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50% Increased Risk for Myocardial Infarction (MI) Rate in HIV+ in Veterans Cohort (VACS)
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Getting to the Heart of HIV and Myocardial Infarction, Comment on "HIV Infection and the Risk of Acute Myocardial Infarction"....."HIV-positive populations carry an approximately 50% relative increased risk of incident MI......The persistent immune dysfunction in ART-treated, HIV-positive people also raises concerns that potential associated systemic inflammation may contribute to increased MI.....effective interventions to reduce inflammation or modify the immune response in chronic HIV infection that also result in reductions in MI rates are not currently available......Unsuppressed HIV viremia, low CD4 cell count, Framingham risk factors, hepatitis C virus, renal disease, and anemia are also associated with AMI. Moreover, this risk also extends to HIV-positive veterans with an HIV-1 RNA level less than 500 copies/mL over time compared with uninfected veterans."
"Together, these data point to a significant excess risk of MI in HIV-positive people, the pathogenesis of which we do not clearly understand and which cannot be explained by traditional cardiovascular risk factors or accurately estimated using conventional cardiovascular risk assessments. Taking this into account, presuming that interventions used in the general population to reduce the risk of MI will translate into similar reductions in MI incidence in HIV-positive populations is arguably naive. That the HIV-positive cohort in the study by Freiberg et al3 experienced a 50% increased risk of MI highlights the need for further research in women, research into the underlying mechanisms of the increased risk, and the development of specific interventions to reduce the risk of MI in HIV-positive populations."
"HIV-specific assessment tools have been developed to estimate cardiovascular disease risk in people with HIV (see http://www.cphiv.dk/tools.aspx). Furthermore, prospective, controlled studies, such as the Pharmacokinetic and Clinical Observations in People Over Fifty Study (http://clinicaltrials.gov/ct2/show/NCT01737047), focused on clinical end points, including MI, in HIV-positive and HIV-negative cohorts older than 50 years, an age range in which the majority of MI events occur, will help to better define the relative contribution of specific socioeconomic and lifestyle factors as well as HIV infection and exposure to ART on clinical outcomes."
"The mechanism by which HIV infection increases the risk of AMI is not known. Possible mechanisms may involve inflammation,27 CD4 cell count depletion,28 altered coagulation,29 dyslipidemia,30 impaired arterial elasticity,31 and endothelial dysfunction.32 Among HIV-infected people, ART is associated with metabolic changes33 and abnormal fat distribution,34- 35 which in turn are linked with insulin resistance,33 diabetes,33 and dyslipidemia.33,36 Although HIV and ART are associated with AMI risk, results from the Strategies for Management of Antiretroviral Therapy study25 showing that HIV viral suppression results in lower cardiovascular disease risk than drug conservation therapy suggest that the virus plays the larger role."
Invited Commentary
JAMA Intern Med. 2013
Patrick W. G. Mallon, MB, BCh, PhD, FRACP, FRCPI
"results demonstrate a clear and consistent excess risk of MI (approximately 50% increase) in HIV-positive people across a range of age groups, with the association between HIV status and MI remaining significant when controlled for a number of covariates including traditional cardiovascular risk factors, such as lipids, blood pressure, and smoking status. In addition, study findings suggest that use of the Framingham risk assessment likely underestimates the risk of MI in HIV-positive populations."
For people infected with the human immunodeficiency virus (HIV) with access to antiretroviral therapy (ART), the benefits, particularly for those with low CD4+ T-cell counts, have been clearly established.1 Management strategies have shifted firmly toward earlier HIV diagnosis to reduce HIV-related morbidity alongside increased ART access to maximize its benefits with a view to mitigating the potential detrimental effects of HIV infection on overall lifelong survival.
As the current era in HIV management evolves, it is increasingly apparent that, despite effective ART, people living with HIV experience excess comorbidities that may increase mortality and limit overall survival. Not surprisingly, as in the general population, cardiovascular diseases, such as myocardial infarction (MI), rank among the most common causes of death in treated HIV-positive populations.
In determining the causes of excess comorbidities such as MI, 3 main issues arise:
1. Is there a truly increased incidence of MI as a result of HIV infection or do observed, elevated rates simply reflect background disease rates that would be expected in a group of people with the demographic characteristics and risk factor profiles present within a HIV-positive population?
