Two DAD Study analyses,2,20 a EuroSIDA review,1 the SMART cardiovascular endpoint dissection,3 and a combined analysis of the ESPRIT and SILCAAT interleukin 2 (IL-2) trials37 discerned no link between CD4 count (measured various ways) and risk of cardiovascular disease (also measured various ways) (Table 1). But since the last of those reports in 2010,1,37 five other cohort studies,6,34,38-40 including a new DAD analysis,40 did yoke CD4 count to cardiovascular endpoints (Table 2). Two other studies tied lower CD4 counts to subclinical signals of arterial disease,41,42 and one linked lower CD4 nadir to sustained hypertension.43
|Table 1. Studies Finding No Association Between CD4 Measures and Cardiovascular Endpoints|
|Study (Years)||n (% Male)||Age, CD4 Count||Study Group||CD4 Measure||CVD Endpoint||Main Results|
|EuroSIDA1 (2001-2009)||12,844 (73.2%)||BL 39 y|
Nadir 178, BL 403
|Prospective cohort from Europe, Israel, Argentina||Doubling of current CD4 count||MI, stroke, CABG, coronary angioplasty, carotid endarterectomy (n = 384)||Every doubling of current CD4 count predicted lower risk of 4 non-AIDS illnesses, but not CVD|
|DAD2 (1999-2002)||23,468 (75.9%)||BL 39 y|
Nadir 226, BL 418
|Prospective cohort from Europe, United States, Australia||Per 50-cell higher nadir CD4 count and BL CD4 count (at enrollment)||MI (n = 126)||Every 50-cell higher nadir CD4 count or BL CD4 count had no impact on MI risk|
|DAD20 (1999-2005)||23,437 (75.9%)||BL 39 y, last FU 43 y|
BL 420, last FU 461
|Prospective cohort from Europe, United States, Australia||Per 50-cell higher nadir CD4 count||MI (n = 345)||Every 50-cell higher nadir CD4 count had no impact on MI risk|
|SMART3 (2002-2006)||5742 (73%)||BL 44 y|
|People randomized to continuous or interrupted cART||Per 100-cell higher current CD4 count||Clinical or silent MI, nonfatal stroke, CAD requiring surgery or invasive procedure (n = 79)||Every 100-cell higher current CD4 count had marginal impact in interruption arm (P = 0.08) and no impact in combined trial arms|
|ESPRIT and SILCAAT37 (NR)||3012 (82.3%)||BL 41 y|
Nadir 167, BL 400
|People randomized to standard cART (no IL-2) in two IL-2 trials||Per doubling of latest CD4 count||MI, stroke, CAD requiring procedure, other fatal heart/vascular events, sudden death (n = 95)||Every doubling of latest CD4 count had no impact on rate of fatal or nonfatal CVD events|
BL, baseline; CABG, coronary artery bypass graft; CAD, coronary artery disease; CVD, cardiovascular disease; FU, follow-up; IL-2, interleukin 2; MI, myocardial infarction; NR, not reported.
|Table 2. Studies Finding an Association Between CD4 Measures and Cardiovascular Endpoints|
|Study (Years)||n (% Male)||Age, CD4 Count||Study Group||CD4 Measure||CVD Endpoint||Main Results|
|FHDH6 (2000-2006)||289 cases, 884 controls (89%)||BL 47 y|
Nadir 135, BL 427
|Case-control study of HIV+ with first MI or no MI||Doubling of nadir CD4, highest tertile CD8||MI (n = 289)||Every doubling of CD4 nadir cut MI risk 10%; highest (vs lowest) CD8 tertile raised risk 48%|
|Boston34 (1998-2008)||6517 (69.4%)||46 y|
|HIV+ in two large Boston hospitals||Current CD4 count <200, every 50-cell higher CD4 count||MI (n = 273)||Current CD4 count <200 raised MI odds 74%; every 50-cell higher current CD4 lowered MI odds 7%|
|HOPS38 (2002-2009)||2005 (76%)||42 y|
Nadir 197, BL 395
|Prospective cohort from 10 US centers||BL CD4 count <350 vs >500, every 100-cell lower BL CD4 count||MI, stroke, CAD, angina, PAD (n = 148)||BL CD4 count <350 raised CVD risk 58%; every 100-cell lower BL CD4 count raised risk 8%|
|ATHENA39 (2000-2009)||3068 (83.4%)||41 y|
Nadir 170, BL 360
|Prospective cohort on cART in Netherlands||CD4 count <200, 200-350, 351-500, >500 2 years after starting cARTt||MI, CABG, coronary stenting and/or angioplasty, cerebrovascular attack (n = 57)||CD4 count of 200-350 (vs <200) 2 years after starting cART cut CVD risk 66%|
|DAD40 (1999-2008)||33,308 (74.1%)||BL 39 y|
|Prospective cohort from Europe, United States, Australia||Every 50-cell higher current CD4 count||Cardiovascular death (n = 289)||Every 50-cell higher current CD4 count cut CVD death risk 3%|
BL, baseline; CABG, coronary artery bypass graft; CAD, coronary artery disease; CVD, cardiovascular disease; FHDH, French Hospital Database on HIV; HOPS, HIV Outpatient Study; MI, myocardial infarction; PAD, peripheral arterial disease.
