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Racial and Sex Disparities in Life Expectancy Losses among HIV-Infected Persons in the United States: Impact of Risk Behavior, Late Initiation, and Early Discontinuation of Antiretroviral Therapy
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from Jules: in light of the recent DHHS Guidelines recommending starting HAART earlier, with CD4s 350-500, and optional above 500 cd4s, this modeling study discusses that the DHHS has implemented several prevention programs targeting minority women, programs to expand routine testing, to diagnose patients wit HIV earlier, with "special attention to linkage of care". The study reports ALL patients have reduced survival in number of years when starting HAART according to the current guidelines (study written before new guidelines issued this month). High-risk behaviors contribute to reduced survival with HIV and include MSM and history of STDs. This study goes on to discuss that Blacks & Latinos suffer the most due to late diagnosis, discontinuation of therapy, depression, compromised linkages to care and retention in care, survival loss: high-risk behaviors, substance abuse housing problems etc; High-risk behavior for the SMR derivations was defined to include men who have sex with men, injection drug use, having multiple sex partners, being a commercial sex worker, and having a history of sexually transmitted infections. The authors report reduced survival results from high-risk behaviors and were greater in women, we know that in the USA Black & Latino women number much more than white women.
Clinical Infectious Nov 15 Diseases 2009;49:1570-1578
"Survival losses for racial/ethnic minority women with HIV infection were higher than for whites by as much as 83%, and these disparities were greatest for Hispanic individuals....Future studies should focus on earlier testing, linkage to care, and retention in care for all HIV-infected persons, with an emphasis on women, as well as on racial and ethnic minorities......This study underscores the importance of developing interventions that are focused on better linkage to and retention in care, especially for racial/ethnic minorities. The US Department of Health and Human Services has implemented several HIV prevention programs that target minority women [48]. Recent efforts to expand routine HIV testing in the United States may also begin to address the problem of earlier diagnosis [49-51]. Special attention to linkage to care after HIV testing will be critical [52].
---This study also demonstrates that treatment discontinuation adds substantially to survival losses from HIV infection....Data from the United States show even higher treatment discontinuation rates, ranging from 7% to 40% over 2-7 months [9, 54], with the highest rates among racial/ethnic minority women [3, 37, 54-56]. Because ART initiation generally occurs at lower CD4+ cell counts for men, especially among minorities, late initiation results in larger life expectancy losses for Hispanic and black men than for women. These results are consistent with the findings of Giordano et al, which show clear survival benefits for HIV-infected patients who receive consistent care, compared with irregular care, despite the observation that those who received consistent care presented with more-advanced disease
---critical importance of interventions focused on reducing substance abuse and other high-risk behaviors....Racial/ethnic minority women had greater survival losses, compared with their white counterparts (26% and 83% more in black and Hispanic women, respectively)....losses in life expectancy attributable to high-risk behavior were greater among women than among men across all races/ethnicities.....Major survival losses were also attributable to inadequate retention in care....white women, which was the group that presented to care earliest
If all HIV-infected individuals initiated ART according to current US treatment guidelines and without discontinuation, the estimated life expectancy of HIV-infected persons infected at age 33.0 years would be 22.66 years, accounting for the excess non-HIV-related mortality. Thus, with the current standard of HIV care, estimated life lost as a result of HIV infection was 11.92 years (34.58 years minus 22.66 years; Figure 1).....The combined effects of late treatment initiation and premature treatment discontinuation led to life expectancy losses of 3.30 years.....late presentation (CD4+ cell count <200 cells/µL) resulted in an estimated life expectancy of 18.75 years from age 33.0 years, representing an additional 3.90 years of life expectancy lost, compared with patients who initiated ART with a CD4+ cell count >200 cells/µL; life expectancy for those initiating ART very late (CD4+ cell count <50 cells/µL) was estimated at 13.82 years, resulting in an additional 8.83 years of life lost compared with patients who initiated ART with CD4+ cell counts >200 cells
