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Incident Non-AIDS Comorbidity Burden among Women with or at-risk for HIV in the U.S - suggest high susceptibility to -premature aging
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from Jules: these are not surprising data & are in line with previous research & WIHS research. This paper recommends Novel comorbidity screening and prevention tools that take into account HIV- and female-specific pathogenic processes are needed
Incident Non-AIDS Comorbidity Burden among Women with or at-risk for HIV in the U.S - suggest high susceptibility to -premature aging
The rate of NACM accrual was high for all women, though higher for WLWH, and associated with traditional comorbidity risk factors including social determinants of health - Strikingly, comorbidity incidence among women began in the third decade of life, suggesting high susceptibility to -premature aging and supporting the need for earlier, more aggressive NACM risk assessment and interventions for young WLWH and at-risk women that could be integrated into a broader women's health agenda during reproductive age. - Novel comorbidity screening and prevention tools that take into account HIV- and female-specific pathogenic processes are needed
⋅ 3-fold higher for kidney disease for HIV women vs women without HIV
⋅ liver disease 2.5 higher
⋅ bone disease 35% higher etc
The incidence was higher among WLWH than women without HIV for CKD (IRR 3.14; 95% CI 1.80- 5.49), liver disease (IRR 2.56; 95% CI 1.85-3.54), psychiatric illness (IRR 1.38; 95% CI 1.02-1.86), dyslipidemia (IRR 1.36; 95% CI 1.14-1.62) and bone disease (IRR 1.35; 95% CI 1.14-1.58).
WLWH had a significantly higher incident NACM rate compared with women without HIV (IRR 1.36, 95% CI 1.02-1.81). The incident NACM burden was significantly higher among WLWH compared with women without HIV in most age strata (Figure 2, HIV*age interaction p=0.0438). Women aged <25 years had the greatest IRR at 1.48 (95% CI 1.19-1.84) versus those aged 25-29 (IRR 1.31; 95% CI 1.09-1.57), 30-34 (IRR 1.25; 95% CI 1.09-1.43), 35-39 (IRR 1.12; 95% CI 1.003-1.25), 40-44 (IRR 1.01; 95% CI 0.90-1.14), 45-49 (IRR 1.28; 95% CI 1.08-1.53), 50-54 (IRR 1.18; 95% CI 0.95-1.46), ≥55 years (IRR 1.36; 95% CI 1.02-1.81).
.......incident NACM burden among WLWH was associated with elevated BMI, current substance use and certain sociodemographics, but not HIV-related factors. This underscores the important contribution of social determinants of health in driving comorbidity burden among WLWH, as also found for women without HIV, and argues for increased attention and resources dedicated to improving women's health systematically, especially for those from high-risk communities27 ......Female-specific anatomic, chromosomal, immunologic, hormonal and lifestyle factors likely interplay in a complex fashion to expedite aging and comorbidity incidence among WLWH14,32. -Immunoaging,‖ the natural waning of immunity occurring with advanced age, is accelerated by HIV33. Among PLWH despite ART-induced virologic suppression, immunoaging is attributed to persistent systemic inflammation as well as ongoing T-cell activation (from residual HIV replication, chronic viral co-infections, and translocated gut microbial products) and is associated with dysfunctional immunometabolism, dysregulated coagulation and inflammatory vasculopathy34-36. Such mechanisms have been implicated in contributing to early NACM accrual among PLWH, which may be exacerbated by estrogen insufficiency among WLWH32. A hallmark of natural aging in women, hypoestrogenism leads to a pro-inflammatory state thereby compounding the systemic inflammation of chronic HIV32,37. While pre-menopausal status in the general population is protective against the development of several NACM, e.g., CVD and osteoporosis38,39, this biologic benefit may be attenuated among WLWH who may experience menopause earlier and more severely40.
