Women and HIV: Gaps in Care

BY JACOB BOUDREAUX, MD, AND JULIA GARCIA-DIAZ, MD, MSC, FACP, FIDSA, CPI

The first cases of the US HIV epidemic were recognized in 1981, primarily among men who have sex with men (MSM). By 1988, the incidence of men living with HIV was nearly 15 times the rate of women.1 At the time, HIV affected the MSM community, as well as racial and ethnic minorities, at disproportionally higher rates. In the decades since then, research into HIV treatment protocols, HIV-related disease, comorbidities, and outcomes has been heavily focused on these groups. However, the incidence of HIV among these subgroups has changed significantly in the last 40 years in relation to the incidence of women living with HIV. By 2010, a shift was seen among women who comprised 21% of total HIV cases in the United States, while the incidence rate for men dropped to 3 times the rate seen in women.1

At the end of 2016, women accounted for 23.7% of all people living with HIV in the United States, and as of 2020, women represent one-fourth of all HIV cases nationally.2 In 2017, women represented a larger percentage of people living with HIV globally, accounting for 52% of total cases, or 18.2 million women. This trend has remained stable, as women continue to represent nearly half of all cases globally each year.3 Despite being equally represented in total global cases of HIV, women continue to be underrepresented in HIV research. This gap in representation is especially shocking as HIV and HIVrelated disease are the leading causes of death among women of reproductive age (ie, 15-49 years).4 In 2019, the Department of Health and Human Services announced a new goal to reduce the incidence of HIV infections by 90% within the decade.5 To achieve this goal, the importance of addressing the health care needs of women living with HIV—both diagnosed and undiagnosed—needs a sharper focus. This review serves as an update to information published in 2019 in Infectious Disease Special

Edition and examines the needs of 3 subgroups of women living with HIV, presents updated treatment regimens for pregnant women living with HIV, and discusses the areas of increased need for women in HIV research (https://www.idse.net/Review-Articles/ Article/06-19/The-Forgotten-Patient/55122).

The health care needs of women living with HIV in the United States vary due to several interwoven factors—including age, race, sex, and region—that pose challenges to achieving early diagnosis, treatment, and management of comorbid conditions. Three important subgroups include women who are of reproductive age, older women, and transgender women.

Women of Reproductive Age With HIV

According to a 2018 study, approximately 40% of women of reproductive age with HIV may choose to have children.6 Special attention, including comprehensive reproductive care inclusive of planning considerations, antiretroviral therapy (ART), and infant feeding practices, should be offered to this group; an estimated 5,000 American women living with HIV give birth annually.7 In the United States, the annual incidence of vertical HIV transmission has declined nearly 95% in the last 30 years with increased uptake of ART.8 This includes daily ART throughout pregnancy and neonatal ART for 4 to 6 weeks after delivery; when successfully combined, these interventions have reduced the rate of vertical HIV transmission to 1%.8 While protecting a developing fetus may be a strong incentive for encouraging and maintaining ART adherence throughout the gestational period, patient concerns of potential effects of ART contributing to adverse birth outcomes remain an important area of research. A 2019 study that explored adverse pregnancy outcomes among women who conceive on ART stated that the “relatively low risks of adverse pregnancy outcomes must be weighed against the tremendous benefit of lifelong, uninterrupted ART.”9 However, higher quality data on a large population of pregnant women with HIV into the effects of newer ART regimens in particular and potential effects are needed.

