 |
|
|
| |
Prognosis Prediction in START Similar
with IL-6, D-dimer, CD8s, and CD4:CD8 Ratio
|
| |
| |
25th Conference on Retroviruses and Opportunistic Infections (CROI), March 4-7, 2018, Boston
from Jules: this was a very interesting paper with lots of unanswered questions like why is the CD4/CD8 ratio so crucial, perhaps the inverse ratio we see in HIV is associated with the immunosenescence we see, and the gaps in immunity we see despite full CD4 recovery which was discussed in the early days but not now, and may be associated with immune exhaustion.
Mark Mascolini
In the START trial of immediate versus delayed antiretroviral therapy (ART), four markers (IL-6, D-dimer, CD8 count, and CD4:CD8 ratio) had similar abilities to predict prognosis [1]. Because IL-6, D-dimer, and CD4:CD8 ratio had independent contributions to clinical risk, the researchers believe their impact reflects distinct pathways.
Randomizing participants with a CD4 count above 500 to immediate or delayed ART, START determined that immediate treatment cuts the risk of death or a serious AIDS or non-AIDS disease by 57% [2]. Each arm of the study population included almost 2000 people with baseline and month 8 levels of IL-6 (an inflammation marker), D-dimer (a coagulation marker), and CD4 and CD8 cells. The researchers used Cox proportional hazards models to explore associations between latest marker level (baseline or month 8) and subsequent risk of AIDS, a serious non-AIDS disease, or death. They calculated the percent of the treatment effect (PTE) explained by the latest (time-updated) marker level.
Among all 4273 START participants, median age stood at 36 years, 27% were women, 45% white, 30% black, 13% Hispanic, and 8% Asian. Median known duration of HIV infection stood at 1 year and median CD4 count at 651. From baseline to the 8-month visit, the immediate and deferred arm differed significantly in D-dimer change (rose with deferred, fell with immediate, absolute I-D difference -19.1%), IL-6 change (rose with deferred, fell with immediate, absolute I-D difference -11.6%), CD4 change (rose with immediate, fell with deferred, absolute I-D difference 23.9%), CD8 change (fell more with immediate than deferred, absolute I-D difference -16.7%), and CD4:CD8 change (rose with immediate, fell with deferred, absolute I-D difference 53.9%) (P < 0.001 for all differences).
During follow-up 129 people in the marker analysis had a primary event, including 19% who died, 44% with AIDS, 22% with cardiovascular disease, 21% with non-AIDS cancer, and 3% from kidney or liver disease. Latest level of 4 markers (per 1 standard deviation higher or lower) had similar impacts on predicting a clinical event: IL-6 (hazard ratio [HR] 1.36), D-dimer (HR 1.58), CD8 count (HR 1.36), and CD4:CD8 ratio (HR 1.34) (P < 0.001 for all associations). Associations for IL-6, D-dimer, and CD4:CD8 ratio each remained significant when adjusted for the other two markers.
Percent of treatment effect explained by markers was 9.5% for IL-6 plus D-dimer, 19.9% for CD4:CD8 ratio, and 29.3% for all three markers combined. Percent of treatment effect explained by CD4:CD8 ratio rose from 19.9% based on baseline plus month 8 measures, to 25.1% based on baseline plus months 1, 4, and 8 measures, and to 43.3% based on all data from baseline through a median 3 years of follow-up.
START investigators concluded that in their trial populations IL-6, D-dimer, CD8 count, and CD4:CD8 ratio had similar abilities to predict major clinical outcomes. Because of the small number of outcomes, they could not evaluate the impact of these markers on individual causes of disease. The researchers also cautioned that focusing on IL-6 and D-dimer could miss contributions of other inflammation pathways.
Webcast/CROI: IL-6, D-dimer or T-cells: which best predict events or explain benefits of early ART? - (03/07/18)
References
1. Baker JV, Grund B, Sharma S, et al. IL-6, D-dimer or T-cells: which best predict events or explain benefits of early ART? 25th Conference on Retroviruses and Opportunistic Infections (CROI). March 4-7, 2018. Boston. Abstract 74.
2. INSIGHT START Study Group, Lundgren JD, Babiker AG, Gordin F, et al. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373:795-807. http://www.nejm.org/doi/full/10.1056/NEJMoa1506816
|
| |
|
|
|
|
|
