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Heart Disease Marker Rises in Women During 96 Weeks of Suppressive Efavirenz
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16th Conference on Retroviruses and Opportunistic Infections, February 8-11, 2009, Montreal
Mark Mascolini
High-sensitivity C-reactive protein (hsCRP), a cardiovascular risk marker, rose throughout 96 weeks of successful treatment with efavirenz (with or without abacavir) in AIDS Clinical Trials Group (ACTG) study A5095 [1]. The 96-week jump was statistically significant in women, but not in men.
Earlier research linked hsCRP to HIV disease progression independently of CD4 count and viral load [2], and one study singled out hsCRP as an independent mortality predictor in women with HIV [3]. Some evidence suggests hsCRP remains stable or falls somewhat through 42 months of indinavir therapy [4].
Because hsCRP had never been tracked in people taking a nonnucleoside regimen, Cecilia Shikuma and ACTG colleagues measured the marker in stored samples of 39 women and 61 men enrolled in ACTG A5095, which randomized previously untreated people to (1) coformulated abacavir, zidovudine (AZT), and lamivudine (3TC), (2) coformulated AZT/3TC plus efavirenz, or (3) coformulated AZT/3TC plus efavirenz and abacavir. This analysis included all women and randomly selected men who took one of the efavirenz regimens for 96 weeks and had a viral load below 50 copies between week 24 and week 96.
Median age was 40 years among men and 39 years among women; 33% of men and 41% of women were black, and 23% and 13% were Hispanic. Four men (6.6%) and no women had injected drugs. Median CD4 count stood at 249 in men and 195 in women, and viral load at 4.8 and 4.7 log (about 65,000 and 50,000 copies). Women were heavier than men, with a median body mass index of 28 kg/m(2) versus 25 kg/m(2) in men.
At study entry, hsCRP levels were higher in women than men, but the difference lacked statistical significance (median 2.6 vs 1.6 mg/L, P = 0.36). In the group as a whole, hsCRP rose by a median 1.3 mg/L (95% confidence interval [CI] 0.7 to 2.7) over 96 weeks, a highly significant gain (P < 0.001). Week-96 hsCRP concentrations were significantly higher in women than men (median 6.6 vs 2.3 mg/L, P = 0.001). Through the 96 weeks of follow-up, hsCRP rose significantly in women by 3.7 mg/L (P = 0.001) but not in men (+0.5 mg/L).
Because the American Heart Association recommends discarding hsCRP values above 10 mg/L and repeating the measure, the ACTG team reran the analyses after excluding values above 10 mg/L. The new analyses did not change the overall significant rise in hsCRP through 96 weeks, although the median change difference between women and men now fell short of statistical significance (1.9 vs 0.5 mg/L, P = 0.094).
An hsCRP below 1 mg/L signifies low risk, according to the American Heart Association, while a reading between 1 and 3 mg/L indicates average risk and above 3 high risk. According to this ranking, 53.8% of women and 33.3% of men jumped into a higher risk bracket during 96 weeks of efavirenz therapy, 26.9% and 45.1% stayed in the same bracket, and 19.2% and 21.6% fell into a lower bracket (P = 0.20).
Comparing people who took abacavir with efavirenz and those who did not, Shikuma and coworkers discerned no significant difference in pretreatment hsCRP values or values after 96 weeks of therapy. This finding held true after the investigators tossed out hsCRP readings above 10 mg/L. The investigators found no difference in risk-grade distribution when comparing abacavir and nonabacavir regimens. The 96-week change in hsCRP did not correlate with changes in body mass index, CD4 count, fasting lipids, insulin resistance, or glucose.
Shikuma and colleagues noted that their analysis may be limited by the small sample size and potential biases introduced by sample selection. With those possible limitations in mind, it appears that suppressing HIV replication with an efavirenz-based regimen has no impact on this marker of cardiovascular risk. In fact, marker levels rose in the women studied. That result underlines the complexity of sorting out links between markers and morbidity or mortality in people taking antiretrovirals. In a SMART study analysis presented at this meeting, hsCRP at study entry and during follow-up independently predicted new opportunistic disease [5].
References
1. Shikuma C, Zheng E, Ribaudo H, et al. 96-week effects of suppressive efavirenz-containing ART, abacavir, and sex on high-sensitivity C-reactive protein: ACTG A5095. 16th Conference on Retroviruses and Opportunistic Infections. February 8-11, 2009. Montreal. Abstract 736.
(Poster online at http://www.retroconference.org/2009/PDFs/736.pdf.)
2. Lau B, Sharrett AR, Kingsley LA, et al. C-reactive protein is a marker for human immunodeficiency virus disease progression. Arch Intern Med. 2006;166:64-70.
3. Feldman JG, Goldwasser P, Holman S, DeHovitz J, Minkoff H. C-reactive protein is an independent predictor of mortality in women with HIV-1 infection. J Acquir Immune Defic Syndr. 2003;32:210-214.
4. Henry K, Kitch D, Dube M, et al. C-reactive protein levels over time and cardiovascular risk in HIV-infected individuals suppressed on an indinavir-based regimen: AIDS Clinical Trials Group 5056s. AIDS. 2004;18:2434-2437.
5. Rodger A, Fox Z, Lundgren J, et al. Does activation of inflammatory and coagulation pathways independently predict the development of opportunistic disease in patients with HIV infection? 16th Conference on Retroviruses and Opportunistic Infections. February 8-11, 2009. Montreal. Abstract 733.
(Poster online at http://www.retroconference.org/2009/PDFs/733.pdf.)
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