Ischemic Cardiovascular Disease in Persons with Human Immunodeficiency Virus Infection

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1 HIV/AIDS MAJOR ARTICLE Ischemic Cardiovascular Disease in Persons with Human Immunodeficiency Virus Infection Max H. David, 1,3 Richard Hornung, 2 and Carl J. Fichtenbaum 1 1 Department of Medicine, Division of Infectious Diseases, and 2 Institute for Health Policy and Health Services Research, University of Cincinnati College of Medicine, Cincinnati; and 3 St. Johns Mercy Medical Center, St. Louis University, St. Louis Persons with human immunodeficiency virus (HIV) infection might be at risk for ischemic cardiovascular disease (CVD). We reviewed the records of 16 HIV-infected persons with proven CVD (8 cases of angina and 8 cases of myocardial infarctions). This represents 1.7% of HIV-infected persons seen at our institution from 1 April 1999 through 25 April In comparison with 32 HIV-infected age- and sex-matched controls, case patients had more risk factors for CVD (median number of risk factors for CVD, 3 versus 1; P!.001), lower nadir CD4 + lymphocyte counts (median, 101 cells/mm 3 versus 278 cells/mm 3 ; P p.02), and a longer duration of prior exposure to nucleoside analogs (median, 190 weeks versus 130 weeks; P p.02). There was no difference in the duration of exposure to protease inhibitors. Ischemic CVD occurs in HIV-infected persons and appears to be most closely associated with traditional risk factors for coronary artery disease (for example, hypertension and hypercholesterolemia). Lower CD4 + lymphocyte counts and duration of HIV infection might also be risk factors or markers for the development of ischemic CVD. Cardiovascular disease (CVD) continues to be the leading cause of mortality in men aged 135 years and all persons aged 145 years [1]. CVD has generally been uncommon in persons with HIV infection. Before the advent of potent antiretroviral therapy, the most common cardiac complications associated with HIV infection were congestive heart failure, idiopathic cardiomyopathy, endocarditis (largely as a result of the use of injection drugs), cardiomyopathy secondary to opportunistic infections or medications, and ventricular arrhythmia (typically related to the use of such medications as pentamidine) [2 4]. Reports of premature myocardial infarctions and hy- Received 26 March 2001; revised 1 August 2001; electronically published 20 November Financial support: National Institute of Allergy and Infectious Disease, National Institutes of Health (grant NIH AI-25897). Reprints or correspondence: Dr. Carl J. Fichtenbaum, Div. of Infectious Diseases, University of Cincinnati College of Medicine, Holmes Division, Mail Location 0405, Eden and Albert Sabin Way, PO Box , Cincinnati, OH (carl.fichtenbaum@uc.edu). Clinical Infectious Diseases 2002; 34: by the Infectious Diseases Society of America. All rights reserved /2002/ $03.00 perlipidemia have been noted in HIV-infected persons receiving potent antiretroviral therapy [5 7]. It is unclear whether ischemic CVD is accelerated in persons with HIV infection. Protease inhibitors have been indirectly implicated in the development of ischemic CVD because of several recently observed metabolic complications, although there are insufficient data to confirm this hypothesis [8 12]. Specifically, protease inhibitors have been reported to induce insulin resistance (diabetes mellitus), arterial hypertension, and dyslipidemia. All of these factors have been associated with the development of ischemic CVD in HIV-seronegative persons. We identified several patients with ischemic CVD and reviewed our experience. The objective of this study was to identify factors associated with proven ischemic CVD in persons with HIV infection. PATIENTS AND METHODS We reviewed the medical records of all HIV-infected persons seen at the University of Cincinnati Infectious Diseases Center (IDC) from 1 April 1999 through 25 April 2000 to identify patients with proven ischemic 98 CID 2002:34 (1 January) HIV/AIDS

