October 19, 2010 (Baltimore, Maryland) — Editor's note: The First International Workshop on HIV & Aging, held here October 4 and 5, was organized to promote the scientific and clinical synergy between the 2 fields.
Many people with long-term HIV infection that is controlled with highly active antiretroviral treatment (HAART) appear to have clinical manifestations of premature aging, although this is a highly controversial topic. The fact that chronic low-level inflammation persists during long-term effective antiretroviral therapy is now well accepted. This phenomenon might be contributing to some of the complications that are occurring in some HIV-infected people.
Steven G. Deeks, MD, is a professor of medicine in residence at the University of California, San Francisco (UCSF), and codirector of the Population and Clinical Sciences Core at the UCSF-GIVI Center for AIDS Research. He is a leading expert on the immunopathogenesis of HIV. Much of his recent work has focused on the persistence of low-level inflammation in the face of HIV controlled with long-term HAART.
|Dr. Steven Deeks|
Medscape: Is there a difference in the levels of inflammation between healthy individuals and people with HIV that has been well controlled with HAART?
Dr. Deeks: Markers of inflammation are elevated in patients on HAART that has been controlling the virus for years, but the effect is not particularly dramatic. Many of the more common markers of interest are only approximately 50% higher in treated patients than in people who are not infected with HIV.
Since we are talking a lot about aging, it is of interest that some of the immunologic features of advanced aging appear to characterize the immune system of patients who are otherwise doing well on treatment. For example, T cells in treated patients have lower-than-normal levels of CD28, a molecule involved in T cell function. This is also commonly seen the elderly.
Medscape: Does HIV itself contribute to inflammation?
Dr. Deeks: About 80% of patients on HAART with HIV RNA that is undetectable with conventional assays have detectable virus when very sensitive research-quality tests are used. Based on the few studies that have attempted to quantify virus in tissues, it is clear that the overall viral burden is much higher in tissue than in blood. The critical question is whether this virus has clinical significance. For example, could it be causing chronic inflammation? There is some disagreement in the field, but our data suggest that there is no strong relationship between the amount of virus in the blood and the amount of T cell activation.
Based on a number of studies in which nothing happened when standard regimens were intensified with additional agents, we concluded that low-level cryptic viral replication probably is not a major cause of inflammation and activation, and, by extension, age-associated diseases in these patients. We struggled to prove that HIV is the cause of this inflammation and we failed.
Medscape: Then what causes the persistent inflammation?
Dr. Deeks: There is robust literature in the elderly showing that there are dramatic differences between those who are CMV [cytomegalovirus]-positive and those who are CMV-negative. Those who are positive have reduce proliferative regenerative capacity, low naïve to memory T cell ratios, low CD4 cell counts, lots of activation, lots of interleukin-6, and C-reactive protein. These are all markers of immunologic aging, or immunosenescence.
We see comparable effects in people infected with HIV who are on HAART. Despite the lack of any obvious CMV disease, many patients, otherwise doing well, have very high levels of CMV-specific T cells. We estimate that up to 30% to 50% of circulating T cells are directed at CMV. These cells can certainly cause inflammation. The level of inflammation probably depends on individual titers of CMV and the extent of immune activation. We think that these factors are underappreciated.
Medscape: What happens when you treat for CMV?
Dr. Deeks: In a randomized trial with valganciclovir conducted by my colleague Dr. Peter Hunt [professor of medicine at the University of California at San Francisco], CMV levels went down and the amount of excess T cell activation that was unexplained dropped by about 25%. This suggests that a large portion of immune activation and inflammation is related either directly or indirectly to CMV infection.
Medscape: So why not simply treat for CMV?
Dr. Deeks: Most of the available drugs that are active against CMV are "toxic." Acyclovir is a benign drug that is active against other viruses from the CMV family, but it is not active against CMV. As Peter Hunt says, "the juice probably isn't worth the squeeze." We clearly need new therapeutic interventions.
Medscape: There probably are other factors contributing to this chronic inflammation. What about interventions such as low-dose aspirin and statins?
Dr. Deeks: There are good data in other populations demonstrating the anti-inflammatory benefits of aspirin, statins, and other drugs, but we simply don't have that kind of data in an HIV population. Some studies are planned or are underway.
For now, lifestyle changes such as diet and exercise may be the most useful interventions. They have demonstrated efficacy in dampening immune overactivation and restoring a more normal homeostasis.
Medscape: Does HAART have any anti-inflammatory value?
Dr. Deeks: Definitely yes. All of the information that I have seen consistently shows that inflammation levels are much higher in people who are untreated than in those who are treated. The effect of treatment can be profound. The problem is that treatment does not fully restore values to what might be considered normal.
It is hard to reverse the effect of inflammation. We need to prevent it. If the infection starts in the 40s, or earlier, then 20 years later we are going to see evidence of premature aging. Since people who start HAART earlier tend to have less inflammation once therapy is successful, I think we should get people on HAART earlier rather than later.
Dr. Deeks has disclosed no relevant financial relationships.
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Cite this: HIV and Aging -- Inflammation: An Expert Interview With Steven G. Deeks, MD - Medscape - Oct 19, 2010.