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Inflammation and Fibrosis Markers Tied to
AIDS or Death After Good Virologic Response
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17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010, San Francisco
Mark Mascolini
High levels of C-reactive protein (CRP, an inflammation marker) and hyaluronic acid (a tissue fibrosis marker) before antiretroviral therapy began independently raised the risk of early immune reconstitution inflammatory syndrome (IRIS), AIDS, or death in people who responded well in their first month of antiretroviral therapy [1]. Persistent elevation of these and other markers through the first month of treatment made IRIS, AIDS, or death more likely.
This study involved 1397 previously untreated people who enrolled in the FIRST trial in 1999-2001; FIRST compared three antiretroviral strategies [2]. Study participants had a median starting viral load of 143,884 copies and a median CD4 count of 163. FIRST follow-up ended in September 2005. Earlier FIRST analyses found that slow CD4 responders ran a higher risk of AIDS, a non-AIDS diagnosis, or death through 5 years of follow-up [3,4].
A new case-control comparison involved 1157 people who had at least a 10-fold viral load drop in the first month of therapy. The 63 cases had a new AIDS diagnosis or died within the first year of treatment. FIRST investigators matched them by randomization date and CD4 count to 126 controls who survived free of AIDS for 1 year. When possible, the FIRST team also matched cases and controls by hepatitis B or C status. The investigators evaluated plasma samples collected before treatment and after 1 month of therapy for CRP, hyaluronic acid, D-dimer (a coagulation marker), and 16 other markers.
Cases were similar to controls in age, pretreatment viral load, and proportion with hepatitis B or C, but a higher proportion of cases than controls had AIDS before treatment (73% versus 51%, P = 0.004). Twenty-three of 28 cases (82%) with subsequent IRIS had AIDS before starting therapy. During follow-up 22 people with or without IRIS died, only 5 of them because of an AIDS diagnosis. Forty-six cases had a new AIDS diagnosis.
Before treatment, tumor necrosis factor alpha (TNF-alpha, an inflammation marker) levels were significantly higher in people with subsequent IRIS than in those without IRIS (21.9 versus 14.8 pg/mL, P = 0.02). People with IRIS also had a higher median pretreatment viral load (5.5 versus 5.1 log, P < 0.01) and higher TNF-alpha levels than their matched controls (P < 0.01).
Compared with controls, cases had higher pretreatment levels of CRP (inflammation marker), hyaluronic acid, D-dimer (inflammation marker), interleukin (IL)-6 (inflammation marker, and IL-10. Compared with their controls, IRIS cases had higher D-dimer, IL-10, and TNF-alpha levels before starting therapy. One month after therapy began, all cases (including IRIS cases) had higher concentrations of CRP, D-dimer, IL-6, IL-8, TNF-alpha, and interferon gamma than did controls.
A multivariate model that considered pretreatment CRP, D-dimer, hyaluronic acid, IL-6, and IL-10 determined that higher CRP and hyaluronic acid independently raised the risk of AIDS or death. To estimate the impact of pretreatment CRP and hyaluronic acid on IRIS, AIDS, and death risks, statisticians built a multivariate model based on interquartile ranges of these biomarkers and adjusted for viral load and AIDS before treatment began. Compared with people whose CRP lay below 2.1 mg/L and whose hyaluronic acid lay below 49.9 pg/mL before treatment, those with higher levels of both markers had more than a doubled risk of AIDS or death and a 5 times higher risk of IRIS:
· Odds ratio for AIDS or death: 2.6, 95% confidence interval [CI] 1.1 to 5.8, P = 0.003
· Odds ratio for IRIS: 5.1, 95% CI 1.0 to 26.1, P = 0.05
A high CRP with a low hyaluronic acid, or a high hyaluronic acid with a low CRP, did not up the odds of IRIS, AIDS, or death in this analysis.
The FIRST team proposes that CRP, hyaluronic acid, D-dimer, and IL-6 in people with good early responses to their first antiretrovirals "may be useful in identifying patients at risk of AIDS or death during the first year" of therapy. Persistently high levels of D-dimer, CRP, and other inflammatory markers after 1 months of therapy, the researchers surmise, could point to impending IRIS.
References
1. Boulware D, Huppler Hullsiek K, Puronen C, et al. Higher levels of D-dimer, C-reactive protein, hyaluronic acid, and IL-6 before initiation of ART are associated with AIDS, IRIS, or death among ART-naive patients with a good virologic response to initial ART. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 335.
2. MacArthur RD, Novak RM, Peng G, et al. A comparison of three highly active antiretroviral treatment strategies consisting of non-nucleoside reverse transcriptase inhibitors, protease inhibitors, or both in the presence of nucleoside reverse transcriptase inhibitors as initial therapy (CPCRA 058 FIRST Study): a long-term randomised trial. Lancet. 2006;368:2125-2135.
3. Baker JV, Peng G, Rapkin J, et al. Poor initial CD4+ recovery with antiretroviral therapy prolongs immune depletion and increases risk for AIDS and non-AIDS diseases. J Acquir Immune Defic Syndr. 2008;48:541-546. http://journals.lww.com/jaids/toc/2008/08150.
4. Baker JV, Peng G, Rapkin J, et al. CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS. 2008;22:841-848. http://journals.lww.com/aidsonline/Fulltext/2008/04230/CD4__count_and_risk_of_non_AIDS_diseases_following.6.aspx.
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