Interventions focused on risk behaviors, as well as on earlier linkage to and better retention in care, will lead to improved survival for HIV-infected persons in the United States.. The high-risk profile of HIV-infected persons, HIV infection itself, as well as late initiation and early discontinuation of care, all lead to substantial decreases in life expectancy. Survival disparities resulting from late initiation and early discontinuation of therapy are most pronounced for Hispanic HIV-infected men and women....Late initiation of care, inconsistent adherence, and premature discontinuation of therapy continue to exert a substantial impact on survival [3-9]. Sex and racial/ethnic disparities in access to care, adherence to therapy, and risk further compound the difficulty of addressing these problems. Racial and ethnic disparities in access to care have been well documented"
Elena Losina,1,3,4,7,8 Bruce R. Schackman,9 Sara N. Sadownik,1,6 Kelly A. Gebo,10 Rochelle P. Walensky,1,2,3,5 John J. Chiosi,1 Milton C. Weinstein,6 Perrin L. Hicks,10 Wendy H. Aaronson,1 Richard D. Moore,10 A. David Paltiel,11 and Kenneth A. Freedberg1,2,3,6,7,8
Divisions of 1General Medicine and 2Infectious Disease, Department of Medicine, Massachusetts General Hospital, and the 3Harvard University Center for AIDS Research, Harvard Medical School, 4Department of Orthopedic Surgery and 5Division of Infectious Disease, Brigham and Women's Hospital, 6Department of Health Policy and Management, Harvard School of Public Health, and Departments of 7Biostatistics and 8Epidemiology, Boston University School of Public Health, Boston, Massachusetts; 9Department of Public Health, Weill Cornell Medical College, New York, New York; 10Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and 11Department of Epidemiology and Public Health, Yale School of Medicine, New Haven, Connecticut
ABSTRACT
Background. Most persons with human immunodeficiency virus (HIV) infection in the United States present to care with advanced disease, and many patients discontinue therapy prematurely. We sought to evaluate sex and racial/ethnic disparities in life-years lost as a result of risk behavior, late presentation, and early discontinuation of HIV care, and we compared these survival losses for HIV-infected persons with losses attributable to high-risk behavior and HIV disease itself.
Methods. With use of a state-transition model of HIV disease, we simulated cohorts of HIV-infected persons and compared them with uninfected individuals who had similar demographic characteristics. We estimated non-HIV-related mortality with use of risk-adjusted standardized mortality ratios, as well as years of life lost because of late presentation and early discontinuation of antiretroviral therapy (ART) for HIV infection. Data from the national HIV Research Network, stratified by sex and race/ethnicity, were used for estimating CD4+ cell counts at ART initiation.
Results. For HIV-uninfected persons in the United States who have risk profiles similar to those of individuals with HIV infection, the projected life expectancy, starting at 33 years of age, was 34.58 years, compared with 42.91 years for the general US population. Those with HIV infection lost an additional 11.92 years of life if they received HIV care concordant with guidelines; late treatment initiation resulted in 2.60 additional years of life lost, whereas premature ART discontinuation led to 0.70 more years of life lost. Losses from late initiation and early discontinuation were greatest for Hispanic individuals (3.90 years).
Conclusions. The high-risk profile of HIV-infected persons, HIV infection itself, as well as late initiation and early discontinuation of care, all lead to substantial decreases in life expectancy. Survival disparities resulting from late initiation and early discontinuation of therapy are most pronounced for Hispanic HIV-infected men and women. Interventions focused on risk behaviors, as well as on earlier linkage to and better retention in care, will lead to improved survival for HIV-infected persons in the United States.
Despite the remarkable success of antiretroviral therapy (ART) in improving the survival of patients with human immunodeficiency virus (HIV) disease, challenges of competing risk and access to care persist. Persons at risk for HIV infection are also at an increased mortality risk from non-HIV-related causes, including substance and alcohol abuse [1, 2]. Late initiation of care, inconsistent adherence, and premature discontinuation of therapy continue to exert a substantial impact on survival [3-9]. Sex and racial/ethnic disparities in access to care, adherence to therapy, and risk further compound the difficulty of addressing these problems [3-5, 7-17].
