Contemporary Issues on the Treatment of Women Living with HIV in the US

Women comprised 19% of new HIV cases in 2019, and approximately 22% of individuals with HIV as of 2018 were women.¹ Women face a number of unique issues related to HIV care. Sex disparities in treatment and adherence continue to exist, and investigators strive to better understand issues around antiretroviral pharmacokinetics, contraception, pregnancy, other AIDS-related conditions, and prevention for women with or at risk for acquiring HIV.

In the past 40 years, antiretroviral therapy has advanced in ways that make achieving viral suppression tangible for many. Individuals with HIV in the United States are living longer.² As this cohort ages, increasing focus has been placed not only on controlling the virus, but also on understanding the development and prevalence of other common chronic diseases in the setting of HIV and the impact of these combined factors on an individual’s health. Several recent studies have examined non-AIDS comorbidities in women with HIV in order to raise awareness of the opportunities to provide preventative screenings and improve overall care for this population.

HIV Increases the Risk of Multiple Comorbidities

Living with HIV appears to accelerate or intensify comorbidities. In the Women’s Interagency HIV Study (WIHS), 2309 women with HIV who were virally suppressed on treatment were compared with 923 HIV-seronegative women.³ The long-standing WIHS cohort has lengthy follow-up, and on average the participants were observed for greater than 15 years. Women with HIV accumulated a higher number of non-AIDS comorbidities than HIV-seronegative women (3.6 vs 3.0, P < .0001). This trend was also observed in a retrospective study of administrative claims from the Optum database. Women with HIV more frequently had multiple (>2) comorbidities (59.4% vs 52.9%) and more than 5 nonantiretroviral medications (81.5% vs 74.9%) when compared with women without HIV across any age strata.⁴

These 2 recent studies, along with several other published studies, strongly suggest that having HIV imparts higher risk for multimorbidity.^5-9 Investigators also have attempted to identify specific comorbidities driving this increase. In the WIHS study, psychiatric illness, dyslipidemia, non-AIDS cancers, kidney, liver, and bone disease were more prevalent in women with HIV compared with the HIV-seronegative control participants. The WIHS results did not show differences in hypertension, diabetes, and cardiovascular and lung disease by HIV status.3 In contrast, a study of a large US population database included 10,590 women with HIV on antiretroviral treatment who were active in the database from 2015 to 2020 and compared them with 14,546,020 women controls. This study’s results found that cardiovascular disease (PR 2.05, 95% CI, 1.96-2.15), hypertension (PR 1.37, 95% CI, 1.35-1.40), lung disease (2.06, 95% CI, 2.01-2.11), and diabetes (PR 1.48, 95% CI, 1.43-1.53) were more prevalent in women with HIV after adjustment for age and race.¹⁰ The Optum administrative claims database also showed an increased prevalence of hypertension (44.6% vs 38.8%), cardiovascular disease (14.3% vs 12.6%), and diabetes (21% vs 19.5%) in women with HIV compared with those without.⁴ The contrasting findings between the database-driven studies and the WIHS study are likely due to differences in control groups; WIHS includes a cohort of women at risk for HIV whereas the latter studies used a more generalized population database.

Associations Between Sex, HIV, and Comorbidities

Althoughmany studies have documented an increased prevalence of comorbid conditions for individuals with HIV compared with those without, biological sex may add an additional layer of risk. The (Multicenter AIDS Cohort Study) MACS/WIHS Combined Cohort Study (MWCCS) examined non-AIDS comorbidities among its participants.¹¹ In the study there were significant differences between the male and female populations by race, income, and other characteristics; the MWCCS attempts to recruit a cohort that represents populations most affected with HIV in the United States. Overall, women (HIV-infected and noninfected) had an increased number of comorbidities compared with men (3.4 vs 3.2, P = 0.015). In the group of individuals living with HIV, women had significantly more comorbidities than men across all age strata. Amongst HIV-seronegative individuals, this pattern of increased comorbidity burden by sex was not observed. When adjusted for self-reported race, tobacco, alcohol, or crack/cocaine use as well as socioeconomic status, HIV and age remained important modifiers of the relationship between sex and non-AIDS comorbidities (P for interaction term= 0.038).

Another study examined the relationships between sex, HIV, and diabetes using a large US electronic medical records database.¹² The cohort included 39,485 individuals with HIV and 13,015,560 seronegative controls seen between 2015 and 2020. Diabetes was present in more women with HIV compared with those without HIV (22% vs 14%, P< 0.001) whereas the opposite was true for men living with HIV (16% vs 17%, P<0.002). Women with HIV had consistently higher rates of diabetes across different age categories, whereas for men the prevalence differed across the age strata. In the regression analysis examining the relationship between type 2 diabetes and HIV, women had a significantly higher odds of diabetes (OR 1.31, 95% CI, 1.06-1.13) even after adjustment for age, race, obesity, hypertension, hyperlipidemia, and smoking.

