IDWeek 2014: Acute Retroviral Syndrome Linked to Higher HIV Levels in Blood, Gut and Brain

People with acute or very recent HIV infection who experience the flu-like symptoms of acute retroviral syndrome (ARS) have higher levels of HIV RNA and proviral DNA in their blood, colon, and brain tissue, indicating more active viral replication, as well as higher levels of certain inflammatory biomarkers researchers reported at IDWeek 2014 this month in Philadelphia.

Trevor Crowell from Johns Hopkins University School of Medicine and fellow investigators with the RV 254/SEARCH 010 Study Group compared HIV viral load and various biomarkers among patients in Bangkok, Thailand, who experienced ARS and those who did not.

This prospective analysis included 150 participants -- out of nearly 98,000 screened from May 2009 through February 2014 -- who were enrolled during acute HIV infection. More than 90% were men and the median age was approximately 28 years.

Participants were enrolled an average of 18 days after HIV exposure, during Fiebig stages I through V. Fiebig stages indicate when HIV RNA, p24 antigen, and antibodies become detectable. Stage F-I indicates initial ramp-up of viral replication, with peak viral load occurring during stage F-IV.

Study physicians completed a standardized checklist for each participant and those with at least 3 qualifying symptoms were considered to have ARS. Blood samples were obtained (n=75), and consenting patients also underwent colon tissue biopsies (n=42) and cerebrospinal fluid (CSF) collection (n=37).

Results

• A total of 114 participants (76%) experienced acute retroviral syndrome, while 36 did not.
• The most common ARS symptoms were fever (94%), fatigue (81%), headache (72%), pharyngitis or sore throat (60%), and myalgia or muscle aches (60%).
• Participants with ARS had significantly higher HIV RNA levels than those without acute symptoms (median 5.7 vs 4.6 logcopies/mL).
• Total HIV DNA in peripheral blood mononuclear cells -- indicating establishment of a viral reservoir -- was also significantly higher among people with ARS, both at baseline (145 vs 8 copies/10⁶ PBMCs) and over time.
• Levels of inflammation and coagulation biomarkers were likewise higher among participants with ARS compared to those without:

o   C-reactive protein: 1431 vs 644 mcg/mL;

o   Tissue necrosis factor-alfa: 7.4 vs 4.7 pg/mL;

o   D-dimer: 310 vs 179 mcg/mL.

• In colon tissue samples, participants with ARS had significantly lower absolute numbers of CD4 T-cells (6.6 vs 11.8 x 10⁶ cells/gm) and lower HIV RNA levels (3.1 vs 1.7 log copies/gm), but higher levels of activated CD8+ T-cells (8.7% vs 4.4%).
• In cerebrospinal fluid, people with ARS had higher HIV RNA viral load (3.6 vs 1.8 log copies/mL) and higher neopterin levels (2410 vs 1101 pg/mL).
• CD8 cell activation and levels of D-dimer and neopterin in the ARS group dropped over time, and were no longer significantly higher compared with the non-ARS group after 24 or 96 weeks.
• However, there were no evident correlations between these biomarkers levels and gastrointestinal or central nervous system symptoms.

"ARS was associated with depletion of CD4+ T-cells and increased CD8 T-cell activation in the sigmoid colon as well as heightened inflammation in the periphery," the researchers concluded. "Patients with ARS may have poorer outcomes than those without ARS, particularly if they continue to display this unfavorable profile after treatment."

10/28/14

Reference

T Crowell, JLK Fletcher, E Kroon, J Ananworanich, et al. Acute Retroviral Syndrome is Associated with Gut Mucosal CD4 Depletion, Inflammation and High Viral and Proviral Burden in Systemic and Tissue Compartments. IDWeek 2014. Philadelphia, October 8-12, 2014. Abstract 641.