Our data highlight the need to prioritize WLWH, particularly young women, for early NACM screening to identify those at highest risk of amassing comorbidities and to offer timely, targeted risk-modification interventions. Since PLWH experience multimorbidity at least a decade earlier than peers without HIV, age-anchored clinical guidance on comorbidity screening for the general adult population is inappropriate for use among PLWH. Such guidance misses the opportunity for early NACM detection among PLWH who may have decades of comorbidity-free life to preserve10. Furthermore, prior reports indicate WLWH experience higher NACM burden and more severe disease than men5,12 thus sex attributes may differentially affect comorbidity onset and progression among PLWH compared with the general population. Primary care guidelines for PLWH22 should consider more comprehensive and sex-stratified recommendations for comorbidity screening and prevention as data evolve on differential biologic risks and associated lifestyle factors driving NACM burden among WLWH versus men.
The early occurrence of multimorbidity among WLWH is likely multifactorial, related to a higher prevalence of traditional comorbidity risk factors and viral co-infections compared with the general population, the type and duration of ART exposure, and HIV-associated chronic inflammation and immune activation hastening the natural aging process11. Elevations in inflammatory biomarkers (i.e., hs-CRP, IL-6, D-dimer) have been associated with NACM events and all-cause mortality among PLWH on suppressive ART28,29. While only 45% of WLWH in this analysis were virologically suppressed at baseline, the vast majority (>80%) were suppressed by end of observation. Measures of longitudinal HIV viremia have been associated with incident myocardial infarction and mortality among male-predominant cohorts of PLWH30,31. However, the effect of cumulative viremia on incident comorbidity burden and its relationship to chronic inflammation and immune activation warrants additional investigation.
We previously showed in a cross-sectional analysis of the WIHS that the burden of prevalent NACM [non-AIDS comorbidities]was significantly higher among WLWH than women without HIV overall and in certain age groups6. The current longitudinal study builds on those data by illustrating that women, regardless of HIV serostatus, began accruing comorbidities early in life (i.e., as young as in their twenties), that incident NACM burden was higher among WLWH, and that the impact of living with HIV on comorbidity development may be most significant among young women. These findings substantiate that WLWH are susceptible to -premature‖ multimorbidity, as suggested by other male-predominant cohorts examining NACM among PLWH2,3,7, and that comorbidity risk assessment and intervention should optimally begin for women in their childbearing years.
The greatest difference in incident comorbidity burden by HIV serostatus occurred among women <25 years old. In comparison, among 39,000 PLWH and 387,785 HIV-negative adults insured through Kaiser Permanente, comorbidity-free life expectancy (assessed 2014-2016) at age 21 was 14.5 and 30.9 years, respectively9. Our data, among women specifically, revealed a difference in NACM incidence by HIV serostatus that commenced at least a decade earlier. This dramatic disparity in age at-risk for comorbidity onset among the cohorts is likely due to differences in participant sociodemographics. While WIHS participants are predominantly urban women of color with a high prevalence of obesity, substance use, and poverty17, participants from other multisite cohorts examining multimorbidity among PLWH primarily comprise white men with stable access to care and higher income2,3,9. Additional studies are needed to investigate the interactions of sex, race, access to care and other social determinants of health on mediating comorbidity development among PLWH20.
Notably, women without HIV in our study also began accruing NACM as early as in their third decade of life. In a recent multicohort, multiethnic analysis of 32,833 participants (>50% female), women compared with men exhibited a significantly steeper increase in blood pressure trajectory that began as early as in their twenties and continued throughout their life19. It is possible that young women, regardless of HIV serostatus, may be particularly vulnerable to comorbidity incidence and progression18,19. Along with female-specific biology, complex socioeconomic, environmental and structural factors can affect physiology and coalesce to increase the risk of several comorbidities, and even premature mortality, among women compared with men21.
Due to combination antiretroviral therapy (ART), HIV infection has become a chronic condition for individuals with access to care1. Along with increased longevity, persons living with HIV (PLWH) experience a high burden of age-related non-AIDS comorbidities (NACM)2-6. Compared with persons without HIV, NACM occur disproportionately and prematurely among PLWH7-9. Multimorbidity is costly not only to the individual aging with HIV (i.e., affected quality of life)10, but to the healthcare system, leading to higher resource utilization and direct medical costs (i.e., $300-$5,000 more per patient month for PLWH with comorbidities than for those without)11.