2. If HIV infection is implicated, what are the mechanisms whereby HIV infection and/or immune dysfunction drive increased MI?
3. How do potential ART-related toxicities influence the incidence of MI?
Until recently, much of the estimation of MI risk in HIV relied on cross-study comparisons of MI rates in HIV-positive populations with either published population rates or those derived from separate cohort studies of uninfected populations. These comparisons were based on a presumption that the HIV-positive populations were broadly similar to the comparator populations, with most studies unable to consider the likely effect of differences in socioeconomic and lifestyle factors within HIV-positive populations on resulting MI rates. Indeed, the potential effects of socioeconomic factors on treatment outcomes in HIV were recently discussed in this journal, where a study of mortality rates within an HIV-positive population showed significantly different mortality depending on sex, educational status, and race/ethnicity.2 To date, relatively few studies have attempted to correct for this potential bias.
In this issue of JAMA Internal Medicine, Freiberg and colleagues3 attempt to do exactly this by drawing their control population from broadly similar demographic and geographic backgrounds, therefore attempting to limit potential bias. They followed up a large (82 459 participants and 33.2% HIV positive) prospective cohort, examining incident MI rates in participants with and without HIV drawn from the Veterans Aging Cohort Study Virtual Cohort. The cohort has several advantages: its large size, the ability to draw detailed data on both HIV and MI from a number of linked databases, the diverse population, and the ability to match HIV-positive participants and HIV-negative controls for a variety of potential confounders, providing the capacity to better estimate the effect of HIV infection itself on MI rates.
Although the cohort studied was almost exclusively male (>97%), the results demonstrate a clear and consistent excess risk of MI (approximately 50% increase) in HIV-positive people across a range of age groups, with the association between HIV status and MI remaining significant when controlled for a number of covariates including traditional cardiovascular risk factors, such as lipids, blood pressure, and smoking status. In addition, study findings suggest that use of the Framingham risk assessment likely underestimates the risk of MI in HIV-positive populations.
For HIV-positive men, this study goes a long way toward clearly addressing the first of the 3 fundamental issues previously mentioned: that HIV-positive populations carry an approximately 50% relative increased risk of incident MI. That this excess risk cannot be explained by correction for traditional risk factors implicates either HIV infection or exposure to ART among potential underlying drivers.
Human immunodeficiency virus is characterized by a particular dyslipidemia; in untreated HIV infection, decreased high-density lipoprotein (HDL) cholesterol is prevalent and inversely correlates with HIV RNA levels, likely reflecting HIV-mediated interruption of the reverse cholesterol transport pathway through which cholesterol is cleared from peripheral tissues.4 Contemporary ART-treated populations exhibit persistently decreased HDL cholesterol accompanied by modest increases in triglycerides rather than elevated low-density lipoprotein cholesterol, a pattern of dyslipidemia reflected in the study population of Freiberg et al.3 Despite its being second only to age as the largest contributor to estimated 10-year cardiovascular risk in a cohort study5 of HIV-positive people, we have only a limited understanding of why HDL cholesterol remains low in ART-treated, HIV-positive patients, and interventions to increase HDL cholesterol have been shown to be relatively ineffective in altering cardiovascular risk.
The persistent immune dysfunction in ART-treated, HIV-positive people also raises concerns that potential associated systemic inflammation may contribute to increased MI. In a large, prospective study6 of HIV-positive patients both receiving and not receiving ART, those with higher markers of systemic inflammation experienced more cardiovascular disease events. Other than ART, effective interventions to reduce inflammation or modify the immune response in chronic HIV infection that also result in reductions in MI rates are not currently available.
Although, as Freiberg et al3 rightly point out, the overall benefit of ART on mortality in HIV-positive people is clear, their study has limited capacity to determine associations between ART and the risk of MI. However, the Data Collection on Adverse Events of Anti-HIV Drugs study, a large (>170 000 person-years of follow-up), multicenter, prospective study examining incident MI in HIV-positive people, has determined an association between cumulative exposure to some protease inhibitors and nucleoside reverse-transcriptase inhibitors and MI, an effect that is not fully explained by traditional cardiovascular risk factors, including dyslipidemia.7 However, although nontraditional pathways, such as altered platelet reactivity, have been implicated,8 our understanding of the pathogenesis of how specific antiretrovirals contribute to cardiovascular disease risk and our options for mitigating these effects are limited.