2 Table 1. Clinical characteristics of patients with ischemic cardiovascular disease (ICVD) and controls. Characteristic (n p 32) P Age, median years (range) 43 (42 66) 45 (37 65).62 Sex.46 Male 13 (81) 26 (81) Female 3 (19) 6 (19) Race.61 White 8 (50) 15 (47) African American 8 (50) 17 (53) CD4 count, a median cells/mm 3 (range) 234 (74 731) 444 ( ).03 HIV RNA, a median copies/ml (range) 7656 (49 117,713 )!400 (22 428,000).14 HIV RNA level of!400 copies/ml, % NOTE. Data are no. (%) of patients, unless otherwise indicated. a Within 3 months of cardiac event, for patients, or last follow-up visit, for controls. CVD. had to be HIV-infected adults aged 18 years and to have evidence of ischemic CVD documented by angiography, echocardiography, exercise stress testing, or myocardial infarction. We reviewed notes made by doctors and nurses, medication records, hospital discharge summaries, and laboratory records from the initial visit to the final visit to the IDC for case patients and controls. Records were reviewed for documentation of traditional CVD risk factors (i.e., cigarette smoking, family history of heart disease, hyperlipidemia, hypertension, and diabetes mellitus), use of antiretroviral medications, and presence of underlying illnesses. Blood pressure data from each recorded IDC visit (approximately every 3 4 months) were also reviewed. Cholesterol levels were reviewed from laboratory records and hyperlipidemia was defined as a cholesterol level of 1240 mg/dl, in accordance with the guidelines of the National Cholesterol Education Program, because findings from fasting lipid studies were not available for many subjects [13]. Body-mass index measurements (height) were unavailable for most patients and, thus, were not analyzed. Control subjects had HIV infection without evidence of ischemic CVD. were selected at random from patients enrolled at the IDC and were matched by age and sex. Two controls were identified for each case patient. Medical records were reviewed in a similar manner for case patients and controls. We hypothesized that there would be a dose-response relationship between the probability of a cardiac event and the level of traditional CVD risk factors in HIV-infected persons. Statistical analysis was performed by use of SAS, version 8.0 (SAS Institute). Univariate analysis of risk factors was performed by the Wilcoxon rank-sum test for continuous data and the x 2 test for categorical data. Conditional logistic regression analysis was used to evaluate the impact of specific variables. A matched case-control analysis was conducted to examine the following factors: nadir CD4 lymphocyte count, duration of protease inhibitor exposure, duration of nucleoside analog exposure, cigarette smoking, hypertension, hyperlipidemia, recent plasma HIV RNA level, family history of heart disease, race, and recent CD4 lymphocyte count. Several multivariate models were created for variables that were statistically significant on univariate analysis. In all analyses, a P value of.05 was considered significant. Institutional approval was obtained by the University of Cincinnati Institutional Review Board in accordance with guidelines for human experimentation as specified by the US Department of Health and Human Services and the University of Cincinnati (Cincinnati, Ohio). RESULTS A total of 951 persons with HIV infection were seen at the University of Cincinnati IDC. Sixteen persons (1.7%) had documented evidence of ischemic CVD. Table 1 shows the baseline characteristics of the case patients and controls. The CD4 lymphocyte counts were lower and plasma HIV-1 RNA levels were higher in case patients than they were in controls. Fifty percent of the controls had achieved virus suppression at!400 copies/ml, compared with 33% of the case patients ( P p.14). Eight case patients initially presented with angina, and 8 had a myocardial infarction. Eleven case patients underwent angioplasty, 2 underwent coronary artery bypass grafting, and 3 were treated with medical therapy alone. Of the 3 women with ischemic CVD, 2 had angina (1 underwent angioplasty and 1 was treated with medication) and 1 had a myocardial infarction (treated by means of angioplasty). Univariate analysis of cardiovascular risk factors is shown in table 2. Cigarette smoking, arterial hypertension, an elevated HIV/AIDS CID 2002:34 (1 January) 99

3 Table 2. Risk factor Univariate analysis of cardiovascular risk factors. No. (%) of (n p 32) Smoking 13 (81) 12 (38).001 Diabetes 2 (13) 2 (6).39 Hypertension 10 (63) 7 (22).008 Elevated cholesterol level 8 (50) 1 (3).001 Family history 5 (31) 0 (0).001 Cocaine use 10 (63) 7 (22).36 Treatment before cardiac event Protease inhibitor 11 (69) 23 (72).79 Potent antiretroviral therapy 11 (69) 27 (84).50 CD4 count of!200 cells/mm 3 10 (63) 11 (34).03 NOTE. ICVD, ischemic cardiovascular disease. cholesterol level, and family history of premature coronary artery disease were all more common in case patients than they were in controls. Case patients had an increased number of traditional cardiovascular risk factors than did controls (median number of risk factors, 3 vs. 1; P!.001). Analysis of traditional cardiovascular risk factors, excluding family history of premature coronary artery disease, remained significant (median number of factors, 2 vs. 1; P!.001). Duration of protease inhibitor therapy before the cardiac event was