Much research is still required to untangle the biological pathways through which sex influences the development of these comorbidities and subsequent outcomes. Differences in inflammatory biomarkers may provide some insight.¹³ A recent study conducted in the CFAR Network of Integrated Clinical Systems cohort evaluated participants who were suppressed on antiretroviral (ART for at least 1 year and had received a diagnosis of myocardial infarction, ischemic stroke, or venous thromboembolism (VTE). It compared them with a cohort of individuals who did not develop any of these events.¹⁴ The study examined 11 inflammatory markers and their association with vascular event risk, age, sex at birth, CD4+ nadir, smoking, injection drug use, Atherosclerotic cardiovascular disease( ASCVD risk scores, and hepatitis C history. There were 159 cases of myocardial infarction or stroke and 80 cases of VTE among 979 eligible individuals. The investigators found a significant interaction between age and inflammation for women. Women had higher levels of C-reactive protein (CRP), Low back pain (LBP), sCD¹⁴, soluble urokinase Plasminogen Activator Receptor

(suPAR), ICAM-1 and Cytomeglovirus (CMV) Immunoglobulin G (IgG) compared with men (1.4-fold to 2.5-fold increased interquartile range, P<0.03). For women, inflammatory biomarkers were more closely associated with myocardial infarction and stroke, whereas in men, the biomarkers were more strongly associated with VTE events. This study’s results suggest that although inflammation plays an important role in all types of cardiovascular and thromboembolic events, sex differences influence their occurrence.

Multimorbidity and its consequences are influenced by a complex set of factors that include sex, HIV infection, and more. The ProjEcting Age, MultimoRbidity, and PoLypharmacy model is a simulation tool that utilizes data from the North American AIDS Cohort Collaboration on Research and Design to predict the burden of multiple morbidities in key HIV populations in the United States through 2030.¹⁵ This program predicts that the highest overall comorbidity burden will be seen in Black women with HIV who use injection drugs, and the steepest increase in comorbidities will be seen in Hispanic heterosexual women with HIV. The conditions that were most prevalent in the model included hypertension, diabetes, chronic kidney disease, anxiety, and depression. The ability to predict potential comorbidities that will affect women and other specific populations can be deeply informative for screening, prevention, resource allocation, and differentiated care models.

Implications for Care

Awareness of the influence of HIV and sex on the development of non-AIDS comorbidities has several implications for the clinician. Prior studies have suggested disparities in the quality of preventative care provided for individuals with HIV.¹⁶ At minimum, this growing body of information regarding the associations between sex, HIV, and multimorbidity advocates for increased vigilance around screening for common chronic conditions in women and others with HIV. As specific comorbidities are identified by sex and age earlier, more targeted screenings may also play a role. The increasing presence of multiple non-AIDS comorbidities in women and others living with HIV challenges clinicians to steer away from the approach of optimizing individual chronic conditions but to think more holistically. It is difficult to untangle the biological, social, and environmental factors that are interconnected with HIV and sex, and clinicians must consider all of these as they manage HIV and other chronic conditions.

Managing comorbidities can be challenging due to lack of specific guidance for certain conditions in the setting of HIV as well as the difficulty of staying abreast of updates and changes. The Primary Care Guidance for Persons Living with HIV as published by the HIV Medicine Association HIV Medicine Association of the Infectious Diseases Society of America released in 2020 is a compact compendium of recommendations.¹⁷ Another helpful resource is the HIV & Aging website developed by the American Academy of HIV Medicine. It has a number of articles on managing chronic conditions.18 As women with HIV age, their care needs will continue to change across their lifespans. Further research around HIV, comorbid conditions, and sex will help to inform best care practices.