Together, these data point to a significant excess risk of MI in HIV-positive people, the pathogenesis of which we do not clearly understand and which cannot be explained by traditional cardiovascular risk factors or accurately estimated using conventional cardiovascular risk assessments. Taking this into account, presuming that interventions used in the general population to reduce the risk of MI will translate into similar reductions in MI incidence in HIV-positive populations is arguably naive. That the HIV-positive cohort in the study by Freiberg et al3 experienced a 50% increased risk of MI highlights the need for further research in women, research into the underlying mechanisms of the increased risk, and the development of specific interventions to reduce the risk of MI in HIV-positive populations.
Advances are being made; in addition to the publication of well-designed, robust studies such as that by Freiberg et al,3 HIV-specific assessment tools have been developed to estimate cardiovascular disease risk in people with HIV (see http://www.cphiv.dk/tools.aspx). Furthermore, prospective, controlled studies, such as the Pharmacokinetic and Clinical Observations in People Over Fifty Study (http://clinicaltrials.gov/ct2/show/NCT01737047), focused on clinical end points, including MI, in HIV-positive and HIV-negative cohorts older than 50 years, an age range in which the majority of MI events occur, will help to better define the relative contribution of specific socioeconomic and lifestyle factors as well as HIV infection and exposure to ART on clinical outcomes. The collection of linked clinical samples within such studies will enable interrogation of disease pathogenesis that may provide a platform for the development of HIV-specific interventions to reduce this excess MI risk and ensure that the benefits derived from safe, effective, long-term control of HIV replication by ART translate into reduced mortality for all people living with HIV.
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JAMA Intern Med. 2013
HIV Infection and the Risk of Acute Myocardial Infarction
Matthew S. Freiberg, MD, MSc; Chung-Chou H. Chang, PhD; Lewis H. Kuller, MD, DrPH; Melissa Skanderson, MSW; Elliott Lowy, PhD; Kevin L. Kraemer, MD, MSc; Adeel A. Butt, MD, MS; Matthew Bidwell Goetz, MD; David Leaf, MD, MPH; Kris Ann Oursler, MD, ScM; David Rimland, MD; Maria Rodriguez Barradas, MD; Sheldon Brown, MD; Cynthia Gibert, MD; Kathy McGinnis, MS; Kristina Crothers, MD; Jason Sico, MD; Heidi Crane, MD, MPH; Alberta Warner, MD; Stephen Gottlieb, MD; John Gottdiener, MD; Russell P. Tracy, PhD; Matthew Budoff, MD; Courtney Watson, MPH; Kaku A. Armah, BA; Donna Doebler, DrPH, MS; Kendall Bryant, PhD; Amy C. Justice, MD, PhD
"recent HIV-1 RNA of at least 500 copies/mL (HR, 1.60; 95% CI, 1.14-2.22) and recent CD4 cell count less than 200 cells/mL (1.57; 1.10-2.24) were associated with AMI, and recent protease inhibitor use (1.34; 0.98-1.81; P = .06) had borderline significance with AMI after being included in a model that adjusted for Framingham risk factors, comorbidities, and substance use (data otherwise not shown)......
After adjusting for Framingham risk factors, comorbidities, and substance use, HIV-positive veterans had an increased risk of incident AMI compared with uninfected veterans (HR, 1.48; 95% CI, 1.27-1.72) (Table 3). Framingham risk factors, hepatitis C virus infection, renal disease, and anemia were independently associated with AMI (Table 3). This association persisted when we restricted the sample to never smokers (HR, 1.75; 95% CI, 1.27-2.42) or to those without hepatitis C virus infection, renal disease, and obesity (1.50; 1.20-1.88) or when we expanded our outcomes to include VA, Medicare, and Medicaid events (1.58; 1.25-1.99). Although AMI risk was highest among those with HIV-1 RNA levels of at least 500 copies/mL and CD4 cell count less than 200 cells/mL in time-updated analyses (Table 4), this higher risk remained even among those who achieved HIV-1 RNA levels less than 500 copies/mL over time compared with uninfected veterans (Table 4).This was also true after adjusting for competing risk of death (HR, 1.45; 95% CI, 1.25-1.69). The C statistic for a model to predict AMI was 0.71 (95% CI, 0.70-0.73). When we added HIV infection to the model, the C statistic increased by 0.01 (P < .001)."
