HIV Infection Ups Heart Failure Risk: "rate of incident heart failure was 7.12 per 1,000 person-years among those with HIV and 4.82 per 1,000 person-years in the rest of the cohort.....But the risk was not seen if baseline and recent HIV levels were less than 500 copies/mL"
Published: April 25, 2011|
* Explain that HIV-infected veterans were more likely to develop heart failure than their HIV-negative peers after adjusting for traditional risk factors.
* Note that those with viral loads >500 copies/mL were most at risk.
HIV infection is associated with an increased risk of heart failure, researchers reported.
In a retrospective analysis of data from two large cohorts of veterans, those with HIV had more than an 80% increase in the risk of heart failure, according to Adeel Butt, MD, of the University of Pittsburgh School of Medicine, and colleagues.
On the other hand, the risk increase was confined to those whose virus was not controlled, Butt and colleagues reported in the April 25 issue of Archives of Internal Medicine.
HIV infection has been reported as an independent risk factor for cardiovascular disease in some but not all studies, the researchers noted, and its role in heart failure has not been known.
To help clarify the issue, the researchers looked at veterans enrolled in two studies, the Veterans Aging Cohort Study Virtual Cohort and the 1999 Large Health Study of Veteran Enrollees.
All participants were eligible, but the investigators excluded subjects with coronary heart disease, angina, heart failure, or cancer at baseline. Because there were only 276 of them, women were also excluded from the analysis, leaving 8,486 patients, including 2,391 men with HIV (or 28.2%).
The median duration of follow-up was 7.3 years, during which there were 286 incident cases of heart failure and 1,096 deaths, Butt and colleagues reported.
After adjusting for age, race, and ethnicity, Butt and colleagues found the rate of incident heart failure was 7.12 per 1,000 person-years among those with HIV and 4.82 per 1,000 person-years in the rest of the cohort.
After adjusting for traditional risk factors, the hazard ratio for heart failure among those with HIV was 1.81, with a 95% confidence interval from 1.39 to 2.36, they reported.
The usual suspects were also independent risk factors, Butt and colleagues found: increasing age, African-American race, current smoking, body mass index greater than 30, hypertension, diabetes, and a diagnosis of alcohol abuse or dependence.
Among those with HIV, immune status did not appear to play a role; the risk of heart failure was increased regardless of the number of CD4-positive T cells.
On the other hand, ongoing HIV replication did play a role, Butt and colleagues found. Specifically, compared with patients without HIV infection:
* HIV-positive patients who had baseline HIV RNA levels of 500 or more copies per milliliter (mL) had an adjusted hazard ratio for heart failure of 2.28, with a 95% confidence interval from 1.57 to 3.32.
* The same risk was seen if HIV-positive participants had a baseline viral load below 500 copies/mL but whose recent viral loads exceeded that. The hazard ratio was 2.39, with a 95% confidence interval from 1.25 to 4.58.
* But the risk was not seen if baseline and recent HIV levels were less than 500 copies/mL. The hazard ratio was 1.10, with a 95% confidence interval from 0.64 to 1.89.
* The difference between those with low and high viral loads was statistically significant (P<0.001).
The association persisted when the researchers excluded those who were diagnosed with coronary heart disease during the follow-up period before the heart failure diagnosis, or had a diagnosis of alcohol abuse or dependence, or both.
Butt and colleagues cautioned that the study relies on ICD-9 codes, rather than adjudicated clinical outcomes. Also, the results may not be applicable to women because they were excluded, they noted.
The study had support from the National Institute on Alcohol Abuse and Alcoholism, the Veterans Health Administration, the National Heart, Lung and Blood Institute, and the National Institute on Aging. The authors said they had no disclosures.
Risk of Heart Failure With Human Immunodeficiency Virus in the Absence of Prior Diagnosis of Coronary Heart Disease
Adeel A. Butt, MD, MS; Chung-Chou Chang, PhD; Lewis Kuller, MD, DrPH; Matthew Bidwell Goetz, MD; David Leaf, MD; David Rimland, MD; Cynthia L. Gibert, MD; Krisann K. Oursler, MD, MSc; Maria C. Rodriguez-Barradas, MD; Joseph Lim, MD; Lewis E. Kazis, ScD; Stephen Gottlieb, MD; Amy C. Justice, MD, PhD; Matthew S. Freiberg, MD, MSc
Arch Intern Med. 2011;171(8):737-743. doi:10.1001/archinternmed.2011.151
from Jules: although this study found patients with undetectable viral load did not have increased risk I don't believe that, if they stratified at looked at other risk factors like inflammation, by CD4 and other considerations they would have found increased risk despite undetectable viral load.
Background Whether human immunodeficiency virus (HIV) infection is a risk factor for heart failure (HF) is not clear. The presence of coronary heart disease and alcohol consumption in this population may confound this association.
