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AIDS 2012: Studies Shed Light on Inflammation and Immune Activation in People with HIV

HIV and aging was a major medical themes at the recent XIX International AIDS Conference (AIDS 2012) in Washington, DC. A growing body of evidence indicates that inflammation and excessive immune activation contribute to cardiovascular disease and other non-AIDS conditions in people with HIV as they live to older ages, despite viral suppression on antiretroviral therapy (ART). Several studies presented at the conference looked at the causes and consequences of inflammation in this population.

[VIDEO: Steven Deeks offers a brief overview of the causes and implications of inflammation in people with HIV]

Inflammatory Markers and Non-AIDS Events

Grace McComsey from Case Western Reserve University presented findings from AIDS Clinical Trials Group A5224s, a sub-study looking at associations between inflammatory markers and AIDS-defining and non-AIDS clinical events among people starting ART in ACTG study A5202.

In the parent study 1857 HIV positive participants starting treatment for the first time were randomly assigned to receive abacavir/lamivudine (the drugs in Epzicom) or tenofovir/emtricitabine (the drugs in Truvada), in combination with either efavirenz (Sustiva) or ritonavir-boosted atazanavir (Reyataz).

Sub-study A5224s measured multiple inflammatory biomarkers in 269 participants with available plasma samples from baseline and weeks 24 or 96. Most (about 85%) were men, half were white, the median age was 39 years, and the median CD4 T-cell count was 240 cells/mm³.

Markers included high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), tumor-necrosis factor-alfa (TNF-a), soluble tumor-necrosis factor receptors I and II (sTNF-RI, sTNF-RII), soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble intercellular adhesion molecule-1 (sICAM-1).

The researchers determined associated between levels of these biomarkers and time to development of AIDS-defining and non-AIDS-defining clinical events, adjusting for ART regimen and HIV viral load or CD4 T-cell count. McComsey explained that these categories of clinical events were combined because both types were uncommon.

Results

• As previously reported, the biomarker study's primary analysis showed decreases in TNF-a, sTNF-RI, sTNF-RII, sVCAM-1, and sICAM-1 occurred after starting ART, with no significant differences between regimens.
• sCRP and IL-6, however, showed more favorable changes at weeks 24 and 96 in the tenofovir/emtricitabine arm compared with the abacavir/lamivudine arm.
• A total of 13 AIDS-defining events occurred during follow-up: 9 opportunistic infections, 3 AIDS-defining cancers, and 1 case of recurrent bacterial pneumonia; 7 of these occurred during the first 24 weeks.
• A total of 18 non-AIDS events were observed: 6 diabetes, 4 non-AIDS cancers, 3 cardiovascular events, and 5 cases of pneumonia; 4 occurred during the first 24 weeks.
• Higher baseline levels of IL-6, sTNF-RI, sTNF-RII, and sICAM-1 were significantly associated with increased risk of AIDS-defining events.
• Results were similar after adjusting for baseline viral load.
• After adjusting for CD4 count, only sTNF-RI and sICAM-1 remained significantly associated with AIDS-defining event risk.
• Time-updated analysis showed these biomarkers were still associated with increased risk of AIDS-defining events after adjusting for ART assignment, baseline CD4 count and HIV RNA level, and changes in CD4 count and viral load.
• Only baseline hsCRP was significantly associated with increased risk of non-AIDS events.
• After adjusting for baseline CD4 count, IL-6 also became significantly associated with higher risk.
• Time-updated analysis showed TNF-a was significantly associated with increased risk of non-AIDS-defining events even after adjusting for ART, baseline CD4 count and HIV RNA, and changes in CD4 count and viral load.
• A total of 15 traumatic bone fractures occurred.
• Neither baseline nor time-updated biomarker levels were associated with increased fracture risk.
• Baseline CD4 count was correlated with IL-6 and sTNF-RI and sTNF-RII, while CD4 cell changes were correlated with changes in TNF-a.
• Baseline HIV RNA was correlated with all markers except hsCRP.
• The only biomarker that differed significantly between people with undetectable viral load and HIV RNA > 50 copies/mL was sTNF-RI.

