More research, understanding needed for women with HIV

In 2020, there were 37.7 million women with HIV, comprising approximately half of the global population with HIV.¹ Women with HIV have a high burden of comorbidities, leading to AIDS-related illnesses being the leading cause of death globally among women of reproductive age.² There is a well-recognized sexual dimorphism in people with HIV, and sex differences in HIV acquisition.³ There is a known association between sex and immune activation in people with HIV, with many other sex differences. While some of these differences are influenced by social, behavioral, and societal factors, there are important biological factors, including anatomic, physiologic, hormonal, and genetic differences.³ A better understanding of sex differences and an awareness of the current data are needed to treat women with HIV successfully.

Women develop more robust immune responses to various pathogens compared with men, and innate immune sensing of HIV is stronger in women than men.⁴ Women with HIV also gain more weight than men after starting antiretroviral therapy (ART), regardless of ART regimen.⁴ Sex differences exist in navigating the HIV care continuum, especially the ability to maintain virologic suppression.⁵ Female sex is an independent predictor of low bone mass.⁶ In fact, bone mineral density declines at twice the rate in women compared with men. Special consideration should be given to the impact of bone loss during pregnancy, lactation, and menopause.⁶

There are sex-specific factors of HIV infection dynamics. The HIV reservoir in women has different characteristics than that in men.^2,7 The total amount of HIV DNA declines more slowly in women, and the inducible HIV RNA reservoir (enriched with replication-competent virus) increases in women after menopause.⁷ This phenomenon is becoming more critical as the population with HIV ages, and more women with HIV are entering menopause. Of note, women with HIV experience more menopausal symptoms at an earlier age than those without HIV.⁷ Hormonal changes, particularly estradiol, should be considered for “kick and kill” interventions. These interventions should be tailored to the specific environment of the reservoir, including the effect of hormones and other immunologic changes.⁷

It is known that HIV-associated cognitive impairment occurs with uncontrolled viral replication.⁸ However, a cross-sectional study of 104 people with HIV (women, n=33; men, n=71) who were virologically suppressed noted that women with HIV are more vulnerable to cerebrovascular injury leading to effects on cognitive health compared with men.⁹ A meta-analysis pulled data from 27 studies and 801,017 participants and found that women with HIV are more likely to experience suicidal ideation (odds ratio [OR], 1.3; 95% CI, 1.1-1.6; P<0.05) and suicide attempts (OR, 1.3; 95% CI, 1.0-1.8; P<0.05) compared with men.¹⁰ There is no reported difference in the risk for death by suicide between sexes. This trend is also seen in the general population despite a recently increased recognition of and prevention efforts for suicide.

In a study of 2,304 people with HIV naive to ART, including 15% women, who were starting a dolutegravir-based regimen, there was a higher risk for dolutegravir discontinuation due to toxicity in women than in men (adjusted hazard ratio, 1.6; 95% CI, 1.1-2.4).¹¹ Both neuropsychiatric and other toxicities were reported in women. However, it was noted that the absolute risk for discontinuing dolutegravir due to toxicity was low.¹¹ In women with HIV, coronary endothelial function is impaired, which should be considered when looking at all potential contributors to cardiovascular events.¹² In addition, levels of proprotein convertase subtilisin/kexin type 9 were higher in women with HIV (306 ng/mL [200-412 ng/mL] compared with those without HIV (180 ng/mL [154-223 ng/mL]; P<0.001). In a study of lung function in women with HIV and those without, HIV was associated with impaired respiratory gas exchange.¹³ Among women with HIV, lower nadir CD4 T-lymphocyte cell count and hepatitis C were also associated with decreased respiratory gas exchange.

Greater inclusion of women in clinical research will be required to end the US HIV epidemic.¹⁴ The ability to detect sex differences in HIV treatment and prevention will continue to be hindered until more female participants are included in clinical trials. Innovative approaches to recruiting female participants and retaining them in care are needed.¹⁵ There has also been a longtime need for more female-centered and culturally competent HIV care.¹⁶ In addition, more treatment and prevention efforts, access to medication, and other wraparound services are needed. Specific attention should be given to cure efforts in women with HIV.

References

1. UNAIDS. UNAIDS Data 2021. Accessed April 20, 2023. https://www.unaids.org/sites/default/files/media_asset/JC3032_AIDS_Data_book_2021_En.pdf
2. Rao S. Sex differences in HIV-1 persistence and the implications for a cure. Front Glob Womens Health. 2022;3:942345.
3. Moran JA, Turner SR, Marsden MD. Contribution of sex differences to HIV immunology, pathogenesis, and cure approaches. Front Immunol. 2022;13:905773.
4. Bares SH, Smeaton LM, Scott SE, et al. The association between weight gain, sex, and immune activation following the initiation of antiretroviral therapy. J Infect Dis. 2021;224(10):1765-1774.
5. Maragh-Bass AC, Gamble T, El-Sadr WM, et al. Examining stigma, social support, and gender differences in unsuppressed HIV viral load among participants in HPTN 065. J Behav Med. 2021;44(2):159-171.
6. Tang MJ, Alexander A, Hoy JF. Gender and sex considerations in HIV and bone health. Curr Opin HIV AIDS. 2023;18(2):75-80.
7. Gianella S, Rawlings SA, Dobrowolski C, et al. Sex differences in human immunodeficiency virus persistence and reservoir size during aging. Clin Infect Dis. 2022;75(1):73-80.
8. Dreyer AJ, Munsami A, Williams T, et al. Cognitive differences between men and women with HIV: a systematic review and meta-analysis. Arch Clin Neuropsychol. 2022;37(2):479-496.
9. Chow FC, Zhao F, He Y, et al. Brief report: sex differences in the association between cerebrovascular function and cognitive health in people living with HIV in urban China. J Acquir Immune Defic Syndr. 2023;92(3):217-222.
10. Hu FH, Zhao DY, Fu XL, et al. Gender differences in suicidal ideation, suicide attempts, and suicide death among people living with HIV: a systematic review and meta-analysis. HIV Med. Published online November 8, 2022. doi:10.1111/hiv.13435
11. D’Arminio Monforte A, Tavelli A, Sala M, et al. Long-term outcome of dolutegravir-containing regimens according to sex: data from the ICONA study. J Antimicrob Chemother. Published online February 13, 2023. doi:10.1093/jac/dkad026
12. Minhas AS, Leucker TM, Goerlich E, et al. Effect of sex on coronary endothelial dysfunction in people living with HIV. J Am Heart Assoc. 2022;11:e026428.
13. Wang RJ, Nouraie M, Kunisaki KM, et al. Lung function in women with and without human immunodeficiency virus. Clin Infect Dis. 2023;76(3):e727-e735.
14. Adimora AA, Ramirez C, Poteat T, et al. HIV and women in the USA: what we know and where to go from here. Lancet. 2021;397(10279):1107-1115.
15. Zhou S, Qi K, Nugent BM, et al. Participation of HIV-1 infected treatment-naÏve females in clinical trials and sex differences in efficacy and safety outcomes. AIDS. Published online January 9, 2023. doi:10.1097/QAD.0000000000003478
16. Pomeroy C. Social determinants of HIV risk in women. Virtual Mentor. 2008;10(7):457-464.

By Milena Murray, PharmD, MSc, BCIDP, AAHIVP, FCCP