I don't plan to grow old gracefully. I plan to have facelifts until my ears meet.
-- Rita Rudner
Inflammation is the hottest topic in HIV/AIDS research. We've known for many years that, left untreated, HIV disease produces widespread inflammation. The higher the HIV plasma viral load the more dramatic the inflammatory response. Treatment with potent combination antiretroviral therapy decreases not only HIV replication and consequently HIV viral load, but also HIV-associated inflammation. More recently we've learned that even when we drive the HIV viral load to undetectable levels, we don't completely turn off the inflammatory process.
"So what?" you may wonder. Well, glad you asked.
This ongoing HIV-related inflammation is now being linked to or at least associated with a wide array of HIV comorbidities. (That's doctor-speak for nasty HIV compilations.) These complications are far from trivial. Ongoing HIV-related inflammation is being blamed for the lack of response to vaccinations, the increased incidence of non-AIDS-defining cancers, increased neurocognitive decline, the lack of immune reconstitution (CD4 counts that don't rise as expected with treatment), accelerated bone demineralization, accelerated hardening of the arteries leading to increased incidence of stroke and heart attacks, and the rise of the Tea Party Movement!
OK, I made that last one up, but the others are true. And here's the real kicker: HIV (presumably HIV-related inflammation) causes accelerated aging! Yep! We're talking "HIV Inflammaging!" Now I know what you're all thinking: "Damn! Now that's just not fair! Haven't we got enough to deal with?" And I agree with you! I will add this whole HIV inflammaging concept is still incompletely understood but it is rapidly evolving. In fact the evidence supporting this scary concept is piling up faster than AARP notices in my mailbox. Consequently I felt we should discuss it. Besides, the prescribed mechanism underlying all this malicious geriatric-inducing mayhem is immunological. Since that's my specialité, so to speak, I thought I should try to review what we know so far. (Before the Alzheimer's kicks in.)
There is increasing indirect, as well as direct, evidence that we HIVers are at increased risk of morbidity (illness) and mortality (pushing up daisies) from a wide variety of non-opportunistic, non-AIDS-defining, serious conditions like the ones I listed above. And it has become increasingly clear that inflammation underlies this entire worrisome problem.
One piece of supporting evidence comes from the SMART trial (Strategies for Management of AntiRetroviral Therapy). Clever title, eh? In this well-designed clinical trial, a treatment interruption strategy (intermittent use of antiretrovirals to maintain CD4 count above 250) was compared to ongoing uninterrupted treatment with antiretrovirals. The question that trial was designed to answer was whether reducing overall antiretroviral drug exposure would reduce non-AIDS-related complications. We knew some antiretroviral drugs were most likely increasing the risk of heart disease, stroke and liver failure in some patients. So we hoped that decreasing overall drug exposure would decrease these related problems.
WRONGO! The study was stopped prematurely (studius interruptus!?!?), because it was noted that HIVers in the drug-conservation group actually had a higher risk of these oh-so-annoying conditions (including death!) than those in the continuous treatment group! WOWZA, that was a shocker! The take home message was that the increased risk of these conditions was more closely linked to uncontrolled HIV replication than to drug toxicity. We sure didn't see that one coming!
A detailed analysis of all the biomarkers in this study showed markers of inflammation (C-reactive protein, interleukin-6) and a blood coagulation marker (D-dimer) were significantly higher in the patients who were in the intermittent antiretroviral arm of the study. Stay with me; I know this is a bit complicated! (We immunologists just love the uber-complexities of life and death. Yeah, I know we're weird, but hey, we wind up figuring out really cool and scary stuff like the mechanisms responsible for HIV's grow-old-quick trick!) So what we learned from the SMART trial is that ongoing HIV-induced inflammation and a procoagulant state (increased risk of forming blood clots) underlie the increased risk of non-AIDS-related events observed in us HIVers and that in turn accounts for our increased mortality!
So AIDS: Acquired Immunodeficiency Syndrome may wind up being AIDS: Acquired Inflammatory Disease Syndrome!!!