Methods To determine whether HIV infection is a risk factor for incident HF, we conducted a population-based, retrospective cohort study of HIV-infected and HIV-uninfected veterans enrolled in the Veterans Aging Cohort Study Virtual Cohort (VACS-VC) and the 1999 Large Health Study of Veteran Enrollees (LHS) from January 1, 2000, to July 31, 2007.
Results There were 8486 participants (28.2% HIV-infected) enrolled in the VACS-VC who also participated in the 1999 LHS. During the median 7.3 years of follow-up, 286 incident HF events occurred. Age- and race/ethnicity-adjusted HF rates among HIV-infected and HIV-uninfected veterans were 7.12 (95% confidence interval [CI], 6.90-7.34) and 4.82 (95% CI, 4.72-4.91) per 1000 person-years, respectively. Compared with HIV-uninfected veterans, those who were HIV infected had an increased risk of HF (adjusted hazard ratio [HR], 1.81; 95% CI, 1.39-2.36). This association persisted among veterans who did not have a coronary heart disease event or a diagnosis related to alcohol abuse or dependence before the incident HF event (adjusted HR, 1.96; 95% CI, 1.29-2.98). Compared with HIV-uninfected veterans, those who were HIV infected with a baseline Human immunodeficiency virus 1 (HIV-1) RNA level of 500 or more copies/mL had a higher risk of HF (adjusted HR, 2.28; 95% CI, 1.57-3.32), while those with baseline and a recent HIV-1 RNA level less than 500 copies/mL did not (adjusted HR, 1.10; 95% CI, 0.64-1.89; P < .001 for comparison between high and low HIV-1 RNA groups).
Conclusions Our data suggest that HIV infection is a risk factor for HF. Ongoing viral replication is associated with a higher risk of developing HF.
Human immunodeficiency virus (HIV) infection as an independent risk factor for cardiovascular disease has been reported in some1-2 but not all studies.3-4 Whether HIV infection is an independent risk factor for heart failure (HF), particularly among patients without a prior coronary heart disease (CHD) event or significant alcohol use before developing HF, is not known.5 Prior reports2, 6 suggest that class of antiretroviral drugs (particularly protease inhibitors), Human immunodeficiency virus 1 (HIV-1) RNA levels,7 and low CD4+ lymphocyte counts8 are each associated with an increased risk of cardiovascular disease events, an important risk factor for HF. Heavy alcohol consumption, which is more prevalent among HIV-infected people, is also an established risk factor for HF.9-10 In addition, zidovudine (azidothymidine) use has been associated11-12 with a specific dose-dependent skeletal myopathy attributed to mitochondrial toxicity and with cardiac dysfunction that resolves with discontinuation of the drug. In addition, HIV infection has been linked with dilated cardiomyopathy, myocarditis, and left ventricular dysfunction, the last even in the absence of clinically advanced HIV disease.13-14 However, not all studies have confirmed the association between HIV, antiretroviral therapy, and myocardial dysfunction.5 Other important risk factors for HF in the general population include increasing age, hypertension, diabetes mellitus, and obesity,15 factors that are being seen with increasing frequency among the HIV-infected population. With improved survival among individuals with HIV infection and possible effects of HIV infection and antiretroviral therapy on body habitus and metabolic factors, it is important to understand the associations of established and novel risk factors and define the role of HIV itself in the risk of HF. An understanding of risk factors is critical in designing targeted intervention strategies to reduce such risk and improve cardiovascular clinical outcomes in this population. The objective of this study, therefore, was to determine whether HIV infection was independently associated with an increased risk of incident HF. We performed additional analyses in patients without a prior CHD event or alcohol abuse or dependence diagnosis before developing HF and assessed the association between suppressed HIV-1 RNA viral loads and HF to further understand the impact of HIV itself on the risk of HF.
Between January 1, 2000, and July 31, 2007, a total of 8486 patients met our criteria for inclusion, of whom 2391 (28.2%) were HIV infected and 6095 (71.8%) were HIV uninfected (Table 1). The median duration of follow-up was 7.3 years (range, 0.01-7.48 years) for the entire cohort. There were 286 incident HF events and 1096 deaths during the follow-up period. Among patients who did not develop HF or die (n = 7104), 87.1% completed follow-up to within 1 year of the end of the follow-up period.
The median age was 48.0 years in both groups. Participants with HIV infection were more likely to have hepatitis C virus coinfection (30.5% vs 11.4%) and cocaine abuse or dependence (21.9% vs 15.7%) and higher reported rate of current smoking (55.0% vs 45.3%), but were less likely to have hypertension (18.7% vs 28.8%) or diabetes (16.7% vs 24.8%) (P < .001 for all comparisons). The proportion of subjects with dyslipidemia or a diagnosis of alcohol abuse or dependence was similar in both groups. Patients with HIV infection had a lower mean (SD) body mass index compared with those without HIV infection (25.1 [4.2] vs 28.1 [5.3]).
