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Menopause Is Associated With Immune Activation in Women With HIV; mortality, heart disease, discrimination, stigma
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JID June 2021 Brandilyn A. Peters,1, Xiaonan Xue,1 Lila A. Sheira,2 Qibin Qi,1 Anjali Sharma,3 Nanette Santoro,4 Maria L. Alcaide,5 Igho Ofotokun,6 Adaora A. Adimora,7Heather S. McKay,8 Phyllis C. Tien,9,10 Katherine G. Michel,11 Deborah Gustafson,12 Bulent Turan,13,aAlan L. Landay,14 Robert C. Kaplan,1,15 and Sheri D. Weiser2,10,
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Women with HIV suffer more with higher rates of inflammation and higher rates of comorbidities, as reported in studies over the past year, as well it appears of mortality, higher death rates. The question of the impact of menopause on this worse aging phenomenon has been discussed with many doctors & researchers saying menopause is a contributing factor. Here is the latest study supporting that women with Hiv suffer worse consequences of aging with HIV. Yet for years the many of their needs & concerns have remained unaddressed. Racial discrimination & stigma increase inflammation & worsen the affects of aging among PWH. More, the aging & HIV problem remains underestimated & misunderstood by PWH, some federal officials & by advocates - all of whom have neglected this problem because they do not fully understand or appreciate it. The new published study from he NY Weill-Cornell HIV Clinic depicts exactly the impact of aging on older PWH in NYC and its a clear but not pretty picture with high rates of mental & physical impairment, reduced ability with aging to function normally & perform normal daily activities and high rates of comorbidities. When will our broad community face this reality and recognize the problem. False narratives about "near normal" lifespan for all PWH are common and reflect not knowing the data nor the real world problem, here is the latest study reported last week at IDWeek reporting higher mortality rates for Black women with HIV & the HRSA study published December 2020 reporting higher rates of mortality, death for PWH on Medicare with African-Americans & Latinos bearing the worst brunt. Its not only women, men with HIV, all PWH suffer greater stigma & lifetime trauma that no doubt contributes to "accelerated" or premature aging for PWH. Kaiser & Julia Marcus reported at CROI & in Annals in 2020 9 years reduce life expectancy for PWH which was of note tied with worse social determinants of health, but also reported premature onset of comorbidities by 10-15 years, which we have seen from other studies. Yet all of this remains not getting the recognition & attention it deserves, have older aging PWH no dif=gnity, do we get so disregarded by the broader community & federal leaders? yes. Jules Levin, NATAP
IDWeek: Sex and race disparities in premature mortality among people with HIV: a 21-year observational cohort study - Premature Mortality Higher in Women and Blacks in US HIV Group - (10/01/21)
HRSA Aging/HIV Medicare Paper - "need for personalized care & maximizing functional status....training medical professionals....increased coordination & integration of services, geriatric services " - (09/08/21)
Black and Hispanic women in the United States are disproportionally affected by the HIV infection - (09/25/21)
Racial Discrimination & Inflammation/Comorbidities - Experienced discrimination and racial differences in leukocyte gene expression - (09/10/21)
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A recent report of 65 women without HIV found that biomarkers of gut barrier dysfunction, microbial translocation, and immune activation increased during the menopausal transition [12]. Menopause marks the end of the reproductive phase of a woman's life, when complete depletion of ovarian follicles leads to loss of ovarian production of sex hormones estradiol and progesterone [13]. Both hormones appear important for gut barrier integrity [14-18], and estradiol also has well known cardioprotective properties [19-21]. In the context of HIV infection, estradiol and progesterone can inhibit HIV replication and are thought to maintain HIV latency [22, 23]. Women with HIV have lower estradiol and ovarian reserve [24, 25], higher levels of microbial translocation and immune activation [26], and higher cardiovascular risks [27-29] than women without HIV, suggesting that menopause-related decline in sex hormones may pose unique morbidity risks. However, the effect of the menopausal transition on microbial translocation, immune activation, and inflammation is unknown in women with HIV.
Here, we examined the association of menopause status with plasma biomarkers of gut barrier dysfunction, innate immune activation, and systemic inflammation in women with HIV from the Women's Interagency HIV Study (WIHS). Additionally, we explored changes in these biomarkers over time relative to the final menstrual period, to understand effects of the menopausal transition above those of chronological aging alone [30].