not associated with higher risk. We evaluated the relationship between the development of hypertension and hypercholesterolemia and the use of protease inhibitors. Ten patients with ischemic CVD reported a history of hypertension. Hypertension was documented before the initiation of protease inhibitor therapy in 8 of 10 of these patients. Eight patients with ischemic CVD had hypercholesterolemia. Hypercholesterolemia was present in 3 patients before the initiation of protease inhibitors. Two patients with hypercholesterolemia Table 3. Characteristic P Characterization by CD4 + lymphocyte counts and antiretroviral therapy. were not prescribed protease inhibitors before their ischemic cardiac events. In 3 patients, cholesterol values were not available before the initiation of protease inhibitors. The immunologic, virologic, and treatment-related characteristics are summarized in table 3. When compared with controls, case patients had lower CD4 lymphocyte count nadirs and a longer duration of CD4 lymphocyte counts of!200 cells/mm 3. The following characteristics were not associated with increased risk of CVD: age; race; sex; use of nonnucleoside reverse-transcriptase inhibitors (NNRTIs), cocaine, any regimen of potent antiretroviral therapy, or protease inhibitors; and HIV RNA levels. Multivariate analysis confirmed that a decrease in the nadir CD4 lymphocyte count was associated with greater risk of CVD in case patients, as compared with controls ( P p.04; OR, 0.56 per 100 cells; 95% CI, ). Adjusted for age, the nadir CD4 lymphocyte count was a risk factor until the subject reached the age of 59 years. A lower nadir CD4 lymphocyte count remained significant ( P p.05; OR, 0.51 per 100 cells; 95% CI, ) when adjusted for high cholesterol levels ( P p.02; OR, 20.73; 95% CI, ). Case patients also had a longer duration of exposure to nucleoside reverse-transcriptase inhibitors NRTIs ( P p.04; OR, 2.14 per 100 weeks; 95% CI, ) when adjusted for high cholesterol levels ( P p.005; OR, 36.84; 95% CI, ). Thus, on average, there would be an increase in risk of 114% per 100 weeks additional use of NRTIs. DISCUSSION Ischemic CVD is increasingly being reported in association with HIV infection and treatment with protease inhibitors [2 7]. We reviewed the records of 16 HIV-infected persons with ischemic CVD. Traditional risk factors for ischemic CVD include cigarette smoking, arterial hypertension, a family history of early ischemic CVD, and hypercholesterolemia. And indeed, (n p 32) P Nadir CD4 count, median cells/mm 3 (range) 101 (5 534) 278 (0 822).02 Potent antiretroviral therapy before cardiac event, no. (%) 11 (69) 27 (84).50 Previous AIDS-defining opportunistic illness, no. (%) 5 (31) 7 (22).41 Duration of CD4 count of!200 cells/mm 3, median weeks (range) 54 (0 258) 0 (0 260).02 Time from CD4 nadir to event, median weeks (range) 78 (20 208) 110 (9 280).46 Duration of NNRTI use, median weeks (range) 0 (0 100) 0 (0 156).09 Duration of NRTI use, median weeks (range) 190 (31 624) 130 (0 316).02 Duration of protease inhibitor use, median weeks (range) 118 (0 190) 64 (0 240).46 NOTE. ICVD, ischemic cardiovascular disease; NRTI, nucleoside reverse-transcriptase inhibitor; NNRTI, nonnucleoside reverse-transcriptase inhibitor. 100 CID 2002:34 (1 January) HIV/AIDS

4 these risk factors were more common among persons with proven ischemic CVD than they were among controls. Reports of diabetes mellitus were too uncommon to judge whether there was any association with ischemic CVD. People who developed ischemic CVD were also more likely to have used NRTIs for a longer period of time and to have had a lower nadir CD4 lymphocyte count than were controls. The use of protease inhibitors was not clearly associated with the development of an ischemic CVD. Most patients reported a history of hypertension (80%) before the use of protease inhibitors. Of the 8 patients with hypercholesteremia, 3 received diagnoses before they commenced use of protease inhibitors, and 2 others were never prescribed protease inhibitors. However, we cannot exclude the possibility that hypertension or hypercholesterolemia were exacerbated by the use of protease inhibitors. There are several important limitations to our study. The number of patients and relatively short duration of follow-up limits the conclusions of our study. It is possible that longer durations of exposure to protease inhibitors might reveal an association with an increased risk of CVD. It is also possible that the association of traditional cardiac risk factors with the development of ischemic CVD is a marker for protease inhibitor use. Hyperinsulinemia, dyslipidemia, and hypertension have all been reported in association with the