The age- and race/ethnicity-adjusted rates of incident HF were 7.12 per 1000 person-years (95% CI, 6.90-7.34) for HIV-infected patients and 4.82 per 1000 person-years (95% CI, 4.72-4.91) for HIV-uninfected patients. Compared with HIV-uninfected patients, HIV-infected patients had a significantly increased risk of HF after adjusting for traditional risk factors (HR, 1.81; 95% CI, 1.39-2.36; Table 2 and Figure 1). Other factors significantly and positively associated with a risk of HF were increasing age, African American race, current smoking, body mass index greater than 30, hypertension, diabetes, and a diagnosis of alcohol abuse or dependence. Compared with patients without HIV infection, those with HIV infection who had baseline HIV-1 RNA levels of 500 or more copies/mL had a significantly higher risk of HF (adjusted HR, 2.28; 95% CI, 1.57-3.32). Those with HIV infection who had baseline and recent HIV-1 RNA levels less than 500 copies/mL, however, did not have an increased risk of HF (adjusted HR, 1.10; 95% CI, 0.64-1.89). The difference between the low HIV-1 RNA and high HIV-1 RNA group was statistically significant (P < .001) (Table 2).
Although all participants in our study did not have CHD, HF, or angina at the time of enrollment, we conducted additional analyses excluding patients who developed CHD during the follow-up period prior to the diagnosis of HF, had a diagnosis of alcohol abuse or dependence, or both (Table 3 and Figure 2). Among patients without a CHD event prior to the diagnosis of HF, the association between HIV infection and HF persisted (HR, 1.92; 95% CI, 1.42-2.61). Similarly, among patients who did not have a diagnosis of alcohol abuse or dependence at baseline or during the follow-up period, HIV infection remained significantly associated with an increased risk of HF (HR, 1.94; 95% CI, 1.36-2.76). These results persisted when we further restricted the sample to patients who had neither a diagnosis of CHD during the follow-up period prior to the diagnosis of HF nor a diagnosis of alcohol abuse or dependence (HR, 1.96; 95% CI, 1.29-2.98).
Our data suggest that HIV infection is associated with an increased risk of HF after adjusting for traditional CHD risk factors. This risk persisted even after restricting the sample to patients who did not have a diagnosis of CHD, HF, or angina at baseline or a diagnosis of CHD during the follow-up period prior to the diagnosis of HF, a diagnosis of alcohol abuse/dependence, or both. Ongoing viral replication (HIV-1 RNA level ≥500 copies/mL) was associated with a higher risk of developing HF. However, HIV-infected participants with baseline and recent HIV-1 RNA level less than 500 copies/mL did not have an increased risk of HF compared with HIV-uninfected participants.
To our knowledge, there are no definitive studies on the risk of HF that compared HIV-infected with HIV-uninfected people who are free of baseline CHD. Diastolic dysfunction has been reported in 48% to 50% of HIV-infected persons, but the proportion of this dysfunction attributable to preexisting CHD is not known.29-31 Myocarditis is present in up to half of patients with AIDS in autopsy studies,32-33 but overt antemortem HF or autopsy evidence of ventricular dysfunction is not present in all such cases. In addition, these smaller studies are from the pre-CART era and lack HIV-uninfected controls to determine a direct association with HIV infection. In contrast, one study5 of 91 HIV-infected participants did not find any significant evidence of right or left ventricular dysfunction as measured by radionuclide ventriculography. To our knowledge, our study is the largest to investigate the relationship between HF and HIV infection and the first to demonstrate such an association and provide evidence of HIV infection as an independent risk factor for HF.
Although the exact mechanism by which HIV infection is associated with HF is not well understood, several possible mechanisms exist, including direct effects of the HIV, comorbidities associated with HIV infection (eg, heavy alcohol consumption), antiretroviral therapy leading to an increased risk of CHD and subsequent HF, nutritional deficiencies, and immunologic damage to the myocardium. Our results suggest that HIV itself is playing an important and independent role. Even after excluding patients with a baseline history of CHD, HF, and angina, as well as a CHD event in the follow-up period prior to the diagnosis of HF and a history of alcohol abuse or dependence diagnosis, the risk of incident HF was still substantial among the HIV-infected cohort. Ongoing HIV replication appears to play an important role. Compared with HIV-uninfected participants, only participants with an HIV-1 RNA level greater than 500 copies/mL had a significantly increased risk of HF. For participants who had baseline and recent HIV-1 RNA levels less than 500 copies/mL, there was no significantly increased risk of HF (Table 2). Antiretroviral therapy was associated with a slightly attenuated risk, although the difference between CART-naive and CART-experienced groups did not reach statistical significance. However, these results should be interpreted carefully given the small number of events in the stratified categories. Our findings that hypertension, obesity, alcohol abuse or dependence, and diabetes mellitus were associated with an increased risk of HF are consistent with reports34-35 from other established cohort studies of people without HIV infection and offer the possibility of interventions to reduce the risk of HF. In the current study, we were not able to assess the differential risk between controlled and uncontrolled hypertension or diabetes, but this is an attractive topic for further research.
