Markers of Immune Exhaustion Predict Post-Treatment Control in HIV Patients

Biomarkers of immune exhaustion were associated with how long a patient was able to control HIV after treatment was interrupted, according to a study presented at CROI 2015.

The study, which was presented by John Frater, M.D., analyzed a sub-group of patients in the SPARTAC study, a randomized trial of individuals during primary HIV infection, which included a planned treatment interruption after 48 weeks of antiretroviral therapy for some participants.

Remarkably, 14% of those who interrupted treatment after 48 weeks still had undetectable viral loads a year later, showing that treatment within the first few weeks or months after infection may induce a state of post-treatment control. The researchers found that the amount of HIV DNA present at the time of the treatment interruption predicted how quickly the virus would rebound.

In this sub-analysis, the researchers wanted to see if other biomarkers also helped predict viral rebound after treatment interruption. After analyzing 18 immunological and virological biomarkers, they found three in particular -- PD-1, Tim-3 and Lag-3 (markers of T cell exhaustion) -- predicted viral rebound.

Specifically, when levels of PD-1, Tim-3 and Lag-3 were higher at the time when treatment was started, and not at the point of treatment interruption, HIV rebounded quicker. Conversely, when levels of these markers were lower, HIV rebounded less quickly.

"These three markers open questions as to mechanism, which we really don't understand. Why does the virus not come back? Understanding these markers will help [answer] that," Frater said at a press conference.

John Mellors, M.D., provided some context, while moderating the press conference:

I would interpret it as in those individuals whose immune system has said, 'We can't handle this infection. We're shutting down. We're shutting down the immune response,' those are the ones who are going to rebound quickly.

Cancer therapy has been revolutionized by blocking these receptors. Some individuals with cancer have high levels of exhaustion markers, the tumor progresses. But by reversing that exhaustion, waking up the immune system and powering it to respond, has resulted in very dramatic responses in cancer.

Although John [Frater] didn't imply this because he's very careful not to go beyond his data, it suggests that blocking these receptors in HIV infection might improve outcome and there is a clinical trial going on to look at blockade of one of the receptors (PD-1 and PD-L1).

The other biomarkers in this sub-analysis that were not associated with predicting viral rebound included: CD4+ cell count, plasma viral load and CD4/CD8 ratio (clinical measures); CD4 ELISPOT and CD8 ELISPOT (markers of HIV T cell immunity); HLA DR, CD38, CD25 and CD69 (markers of T cell activation); D-dimer, IL-6 (soluble markers); and cell-associated unspliced HIV-1 RNA.

"These data indicate that pre-therapy measurements may be informative and that markers of T cell exhaustion should be included alongside HIV-1 DNA levels. This may also open critical new avenues for understanding the mechanisms underlying [post-treatment control], which need to be explored in larger cohort," the authors concluded.