References

1. ^{CDC. HIV and women: viral suppression. July 20, 2021. Accessed August 26, 2021. https://www.cdc.gov/hiv/group/gender/women/viral-suppression.html}
2. ^{Frank TD, Carter A, Jahagirdar D, et al. Global, regional, and national incidence, prevalence, and mortality of HIV, 1980-017, and forecasts to 2030, for 195 countries and territories: a systematic analysis for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. Lancet HIV. 2019;6(12):e831-e859. doi:10.1016/S2352-3018(19)30196-1}
3. ^{Collins LF, Sheth AN, Mehta CC, et al. The prevalence and burden of non-AIDS comorbidities among women living with or at risk for human immunodeficiency virus infection in the United States. Clin Infect Dis. 2021;72(8):1301-1311. doi:10.1093/cid/ciaa204}
4. ^{Paudel M, Prajapati G, Buysman E, Goswami S. Higher comorbidity and comedication burden in women and young people living with HIV. [Abstract OAA0104]. In: Abstracts From the Virtual IAS 2021 Conference on HIV Science. https://ias2021.org/wp-content/uploads/2021/07/IAS2021_Abstracts_web.pdf}
5. ^{Pourcher V, Gourmelen J, Bureau I, Bouee S. Comorbidities in people living with HIV: An epidemiologic and economic analysis using a claims database in France. PLoS One. 2020;15(12):e0243529. doi:10.1371/journal.pone.0243529}
6. ^{Allavena C, Hanf M, Rey D, et al. Antiretroviral exposure and comorbidities in an aging HIV-infected population: The challenge of geriatric patients. PLoS One. 2018;13(9):e0203895. doi:10.1371/journal.pone.0203895}
7. ^{Kong AM, Pozen A, Anastos K, Kelvin EA, Nash D. Non-HIV comorbid conditions and polypharmacy among people living with HIV age 65 or older compared with HIV-negative individuals age 65 or older in the United States: a retrospective claims-based analysis. AIDS Patient Care STDS. 2019;33(3):93-103. doi:10.1089/apc.2018.0190}
8. ^{Yu X, Westra JR, Giordano TP, Berenson AB, Baillargeon JG, Kuo YF. Assessing comorbidities and survival in HIV-infected and uninfected matched Medicare enrollees. AIDS. 2021;35(10):1667-1675. doi:10.1097/QAD.0000000000002963}
9. ^{Williams ND, Huser V, Rhame F, Mayer CS, Fung KW. The changing patterns of comorbidities associated with human immunodeficiency virus infection, a longitudinal retrospective cohort study of Medicare patients. Medicine (Baltimore). 2021;100(16):e25428. doi:10.1097/MD.0000000000025428}
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11. ^{Collins LF, Palella F, Mehta CC, Holloway J. HIV differentially impacts age-related comorbidity burden among US women and men. [Abstract 526]. In: Abstracts From the Virtual CROI 2021 Conference on Retroviruses and Opportunistic Infections. Abstract eBook. https://www.croiconference.org/wp-content/uploads/sites/2/resources/2021/vCROI-2021-Abstract-eBook.pdf}
12. ^{Birabaharan M, Kaelber D, Martin T. Sex differences in diabetes prevalence among persons with HIV in the United States. [Abstract 520]. In: Abstracts From the Virtual CROI 2021 Conference on Retroviruses and Opportunistic Infections https://www.croiconference.org/wp-content/uploads/sites/2/resources/2021/vCROI-2021-Abstract-eBook.pdf}
13. ^{Peterson TE, Baker JV. Assessing inflammation and its role in comorbidities among persons living with HIV. Curr Opin Infect Dis. 2019;32(1):8-15. doi:10.1097/QCO.0000000000000510}
14. ^{Schnittman SR, Beck-Engeser GB, Shigenaga JK, et al. Sex modifies the association between inflammation and vascular events in treated HIV. [Abstract 98]. In: Abstracts From the Virtual CROI 2021 Conference on Retroviruses and Opportunistic Infections. https://www.croiconference.org/wp-content/uploads/sites/2/resources/2021/vCROI-2021-Abstract-eBook.pdf}
15. ^{Kasaie P, Stewart C, Humes E, et al. Multimorbidity in people with HIV using ART in the US: projections to 2030. [Abstract 102]. In: Abstracts From the Virtual CROI 2021 Conference on Retroviruses and Opportunistic Infections. Abstract eBook. https://www.croiconference.org/wp-content/uploads/sites/2/resources/2021/vCROI-2021-Abstract-eBook.pdf}
16. ^{Landovitz RJ, Desmond KA, Gildner JL, Leibowitz AA. Quality of care for HIV/AIDS and for primary prevention by HIV specialists and nonspecialists. AIDS Patient Care STDS. 2016;30(9):395-408. doi:10.1089/apc.2016.0170}
17. ^{Thompson MA, Horberg MA, Agwu AL, et al. Primary care guidance for persons with HIV. November 6, 2020. Accessed August 30, 2021. https://www.idsociety.org/practice-guideline/primary-care-management-of-people-with-hiv/}
18. ^{HIV & Aging. AAHIVM Provider Education Center. Accessed August 30, 2021. https://aahivm-education.org/hiv-age/contents}