In summary, postmenopausal women with HIV had evidence of increased innate immune activation relative to premenopausal women, with this increase occurring during the menopausal transition. However, menopause was not associated with increases in key markers of systemic inflammation, making the consequences of the menopause-related immune activation unclear. Additional longitudinal research following women with HIV through the pre- and postmenopausal stages is necessary to explore whether women who experience an increase in immune activation during menopause also experience increased inflammation and other disease risks. Compounded effects of HIV, aging, and menopause on immune activation could put aging women with HIV at particularly high risk of non-AIDS-related disease and mortality. Thus, research on the health of women with HIV during and after the menopausal transition is of paramount importance, including clinical research on the effectiveness of interventions (eg, health monitoring, lifestyle modifications, hormone therapy) to reduce disease risk.
In this study of women with HIV, we observed higher levels of innate immune activation, measured by plasma sCD14 and sCD163, in postmenopausal compared to premenopausal women. sCD14 and sCD163 may indicate microbial translocation, but could also relate to other homeostatic or inflammatory processes. sCD14 and sCD163 have been associated with CVD risk [7-10] and mortality [4-6] in HIV, suggesting that menopause-related increases in sCD14 and sCD163 may have clinical consequences. For example, the magnitude of increase in sCD14 we observed per year during the menopausal transition is comparable to the difference in sCD14 observed between HIV patients who died and controls in a mortality study. However, the observed increase in sCD14 during the menopausal transition did not appear to be maintained postmenopause-in our piece-wise linear regression, the trajectory in the postmenopausal period did not align with the accelerated trajectory during the menopausal transition (Figure 2); and, although sCD163 was elevated in post- compared to premenopausal women, the increase during the menopausal transition was not statistically significant in our piece-wise models. The menopausal transition itself is increasingly recognized as a pivotal time for CVD prevention [21]. Whether the sharp but fleeting observed increase in sCD14 during the menopausal transition in women with HIV is important for disease risk will need to be evaluated in future research.
A plausible mechanism for the observed menopause-related increase in innate immune activation may be preventive effects of sex hormones on gut permeability and microbial translocation. Experimental evidence indicates that estrogen and progesterone maintain the gut barrier [14-18], and in human studies progesterone has been inversely correlated with microbial translocation [38, 39]. Thus, declines in estrogen and progesterone during the menopausal transition could impair the gut barrier and increase microbial translocation and immune activation. Only 1 study has examined the effect of menopause on the gut barrier, microbial translocation, and immune activation: in 65 women without HIV from the Study of Women's Health Across the Nation (SWAN), plasma IFAB, lipopolysaccharide binding protein (LBP), and sCD14 increased significantly within woman from pre- to postmenopause, while lower plasma estradiol was associated with higher IFAB and sCD14 [12]. Although that analysis did not adjust for concurrent age, it suggests that microbial translocation increases over the menopausal transition, related to sex hormone changes. In our analysis, we did not observe an association of menopause with plasma IFAB after adjustment for age. IFAB is a cytosolic protein in enteroctyes, found to a greater extent in the small intestine than the colon, that is released upon gut epithelial damage [40]. Sex hormones may modulate the gut barrier via other mechanisms not captured by the IFAB biomarker, such as through maintenance of tight junctions [41]. Thus, an effect of menopause on gut barrier dysfunction cannot be ruled out here.
Aside from effects of menopause on the gut barrier, there may be other mechanisms for menopausal effects on immune activation in HIV. Estradiol and progesterone can inhibit HIV replication and regulate HIV latency [22, 23], suggesting that HIV reactivation may occur during menopause and cause immune activation. The effect of menopause on sCD14 in our study was only observed in women with controlled HIV, suggesting that HIV control may be an important effect modifier although the mechanism is unclear. Estrogens also interact with the gut microbiota [42], which in turn may modulate host immunity in HIV [43, 44]. In a previous study in WIHS we observed that postmenopausal status in women with HIV was associated with increased Enterobacteriales [45], which may preferentially translocate from the gut to the circulation in HIV infection [46], and lead to immune activation [44]. Research incorporating the gut microbiome and biomarkers of microbial translocation will assist with connecting these factors during menopause.