Racial and ethnic disparities in access to care have been well documented [18, 19]. It is less clear, however, how to measure the impact of these disparities on mortality or how to evaluate the improvements in survival that result from interventions designed to address these disparities. We sought to define and evaluate 3 categories of survival losses associated with HIV: first, the years of life lost as a result of non-HIV-related causes in persons at risk for HIV infection in the United States; second, the years of life lost as a result of HIV infection itself, under conditions of guideline-concordant care; and third, the additional life-years lost as a result of late initiation and premature discontinuation of ART.
Results
Primary analysis
Years of life lost from high-risk behaviors and from HIV infection.The estimated life expectancy in the general, HIV-uninfected US population from age 33.0 years was estimated at 42.91 years. A simulated cohort of HIV-negative people in the United States with a demographic and risk profile similar to that of the HIV-infected population had an estimated life expectancy from age 33.0 years of 34.58 years. The difference resulted in an estimated 8.33-year reduction in life expectancy (Figure 1).
If all HIV-infected individuals initiated ART according to current US treatment guidelines and without discontinuation, the estimated life expectancy of HIV-infected persons infected at age 33.0 years would be 22.66 years, accounting for the excess non-HIV-related mortality. Thus, with the current standard of HIV care, estimated life lost as a result of HIV infection was 11.92 years (34.58 years minus 22.66 years; Figure 1).
Losses attributable to late initiation and early discontinuation of ART.
Late presentation (CD4+ cell count <200 cells/µL) resulted in an estimated life expectancy of 18.75 years from age 33.0 years, representing an additional 3.90 years of life expectancy lost, compared with patients who initiated ART with a CD4+ cell count >200 cells/µL; life expectancy for those initiating ART very late (CD4+ cell count <50 cells/µL) was estimated at 13.82 years, resulting in an additional 8.83 years of life lost compared with patients who initiated ART with CD4+ cell counts >200 cells/µL (Table 3). We also estimated the life expectancy of HIV-infected persons stratified by the time that ART was initiated, as well as by the number of regimens received prior to ART discontinuation (Table 3). For example, among HIV-infected individuals with CD4+ cell counts >200 cells/µL who initiated treatment according to guidelines, life expectancy for those who discontinued treatment after 4 regimens, compared with that for those who did not discontinue ART, was reduced from 22.66 to 21.92 years.
The combined impact of late presentation and early treatment discontinuation.
The estimated life expectancy of HIV-infected patients in the cohort with the characteristics of the HIV Research Network participants decreased by 2.60 years because of the late or very late presentation of a substantial proportion of patients (Table 4). Early discontinuation alone decreased overall life expectancy by 0.70 years.
The combined effects of late treatment initiation and premature treatment discontinuation led to life expectancy losses of 3.30 years (Table 4; Figure 1). The combined impact of late presentation and early discontinuation of treatment resulted in higher survival losses for Hispanic individuals, compared with black and white individuals. Hispanic men had the highest life expectancy losses (3.91 years), followed by Hispanic women (3.76 years; Table 4). Among women, racial/ethnic minorities had greater survival losses, compared with their white counterparts.
Secondary analyses
The impact of decreasing disparities in presentation to and discontinuation of HIV care.If black and Hispanic women were to initiate and discontinue ART at rates similar to those for white women, life expectancy after risk adjustment would increase by 0.90 years for black women (from 16.52 to 17.42 years) and by 1.52 years for Hispanic women (from 18.87 to 20.39 years). The estimated overall life expectancy for all HIV-infected women in the United States would increase by 0.87 years (from 17.14 to 18.01 years; Figure 2).
Treatment discontinuation and timing of presentation to care.
We also performed sensitivity analyses to estimate the survival impact of early treatment discontinuation rates, ranging from 0% to 20%. A decrease in discontinuation rates from 10% to 5% increased life expectancy by 0.43 years in black men; a decrease in discontinuation from 5% to 0% increased life expectancy by 0.53 years in white women. A sensitivity analysis using sex and race/ethnicity data on CD4+ cell counts at the time of presentation, as reported by Swindells et al [15], rather than from the HIV Research Network, revealed similar trends in survival, with even greater life expectancy losses for Hispanic men and Hispanic women. Results from a sensitivity analysis showed that decreasing the rates of premature treatment discontinuation to 3% reduced life expectancy losses attributable to suboptimal access to care by 0.16 years. A sensitivity analysis increasing and decreasing ART efficacy by 15% resulted in an increase in life expectancy losses of 0.21 years and a decrease in life expectancy losses of 0.18 years, respectively. The relative impact of sex and race/ethnicity did not change meaningfully.