NACM risk appears to be greater among women living with HIV (WLWH) than men5,12,13. Biologic and sociobehavioral sex differences have been implicated in HIV acquisition, pathogenesis, reservoir establishment, responses to ART and curative interventions, and while likely to influence comorbidity development, this remains poorly characterized14. Marcus et al demonstrated that NACM occurred 16 years earlier among insured PLWH than HIV-negative matched controls9.
In this large, multicenter U.S.-based prospective observational cohort of women with and without HIV that included >36,000 person-years of follow-up, we found that WLWH had a significantly higher burden of incident NACM than at-risk women without HIV. The difference in incident NACM rates by HIV serostatus was greatest among young women and in particular those aged <25 years, a group for whom routine comorbidity screening recommendations are not prioritized18,19. Traditional, but not HIV-specific, comorbidity risk factors were significantly associated with incident NACM burden among WLWH. These findings have broad-ranging implications for HIV care models and research priorities, and argue for additional study of NACM pathogenesis among WLWH specifically, and for sex-stratified comorbidity screening and prevention strategy development among PLWH to mitigate the elevated NACM risk in this population.
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Incident Non-AIDS Comorbidity Burden among Women with or at-risk for HIV in the U.S
Clinical Infectious Diseases Jan 3 2021 - Lauren F. Collins, MD1,2, Anandi N. Sheth, MD1,2, C. Christina Mehta, PhD3, Susanna Naggie, MD4, Elizabeth T. Golub, PhD5, Kathryn Anastos, MD6, Audrey L. French, MD7, Seble Kassaye, MD8, Tonya N. Taylor, PhD9, Margaret A. Fischl, MD10, Adaora A. Adimora, MD11, Mirjam-Colette Kempf, PhD12, Frank J. Palella Jr., MD13, Phyllis C. Tien, MD14, Ighovwerha Ofotokun, MD1,2
Abstract
Background
HIV infection may accelerate development of aging-related non-AIDS comorbidities (NACM). The incidence of NACM is poorly characterized among women living with HIV (WLWH).
Methods
WLWH and HIV-seronegative participants followed in the Women's Interagency HIV Study (WIHS) through ≥2009 (when >80% of WLWH used antiretroviral therapy) were included, with outcomes measured through 3/31/2018. Sociodemographics, clinical covariates and prevalent NACM were determined at enrollment. We used Poisson regression models to determine incident NACM burden (number of NACM accrued through most recent WIHS visit out of ten total NACM assessed) by HIV serostatus and age.
Results
There were 3,129 participants (2239 WLWH, 890 HIV-seronegative) with 36,589 person-years of follow-up. At enrollment, median age was 37 years, 65% were black, 47% currently smoked.
In fully-adjusted analyses, WLWH had a higher incident NACM rate compared with HIV-seronegative women (IRR 1.36, 95% CI 1.02-1.81).
Incident NACM burden was higher among WLWH versus HIV-seronegative women in most age strata (HIV*age interaction p=0.0438) and women <25 years old had the greatest incidence rate ratio by HIV serostatus at 1.48 (95% CI 1.19-1.84) compared with those in older age groups. Incident NACM burden was associated with traditional comorbidity risk factors, but not HIV-specific indices.
Conclusions
Incident NACM burden was higher among WLWH than HIV-seronegative women. This difference was most dramatic among women aged <25 years, a group for whom routine comorbidity screening is not prioritized. Established non-HIV comorbidity risk factors were significantly associated with incident NACM burden. More data are needed to inform best practices for NACM screening, prevention and management among WLWH, particularly young women.