We did not find an association of menopause with biomarkers of systemic inflammation: IL-6, an inflammatory cytokine, and TNFR1, receptor for the cytokine tumor necrosis factor-α (TNF-α). Prior studies in women without HIV have observed increases in inflammatory cytokines, including IL-6 and TNF-α, in post- compared to premenopausal women, although not always [47-49]. Our observation of menopause-related increases in immune activation, but not inflammation, obscures the consequences of our findings, as inflammation is typically a direct consequence of immune activation. Alternatively, it is possible that IL-6 and TNFR1 are not ideal biomarkers to capture an effect of menopause on inflammation in the context of women with HIV.
Additionally, our results suggested that plasma sCD14 increases specifically during the menopausal transition, consistent with changes driven by ovarian rather than chronological aging. However, menopause was not associated with IFAB, a biomarker of gut barrier dysfunction, or IL-6 and TNFR1, biomarkers of systemic inflammation. Due to the short follow-up in this study of up to 2 years, we did not have sufficient sample size to explore within-woman change in biomarkers as women transition from pre- to postmenopause-only 8 women transitioned during follow-up. Nevertheless, our results suggest a risk of increased immune activation during the menopausal transition in women with HIV.
Abstract
Background
Persistent immune activation due to gut barrier dysfunction is a suspected cause of morbidity in HIV, but the impact of menopause on this pathway is unknown.
Methods
In 350 women with HIV from the Women's Interagency HIV Study, plasma biomarkers of gut barrier dysfunction (intestinal fatty acid binding protein; IFAB), innate immune activation (soluble CD14 and CD163; sCD14, sCD163), and systemic inflammation (interleukin-6 and tumor necrosis factor receptor 1; IL-6, TNFR1) were measured at 674 person-visits spanning ≤2 years.
Results
Menopause (post- vs premenopausal status) was associated with higher plasma sCD14 and sCD163 in linear mixed-effects regression adjusting for age and other covariates (β = 161.89 ng/mL; 95% confidence interval [CI], 18.37-305.41 and 65.48 ng/mL, 95% CI, 6.64-124.33, respectively); but not with plasma IFAB, IL-6, or TNFR1. In piece-wise linear mixed-effects regression of biomarkers on years before/after the final menstrual period, sCD14 increased during the menopausal transition by 250.71 ng/mL per year (95% CI, 16.63-484.79; P = .04), but not in premenopausal or postmenopausal periods.
Conclusions
In women with HIV, menopause may increase innate immune activation, but data did not support an influence on the gut barrier or inflammation. Clinical implications of immune activation during menopausal transition warrant further investigation.
INTRODUCTION
Human immunodeficiency virus (HIV) infection leads to persistent immune activation and inflammation even with antiretroviral therapy (ART), which may contribute to higher risk of non-AIDS-related conditions (eg, cardiovascular disease [CVD], cancer) [1]. There are several hypothesized causes of immune activation in HIV, including low-level viral replication, coinfections, lymphoid fibrosis, and microbial translocation [2]. Microbial translocation is a process in which damage to the gut epithelial barrier, caused by HIV infection, allows microbial products to translocate from gut to circulation, activating an innate immune response [3]. Gut barrier dysfunction and innate immune activation have been associated with CVD and mortality in treated HIV infection [4-10]. Understanding drivers of immune activation and inflammation in HIV is important for prevention of non-AIDS-related diseases [11].
A recent report of 65 women without HIV found that biomarkers of gut barrier dysfunction, microbial translocation, and immune activation increased during the menopausal transition [12]. Menopause marks the end of the reproductive phase of a woman's life, when complete depletion of ovarian follicles leads to loss of ovarian production of sex hormones estradiol and progesterone [13]. Both hormones appear important for gut barrier integrity [14-18], and estradiol also has well known cardioprotective properties [19-21]. In the context of HIV infection, estradiol and progesterone can inhibit HIV replication and are thought to maintain HIV latency [22, 23]. Women with HIV have lower estradiol and ovarian reserve [24, 25], higher levels of microbial translocation and immune activation [26], and higher cardiovascular risks [27-29] than women without HIV, suggesting that menopause-related decline in sex hormones may pose unique morbidity risks. However, the effect of the menopausal transition on microbial translocation, immune activation, and inflammation is unknown in women with HIV.
Here, we examined the association of menopause status with plasma biomarkers of gut barrier dysfunction, innate immune activation, and systemic inflammation in women with HIV from the Women's Interagency HIV Study (WIHS). Additionally, we explored changes in these biomarkers over time relative to the final menstrual period, to understand effects of the menopausal transition above those of chronological aging alone [30].