Secondary infection of the myocardium in HIV-infected persons may also lead to myocarditis, myocardial dysfunction, and HF. Presence of cytomegalovirus, acid-fast bacilli, Toxoplasma gondii, Candida species, Histoplasma capsulatum, Cryptococcus neoformans, and Staphylococcus aureus in the myocardium of HIV-infected patients has been reported.11, 33, 36 A causal association is not clear in all instances, since in some cases, myocarditis is not associated with adjacent myocyte necrosis on histologic examination and evidence of disseminated disease is not present.
Other causes of heart muscle disease in HIV-infected persons include immunologic damage, nutritional deficiencies (eg, selenium, antioxidant vitamins, and carnitine), and antiretroviral therapy.11, 13 Zidovudine has been associated with a specific dose-dependent skeletal myopathy attributed to mitochondrial toxicity and with cardiac dysfunction that resolves with discontinuation of the drug.11-12 However, in a study37 in HIV-infected children, zidovudine was not associated with worsening of cardiac function. We were unable to analyze the occurrence of HF associated with any specific antiretroviral drugs.
The role of traditional risk factors in the risk of HF needs to be emphasized. Increasing age, African American race, obesity, hypertension, diabetes, and alcohol use are established risk factors and were also significantly associated with a higher risk of HF in our study. Our data tend to suggest that these factors increase the risk of HF independent of their risk on clinically diagnosed CHD, evidenced by the fact that they remained significant even after people with prior CHD were excluded from the study. However, this finding should be interpreted with caution because we could not exclude subclinical CHD. Interventions to minimize the modifiable traditional risk factors, including glycemic and blood pressure control, weight reduction, and abstinence from alcohol, are prudent strategies that should be emphasized. The actual effect of such strategies on risk reduction among HIV-infected persons requires further study.
The strengths of our study include large numbers, participants drawn from validated and well-established cohorts, a national rather than geographically limited sample, and availability of HIV-uninfected controls. Certain limitations need to be understood as well. The diagnosis of HF was based on ICD-9 codes; however, codes for various cardiovascular end points have been extensively used in previous publications3, 24-25 and are considered reasonable alternatives to adjudicated clinical outcomes. Moreover, since HF is a chronic condition, our ability to capture outpatient clinical diagnoses in the present study is advantageous; if the initial diagnosis of HF were made at an outside hospital, the diagnosis could be captured in our study via routine follow-up outpatient care within the VA health care system. We did not assess the effect of specific antiretroviral drugs owing to the small number of events for individual drugs, nor did we assess the role of adherence to medication therapy and control of blood pressure or blood glucose levels in the risk of HF. Our study was limited to men and so may not be generalized to women. Other than men being the predominant population, the HIV infection epidemic in veterans is largely similar to that in nonveterans.20 Since we used administrative data to identify incident HF events, this study was not able to distinguish between HF associated with systolic vs diastolic dysfunction. Finally, while we excluded diagnosed CHD as a preceding event to HF, we did not exclude subclinical atherosclerosis as a cause of HF.
There are major clinical implications of our findings. If HF is a major cardiovascular consequence of HIV infection rather than atherosclerotic heart disease, different approaches to manage such consequences are warranted. Cardiovascular risk factor reduction and antiplatelet agents (eg, aspirin) are the mainstay in the management of atherosclerotic heart disease; however, these strategies, plus aggressive blood pressure control and the treatment of the HIV infection, may also be required to prevent development of HF in this population. The exact approach would depend on the mechanism and mediators of this risk; therefore, further studies are needed. Several risk factors identified are modifiable, and intervention studies may be designed to look at the effect of strict blood pressure control, tight glycemic control, and weight loss on the risk of HF. Additional studies are also warranted to fully understand the mechanism of HF in HIV-infected persons, especially to understand the nature of HF, eg, systolic vs diastolic dysfunction.
In conclusion, HIV infection is associated with an increased risk of HF after adjusting for traditional risk factors for HF. This association persisted even after exclusion of patients with a baseline history of CHD, HF, and angina, as well as a CHD event in the follow-up period prior to the diagnosis of HF and a history of alcohol abuse or dependence diagnosis. Ongoing viral replication is associated with a higher risk of HF. Further studies to fully characterize this association and to understand the underlying mechanisms are warranted.