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Low CD4 Count Raises Risk of Heart Attack, Bone Loss

HIV positive people whose CD4 T-cell count falls below 200 cells/mm³ are at greater risk for myocardial infarction, though the heart attack rate is not elevated for people with counts of 500 cells/mm³ or more, researchers recently reported. Another study found that people with low CD4 counts have a higher likelihood of bone loss after starting antiretroviral therapy (ART).

Myocardial Infarction

As described in the February 1, 2014, Journal of Acquired Immune Deficiency Syndromes, Michael Silverberg from Kaiser Permanente Northern California and colleagues conducted a study to clarify the association between HIV infection, immunodeficiency, and myocardial infarction or heart attack risk.

This cohort study included 22,081 HIV positive and 230,069 demographically matched HIV negative Kaiser Permanente California health plan members who received care between 1996 and 2009. Most (about 90%) were men and 70% were between 30 and 49 years of age.

The researchers compared myocardial infarction rates between the HIV positive and negative groups, both overall and stratified by recent and nadir (lowest-ever) CD4 count, and adjusted for confounding factors including age, sex, race/ethnicity, socioeconomic status, smoking, alcohol and drug use, obesity, diabetes, hypertension, and use of lipid-lowering medications. Within the HIV positive group they also looked at the independent association of CD4 count, HIV viral load, and use of antiretroviral therapy (ART).

Results

• HIV positive participants had a total of 283 myocardial infarctions over a mean follow-up period of 4.5 years, giving a crude incidence rate of 283 per 100,000 person-years.
• HIV negative participants had 2064 myocardial infarctions over a mean follow-up period of 5.4 years, for a crude incidence rate of 165 per 100,000 person-years.
• In an unadjusted analysis, HIV positive people had a 70% higher risk of myocardial infarction compared with the HIV negative group (rate ratio 1.70).
• The adjusted rate ratio was 1.44, indicating a 44% higher risk for the HIV positive group compared with the HIV negative group.
• Myocardial infarction rates were similar for HIV positive participants with a recent CD4 count >500 cells/mm³ and HIV negative people (rate ratio 1.18, not a significant difference).
• Heart attacks rates were also similar for HIV positive people with a nadir CD4 count >500 cells/mm³ and the HIV negative group (rate ratio 0.85).
• HIV positive people whose current or nadir CD4 cell count fell below 200 cells/mm³, however, had 76% and 74% greater risk of myocardial infarction, respectively (adjusted rate ratio 1.76 and 1.74).
• Among HIV positive people, those on antiretroviral therapy had a 50% higher heart attack risk (adjusted rate ratio 1.50).
• Among people with HIV, nadir CD4 count was the only HIV-specific factor significantly associated with higher myocardial infarction risk (risk ratio 0.88 -- or a 12% reduction -- per 100 cells/mm³) in an adjusted analysis.
• Recent CD4 count, viral load, prior ART use, and duration of protease inhibitor or NNRTI use were not independently associated with heart attack risk.

"HIV+ subjects with recent or nadir CD4 >500 [cells/mm³] had similar myocardial infarction rates compared with HIV negative subjects," the study authors concluded. "Lower nadir CD4, in particular, seems to be independently associated with myocardial infarctions."

In their discussion they noted that the link between lower nadir CD4 count and increased heart attack risk may be related to chronic inflammation -- which promotes atherosclerosis -- in people with uncontrolled HIV infection. They did not, however, see an independent link between protease inhibitor use and myocardial infarction, as has been reported in some prior studies.

These results, they suggested, "strengthen recommendations for earlier ART initiation." In addition, they noted that traditional controllable risk factors including smoking and diabetes also significantly raise the risk of heart attack.

"These findings argue for increased efforts to diagnose and treat HIV as early as possible, which if combined with aggressive traditional cardiovascular risk factor management might result in a similar myocardial infarction burden as the general population," they concluded.

Bone Loss

Several studies have shown that bone loss is common among people with HIV, but it is not yet clear whether this is due to HIV infection itself, related inflammatory and metabolic changes, antiretroviral drug toxicities, or a combination of factors.

As described in the November 15, 2013, issue of Clinical Infectious Diseases, Philip Grantfrom Stanford University and colleagues looked at the effects of pre-treatment immune deficiency and early immune recovery on changes in bone density after starting ART.

The study authors pooled data from 3 studies of treatment-naive patients starting ART that performed repeat whole-body dual-energy X-ray absorptiometry (DEXA) scans to measure bone mineral density. The analysis included 796 participants, a majority of them middle-aged men.

The researchers evaluated the effects of baseline CD4 T-cell count and CD4 cell gains 16 weeks after starting therapy on bone density changes at 96 weeks, taking into account confounding factors including age, sex, race/ethnicity, body mass index, hepatitis C coinfection, HIV viral load, and use of regimens containing protease inhibitors or tenofovir (Viread, also in the Truvada, Atripla, Complera, and Stribild coformulations).

Results

• Participants had a mean total bone mineral density loss of 2.0% at week 96 -- at the low end of the range seen in prior studies.
• Baseline CD4 count was significantly associated with 96-week bone loss in a multivariable analysis.
• People with a baseline CD4 count <50 cells/mm³ had significantly greater bone loss than those with >500 cells/ mm³.
• Greater relative -- but not absolute -- CD4 cell gains at 16 weeks after treatment initiation were significantly associated with greater bone density declines, but not after controlling for baseline CD4 count.
• Older age, female sex, lower body mass index, higher viral load, and use of protease inhibitors or tenofovir were also associated with greater bone loss in a multivariate analysis.

Based on these findings, the study authors concluded, "Low pretreatment CD4+ count, but not greater CD4+ count increase, is a strong and independent risk factor for bone loss after ART initiation."

"ART initiation at higher CD4+ counts may reduce the burden of osteoporosis and fragility fractures," they suggested.

1/23/14

References

M Silverberg, WA Leyden, L Xu, et al. Immunodeficiency and Risk of Myocardial Infarction Among HIV-Positive Individuals With Access to Care. Journal of Acquired Immune Deficiency Syndromes 65(2):160-166.February 1, 2014.

PM Grant, D Kitch, GA McComsey, et al. Low Baseline CD4+ Count Is Associated with Greater Bone Mineral Density Loss After Antiretroviral Therapy Initiation. Clinical Infectious Diseases 57(10):1483-1488. November 15, 2013.