Compared with WLWH, women without HIV had significantly higher body mass index (BMI) ≥30 kg/m2 (47% vs. 40%, p=0.0008) and current use of cigarettes (54% vs. 44%), crack/cocaine (15% vs. 10%) and alcohol (57% vs. 47%) (all p<0.0001). WLWH were significantly more likely to use anti-hypertensive medication (20% vs. 16%, p=0.0118), have prevalent chronic hepatitis C virus infection (12% vs. 9%, p=0.0051), hepatitis B virus infection (2% vs. 1%, p=0.0216), and worse kidney function (estimated glomerular filtration rate of 99.3 vs. 101.5 ml/min/1.73 m2, p=0.0099) than women without HIV (Table 1). Education level, annual household income and median depressive symptoms score did not significantly differ by HIV serostatus. At baseline, WLWH had a median CD4 count of 484 cells/mm3, 69% were on ART and 45% were virologically suppressed.
Prevalent and Incident NACM Burden
Figure 1 shows the distribution of women with prevalent NACM at baseline and incident NACM at the end of follow-up by HIV serostatus. Of 10 NACM evaluated, mean NACM burden at baseline was higher among WLWH than women without HIV (1.4 vs. 1.2, p=0.0063), though only prevalent liver disease (26% vs. 16%, p<0.0001) and psychiatric illness (26% vs. 21%, p=0.0028) differed by HIV serostatus (Supplemental Table 2). The unadjusted incident NACM rate by HIV serostatus and age is shown in Supplemental Figure 2.
In partially-adjusted models, incident NACM burden was greater in WLWH compared with women without HIV (0.19/PY vs. 0.16/PY; IRR 1.21, 95% CI 1.13-1.29) (Table 2). The incidence was higher among WLWH than women without HIV for CKD (IRR 3.14; 95% CI 1.80- 5.49), liver disease (IRR 2.56; 95% CI 1.85-3.54), psychiatric illness (IRR 1.38; 95% CI 1.02-1.86), dyslipidemia (IRR 1.36; 95% CI 1.14-1.62) and bone disease (IRR 1.35; 95% CI 1.14-1.58). However, incident hypertension, diabetes, CVD, lung disease and non-AIDS cancer did not differ significantly by HIV serostatus (Table 2). Supplemental Table 3 shows the incidence of individual NACM and incident NACM burden stratified by HIV serostatus and age (for incident burden, HIV*age interaction p=0.0063).
Fully-adjusted Incident NACM Burden by HIV and Age
In fully-adjusted models controlling for race, BMI, education, income, marital status, own residence, and current use of cigarettes, alcohol and crack/cocaine (in addition to HIV, baseline age group, HIV*age), WLWH had a significantly higher incident NACM rate compared with women without HIV (IRR 1.36, 95% CI 1.02-1.81). The incident NACM burden was significantly higher among WLWH compared with women without HIV in most age strata (Figure 2, HIV*age interaction p=0.0438). Women aged <25 years had the greatest IRR at 1.48 (95% CI 1.19-1.84) versus those aged 25-29 (IRR 1.31; 95% CI 1.09-1.57), 30-34 (IRR 1.25; 95% CI 1.09-1.43), 35-39 (IRR 1.12; 95% CI 1.003-1.25), 40-44 (IRR 1.01; 95% CI 0.90-1.14), 45-49 (IRR 1.28; 95% CI 1.08-1.53), 50-54 (IRR 1.18; 95% CI 0.95-1.46), ≥55 years (IRR 1.36; 95% CI 1.02-1.81).
Factors Associated with Incident NACM Burden
In fully-adjusted models controlling for the aforementioned baseline covariates, the estimated incident NACM rate was significantly associated with traditional comorbidity risk factors identified in the general population. We observed higher incident NACM rates among women of White race, who had a BMI ≥30 kg/m2, household income <$24,000, did not have their own residence, and reported current use of cigarettes or crack/cocaine (Table 3). Education status and current alcohol use were not associated with incident NACM burden. In an adjusted model including only WLWH (controlling for the aforementioned covariates and HIV-specific indices), enrollment CD4 count, CD4 nadir, ART status and viral load, were not significantly associated with the estimated incident NACM rate (Supplemental Table 4).