Discussion
Despite the tremendous success of HIV treatment in the United States over the past 15 years, substantial avoidable losses in life expectancy persist as a result of non-HIV-related risk factors, as well as late presentation and early discontinuation of care. We estimated that the increased mortality attributable to substance abuse and other high-risk behaviors led to mean per-person survival losses of 8.33 years, even in the absence of HIV disease. Because SMRs for women (7.06) were greater than SMRs for men (2.31; Table A2), losses in life expectancy attributable to high-risk behavior were greater among women than among men across all races/ethnicities. These losses were comparable to those attributable to HIV infection itself and underscore the critical importance of interventions focused on reducing substance abuse and other high-risk behaviors. These findings support previous research highlighting the risk of premature death and mortality attributable to substance abuse [44]. This non-HIV-related premature mortality includes drug overdose, as well as homicide and suicide [1, 38, 39].
We estimated that HIV infection, when acquired at age 33.0 years and treated according to current US guidelines with current regimens, led to 11.92 years of life lost. We found that 3.30 more years were lost per person because of late presentation and early discontinuation of ART. Survival losses from late presentation and early discontinuation were greater for Hispanic individuals than they were for white or black individuals, regardless of sex, with overall survival losses of 3.90 years (21% and 30% more than white and black individuals, respectively). Among all HIV-infected patient subgroups, Hispanic men had the greatest losses in life expectancy, averaging 3.91 years per-person. Racial/ethnic minority women had greater survival losses, compared with their white counterparts (26% and 83% more in black and Hispanic women, respectively). Data on delayed presentation to care for Hispanic and black women have repeatedly shown that rates of HIV-related OIs are disproportionately high in both groups [7, 11, 13, 15, 45]. These differences remain, despite recent data that suggests a narrowing of the survival gap between white and black HIV-infected persons in the United States over the past decade [46].
The estimated life expectancy for HIV-infected individuals in the United States who initiated ART very late (CD4+ cell count <50 cells/µL) was 8.83 years lower than it was for patients who initiated ART according to current guidelines [6, 34]. Major survival losses were also attributable to inadequate retention in care. For white women, which was the group that presented to care earliest, the survival losses attributable to late presentation and early discontinuation were 2.06 years per person. These results further emphasize the gap between guideline-concordant and actual care [47].
This study underscores the importance of developing interventions that are focused on better linkage to and retention in care, especially for racial/ethnic minorities. The US Department of Health and Human Services has implemented several HIV prevention programs that target minority women [48]. Recent efforts to expand routine HIV testing in the United States may also begin to address the problem of earlier diagnosis [49-51]. Special attention to linkage to care after HIV testing will be critical [52].
This study also demonstrates that treatment discontinuation adds substantially to survival losses from HIV infection. Findings from 2 large European cohorts report discontinuation rates ranging from 7% at 1 year to 18% at 2 years [8, 53]. Data from the United States show even higher treatment discontinuation rates, ranging from 7% to 40% over 2-7 months [9, 54], with the highest rates among racial/ethnic minority women [3, 37, 54-56]. Because ART initiation generally occurs at lower CD4+ cell counts for men, especially among minorities, late initiation results in larger life expectancy losses for Hispanic and black men than for women. These results are consistent with the findings of Giordano et al, which show clear survival benefits for HIV-infected patients who receive consistent care, compared with irregular care, despite the observation that those who received consistent care presented with more-advanced disease [57, 58].