The San Francisco Department of Health has recently become the first to recommend that all HIV-infected people be treated immediately with combination antiretroviral drug therapy without regard to CD4 count or HIV plasma viral load. This is a dramatic policy shift from previous recommendations and published guidelines that advised delaying antiretroviral therapy until CD4 counts had fallen into a certain range. The impetus for the policy shift is the concept of "inflammaging" supported by clinical trials, such as the SMART trial discussed above.
The concept that antiretroviral medications are toxic and consequently that we should wait for as long as possible to begin treatment has been replaced with a new paradigm: Although antiretroviral drugs are far from benign, they are less toxic than uncontrolled viral replication and its resultant inflammation.
Widespread early treatment may not only be the best treatment option for the virally enhanced individual, but also have a secondary beneficial effect from a public health HIV-prevention perspective. We know that when antiretroviral therapy drives HIV plasma viral load to undetectable levels, the risk of HIV transmission decreases significantly. Consequently, if a greater portion of positively charged folks is on effective treatment, in essence the "community viral load" decreases and the community risk of HIV transmission falls.
The story of "accelerated immune aging" or what we immunologists refer to as "early senescence" in HIV disease is becoming an increasingly complex and, at least for us whacked immunologists, fascinating aspect of HIV/AIDS. It involves dysfunctional thymus glands, microbial translocation, interferon-inducible genes and proteins, immune activation and shortened telomeres. Yeah, I know, most of you find this stuff about as fascinating as reading a book on elocution authored by George "Dubya" Bush. So I won't go into great detail (unless an overwhelming number of you write in requesting the nitty gritty immunologic details, in which case I'll be happy to pontificate). For now let's just say a lot of complex science and immunologic research is all pointing in the same direction: HIV is accelerating our aging process. (Suddenly I have the Beatles classic "When I'm Sixty-Four" running in a feedback loop through my brain: "Will you still need me, will you still feed me, when I'm sixty-four?")
Speaking of aging, as you may recall from my first HIV and aging blog entitled "Time Warp," I discussed "Angelennie," my loveably dear octogenarian parents. I need to provide you with an update. Just as they were settling into their "new normal" life at the snazzy and stunningly lovely assisted living facility at Saratoga Retirement Community, my mother suffered a massive stroke. She occluded her left middle cerebral artery, which resulted in paralysis of the entire right side of her body and face and inability to speak. This type of severe stroke has a 50% mortality rate, and the other 50% generally are left paralyzed and unable to speak. This horrendous event is a consequence of aging.
Despite the grim prognosis, however, miracles do happen. Due to the fact the stroke was witnessed by my dad, who immediately notified the facility's phenomenally attentive emergency response team, my mother was transported within minutes to a nearby stroke center. Very aggressive treatment with the clot-busting drug (TPA) given both intravenously and intra-arterially failed to dislodge the clot. However, fortunately the stroke center was equipped to perform a very risky procedure whereby the clot was dislodged mechanically with a MERCI retractor. (MERCI = Mechanical Embolism Removal in Cerebral Ischemia.)
She survived, and after several touch-and-go days in the intensive care unit she began to move her right side and say a few words. Within a week of the stroke, instead of being dead or paralyzed, she was being discharged from the hospital and had become something of a celebrity in the local medical community.
The reason I'm sharing this remarkable story is to emphasize three points:
- Aging can and does cause catastrophic events.
- Modern medicine can work miracles, which were unimaginable just a few short years ago.
- There is always hope, and good karma rocks!
I'll have more to say about Acquired Inflammation Disease Syndrome sometime soon. But now, it's time for me to visit my Lazarus-Mom!
Want to get in touch with Dr. Bob? You can reach him through his "Ask the Experts" forum, by sending a message to the Robert James Frascino AIDS Foundation, or by leaving a comment for him below. (If it's a private message, or if it includes personal info such as your e-mail address or phone number, we won't post the comment, but we will send it along to him.)