Why do some cohort studies find no link between CD4 measures and cardiovascular disease (Table 1) while others do (Table 2)? Comparing features of the two groups of studies in these tables yields no easy answer, but perhaps some hints. The no-association studies were generally bigger, but the biggest analysis, the 1999-2008 DAD study,40 did find an link between latest CD4 count and cardiovascular disease, and it had the sternest endpoint -- death. The only case-control study, from the French Hospital Database on HIV, identified ties between both CD4 and CD8 counts and MI risk.6 Median or mean age tended to be older in the positive-association studies (Table 2). Older age would yield more cardiovascular endpoints and so may beef up the statistical power needed to show an association. But two no-association studies, EuroSIDA1 and DAD,20 had the highest number of endpoints.
DAD investigators who worked on the no-association 1999-2005 analysis20 noted that a CD4 metric other than the one they used could have found a link between CD4s and cardiovascular events. Both of the DAD studies that found no link between CD4 count and cardiovascular trouble used a 50-cell higher CD4-nadir measure,2,20 and one of those studies used cohort baseline CD4 count.2 The French study that found a CD4-heart link was the only other analysis to use nadir CD4 count, and they used a doubling of CD4 nadir.6 The 1999-2008 DAD analysis that found a CD4 association with cardiovascular death used latest CD4 count as the yardstick. Perhaps every 50-cell higher CD4 nadir is too fine a gauge to identify an association.
The French team suggested another reason why results of these 10 big studies differ. Their case-control probe showed that a viral load above 50 copies/mL upped the MI risk by half.6 Two other studies reviewed above tied a lower viral load to a lower heart disease or death risk.34,35 In the studies evaluating CD4 impact on cardiovascular disease, the French investigators proposed, "the differences between the studies could be explained by differences in the proportion of patients with controlled viral load."6
Why would lower or higher CD4 count affect risk of cardiovascular disease? On an elementary level, a higher CD4 count indicates better overall health, and healthier people are less likely to get diagnosed with any number of non-AIDS diseases, including heart disease. But there are probably more precise mechanisms. A climbing CD4 count typically mirrors falling numbers of CD8s -- the T cells recruited to kill infected cells and tumor cells. Fewer CD8s in circulation mean less HIV in circulation, in other words, less inflammation and immune activation.
This is not just airy hypothesis. A handful of studies address this issue in one way or another. During untreated HIV infection, CD4s wane and CD8s surge, an immunologic seesaw that sends a normal CD4/CD8 ratio (about 2) into the abnormal range (under 1). A study of 78 HIV-positive men with an average age of 46.5 and no history of coronary artery disease used computed tomography coronary angiography to assess indicators of atherosclerosis.44 Lower (worse) CD4/CD8 ratio was significantly associated with both number of plaque-bearing coronary artery segments and plaque volume. Notably, the relationship between CD4/CD8 ratio and plaque volume proved stronger than the association seen with CD4 count or viral load and plaque volume -- a result suggesting CD4 count and viral load may be relatively blunt instruments for assessing cardiovascular risk.
Two studies in San Francisco found higher levels of CD4 and CD8 activation with lower CD4 counts.47,48 The first study correlated CD8-cell activation with poor CD4 gains despite good virologic control with antiretroviral therapy.47 The 99 adults evaluated kept their viral load at or below 1000 copies/mL for a median of 21 months on cART. Although they had lower levels of CD8-cell activation than untreated HIV-positive people, they had higher levels than HIV-negative controls. Every 5% higher proportion of activated (CD38+/HLA-DR+) CD8 cells meant a 35-cell lower CD4 gain during therapy. The same researchers analyzed CD4- and CD8-cell activation in a cross-sectional study of 30 elite controllers -- people who maintain an undetectable viral load without cART.48 This study linked lower CD4 counts to higher levels of activated CD4s and CD8s (rho = -0.52, P = 0.003 for activated CD4s and rho = -0.37, P = 0.047 for activated CD8s).
HOPS investigators38 noted that lower CD4 counts mean higher activated CD4 numbers, and activated CD4 cells turn up in atherosclerotic lesions in the general population.49 The HOPS team also observed that the chronic inflammation seen in advanced HIV infection is driven by "the same inflammatory cells and proinflammatory cytokines that destabilize atherosclerotic plaques,"38 resulting in plaque rupture and coronary artery thrombosis.49-51
Does the evidence tying higher viral loads and lower CD4 counts to a bigger heart disease risk mean clinicians should consider cART a component of cardiovascular disease prevention? That one might even ponder such a proposition is remarkable. Just over a decade ago, SMART trial investigators planned that seminal study to test the hypothesis that avoiding cART for planned intervals would ease the burden of major cardiovascular, kidney, or liver disease.52 In other words, plenty of HIV luminaries thought cART should be shunned when possible to trim the risk of heart disease -- and lots of clinicians felt the same way. SMART demolished that strategy. But do the data reviewed above mean clinicians should start cART earlier -- as soon as possible, US guidelines say7 -- not only to thwart AIDS but also to ward off cardiovascular disease and other portentous afflictions? Some of the researchers who ran the studies reviewed here think so:
Summing up their 6500-person study of CD4 and viral load impact on MI, Steven Grinspoon, Paul Sax, and other Boston researchers wrote that "treatment of HIV infection to improve immunologic function is likely to be an important component of cardiovascular prevention for HIV patients" and that "cardiovascular risk reduction might therefore be an additional benefit of earlier initiation of ART."34
The HOPS team believes their findings "support prior observations that HIV infection in itself is a risk factor for cardiovascular disease not dissimilar in magnitude to some traditional risk factors for cardiovascular disease events," and they call for "randomized controlled trials to assess whether earlier initiation of antiretrovirals and avoidance of treatment interruptions will reduce the incidence of cardiovascular events."38
In February 2013 antiretroviral guidelines, US experts maintained that "increased risk of cardiovascular events with treatment interruption, the effects of ART on markers of inflammation and endothelial dysfunction, and the association between cardiovascular disease and CD4 cell depletion suggest that early control of HIV replication with ART can be used as a strategy to reduce risk of cardiovascular disease, particularly if drugs with potential cardiovascular toxicity are avoided."7 But they stress that research has yet to prove that cART prevents cardiovascular disease, and "therefore, a role for early ART in preventing cardiovascular disease remains to be established."
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