use of protease inhibitors. Insulin levels were not measured in our study. Fasting cholesterol levels were not available for 3 of our patients with ischemic CVD before the initiation of protease inhibitor therapy. Thus, it is possible that the association of traditional risk factors (e.g., hypercholesterolemia, hypertension) might reflect, in part, the effects of protease inhibitors. Another potential shortcoming is that most retrospective studies are subject to ascertainment bias. It is possible that there were differences in the recording or collection of information about cardiovascular risk factors. Clearly, larger longitudinal cohort studies will be needed to confirm or refute the findings of this study. A number of epidemiologic studies have demonstrated that cigarette smoking, elevated serum cholesterol levels, arterial hypertension, and a family history of premature CVD are important risk factors for ischemic CVD [1]. Our findings are consistent with these results and those of a recent study of HIVinfected persons with evidence of fat redistribution [6]. In addition, our patients had a median age in the fourth decade, whereas the peak incidence of ischemic CVD in the absence of HIV infection is in the fifth decade [14]. This suggests that, although traditional CVD risk factors play an important role, other factors might exist that could result in more rapid progression or presentation of atherosclerosis in persons with HIV infection. Two interesting findings were the associations between lower nadir CD4 lymphocyte counts, duration of NRTI use, and the development of ischemic CVD. The former association suggests that duration or severity of immunosuppression in persons with HIV infection might be a risk factor for ischemic CVD. This is consistent with the findings of a recent prospective observational study that reported a cardiac event rate of 5.5 events per 1000 person-years in persons with HIV infection versus 2.8 events per 1000 person-years in those without HIV infection [7]. In that study, Klein and colleagues also reported that, in HIV-infected persons, there was no difference between patients who used protease inhibitors and those who did not with regard to cardiac event rates. Atherosclerosis and HIV infection are inflammatory processes. Longer periods of inflammation due to HIV infection might play a role in the generation or progression of atherosclerotic plaques. We are not able to generate a biologic explanation for prolonged NRTI use and the development of ischemic CVD. We are unaware of any data that implicate NRTIs in the development of vascular disease. Longer duration of use of NRTIs might simply reflect a longer duration of HIV infection. Despite the small size and retrospective nature of this study, it provides important implications for the treatment of HIVinfected persons. Clinicians should actively question patients about traditional risk factors for ischemic CVD and provide appropriate interventions to lower risk. Additional studies are needed to evaluate the relationship between HIV infection and the formation of atherosclerotic plaques. If HIV infection is proven to be a risk factor for accelerated presentation of ischemic CVD, this might affect the management of other known risk factors. For example, the current goal of treatment of hypercholesterolemia might be lowered in persons with HIV infection, which would be similar to the more-stringent recommendations made by the National Cholesterol Education Program for lowering low-density lipoprotein levels in persons with proven ischemic CVD. It would be premature to make any definitive conclusions regarding the use of NRTIs. This requires a prospective, randomized trial of nucleoside-sparing therapy to determine whether NRTIs are indeed a risk factor for ischemic CVD. In summary, our study suggests that ischemic cardiovascular events in HIV-infected persons are associated with traditional risk factors that include cigarette smoking, hypertension, family history of heart disease, and hypercholesterolemia. Cardiovascular events were more common in patients with a lower nadir CD4 lymphocyte count and in those with more-prolonged exposure to NRTIs. Protease inhibitors were not directly associated with greater risk of development of an ischemic CVD, although an indirect association cannot be excluded. These results underscore the need to focus preventive measures on known cardiovascular risk factors by means of lifestyle modification (smoking cessation, diet, and exercise) and pharmacologic interventions for the treatment of hypertension, hypercholesterolemia, and cigarette smoking. HIV/AIDS CID 2002:34 (1 January) 101

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