ABSTRACT
Importance Whether people infected with human immunodeficiency virus (HIV) are at an increased risk of acute myocardial infarction (AMI) compared with uninfected people is not clear. Without demographically and behaviorally similar uninfected comparators and without uniformly measured clinical data on risk factors and fatal and nonfatal AMI events, any potential association between HIV status and AMI may be confounded.
Objective To investigate whether HIV is associated with an increased risk of AMI after adjustment for all standard Framingham risk factors among a large cohort of HIV-positive and demographically and behaviorally similar (ie, similar prevalence of smoking, alcohol, and cocaine use) uninfected veterans in care.
Design and Setting Participants in the Veterans Aging Cohort Study Virtual Cohort from April 1, 2003, through December 31, 2009.
Participants After eliminating those with baseline cardiovascular disease, we analyzed data on HIV status, age, sex, race/ethnicity, hypertension, diabetes mellitus, dyslipidemia, smoking, hepatitis C infection, body mass index, renal disease, anemia, substance use, CD4 cell count, HIV-1 RNA, antiretroviral therapy, and incidence of AMI.
Main Outcome Measure Acute myocardial infarction.
Results We analyzed data on 82 459 participants. During a median follow-up of 5.9 years, there were 871 AMI events. Across 3 decades of age, the mean (95% CI) AMI events per 1000 person-years was consistently and significantly higher for HIV-positive compared with uninfected veterans: for those aged 40 to 49 years, 2.0 (1.6-2.4) vs 1.5 (1.3-1.7); for those aged 50 to 59 years, 3.9 (3.3-4.5) vs 2.2 (1.9-2.5); and for those aged 60 to 69 years, 5.0 (3.8-6.7) vs 3.3 (2.6-4.2) (P < .05 for all). After adjusting for Framingham risk factors, comorbidities, and substance use, HIV-positive veterans had an increased risk of incident AMI compared with uninfected veterans (hazard ratio, 1.48; 95% CI, 1.27-1.72). An excess risk remained among those achieving an HIV-1 RNA level less than 500 copies/mL compared with uninfected veterans in time-updated analyses (hazard ratio, 1.39; 95% CI, 1.17-1.66).
Conclusions and Relevance Infection with HIV is associated with a 50% increased risk of AMI beyond that explained by recognized risk factors.
With the success of antiretroviral therapy (ART), people infected with human immunodeficiency virus (HIV) are now living longer and are at risk for heart disease. Determining whether HIV-positive people have an increased risk of acute myocardial infarction (AMI) compared with uninfected people is a central question1 with important clinical implications. Although prior studies2- 6 have reported an association between HIV and AMI, the results may have been confounded by the choice of reference group, the lack of adjudicated AMI outcomes, a lack of fatal events, and/or missing risk factor data. We investigated whether HIV is associated with an increased risk of AMI after adjustment for all standard Framingham risk factors among a large cohort of HIV-positive and demographically and behaviorally similar (ie, similar prevalence of smoking, alcohol, and cocaine use) uninfected veterans in care.
RESULTS
Although VACS-VC HIV-positive and uninfected veterans were age- and race-matched at the time of enrollment, after participants with baseline cardiovascular disease were excluded (n = 17 229), some differences by HIV status existed (final sample size = 82 459) (Table 1). The prevalence of Framingham risk factors differed by HIV status (P ² .001 for all). Only current smoking, low high-density lipoprotein (HDL) cholesterol, and elevated triglycerides were more common among HIV-positive veterans. The median baseline coronary heart disease (CHD) risk was intermediate for both groups (Framingham risk score = 6) (Table 1).
During a median follow-up of 5.9 years, there were 871 AMI events (41.7% HIV positive). Of these 871 events, 534 (61.3%) were within or transferred to the VA (Quality Enhancement Research Initiative), 161 (18.5%) were outside the VA and never transferred to VA facilities (Medicare events), and 176 (20.2%) were deaths. The AMI rates per 1000 person-years were significantly higher among HIV-positive compared with uninfected veterans (Table 2), whereas the median age at event (56.4 vs 56.2 years, P = .42) and time to event (3.3 vs 3.4 years, P = .28) were similar.