In the United States, women who are initiating ART while pregnant or trying to become pregnant are recommended dolutegravir (DTG), raltegravir (RAL), atazanavir-ritonavir, and darunavir (DRV)-ritonavir as the “preferred” treatment regimens.10 In 2018, preliminary data from the Tsepamo study in Botswana indicated a slightly significant increased risk in fetal neural tube defects (NTDs) among pregnant women with HIV on DTG, which was 0.19% among women taking DTG versus 0.07% for efavirenz (EFV).10 In response to the Botswanan primary data, Sibiude et al evaluated the risk for birth defects and adverse pregnancy outcomes to exposure of integrase strand transfer inhibitors (INSTIs) around conception.11 Of the 808 women who were on INSTIs for ART during conception (RAL 703, DTG 57, and elvitegravir 48), 6.7% of those on RAL at conception experienced birth defects, compared with 2.9% who initiated RAL later during gestation as first-line treatment and 2.5% as second-line treatment; no NTDs were observed in the study.11 Other prenatal outcomes were not statistically significant between groups exposed to RAL or DRV, such as incidence of stillbirth (RAL 1.6%, or 2 births; DRV 1.2%, or 2 births) or preterm birth (RAL 12.8%, or 16 births; DRV 11.2%, or 14 births).11 In addition, there were no differences in weight, length, or head circumference for those with INSTI exposure.11 In response to the Botswanan data, a randomized cohort study was conducted in Brazil to evaluate whether DTG exposure increased the risk for NTDs, stillbirths, or miscarriages in pregnant women with HIV. Of 1,427 women, 382 were exposed to DTG within 8 weeks of their estimated date of conception. One hundred eighty-three women (48%) of DTG-exposed and 382 (44%) of EFV-exposed women received folic acid supplementation during pregnancy. Results suggest that neither DTG nor EFV was associated with NTDs, stillbirths, or miscarriages.12 These data are reassuring that outcomes in women on DTG-based regimens are safe, but more data are needed. At CROI 2021, 2 abstracts were presented regarding the safety of DTG in pregnancy. First, Chinula et al presented research on 643 pregnant women with HIV-1 from 9 countries randomized 1:1:1 DTG+FTC/

TAF (tenofovir alafenamide with emtricitabine; n=217), DTG+FTC/TDF (tenofovir alafenamide; n=215), or EFV/FTC/TDF (n=211) at 14 to 28 weeks’ gestational age; 607 women completed the study.13 Among the 3 arms of the study at 50 weeks’ postpartum, there were no statistical differences observed in maternal or infant adverse events, infant mortality, or infant HIV infection, although fewer women in the DTG+FTC/TAF arm (24.1%) had an adverse pregnancy outcome than in the DTG+FTC/TDF (32.9%; P=0.043) or EFV/FTC/TDF (32.7%; P=0.047) arm.13

Second, Malaba et al presented results of 268 mothers randomized to receive EFV (n=133) or DTG (n=135); viral loads were measured at 6, 12, 24, 48, and 72 weeks’ postpartum.14 Viral loads less than 50 copies/mL for efficacy and occurrence of maternal or infant drug adverse events were the primary study end points. Women randomized to DTG achieved viral suppression more quickly and maintained suppression longer than those receiving EFV. Women who received DTG achieved the viral load goal with a median time of 4.14 weeks, compared with a median time of 12.14 weeks for those receiving EFV. Regarding

40%

Transgender women who stopped ART due to concerns about interactions with hormone therapy.

adverse events, DTG (2.2%) was better tolerated compared with EFV (3.6%). Only 3% of adverse events were related to the study drug, and no infant drugrelated events were reported.14

Breastfeeding is also an area of special concern among pregnant women with HIV. US guidelines recommend against breastfeeding during the perinatal period, yet a 2019 survey of health care workers stated that 29% have cared for a patient with HIV who chose to breastfeed and that most patients’ primary concerns for choosing to breastfeed over using formula was because of social stigma.15 This is consistent with a 2021 survey in the United Kingdom that indicated one-third of surveyed pregnant women with HIV prefer to breastfeed their infants.16 While ART throughout the gestational period significantly reduces the risk for vertical transmission, it does not eliminate the risk for transmission through breastfeeding postnatally. Further research to guide clinical and virologic monitoring is warranted for women of reproductive age in both high- and low-income countries when mothers living with HIV decide that breastfeeding is right for their children.17

Older Women and HIV

Due to the wider use of ART, people with HIV are living longer, healthier lives; as of 2019, 51% of all people diagnosed with HIV in the United States were 50 years of age or older, and 1 in 6 new cases of HIV was diagnosed in those older than 50 years of age.18 While adult women have many of the same risk factors associated with younger women, there are unique risks to this subgroup: less openness to discuss sexual health or drug use, lack of knowledge of sexual risk and HIV prevention, and perceived stigma associated with HIV and aging. Due to these factors, older women are more likely to be diagnosed later than their younger cohorts and begin treatment later. In 2015, people older than 55 were most likely to have the longest delay in HIV diagnosis—4.5 years, according to the CDC. 18