In a EuroSIDA analysis of 12,844 HIV-positive people (Table 1), every doubling of current CD4 count independently predicted a lower incidence of AIDS, all non-AIDS events combined, non-AIDS malignancies, end-stage renal disease, pancreatitis, and liver-related events, but not cardiovascular events (incidence rate ratio 0.98, 95% CI 0.85 to 1.12, P = 0.78).1 The EuroSIDA team proposed that cardiovascular disease risk depends less on CD4 status than on lipid changes, lifestyle, and inflammation.
Two DAD analyses (Table 1) determined that every 50-cell higher nadir CD4 count2,20 or every 50-cell higher baseline CD4 count2 had no impact on MI risk in prospective follow-up of more than 23,000 people. But the DAD team acknowledged "the possibility that other unmeasured immunologic effects may exert an influence on the development of cardiovascular disease."20 For example, time-updated CD4 count, CD4 count at MI diagnosis, or CD4/CD8 ratio could have an impact in this population. In an updated DAD analysis involving 33,308 people (Table 2), higher latest CD4 count did predict a slightly lower risk of cardiovascular death (see below).40
In the SMART analysis of 79 cardiovascular events in that trial, every 100-cell higher current CD4 count marginally boosted chances of cardiovascular disease (adjusted hazard ratio 1.11 per 100 cells, 95% CI 0.99 to 1.25, P = 0.08) in the cART interruption arm.3 But that CD4 yardstick had no impact on cardiovascular risk in the combined study arms (adjusted hazard ratio 0.99, 95% CI 0.90 to 1.07, P = 0.74).
ESPRIT and SILCAAT randomized antiretroviral-naive adults to standard cART or to standard cART plus IL-2 (Table 1).37 To analyze the impact of various CD4 metrics on AIDS and non-AIDS endpoints, the investigators focused on 3012 people randomized to the standard-cART control arms. Every doubling of the latest CD4 count had no impact on the rate of fatal or nonfatal cardiovascular events (adjusted hazard ratio 1.05, 95% CI 0.77 to 1.43). Among all these analyses (Tables 1 and 2), the ESPRIT/SILCAAT study involved the smallest number of HIV-positive people and only 95 cardiovascular endpoints. The investigators surmised higher rates of cardiovascular and other non-AIDS diseases in people with HIV could reflect a "subtle ongoing inflammatory process stimulated by residual viral replication or the treatment" and "subclinical inflammation may not be best reflected by latest CD4+ count."37
French Hospital Database on HIV investigators planned a case-control study specifically to scrutinize the impact of viral load and CD4 count on risk of first myocardial infarction (Table 2).6 The French team matched 289 HIV-positive people who had a first MI in 2000-2006 to 3 controls of the same age, sex, and clinical center who had not had an MI. A current viral load above 50 copies/mL (versus below) independently raised chances of a new MI 51% (adjusted odds ratio 1.51, 95% CI 1.09 to 2.10).
