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Inflammation Markers Predict AIDS and non-AIDS Disease in ACTG Study
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XIX International AIDS Conference, July 22-27, 2012, Washington, DC
Mark Mascolini
Several inflammatory markers predicted new diagnoses of AIDS or non-AIDS diseases--independently of CD4 count and antiretroviral regimen--in AIDS Clinical Trials Group (ACTG) study A5224s, a substudy of the A5202 trial [1]. Interleukin 6 (IL-6) predicted both AIDS and non-AIDS diseases in this analysis.
ACTG protocol A5202 enrolled 1857 antiretroviral-naive people and randomized them to efavirenz or atazanavir/ritonavir plus either abacavir/lamivudine or tenofovir/emtricitabine [2]. The A5524s substudy measured inflammatory markers in 244 people enrolled in A5202 who had plasma available from their baseline (pretreatment) study visit and at trial week 24 or 96. The ACTG used Cox proportional hazards models to assess the association between several markers and time to AIDS or non-AIDS diagnoses after adjustment for baseline or time-updated CD4 count and viral load as well as treatment assignment (efavirenz versus atazanavir/ritonavir and abacavir/lamivudine versus tenofovir/emtricitabine).
Earlier, the ACTG team reported significant decreases in TNF-alpha, sTNFR-I, sTNFR-II, sVCAM-1, and sICAM-1 in all trial arms, with no differences between abacavir/lamivudine versus tenofovir/emtricitabine or atazanavir/ritonavir versus efavirenz [3]. In people randomized to tenofovir/emtricitabine versus abacavir/lamivudine, there were more favorable changes in IL-6 at 24 weeks and in hsCRP at weeks 24 and 96.
Most substudy participants (85%) were men, and 48% were non-Hispanic white. Median age stood at 39 years, median viral load around 45,000 copies, and median pretreatment CD4 count at 240. During follow-up 13 AIDS diseases developed (9 opportunistic infections, 3 AIDS cancers, and 1 recurrent bacterial pneumonia). Seven of these diseases developed during the first 24 weeks of treatment Eighteen non-AIDS diseases were diagnosed, including 6 cases of diabetes, 5 pneumonias, 4 cancers, and 3 cases of cardiovascular disease. Four of these diseases arose in the first 24 weeks of treatment.
After adjustment for antiretroviral assignment and for baseline CD4 count, four inflammatory markers raised the risk of an AIDS-defining diagnosis, at the hazard ratios (HR) and 95% confidence intervals noted in the list below. After adjustment for antiretroviral assignment and time-updated CD4 count, four markers predicted a new AIDS diagnosis:
Baseline associations with time to first AIDS-defining event:
Adjusted for baseline CD4 count and ART assignment:
IL-6 (per log pg/mL higher): HR 1.79 (0.96 to 3.34), P = 0.066
sTNF-RI (per log pg/mL higher): HR 6.25 (1.17 to 33.36), P = 0.032
sTNF-RII (per log pg/mL higher): HR 2.89 (0.99 to 8.46), P = 0.052
sICAM-1 (per log ng/mL higher): HR 6.13 (1.51 to 24.78), P = 0.011
Time-updated associations with time to first AIDS-defining event:
Adjusted for time-updated CD4 count and ART:
IL-6 (per log pg/mL higher): HR 1.92 (1.04 to 3.55), P = 0.037
sTNF-RI (per log pg/mL higher): HR 12.83 (1.99 to 82.59), P = 0.007
sTNF-RII (per log pg/mL higher): HR 3.03 (1.04 to 8.79), P = 0.041
sICAM-1 (per log ng/mL higher): HR 3.65 (0.98 to 13.56), P = 0.053
After adjustment for antiretroviral assignment and baseline or time-updated CD4 count, three markers raised the risk of a non-AIDS diagnosis, at the noted hazard ratios and 95% confidence intervals:
Baseline associations with time to first non-AIDS-defining event:
Adjusted for baseline CD4 count and ART assignment:
hsCRP (per log ug/mL higher): HR 1.66 (1.14 to 2.43), P = 0.008
IL-6 (per log pg/mL higher): HR 1.81 (1.01 to 3.25), P = 0.047
Time-updated associations with time to first non-AIDS-defining event:
Adjusted for time-updated CD4 count and ART assignment:
TNF-alpha (per log pg/mL higher): HR 3.87 (1.34 to 11.18), P = 0.012
Four markers predicted time to first AIDS or non-AIDS diagnosis in baseline and time-updated analyses:
Baseline associations with time to first AIDS or non-AIDS-defining event:
Adjusted for baseline CD4 count and ART assignment:
hsCRP (per log ug/mL higher): HR 1.48 (1.11 to 1.96), P = 0.007
IL-6 (per log pg/mL higher): HR 1.82 (1.16 to 2.85), P = 0.009
sTNF-RI (per log pg/mL higher): HR 4.58 (1.29 to 16.26), P = 0.019
sTNF-RII (per log pg/mL higher): HR 2.41 (1.18 to 4.92), P = 0.016
Time-updated associations with time to first AIDS or non-AIDS-defining event:
Adjusted for time-updated CD4 count and ART assignment:
sTNF-RI (per log pg/mL higher): HR 6.82 (1.58 to 29.32), P = 0.010
sTNF-RII (per log pg/mL higher): HR 2.20 (1.02 to 4.73), P = 0.044
Fifteen traumatic fractures occurred during follow-up, but neither baseline nor time-updated biomarkers were significantly associated with fracture risk.
The researchers noted several study limitations--small numbers of AIDS and non-AIDS events, relatively short follow-up, and time-updated AIDS events driven by early events. They proposed that "larger and longer studies should investigate the use of these markers as predictors of clinical endpoints."
References
1. McComsey GA, Kitch D, Sax PE, et al. Associations of inflammatory markers with AIDS and non-AIDS clinical events after initiation of antiretroviral therapy (ART): AIDS Clinical Trials Group A5224s, a substudy of ACTG A5202. XIX International AIDS Conference. July 22-27, 2012. Washington, DC. Abstract THLBB06.
2. Sax PE, Tierney C, Collier AC, et al. Abacavir/lamivudine versus tenofovir DF/emtricitabine as part of combination regimens for initial treatment of HIV: final results. J Infect Dis. 2011;204:1191-1201.
3. McComsey GA, Kitch D, Daar ES, et al. Inflammation markers after randomization to abacavir/lamivudine or tenofovir/emtricitabine with efavirenz or atazanavir/ritonavir. AIDS. 2012;26:1371-1385.
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