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Sub-100 Latest CD4 Count Tied to Stroke and Cardiovascular Disease in D:A:D
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19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012, Seattle
Mark Mascolini
A latest CD4 count below 100 independently raised the risk of stroke or cardiovascular disease in a 33,000-person D:A:D study analysis [1]. The D:A:D team found no strong associations between current CD4 count, nadir CD4 count, or time spent with a count below 200 and risk of myocardial infarction (MI) or coronary heart disease (CHD).
D:A:D investigators noted that some studies have traced a link between low CD4 count and higher risk of cardiovascular disease in people with HIV [2,3], but one review found no such association [4]. To clarify the impact of CD4 count on cardiovascular disease risk, the D:A:D group considered associations between latest CD4 count, nadir CD4 count, and time spent with a count below 200 and (1) MI, (2) CHD, (3) stroke, and (4) cardiovascular disease, defined as first CHD or stroke.
The analysis involved 33,301 HIV-positive people in the prospective D:A:D study followed from study entry to a cardiovascular endpoint, death, February 2010, or 6 months after the last clinic visit. Statistical analysis to assess potential associations between CD4 variables and cardiovascular endpoints considered gender, age, previous cardiovascular disease, body mass index, smoking status, hypertension (for stroke only), cohort, HIV exposure risk, ethnicity, family history of cardiovascular disease, calendar year, and cumulative and recent exposure to antiretrovirals (for MI, CHD, and cardiovascular events).
During the study period D:A:D investigators recorded 716 MIs, 1056 CHD events, 407 strokes, and 1374 cardiovascular events. Incidence came of 0.321 per 100 person-years for MI, 0.475 for CHD, 0.182 for stroke, and 0.621 for cardiovascular disease.
In unadjusted analyses latest or nadir CD4 count below 350 tended to raise the risk of all four cardiovascular endpoints. Those associations were not significant after statistical adjustment for other factors. But in the adjusted analysis people with a latest CD4 count below 100 had more than a doubled risk of stroke compared with people whose latest CD4 count lay between 200 and 299 (relative rate [RR] 2.39, 95% confidence interval [CI] 1.58 to 3.61). And a latest CD4 count under 100 independently raised the risk of cardiovascular disease 44% (RR 1.44, 95% CI 1.11 to 1.88).
People who never had a CD4 count below 200 had significantly lower rates of all four endpoints, but evidence for was weak a linear association between each event and time spent with a sub-200 count.
After adjustment for nadir CD4 count and time with a count below 200, each doubling of the latest CD4 count lowered the stroke risk 21% (RR 0.79, 95% CI 0.72 to 0.88, P = 0.0001) and cut the cardiovascular disease risk 10% (RR 0.90, 95% CI 0.84 to 0.95, P = 0.0001). But after adjustment for other variables, neither of those associations remained significant.
Further adjustment for prior cytomegalovirus disease did not affect associations between latest CD4 count and risk of stroke or cardiovascular disease. But in this analysis a previous non-CMV AIDS-defining infection raised the cardiovascular disease risk 21% (RR 1.21, 95% CI 1.07 to 1.37, P = 0.003), while boosting the stroke risk 33% (RR 1.33, 95% CI 1.06 to 1.66, P = 0.01). In this analysis every doubling of the latest CD4 count lowered cardiovascular disease risk 10% (RR 0.90, 955 CI 0.85 to 0.94, P = 0.0001) and cut stroke risk 19% (RR 0.81, 95% CI 0.75 to 0.88, P = 0.0001).
The association between latest CD4 count and stroke--but not MI or CHD--suggested to the D:A:D investigators that "stroke appears to be the event that is driving the association with immune suppression" and cardiovascular disease. They cautioned that "comparisons of results from other studies that utilize different cardio- or cerebrovascular endpoints should be made with caution."
The D:A:D team noted that further research is needed to determine whether the associations they identified between latest CD4 count, stroke, and cardiovascular disease are causal or whether they reflect bias or unmeasured confounding.
References
1. Sabin C, and the D:A:D Study Group. Associations between markers of immunosuppression and the risk of cardiovascular disease: the D:A:D study. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 822. http://www.retroconference.org/2012b/PDFs/822.pdf.
2. Lichtenstein KA, Armon C, Buchacz K, et al, HIV Outpatient Study (HOPS) investigators. Low CD4+ T cell count is a risk factor for cardiovascular disease events in the HIV outpatient study. Clin Infect Dis. 2010;51:435-447. http://cid.oxfordjournals.org/content/51/4/435.long.
3. Rasmussen LD, Engsig FN, Christensen H, et al. Risk of cerebrovascular events in persons with and without HIV: a Danish nationwide population-based cohort study. AIDS. 2011;25:1637-1646. http://www.ncbi.nlm.nih.gov/pubmed/21646903.
4. Phillips AN, Neaton J, Lundgren JD. The role of HIV in serious diseases other than AIDS. AIDS. 2008;22:2409-2418. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2679976/?tool=pubmed.
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