Discussion
In this large, multicenter U.S.-based prospective observational cohort of women with and without HIV that included >36,000 person-years of follow-up, we found that WLWH had a significantly higher burden of incident NACM than at-risk women without HIV. The difference in incident NACM rates by HIV serostatus was greatest among young women and in particular those aged <25 years, a group for whom routine comorbidity screening recommendations are not prioritized18,19. Traditional, but not HIV-specific, comorbidity risk factors were significantly associated with incident NACM burden among WLWH. These findings have broad-ranging implications for HIV care models and research priorities, and argue for additional study of NACM pathogenesis among WLWH specifically, and for sex-stratified comorbidity screening and prevention strategy development among PLWH to mitigate the elevated NACM risk in this population.
We previously showed in a cross-sectional analysis of the WIHS that the burden of prevalent NACM was significantly higher among WLWH than women without HIV overall and in certain age groups6. The current longitudinal study builds on those data by illustrating that women, regardless of HIV serostatus, began accruing comorbidities early in life (i.e., as young as in their twenties), that incident NACM burden was higher among WLWH, and that the impact of living with HIV on comorbidity development may be most significant among young women. These findings substantiate that WLWH are susceptible to -premature‖ multimorbidity, as suggested by other male-predominant cohorts examining NACM among PLWH2,3,7, and that comorbidity risk assessment and intervention should optimally begin for women in their childbearing years.
The greatest difference in incident comorbidity burden by HIV serostatus occurred among women <25 years old. In comparison, among 39,000 PLWH and 387,785 HIV-negative adults insured through Kaiser Permanente, comorbidity-free life expectancy (assessed 2014-2016) at age 21 was 14.5 and 30.9 years, respectively9. Our data, among women specifically, revealed a difference in NACM incidence by HIV serostatus that commenced at least a decade earlier. This dramatic disparity in age at-risk for comorbidity onset among the cohorts is likely due to differences in participant sociodemographics. While WIHS participants are predominantly urban women of color with a high prevalence of obesity, substance use, and poverty17, participants from other multisite cohorts examining multimorbidity among PLWH primarily comprise white men with stable access to care and higher income2,3,9. Additional studies are needed to investigate the interactions of sex, race, access to care and other social determinants of health on mediating comorbidity development among PLWH20.
Notably, women without HIV in our study also began accruing NACM as early as in their third decade of life. In a recent multicohort, multiethnic analysis of 32,833 participants (>50% female), women compared with men exhibited a significantly steeper increase in blood pressure trajectory that began as early as in their twenties and continued throughout their life19. It is possible that young women, regardless of HIV serostatus, may be particularly vulnerable to comorbidity incidence and progression18,19. Along with female-specific biology, complex socioeconomic, environmental and structural factors can affect physiology and coalesce to increase the risk of several comorbidities, and even premature mortality, among women compared with men21
Our data highlight the need to prioritize WLWH, particularly young women, for early NACM screening to identify those at highest risk of amassing comorbidities and to offer timely, targeted risk-modification interventions. Since PLWH experience multimorbidity at least a decade earlier than peers without HIV, age-anchored clinical guidance on comorbidity screening for the general adult population is inappropriate for use among PLWH. Such guidance misses the opportunity for early NACM detection among PLWH who may have decades of comorbidity-free life to preserve10. Furthermore, prior reports indicate WLWH experience higher NACM burden and more severe disease than men5,12 thus sex attributes may differentially affect comorbidity onset and progression among PLWH compared with the general population. Primary care guidelines for PLWH22 should consider more comprehensive and sex-stratified recommendations for comorbidity screening and prevention as data evolve on differential biologic risks and associated lifestyle factors driving NACM burden among WLWH versus men.
