Inflammation and Coagulation Biomarkers Linked to Higher Risk of Death in Patients Who Interrupt Antiretroviral Therapy

By Liz Highleyman

Evidence continues to accumulate that a resurgence of HIV replication during interruption of antiretroviral therapy has detrimental effects well before the CD4 cell count falls into the opportunistic infection (OI) "danger zone" below 200 cells/mm3.

In the October 21, 2008 issue of the open-access online journal PLoS Medicine, researchers with the large international SMART trial reported a link between adverse outcomes and abnormal levels of certain blood biomarkers associated with inflammation and coagulation (clotting).

SMART included more than 5000 HIV positive patients with a CD4 cell count above 350 cells/mm3 at baseline who were randomly assigned to either stay on continuous antiretroviral therapy, or else to interrupt treatment when their CD4 count was above 350 cells/mm3 and resume when it fell below 250 cells/mm3. About three-quarters of the participants were men, the median age was about 40 years, and the median baseline CD4 count was about 600 cells/mm3.

As previously reported, participants who episodically interrupted HAART not only were at higher risk of directly AIDS-related OIs or death, but also had a higher rate of serious "non-AIDS-related" cardiovascular, liver, and kidney disease.

The investigators hypothesized that increased HIV RNA levels following interruption of antiretroviral therapy might induce activation of various tissue factor pathways, thrombosis (clotting), and fibrinolysis (clot breakdown). To test this proposition, they measured levels of 6 biomarkers in stored blood samples:

• high sensitivity C-reactive protein (hsCRP);

• interleukin-6 (IL-6);

• amyloid A;

• amyloid P;

• D-dimer;

• prothrombin fragment 1+2.

They performed both a nested case-control study to analyze associations between biomarker levels and mortality, and a second analysis comparing biomarker changes among patients in the treatment interruption ("drug conservation") and continuous therapy ("viral suppression") arms.

The first analysis included biomarker levels at study entry and the last measurement before death in 85 patients who died (55 in the treatment interruption arm, 30 in the continuous therapy arm) and 170 surviving control patients (2 per death) matched according to age, sex, country, and date of randomization. Odds ratios (ORs) were estimated using logistic regression.

In the second analysis, biomarkers were assessed for 249 participants in the treatment interruption arm and 250 in the continuous therapy arm at study entry and 1 month after randomization.

Results

• Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality.

• People with the highest quartile hsCRP values were twice as likely to die as those in the lowest quartile (unadjusted odds ratio [OR] 2.0; P = 0.05).

• Patients with the highest quartile IL-6 values were about 8 times more likely to die than those in the lowest quartile (OR 8.3; P < 0.0001).

• Patients with the highest quartile D-dimer values had more than a 12 times higher risk of death than those in the lowest quartile (OR 12.4; P < 0.0001).

• Associations were significant after adjustment, when the treatment interruption and continuous therapy arms were analyzed separately, and when last levels were assessed.

• In the treatment interruption group, IL-6 increased by 30% and D-dimer increased by 16% at 1 month after randomization.

• In the continuous therapy group, however, levels remains stable, with IL-6 increasing by 0% and D-dimer by only 5% (P < 0.0001 for treatment difference for both biomarkers).

• Increases in these biomarkers in the treatment interruption group were related to HIV RNA levels at 1 month, with levels rising as viral load increased (P < 0.0001).

• In an expanded case-control analysis with 4 control subjects per death, the OR (treatment interruption/continuous therapy) for mortality was reduced from 1.8 to 1.5 for IL-6, and to 1.4 for D-dimer after adjustment for last pre-death levels.

Based on these findings, the study authors concluded, "IL-6 and D-dimer were strongly related to all-cause mortality."

"Interrupting antiretroviral therapy may further increase the risk of death by raising IL-6 and D-dimer levels," they continued. "Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation."

These findings suggest that ongoing or resurgent HIV replication itself -- rather than antiretroviral therapy -- triggers biological changes that lead to cardiovascular disease and other conditions not attributable to immunosuppression.

Presenting an earlier analysis of these findings at this year's Conference on Retroviruses and Opportunistic Infections, the researchers stated that, "The association [of biomarker levels] with all-cause mortality suggests that HIV infection results in activation of coagulation and inflammatory pathways that may impact multiple organs."

Researchers at that meeting presented data from another treatment interruption study (STACCATO) that also showed significant differences in biomarker levels between the treatment interruption and continuous therapy arms, but since none of those participants experienced cardiovascular events (including deaths), they could not determine associations between biomarkers and these outcomes.

10/24/08

Reference
LH Kuller, R Tracy, W Belloso, and others (INSIGHT SMART Study Group). Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Medicine 5(10): e203. October 21, 2008 (doi:10.1371/journal.pmed.0050203). (Abstract and free full text).

Other source
National Institutes of Health. Markers of Inflammation and Blood-clotting Tied to Hazards of Intermittent HIV Treatment. NIH News Release. October 21, 2008.