Based on these findings, the researchers concluded, "Higher levels of several inflammatory biomarkers were associated independently of CD4 count with increased risk of AIDS and non-AIDS events."

"Time-updated levels in markers on TNF-a and/or s-TNF receptors were associated with clinical events whereas this was not observed for hsCRP," they continued.

They added that larger and longer studies are needed to investigate whether these biomarkers might be used to predict clinical events.

D-dimer

The SMART treatment interruption study was among the first to implicate inflammation as a contributor to non-AIDS events among people with HIV. Briefly, SMART showed that people who went off treatment when their CD4 count rose above 350 cells/mm³ not only were at higher risk for opportunistic infections, as expected, but also had higher rates of non-AIDS conditions including heart, liver, and kidney disease.

Extensive follow-up showed that certain biomarkers associated with inflammation and blood clotting were elevated in ART-interrupters. The coagulation marker D-dimer was the strongest predictor of overall mortality.

In the present analysis, researchers aimed to determine factors associated with elevated D-dimer among participants in SMART (n = 5472) and 2 other large trials -- ESPRIT (n = 4111) and SILCAAT (n = 1695) -- that tested whether IL-2 could help raise CD4 cell counts (it didn't).

Factors independently associated with higher D-dimer levels in a linear regression analysis were female sex, black race, older age, ongoing viral replication, worsening kidney function, and higher levels of the inflammation biomarkers CRP and IL-6.

Conversely, use of ART at baseline (either protease inhibitor- or NNRTI-based regimens) and higher HDL "good" cholesterol levels were associated with lower D-dimer, suggesting HDL may have an "anti-thrombotic" effect in people with HIV.

Obesity and Inflammation

Investigators with the CDC's SUN Study (Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy) looked at the link between obesity and inflammatory biomarkers among HIV positive people on ART.

Before widespread use of combination ART, higher body mass index (BMI) was associated with higher CD4 cell counts -- as people often developed wasting as their immune function declined -- but among individuals on effective treatment, obesity may be more of a concern.

This ongoing prospective observational cohort study includes 700 HIV positive participants in 4 U.S. cities. The present analysis looked at 494 people who achieved virological suppression < 400 copies/mL. Nearly 80% were men, about 60% were white, and the median age was 41 years.

The researchers looked at associations between BMI and markers of inflammation, carotid-intima media thickness (IMT, a measure of atherosclerosis), and bone mineral density, as well as differences between people whose baseline body weight was classified as underweight (BMI < 18.5 kg/m²; 2%), normal (BMI 18.5-24.9 kg/m²; 38%), overweight (BMI 25.0-29.9 kg/m²; 38%), or obese (BMI > 30.0 kg/m²; 23%).

The investigators found that heavier patients were more likely to have insulin resistance and had greater carotid IMT. They also had higher levels of several biomarkers including total cholesterol, apolipoprotein E, leptin, TNF-a, IL-6, hsCRP, TNF-alpha, and D-dimer. Further, obese people had significantly lower vitamin D levels than either overweight or normal weight people.

Over 2 years of follow-up, 10% of participants moved into a higher BMI category, but biomarker levels did not change significantly (though vitamin D levels did fall in people who gained weight).

"In this contemporary virologically suppressed HIV cohort, obese participants exhibited higher levels of markers of inflammation and atherosclerosis as well as lower vitamin D levels, despite a similar degree of immunosuppression compared with normal weight participants," the researchers concluded.

Injection Drug Use

Saurabh Mehandru and Martin Markowitz from Aaron Diamond AIDS Research Center and colleagues looked at the link between injection drug use and immune activation. They hypothesized that drug injection is associated with increased systemic and mucosal immune activation, which might help explain more rapid HIV disease progression in this population.

This pilot study included 13 HIV negative non-drug users, 19 HIV negative injection drug users (IDUs), 8 HIV positive non-drug users with detectable viral load, and 10 HIV positive IDUs with detectable viral load.