Current risk assessment tools developed in the general population, such as for CVD and bone fracture risk, underperform among PLWH23,24, thus failing to identify substantial numbers of WLWH who may benefit from earlier interventions to mitigate premature NACM onset. Novel comorbidity screening and prevention tools that take into account HIV- and female-specific pathogenic processes are needed25, and should be integrated into comprehensive strategies focused on aggressive modification of traditional comorbidity risk factors as well as HIV disease control. Corroborating prior studies6,26, incident NACM burden among WLWH was associated with elevated BMI, current substance use and certain sociodemographics, but not HIV-related factors. This underscores the important contribution of social determinants of health in driving comorbidity burden among WLWH, as also found for women without HIV, and argues for increased attention and resources dedicated to improving women's health systematically, especially for those from high-risk communities27.
The early occurrence of multimorbidity among WLWH is likely multifactorial, related to a higher prevalence of traditional comorbidity risk factors and viral co-infections compared with the general population, the type and duration of ART exposure, and HIV-associated chronic inflammation and immune activation hastening the natural aging process11. Elevations in inflammatory biomarkers (i.e., hs-CRP, IL-6, D-dimer) have been associated with NACM events and all-cause mortality among PLWH on suppressive ART28,29. While only 45% of WLWH in this analysis were virologically suppressed at baseline, the vast majority (>80%) were suppressed by end of observation. Measures of longitudinal HIV viremia have been associated with incident myocardial infarction and mortality among male-predominant cohorts of PLWH30,31. However, the effect of cumulative viremia on incident comorbidity burden and its relationship to chronic inflammation and immune activation warrants additional investigation.
Female-specific anatomic, chromosomal, immunologic, hormonal and lifestyle factors likely interplay in a complex fashion to expedite aging and comorbidity incidence among WLWH14,32. -Immunoaging,‖ the natural waning of immunity occurring with advanced age, is accelerated by HIV33. Among PLWH despite ART-induced virologic suppression, immunoaging is attributed to persistent systemic inflammation as well as ongoing T-cell activation (from residual HIV replication, chronic viral co-infections, and translocated gut microbial products) and is associated with dysfunctional immunometabolism, dysregulated coagulation and inflammatory vasculopathy34-36. Such mechanisms have been implicated in contributing to early NACM accrual among PLWH, which may be exacerbated by estrogen insufficiency among WLWH32. A hallmark of natural aging in women, hypoestrogenism leads to a pro-inflammatory state thereby compounding the systemic inflammation of chronic HIV32,37. While pre-menopausal status in the general population is protective against the development of several NACM, e.g., CVD and osteoporosis38,39, this biologic benefit may be attenuated among WLWH who may experience menopause earlier and more severely40.
This study warrants mention of limitations. First, some of the NACM relied on self-report due to lack of available objective measures for confirmation, such as tissue pathology or imaging results6. This could have resulted in underestimation of incident NACM burden. Second, given the study objective to describe NACM accumulation over the life course of women, time-varying factors, such as the onset of menopause or obesity, were not evaluated. Third, we were not able to assess the longitudinal effects of using different antiretroviral classes, considering the effects of ART switching and nonadherence. Finally, nor were we able to describe the relationship between time-updated HIV viremia and incident NACM given the scope of this analysis.
In conclusion, this study is the first of its scale to comprehensively examine incident age-stratified comorbidity burden, and associated risk factors, among WLWH and at-risk women without HIV. The rate of NACM accrual was high for all women, though higher for WLWH, and associated with traditional comorbidity risk factors including social determinants of health. Strikingly, comorbidity incidence among women began in the third decade of life, suggesting high susceptibility to -premature aging‖ and supporting the need for earlier, more aggressive NACM risk assessment and interventions for young WLWH and at-risk women that could be integrated into a broader women's health agenda during reproductive age. Implementation science, including innovative HIV- and female-specific clinical risk-assessment and risk-reducing tools, tailored to the needs of young WLWH will be paramount to address the synergy of HIV and premature multimorbidity, fueled by underlying social determinants, in this high-risk population.
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