After adjusting for Framingham risk factors, comorbidities, and substance use, HIV-positive veterans had an increased risk of incident AMI compared with uninfected veterans (HR, 1.48; 95% CI, 1.27-1.72) (Table 3). Framingham risk factors, hepatitis C virus infection, renal disease, and anemia were independently associated with AMI (Table 3). This association persisted when we restricted the sample to never smokers (HR, 1.75; 95% CI, 1.27-2.42) or to those without hepatitis C virus infection, renal disease, and obesity (1.50; 1.20-1.88) or when we expanded our outcomes to include VA, Medicare, and Medicaid events (1.58; 1.25-1.99). Although AMI risk was highest among those with HIV-1 RNA levels of at least 500 copies/mL and CD4 cell count less than 200 cells/mL in time-updated analyses (Table 4), this higher risk remained even among those who achieved HIV-1 RNA levels less than 500 copies/mL over time compared with uninfected veterans (Table 4).This was also true after adjusting for competing risk of death (HR, 1.45; 95% CI, 1.25-1.69). The C statistic for a model to predict AMI was 0.71 (95% CI, 0.70-0.73). When we added HIV infection to the model, the C statistic increased by 0.01 (P < .001).
Among HIV-positive veterans, baseline HIV-1 RNA, CD4 cell count, and ART (both by class and regimen), as well as recent NNRTI, NRTI, and ART regimens were not associated with AMI. However, recent HIV-1 RNA of at least 500 copies/mL (HR, 1.60; 95% CI, 1.14-2.22) and recent CD4 cell count less than 200 cells/mL (1.57; 1.10-2.24) were associated with AMI, and recent protease inhibitor use (1.34; 0.98-1.81; P = .06) had borderline significance with AMI after being included in a model that adjusted for Framingham risk factors, comorbidities, and substance use (data otherwise not shown).
COMMENT
Veterans with HIV infection have a significantly higher risk of AMI compared with demographically and behaviorally similar uninfected veterans even after adjustment for Framingham risk factors, comorbidities, and substance use. This risk persisted among those achieving HIV-1 RNA levels less than 500 copies/mL over time. When added to a model including Framingham risk factors, HIV status modestly improved AMI risk discrimination.
Although consistent with prior studies,2- 6 our analyses are more definitive. This study included adjudicated AMI events within the VA, transfers to the VA and events not treated at the VA (Medicare and Medicaid), and fatal and nonfatal AMI events. Moreover, most of the prior studies were missing confounders such as smoking,3- 6 and none had fatal events or compared rates with uninfected demographically and behaviorally similar participants.
Our results are consistent with prior studies23- 24 linking ART with AMI risk among HIV-positive people. Although the association between recent protease inhibitor use and AMI achieved only borderline significance, in combination with our analysis reporting an excess risk of AMI among HIV-positive veterans who have HIV-1 RNA levels less than 500 copies/mL over time compared with uninfected veterans, this suggests that ART contributes to AMI risk.
Findings from this and prior studies suggest that the increased risk of AMI among HIV-positive people is likely a function of HIV,25 ART,23- 24,26 and the burden of comorbid disease including Framingham risk factors.23 Unlike in prior studies, we did not observe a significant association between HDL cholesterol and AMI in our multivariable models. However, in univariate analyses, HDL less than 40 mg/dL (to convert to millimoles per liter, multiply by 0.0259) was associated with AMI (HR, 1.27; 95% CI, 1.01-1.59). When we added each Framingham risk factor and HIV separately to our univariate HDL model, diabetes (HR, 1.16; 95% CI, 0.92-1.46) and to a lesser extent HIV (1.21; 0.96-1.52) attenuated the association between HDL and AMI.
The mechanism by which HIV infection increases the risk of AMI is not known. Possible mechanisms may involve inflammation,27 CD4 cell count depletion,28 altered coagulation,29 dyslipidemia,30 impaired arterial elasticity,31 and endothelial dysfunction.32 Among HIV-infected people, ART is associated with metabolic changes33 and abnormal fat distribution,34- 35 which in turn are linked with insulin resistance,33 diabetes,33 and dyslipidemia.33,36 Although HIV and ART are associated with AMI risk, results from the Strategies for Management of Antiretroviral Therapy study25 showing that HIV viral suppression results in lower cardiovascular disease risk than drug conservation therapy suggest that the virus plays the larger role.
