members and site staff. Women living with HIV consenting to participate in the study will complete follow-up visits through 31 August 2025 (6 months prior to the funding period end date), or longer if the study receives renewed funding.
Multiple methods to retain participants in HOPE are informed by site staff, the HOPE CAB and HOPE members of the PHACS Community Task Force. Capitalising on existing patient-provider relationships, sites partner with clinical providers and local and national CABs throughout the course of this study to support participants for continued HOPE study retention. Study staff maintain contact with HOPE participants at least every 6 months to maintain rapport, inquire if they had become pregnant or experienced any other significant changes and to support study retention.
Schedule of evaluations
The HOPE study has two schedules of evaluations, one for participants who are pregnant or have recently given birth and another for participants who are not pregnant (online supplemental figure 1). Entry visits are in-person and annual follow-up visits are remote. The entry visit for participants who are pregnant can occur either during pregnancy or in the peripartum period. Participants who enrol while pregnant have follow-up visits at delivery, 6 weeks postpartum, 1-year postpartum and annual remote visits thereafter. Participants who are not pregnant have one in-person entry visit followed by annual remote visits. Annual visits are conducted remotely, and include completion of an online survey by the participant and medical chart abstraction by site staff. Participants who are not pregnant at enrolment but who subsequently experience pregnancy are invited to modify their frequency of evaluations from annually to the pregnancy schedule described above, followed by annual remote visits thereafter.
Data collection and measures
The data collection at each HOPE visit is summarised in table 1. Data collection at the entry visit consists of collection of residential addresses for geocoding, clinical assessments, an interviewer-administered medical and psychosocial history questionnaire, a self-completed online survey and collection of specimens for the HOPE Biorepository. Trained research staff complete medical record abstraction concurrently with each visit.
Health Outcomes around Pregnancy and Exposure to HIV/Antiretrovirals data collection
Health Outcomes around Pregnancy and Exposure to HIV/Antiretrovirals online survey data collection
Geocoding
To examine structural racism and other area-based social, environmental and structural determinants of health (eg, historical redlining, air quality, green space and proximity to high-quality clinics/hospitals), HOPE employs geocoding. Participants who consent to provide their residential addresses for geocoding provide all addresses where they resided for the 2-year period prior to the entry visit and the address where they resided longest between ages 14–18 years. Site staff record the addresses and use ArcGIS Pro V.3.0 software72 to transform each address into a Federal Information Processing System code for the census tract corresponding to each location.
Clinical assessments
Height, weight, waist and hip circumference and blood pressure measurements are collected.
Interviewer-administered questionnaires
A questionnaire collects medical history including medications, diagnoses and family medical history. Participants complete assessments of pregnancy and reproductive history, health literacy measured using the Newest Vital Sign73 and social history (eg, food security via the Six-Item Short Form of the US Household Food Security Scale74 and housing security). In addition, interviewers screen participants for symptoms of depression via the Patient Health Questionnaire-9,75 anxiety symptoms via the Generalised Anxiety Disorder-7 Scale76 and Post-Traumatic Stress Disorder (PTSD) via the Primary Care PTSD screen for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).77
Specimen collection
Site staff collect bio-specimens from HOPE participants at the in-person entry visit. Specimens include serum, plasma, non-viable peripheral blood mononuclear cells, anal, oral and vaginal swabs, hair specimens and saliva. Participants who enrol while pregnant provide bio-specimens again at the delivery visit. All HOPE bio-specimens are stored in a bio-repository, allowing for future investigations of biological processes and conditions (eg, testing for sexually transmitted infections, inflammation, epigenetics, the microbiome and biological markers of stress).