The researchers looked at soluble CD14 and cellular markers of immune activation (CD38) and proliferation (Ki67) in peripheral blood mononuclear cells (PBMCs) and mucosal mononuclear cells (MMCs).
Among HIV negative participants, the IDUs had significantly higher levels of immune activation, immune cell proliferation, and soluble CD14 than the non-drug users.

Among people with HIV, IDUs had significantly greater immune activation of CD4+ PBMCs and CD8+ PBMCs and MMCs than non-users. Differences in expression of soluble CD14 and Ki67, however, did not reach statistical significance.

Very Early ART

Given increased evidence showing that HIV positive people appear to have higher levels of immune activation and inflammation -- and the fact that these are associated with adverse clinical outcomes -- the question becomes how to manage inflammation in this population.

One study presented at the conference evaluated whether aspirin reduces immune activation and platelet aggregation (blood clotting) in people with HIV. In short, they found that daily aspirin reduces immune activation and platelet activity starting from the first day.

Another study by Markowitz' team at Aaron Diamond looked at whether early ART initiation could help overcome the increase in immune activation that persists even in the face of viral suppression when people start treatment later.

This proof-of-concept analysis included 31 men identified as having acute or early HIV infection who remained on treatment with suppressed viral load 48 weeks after starting treatment. All but 1 had symptoms of acute retroviral syndrome, and the estimated duration of infection was about 50 days. The average age was about 38 years.

11 patients received standard 3-drug combination ART including tenofovir/emtricitabine and ritonavir-boosted atazanavir or darunavir (Prezista). The other 20 received an intensive 5-drug combo including the drugs above plus raltegravir (Isentress) and maraviroc (Selzentry) -- in all, 4 different antiretroviral drug classes. At baseline the CD4 count was somewhat higher in the latter group, about 400 vs nearly 600, respectively.

The researchers assessed immune activation of CD8 T-cells (HLA-DR+ and CD38+) and measured soluble CD14 levels at weeks 48 and 96. These results were compared with those of 13 healthy, HIV negative volunteers.

At baseline, HIV positive participants had a significantly higher proportion of activated CD8 cells than HIV negative control subjects (about 40% vs 5%, respectively.

At 48 weeks the researchers saw no statistically significant differences in biomarkers of cellular or systemic immune activation between participants receiving the 3-drug versus the 5-drug regimen.

However, early treated HIV patients in both regimen arms experienced declines in immune activation markers, reaching normal levels similar to those of the HIV negative control subjects by week 48, and maintaining comparable levels at week 96.

"These data suggest that very early initiation of combination ART may result in normalization of markers of immune activation that may provide clinical benefit," the investigators concluded. "These results support well-designed prospective trials to confirm these findings."

8/10/12

References

GA McComsey, D Kitch, PE Sax, 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 (AIDS 2012). Washington, DC, July 22-27, 2012. Abstract THLBB06.

A Borges, J O'Connor, A Phillips, J Lundgren, et al (INSIGHT SMART, ESPRIT and SILCAAT Study Groups). Factors associated with elevated D-dimer levels in HIV-positive individuals. XIX International AIDS Conference (AIDS 2012). Washington, DC, July 22-27, 2012. Poster WEPE094.

L Conley, T Bush, P Patel. Obese HIV-positive persons have higher levels of select inflammatory markers and co-morbid illnesses. XIX International AIDS Conference (AIDS 2012). Washington, DC, July 22-27, 2012. Poster WEPE096.

S Mehandru, DGarmon, A Walker, M Markowitz, et al. Injection drug use is associated with significant levels of immune activation in the mucosal tissues and blood. XIX International AIDS Conference (AIDS 2012). Washington, DC, July 22-27, 2012. Poster MOPE022.

M Markowitz, T Evering, A Figueroa, et al. Very early initiation of combination antiviral therapy results in normal levels of markers of immune activation. XIX International AIDS Conference (AIDS 2012). Washington, DC, July 22-27, 2012. Abstract TUPDB0204.