In this study, HIV-positive veterans had a higher risk of AMI while having the same baseline Framingham risk score as uninfected veterans. Human immunodeficiency virus infection was associated with an increase in AMI risk when added to a model of Framingham risk factors. These findings combined with prior work by the D:A:D37- 38 suggest that the Framingham risk score may underestimate AMI risk among HIV-positive people and that the addition of HIV and ART to a model of established AMI risk factors may be clinically useful.
When the Framingham risk score was validated in other uninfected multiethnic cohorts, recalibration was required in some instances to account for the different prevalences of risk factors and underlying rates of developing CHD.22 A comparison of the VACS-VC with participants in the Framingham Heart Study demonstrates substantial differences in the prevalence of diabetes, smoking, and low HDL cholesterol as well as race/ethnicity.22 Of note, the Framingham risk score does not incorporate risk factors significantly associated with AMI in this study (ie, hepatitis C virus, anemia, renal disease, HIV-1 RNA, or CD4 cell count). Future studies should focus on validating the Framingham risk score as originally described by D'Agostino et al22 and then assess whether the inclusion of HIV status, race/ethnicity, comorbidities (eg, hepatitis C virus, renal disease, and anemia), HIV-specific biomarkers and ART, and/or inflammatory biomarkers improves CHD risk prediction for HIV-positive people.
There are limitations that warrant discussion. First, because this sample is overwhelmingly male, our findings may not generalize to women. Second, as with any observational study, there is always the possibility of residual confounding. For example, we do not have biomarker data beyond what is available in the clinical setting; therefore, we could not incorporate biomarkers, such as C-reactive protein or D-dimer, into our analysis. Similarly, as HIV-1 RNA assays that detect lower HIV-1 RNA levels (<40 copies) were not available in the VA in 2003, we could not use this definition to assess viral suppression. Third, the Framingham risk score predicts CHD (ie, AMI and CHD death). Because this study focused on AMI, we could not validate the Framingham risk score in the VACS-VC to determine whether the Framingham risk score underestimates CHD risk in our cohort. Fourth, the use of ICD-9 codes to identify substance use may have resulted in some misclassification. Fifth, some of our AMI events were defined using only ICD-9 codes and death certificate data without confirmatory data (eg, enzymes and electrocardiography findings). However, it is reassuring that the association between HIV and AMI remained the same across several sensitivity analyses exploring the influence of these data. Sixth, there is the possibility that some non-VA events were not captured. However, after surveying 6000 VACS39 participants (half HIV positive) as to whether or not they had (1) had any cardiovascular event and (2) been hospitalized for it outside the VA, 25% reported an event occurring outside the VA. In this analysis, 23% of the AMI events occurred at non-VA hospitals. Moreover, the association between HIV and AMI remained unchanged when we excluded Medicare and Medicaid events (HR, 1.47; 95% CI, 1.25-1.73), suggesting that non-VA health care use for AMI did not substantially differ by HIV status. Our rates for white uninfected men (2.6 per 1000 person-years) were also similar to the age-adjusted rates in the 2006 Atherosclerosis Risk in Communities study from the community surveillance (2.9 per 1000 persons). More important, these rates are not adjusted for the higher mortality rate among veterans compared with Atherosclerosis Risk in Communities participants and competing risks of death. Finally, we considered differences in the proportion of missing data on all Framingham risk factors by HIV status. Although there were statistically different proportions, these differences were small (eTable).
In conclusion, HIV infection is independently associated with AMI after adjustment for Framingham risk, comorbidities, and substance use. Unsuppressed HIV viremia, low CD4 cell count, Framingham risk factors, hepatitis C virus, renal disease, and anemia are also associated with AMI. Moreover, this risk also extends to HIV-positive veterans with an HIV-1 RNA level less than 500 copies/mL over time compared with uninfected veterans. When added to a model of Framingham risk factors, HIV infection is associated with improved AMI risk discrimination. Future studies should focus on validating the Framingham risk score in cohorts with HIV-positive people using hard CHD end points and assessing whether the inclusion of HIV status; race/ethnicity; comorbidities such as hepatitis C virus, renal disease, and anemia; HIV-specific biomarkers and ART; and/or inflammatory biomarkers improves CHD risk prediction for HIV-positive people.
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