Medical record abstraction
For participants who are nulliparous or enrolling more than 1 year after giving birth and not pregnant at enrolment, site staff abstract data from participant medical records for the period starting 12 months prior to the visit. For participants who are pregnant or recently gave birth or within the 1-year postpartum period, site staff abstract medical record data for the period beginning 6 months prior to conception of the most recent pregnancy. Health conditions abstracted from participants’ medical records include HIV history, general and obstetrical/gynaecological history, mental health history, medical diagnoses and care engagement details. HIV history includes ARV medications, CD4 count including nadir CD4 count and HIV viral load. General history includes non-ARV medications, immunisations, weight, blood pressure and results of selected laboratory tests (eg, lipids, blood urea nitrogen, white blood cell count). Obstetrical/gynaecological history includes gravidity, parity, pregnancy outcomes, results of STI testing, as well as normal and abnormal cervical cancer screening results and associated histology. Mental health diagnoses include depression, anxiety, PTSD, psychosis and substance use disorders. Medical diagnoses include, but are not limited to, diabetes (including gestational diabetes), hypertension (including hypertensive disorders of pregnancy), obesity, dyslipidaemia and anaemia. Care engagement details include HIV, primary care, obstetrics/gynaecologic and mental healthcare engagement.
Online survey
The online survey collects information on socio-demographic characteristics, physical and mental health, behaviours (eg, substance use) and social determinants of health, described in table 2,78–94 and assesses feasibility/acceptability of a wearable actigraphy device for collection of participant sleep and physical activity data. An online survey audio component reads the questions aloud to support the engagement of participants with limited literacy.
Data analysis and sample size considerations
Data analysis
The HOPE study is designed to evaluate the health of women living with HIV over their reproductive lifespan. Detailed statistical analysis plans will be developed for each specific HOPE study question. However, in general, for binary outcomes of interest, such as preterm birth, diagnoses of hypertension or depression, unsuppressed viral load, suboptimal retention in HIV care or substance use, the prevalence or the risk of such outcomes between different exposure groups will be compared using standard modelling techniques such as log-binomial regression, both unadjusted and adjusted for potential confounders. For continuous outcomes, such as body mass index or blood pressure, we will use general linear regression or generalised estimating equation (GEE) models, as appropriate, with and without adjustment for potential confounders. Examples of key ‘exposure’ groups include reproductive life stage and PHIV status.
Based on the longitudinal follow-up in the HOPE study, we will assess associations between exposures which may change over time and incidence rates of various conditions of interest, such as depression or hypertension, using Poisson regression models. We will evaluate key outcomes over time (eg, viral suppression, depression, hypertension, blood pressure, sleep quality), and changes in these outcomes. For binary conditions, we will use log-binomial models using GEEs for repeated measures and time-varying exposures or covariates. For continuous outcomes such as weight, log10 RNA or sleep duration, we will first visually inspect the trajectories by exposure group or risk factors using locally estimated scatterplot smoothing plots then use GEE or mixed effect models as appropriate to fit regression models as a function of age or elapsed follow-up time, spanning the reproductive life stages reflected by the HOPE protocol, adjusting for other risk factors or potential confounders. Finite mixture modelling techniques such as group-based trajectory modelling95 or growth mixture modelling96 will also be applied to identify subgroups with distinct patterns of trajectories.
To manage and account for data missingness, we will describe the reasons for missed study visits (eg, missed a visit due to hospitalisation, incarceration) and compare the characteristics of participants with missing versus non-missing data. Assumptions needed to obtain valid statistical inferences in the presence of missing data will be thoroughly investigated. When appropriate, for example, for accounting for missingness due to incomplete visit follow-up, factors associated with the propensity of missingness will be identified and included in analyses using missing data methods, such as multiple imputation and inverse probability weighting, to address potential selection bias.
Sample size
Some HOPE study aims and hypotheses will apply to all participants in the HOPE study, while others will be specific to a subgroup. For binary outcomes in cross-sectional comparisons, our target sample size of 1630 will provide 80% power at a 0.05 significance level to detect relative risks (RR) ranging from 1.17 to 2.5 depending on the underlying prevalence of the outcome of interest in the reference exposure group and the sample size distribution between the two exposure groups (online supplemental table 2). For continuous outcomes (eg, HIV stigma), the effect size is expressed as a difference in means between the exposure groups relative to a common SD. Online supplemental table 3 summarises the minimum detectable differences between two exposure groups based on a two-sample t-test at 80% power and alpha=0.05. For example, with a sample size of 1600 including 40% reporting food insecurity,97 the minimum detectable difference in mean stigma scores between food secure and food insecure participants is 0.14 SD. The power for longitudinal analyses will increase due to multiple measures for each participant and the corresponding minimal detectable RR or difference in mean will decrease.
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