RESULTS
Participant Characteristics
Of 350 women included in this analysis, 257 were premenopausal and 93 were postmenopausal at the baseline biomarker visit, with 8 switching from pre- to postmenopausal status over the 2 year follow-up of the biomarker study. Average age was 40 and 53 years for pre- and postmenopausal women, respectively. The majority of women identified as black (67%), were born in the United States (79%), and were obese (55%). All were on ART, with 79% virally suppressed and 67% with normal CD4 cell count (≥500 cells/mm3) at the baseline biomarker visit (Table 1). Women with 2-3 biomarker samples differed from women with only 1 sample on demographic characteristics, as expected given differences between northern and southern study sites; however, the proportion of postmenopausal women was the same (Supplementary Table 1). Within women providing longitudinal samples over up to 3 visits spanning up to 2 years, consistency was good for sCD163, moderate for IFAB, and poor for sCD14, IL-6, and TNFR1 (Table 2).
Association of Menopause Status and Biomarker Outcomes
For this analysis, we included all women providing at least 1 (but up to 3) person-visits with menopause and biomarker data (up to 350 women; up to 674 person-visits). Menopause status was associated with plasma sCD14 and sCD163 in linear mixed effects models adjusted for age, race, ethnicity, hormonal contraceptive use, HIV load, CD4 cell count, country of birth, educational attainment, employment status, alcohol use, smoking status, drug use, body mass index (BMI), diabetes, and hypertension (Table 3).Postmenopausal women had an estimated 161.89 ng/mL (95% CI, 18.37-305.41) and 65.48 ng/mL (95% CI, 6.64-124.33) higher plasma sCD14 and sCD163, respectively, than premenopausal women (P = .03 for both). A significant association of menopause status with plasma IFAB was attenuated upon adjustment for age, while menopause status was not associated with plasma IL-6 or TNFR1 in unadjusted or adjusted models (Table 3). Results were similar in a sensitivity analysis matching pre- and postmenopausal person-visits on age (Supplementary Table 2), despite reduced sample size due to exclusion of person-visits that could not be matched on age. Results were also similar in sensitivity analyses excluding premenopausal person-visits for women that later had surgical menopause, or excluding premenopausal person-visits for women who did not have a menstrual period within the last 3 months (Supplementary Tables 3 and 4). Interestingly, the association of menopause with sCD14 was only observed among women with controlled HIV (undetectable viral load and CD4 count ≥ 500 cells/mm3; P interaction = .03; Supplementary Table 5).
Association of Time Before/After the Final Menstrual Period With Biomarker Outcomes
For this analysis, we included a subset of 126 women who had a prospectively observed final menstrual period (ie, gone through the menopausal transition) during their participation in the WIHS, which ranged from 3 to 25 (median 17) years; these women provided 286 biomarker person-visits. Premenopausal women in this subset tended to be older than those in the full dataset (Supplementary Table 6), and there was a strong correlation between age and time before/after the final menstrual period (r = 0.66, P < .0001). Nonparametric locally weighted scatter plot smoothing curves suggested that the change (slope) of plasma sCD14 and sCD163 over time relative to the final menstrual period, may differ during the menopausal transition compared with pre- or postmenopausal periods (Figure 1). Inflection points (knots) for piece-wise linear mixed effects models were chosen visually for sCD14 (0.5 years before/1.7 years after final menstrual period) and sCD163 (0.5 years before/1.5 years after final menstrual period). Default points of 1 year before/after the final menstrual period [30] were used for plasma IFAB, IL-6, and TNFR1 due to lack of obvious change in slope around the final menstrual period.
In piece-wise linear mixed effects models, we observed a significant increase in sCD14 during the menopausal transition (within 0.5 years before and 1.7 years after the final menstrual period); for each year in this period, sCD14 increased by 250.71 ng/mL (95% CI, 16.63-484.79; P = .04). The slope of sCD14 in the menopausal transition period differed from the premenopausal (>0.5 years before final menstrual period) and postmenopausal (>1.7 years after final menstrual period) periods (Table 4 and Figure 2). Additionally, the piece-wise linear model for sCD14 provided a marginally better fit than a linear model (piece-wise AIC = 4420, linear AIC = 4443, LRT P = .06). Results were similar adjusting for covariates (Table 4). For other outcomes (plasma IFAB, sCD163, IL-6, and TNFR1), we did not observe associations with time before/after the final menstrual period in piece-wise models.
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