For these women, increased attention to their health needs and the effects of HIV on aging is appropriate. A 2018 cross-sectional study of the symptom burden for older women living with HIV reported that postmenopausal women had higher symptom burden scores for muscle aches/pains, fatigue, and insomnia.19 A 2019 study by Frazier et al compared cardiovascular risk comorbidities between men and women with HIV in those 50 to 64 and older than 65 years of age.20 Their results indicated that women with HIV between 50 and 64 years of age were more likely to be obese, hypertensive, and have higher total cholesterol levels; women with HIV older than 65 were also more likely than men to have diabetes mellitus and higher total cholesterol levels.20

Also presented at CROI 2021, “Inflammation Could Help Predict HIV Women Cardiovascular Risks” evaluated sex-modified inflammatory predictors of cardiovascular disease (CVD) and venous thromboembolism risks in people with HIV.21 Consisting of a randomized sample of 979 patients (82% male, 18% female) from the Centers for AIDS Research Network of Integrated Clinical Systems with plasma samples after more than 1 year of viral suppression on ART, results indicated that inflammatory markers were more strongly correlated with CVD and associated events in women than men with C-reactive protein, lipopolysaccharide-binding protein, sCD14, suPAR, ICAM-1, cytomegalovirus immunoglobulin G, and soluble tumor necrosis factor receptor 2 markers, pointing toward increased risk prediction in women. The significant effect that these inflammatory markers have on CVD risk in women with HIV underscores the importance of including more women in HIV interventional research.21 Further research and systematic review into the physiologic and psychological health needs of older women with HIV are warranted to address their health care needs.

Transgender Women and HIV

Transgender women in the United States represent an estimated 1.3% of total patients receiving care for HIV, yet represent only 0.28% of the US population.1,22 Prevalence of HIV among trans women, as of 2017, is estimated to be at 14%, which is markedly higher than their cis women counterparts, whose prevalence is less than 1%.2 Data for trans women have been historically lacking, as the CDC used to classify trans women under MSM for surveillance data collection. For trans women who already experience discrimination and physical, emotional, and sexual violence at higher rates compared with cis individuals, increasing access to comprehensive HIV treatment and consistent follow-up poses additional challenges. This is complicated by a lack of research concerning ART and hormone therapy (HT), which can be lifesaving for trans women.1 In 2017, Braun et al observed that among trans women with HIV, only 49% discussed ART–HT drug–drug interaction with their health care provider, and 40% reported not taking ART due to

concerns of drug–drug interactions.23 Enrolling trans women into larger research studies designed to evaluate potential interactions between ART and HT will help guide clinicians in counseling their patients on the safety of ART while on HT. Few trials exist.

In 2017, a study reviewed Medicare fee-for-service claims data to evaluate demographic characteristics and chronic disease burden for the transgender population, which demonstrated that trans individuals experienced multiple chronic conditions at higher rates than cis individuals.24 Coupled with the disproportionality, increased prevalence of HIV among trans women, and societal factors that interfere with their care, trans women represent a uniquely vulnerable population with challenges to meet their basic health care needs. Future trials need to include trans women in their enrollments in sufficient numbers to guide clinical care for this important subgroup.

Conclusion

Management protocols for treating women with HIV continue to adapt to new research, but more studies are needed that enroll women in proportion to their representation of total people living with HIV. New updates provide insight into current and future research and highlight areas of increased need. Women of reproductive age, older women, and transgender women face challenging burdens that deserve consideration and increased recruitment and enrollment in future HIV management and vaccination trials.

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The authors reported no relevant financial disclosures.

About the authors

Jacob Boudreaux, MD, is a 2020 graduate of the University of Queensland/Ochsner Clinical School, in Brisbane, Australia. He is a first-year resident at Ochsner Medical Center, New Orleans, Louisiana.

Julia Garcia-Diaz, MD, MSc, FACP, FIDSA,

CPI, is the director of clinical research, and an associate professor at the University of Queensland, Ochsner Clinical School, in Brisbane, Australia; and a clinical assistant professor at Tulane University School of Medicine, Ochsner Medical Center, in New Orleans, Louisiana.