This study has several limitations. First, patients who entered the HIV Research Network with HIV RNA levels >400 copies/mL and were not receiving ART were assumed to be initiating therapy for the first time, because information on previous ART was unavailable. However, a sensitivity analysis using sex and race/ethnicity data on CD4+ cell count at the time of presentation from another study [15] showed similar results, with even greater survival losses for Hispanic individuals. Second, although we used data from only 7 sites in the HIV Research Network, the demographic characteristics of persons receiving care at those sites were similar to those for persons from CDC HIV surveillance reports [43]. Third, the high-risk definition included in our SMR calculations did not explicitly include tobacco use, but because a majority of HIV-infected individuals smoke at least 1 cigarette per day, this has been indirectly accounted for in the SMR calculations [59]. Fourth, we estimated the survival losses attributable to high-risk behavior and HIV infection independently; however, the biological and social impact of HIV disease may amplify survival losses that are attributable to high-risk behavior.
Using currently available data on HIV care in the US, mean survival losses in HIV-infected patients were 23.55 years per-person compared with the general US population and 15.22 years per person compared with those without HIV infection but with a similar risk profile. Of these 15.22 years, 11.92 years were attributable to HIV infection itself; an additional 3.30 years were lost because of late presentation and early discontinuation of care. Improving access to medical and social services could address the additional risk factors for early mortality [60-62]. Survival losses for racial/ethnic minority women with HIV infection were higher than for whites by as much as 83%, and these disparities were greatest for Hispanic individuals. Future studies should focus on earlier testing, linkage to care, and retention in care for all HIV-infected persons, with an emphasis on women, as well as on racial and ethnic minorities.
Methods
Overview
We used a state-transition model of HIV disease to project the life expectancy of HIV-uninfected persons who had a demographic and risk profile similar to that for HIV-infected persons in the United States, and we compared the life expectancy to that of HIV-infected persons under a range of scenarios regarding ART use [20-22]. Cohort characteristics were derived from the HIV Research Network, a consortium of primary care sites for HIV-infected patients in 4 regions of the United States.
The Cost-Effectiveness of Preventing AIDS Complications (CEPAC) model
The CEPAC model is a widely published computer simulation model of HIV disease [20-22]. In the model, each simulated person transitioned among health states defined by CD4+ cell count, HIV RNA level, history of opportunistic infection (OI), and ART use. Monthly probabilities of CD4+ cell count decrease, OIs, and death in the absence of treatment were derived from secondary data analyses from the Multicenter AIDS Cohort Study [20, 23, 24]. ART efficacy and OI prophylaxis data were from published clinical trials and meta-analyses [25-31]. Further details of the model have been described elsewhere [20-22] and are presented in the Appendix (online only).
Cohort characteristics: The HIV Research Network
Sex and race/ethnicity distribution.
The demographic characteristics of a cohort of HIV-infected individuals were obtained from new enrollees at 7 HIV Research Network sites in the United States (Tables 1 and 2). There were 6 academic sites and 1 community-based site from the Eastern (2 sites), Southern (2), Mid-Western (2), and Western (1) regions of the United States. Further details on the HIV Research Network are published elsewhere [13, 32]. Respondents reported their main racial/ethnic group as White (non-Hispanic), Black (non-Hispanic), Hispanic, or Other (American Indian or Alaskan Native, Asian, or Pacific Islander). The sex and racial/ethnic distribution among enrollees in the HIV Research Network sites were similar to that reported by the Centers for Disease Control and Prevention (CDC) (Table A1).
Patient characteristics at presentation to care.
Patients entered the model at the time of HIV infection with a mean age of 33.0 years and a mean CD4+ cell count of 534 cells/µL [23, 33]. CD4+ cell counts at treatment initiation were stratified by sex and race/ethnicity on the basis of HIV Research Network data (Tables 1 and 2). "Late" presentation to care, with a CD4+ cell count <200 cells/µL, occurred in 42.1% of patients. "Very late" presentation, with a CD4+ cell count <50 cells/µL, occurred in 19.5% of patients. Black and Hispanic individuals, compared with white individuals, were statistically significantly more likely to initiate ART very late (22.3% and 20.7%, respectively, vs 13.6%, p<.001 ; Tables 1 and 2). Because similar data on CD4+ cell count at presentation at a national level were not available from the CDC, we performed a sensitivity analysis on this parameter using data from a second study [15].
Antiretroviral therapy regimens and strategies
In the model, HIV-infected patients presenting to care and eligible for ART had the opportunity to receive 5 sequential ART regimens, based on current US guidelines [6, 34]. Patients continued to receive a fifth and final ART regimen until death, thereby maintaining some of the benefits of ART even after virologic failure [35, 36].