In the same analysis, which adjusted for antiretroviral exposure and classic risk factors, two T-cell variables swayed MI risk: every doubling of CD4-cell nadir trimmed MI risk 10% (adjusted odds ratio 0.90, 95% CI 0.83 to 0.97), and being in the highest current CD8 count tertile (above 1150 cells/mm3) versus the lowest tertile (at or below 760 cells/mm3) hoisted MI odds almost 50% (adjusted odds ratio 1.48, 95% CI 1.01 to 2.18). Current CD4 count did not predict MI, but CD4 nadir/CD8 ratio did. The CD4/CD8 ratio was significantly lower (worse) in cases than controls (0.42 vs 0.50, P < 0.001). A higher CD8 count reflects ongoing immune activation to control HIV, indicated in this study by the parallel link between a detectable viral load and heightened odds of myocardial infarction. Previous studies have also linked MI or cardiovascular disease markers to CD4/CD8 ratio44 or other immune activation markers.44-46
The Boston study described in the preceding section found ties between several viral load measures and acute MI when the analysis excluded CD4 count.34 A multivariate regression model adjusted for viral load, age, gender, race, hypertension, diabetes, dyslipidemia, chronic kidney disease, smoking, years since first cART use, and antiretroviral medications individually associated with MI determined that a current CD4 count under 200 cells/mm3 boosted MI odds almost 75% (adjusted odds ratio 1.74, 95% CI 1.07 to 2.81, P = 0.02). Further analysis determined that every 50-cell higher current CD4 count cut MI risk 7% (adjusted odds ratio 0.93, 95% CI 0.89 to 0.97, P = 0.002). Every 50-cell higher CD4 nadir pared MI risk 5%, but that association did not reach statistical significance (adjusted odds ratio 0.95, 95% CI 0.89 to 1.01, P = 0.09). Thus in this analysis, the impact of CD4 measures on MI appeared to outweigh the impact of viral control, because viral load associations proved significant only when statistical models did not include CD4 count.
An HIV Outpatient Study (HOPS) analysis of 2005 HIV-positive people counted 148 new cardiovascular diagnoses (defined in Table 2) from 2002 through 2009.38 A multivariate model accounting for traditional risk factors determined that a baseline CD4 count below 350 cells/mm3 (versus at or above 500) boosted cardiovascular disease risk 58% (adjusted hazard ratio 1.58, 95% CI 1.09 to 2.31, P = 0.017). Every 100-cell lower baseline CD4 count upped the cardiovascular event risk 8% (adjusted hazard ratio 1.08, 95% CI 1.01 to 1.14). Additional adjustment for baseline injection drug use, frequency of alcohol use, and baseline viral load did not change these results. The HOPS team also calculated that about 20% of cardiovascular disease risk could be attributed to a sub-350 baseline CD4 count (versus above 499), an attributable risk similar to those seen with several classic risk factors (Figure 5).
A 2005-person HIV Outpatient Study (HOPS) analysis figured that cardiovascular disease risk attributable to a baseline CD4 count below 350 cells/mm3 (versus above 499) was similar to risk attributable to classic risk factors like current or former smoking, high LDL or non-HDL cholesterol, low HDL cholesterol, and male gender.38 The HOPS team cautioned that this analysis may not apply to HIV populations with cardiovascular risk factor rates unlike those in these HOPS cohort members.
In the Netherlands ATHENA cohort investigators focused on 3068 people who had taken cART for at least 2 years and reached a viral load below 500 copies/mL, dividing them into 2-year CD4 brackets of below 200, 200 to 350, 351 to 500, and over 500.39 A multivariable model to pinpoint predictors of a new cardiovascular diagnosis (see Table 2) adjusted for age, gender, family history of heart disease, cardiovascular event before baseline, smoking, and alcohol abuse. Compared with a CD4 count below 200 cells/mm3 after 2 years of cART, a count of 200 to 350 cut the cardiovascular event risk by two thirds (adjusted hazard ratio 0.34, 95% CI 0.14 to 0.86, P= 0.02). People who reached a CD4 count above 500 had almost a 50% lower risk of reaching a composite endpoint including death, AIDS, malignancies, liver cirrhosis, and cardiovascular events (adjusted hazard ratio 0.54, 95% CI 0.33 to 0.87, P = 0.01). Because older age, a lower nadir CD4 count, and a higher precART viral load independently predicted poor CD4 recovery, the ATHENA team suggested that "starting HAART at higher CD4 cell counts, especially in older aged patients, may be beneficial."39 DAD investigators offered the biggest study to address CD4 impact on the ultimate cardiovascular endpoint -- death.40 They considered latest CD4 count in six brackets, under 50, 50 to 59, 100 to 199, 200 to 349, 350 to 499, and 500 or higher. Cardiovascular death rates were 3.11 per 1000 person-years for people in the lowest CD4 bracket and 1.16 per 1000 for those in the highest bracket. Every 50-cell higher current CD4 count trimmed the risk of cardiovascular death 3% (adjusted relative rate 0.97, 95% CI 0.95 to 0.99).
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