Initiation.
To represent the range of CD4+ cell counts at which patients might initiate ART, we considered 3 initiation scenarios: (1) current US treatment guidelines-immediately for patients who presented for care with CD4+ cell counts of 200-350 cells/µL, or when CD4+ cell counts decreased to <350 cells/µL if in care, or with the diagnosis of an OI even with CD4+ cell counts >350 cells/µL [6, 34]; (2) late presentation-immediately (CD4+ cell counts of 50-199 cells/µL); and (3) very late presentation-immediately (CD4+ cell counts <50 cells/µL).
Discontinuation.
We defined premature discontinuation of ART as not continuing to the next available regimen after experiencing failure of a current regimen. For example, a 5% discontinuation rate implies that 5% of patients discontinue therapy after the first regimen, 5% of the remaining patients discontinue after the second regimen, and so on. Discontinuation data were derived from the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study, ranged from 5% through 14%, and were highest among black and Hispanic women (Table 1) [3, 9, 37].
Decreased survival with HIV infection
Loss of life expectancy was calculated in 3 sequential components: (1) loss of life-years attributable to non-HIV risk factors, (2) additional loss attributable to HIV disease, and (3) additional loss attributable to late initiation and/or early discontinuation of ART.
Risk adjustment for high-risk behavior.
Persons with risk profiles similar to those with HIV infection in the United States have a higher mortality rate, aside from HIV causes [1, 38, 39]. This is attributable to multiple risks, including substance and alcohol abuse [40, 41]. To adjust for this excess mortality, we derived overall and sex/race/ethnicity-specific standardized mortality ratios (SMRs) by using published risk-group specific SMRs, weighted by the distribution of risk factors among persons living with HIV infection, from CDC surveillance reports (Table A2) [42, 43]. High-risk behavior for the SMR derivations was defined to include men who have sex with men, injection drug use, having multiple sex partners, being a commercial sex worker, and having a history of sexually transmitted infections [42]. All analyses were performed both adjusted and unadjusted for this excess mortality. Results in the article are reported for the adjusted analyses. For unadjusted analyses, see the Appendix (Tables A3 and A4).
Years of life lost because of HIV infection.
We calculated years of life lost because of HIV infection itself as the difference between the life expectancy of HIV-infected persons who received guideline-concordant HIV care in the United States and the life expectancy of HIV-uninfected persons with similar demographic and risk profiles.
Years of life lost because of late initiation and/or early discontinuation of ART.
To examine the individual and aggregate role of late treatment initiation and early treatment discontinuation, we considered 3 possible scenarios: (1) late initiation of ART alone, (2) early discontinuation of ART alone, and (3) both late initiation and early discontinuation of ART. All analyses were performed for the overall cohort; then performed separately for Hispanic individuals, black individuals, and white individuals; and then performed for each of the 3 race/ethnicity groups stratified by sex. For each analysis, we estimated both the absolute and relative reduction in life expectancy. The relative reduction was calculated as the number of years of life lost because of both late presentation and early discontinuation of therapy, divided by the life expectancy under a guideline-concordant scenario with no discontinuation. Details of calculations of the years of life lost are presented in the Appendix (online only).
Secondary analyses
We also performed a "what-if" policy analysis to estimate the potential lifesaving impact of a program designed specifically to improve HIV care among black and Hispanic women. We examined scenarios in which women of all racial/ethnic backgrounds presented to care earlier (ie, with the same CD4+ cell count distribution and ART discontinuation rates as those of white women). We also performed a sensitivity analysis varying ART discontinuation rates from 0% through 20% and examining the impact of CD4+ cell count at the time of ART initiation. We also conducted an additional sensitivity analysis that assumed lower rates of treatment discontinuation (3%) in subsequent ART regimens after discontinuation of the initial regimen. Recognizing that the efficacies observed in clinical trial settings may be different than those observed in clinical practice, we conducted a sensitivity analysis on the ART efficacy assumption, using a range of values extending both 15% above and 15% below the published data.
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