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New Links Provoke Mystery, but Research Lags

By Bob Huff

People with HIV may experience low-level inflammation that erodes health and shortens life spans—even after their virus is undetectable.

A recent and growing worry in the AIDS treatment community concerns premature aging and shortened life spans in people with HIV—despite complete suppression of the virus by successful antiretroviral therapy.

Reports of increased risk for heart disease, kidney disease, cancers, dementia, bone weakness, and frailty in people with HIV even when their viral load is undetectable seem paradoxical, but the concern is real. In an era when antiretroviral drugs are better than ever and when fewer people in the United States are at risk for developing the classic diseases of AIDS, why do the bodies of some people with HIV seem to grow old before their time?

The common assumption holds that inflammation is the culprit. Chronic, low=-level inflammation has been implicated in atherosclerosis, and impaired blood flow may contribute to heart and kidney disease and problems with cognitive function. People with uncontrolled HIV replication often have increased blood markers of inflammation, and these chemical markers may not completely normalize after antiretroviral drugs have stopped the virus. It’s possible that HIVassociated immune activation is directly causing the inflammation, though that is not proven. Other factors may also foster premature aging. Rates of smoking are high in cohorts of people with HIV. Drug toxicity is a possibility. Hepatitis C virus or other, subclinical infections might cloud the picture. Even chronic stress and worry could contribute.

Yet there are strong suggestions that HIV is the underlying issue. But what might be responsible for premature aging in people with HIV who take antiretroviral drugs and have little or no virus in their bloodstreams? For some people, unfortunately, it appears that simply stopping viral replication may not be sufficient to restore normal health.

Is It the Virus, the Body, or the Drugs?

The first possibility to consider is that HIV causes permanent damage to the body and its immune system within days or weeks of infection.

Leading scientists now think that immune cells in the intestinal tract are among the earliest targets of HIV when a new infection is first established. Within a few weeks, HIV ravages the immune defenses of the gut and demolishes a large proportion of the body’s CD4 T-cell reserves. With this breakdown, the theory goes, bacteria and other microbes that normally stay in the gut begin to cross the unprotected border and enter the bloodstream in a process termed microbial translocation. The “leaky gut theory” maintains that these foreign invaders are met by a bodywide immune response that revs up to destroy and expel them. This systemwide activation of immune cells, some say, is like throwing gasoline on a fire, since HIV infects the very cells that are multiplying to defeat the bacterial interlopers.

If an important swath of an individual’s immune capacity is irreversibly wiped out during this frantic initial phase of HIV infection and CD4 cell destruction, then the body may never quite recover—even if HIV replication is subsequently controlled.

A second possibility (and none of these excludes the others) is that the body’s immune capacity slowly and permanently diminishes over time as HIV replication persistently erodes the CD4 cell population, and the count of CD4 cells per cubic millimeter of blood—a key marker of HIV progression—declines. Medical guidelines for offering anti-HIV treatment use the falling CD4 count as a signal for when to start therapy. While the CD4 cell count recommendation in U.S. guidelines has risen from 200 to 350 in recent years, the normal range of CD4 counts runs from 500 to well over 1,000. In most people, CD4 counts will not drop to the 350 level for many years after infection—years in which HIV is actively replicating and possibly destroying unrecoverable immune capacity. It’s possible that when treatment is finally started—and even when the virus is quelled—it is too late to reverse permanent immune damage. If this is the case, then the lowest point of CD4 decline, called the CD4 nadir, might be an important predictor of subsequent premature aging.

A third possibility is that very low levels of HIV can contribute to altered immune regulation—even when the virus has been undetectable in the blood following years of successful treatment. Some viral proteins are known to send signals to the immune system and cause problems even when they are not part of infectious viral particles. Although viral replication may be halted by drugs, HIV is not destroyed in the body. Its DNA is stitched into the genomes of the cells it has infected—and some of these cells (millions, actually) can quietly persist for years, occasionally generating bursts of viral fragments or even whole viruses that show up as “blips” in viral load tests. If these viral proteins can signal the immune system to respond inappropriately when there is no immediate threat, then the inflammation caused by this state of semipermanent activation might contribute to the symptoms of premature aging in people with no apparent HIV in their blood.

A fourth possible explanation for premature aging in people who are successfully controlling their HIV infection with antiretrovirals points to the drugs themselves. Careful comparisons between drugs in clinical trials and sophisticated analyses of large databases have revealed which medicines are most likely to cause problems. The worst offenders have been identified as members of the NRTI class of anti-HIV drugs, and several have been removed from HIV treatment guidelines. NRTI drugs were the first anti-HIV agents discovered, and they have formed the backbone of antiretroviral treatment regimens ever since. Newer-generation NRTI drugs are generally considered by doctors to have very low levels of toxicity that are easily managed in most people who take them. But long-term experience with some drugs notwithstanding, very subtle negative effects on health may be occurring that cannot be clearly identified until studied in a large clinical trial. Drug toxicity has been recognized as causing metabolic disorders and problems with how and where tissues such as fat and bone are created and destroyed in the body. One NRTI drug recently downgraded from “preferred” status in treatment guidelines has been associated with an increased risk for heart disease in certain patients with other serious risk factors for heart problems like family history and smoking. Another widely used drug has been linked to low levels of kidney damage, though the evidence is contradictory. However, other drugs are so ubiquitous in HIV regimens that no rigorous comparison studies have been conducted that might reveal their role in premature aging. These highly effective drugs are far safer than earlier NRTI drugs, and the benefits are currently thought to far outweigh the risks. But if these medicines are having a subtle, chronic impact on the body’s aging process, it will be hard to pin down that effect until a new set of clinical trials can be undertaken.

Premature aging in people with HIV who have successfully suppressed their virus with antiretroviral drugs is still a vague and unproven problem. But the early warning signs are there.

Where Is the Research?

Research is needed that can better describe the phenomenon of premature aging in people with HIV and elucidate what may be causing it. Some of this research is already underway; some has yet to be planned.

A new treatment strategy that uses no drugs from the NRTI class is being tested in a few small pilot studies. These trials may give the first glimpse of the role that NRTI drugs—even those with no apparent toxicity—are playing in the subtle, longterm effects of HIV infection on aging.

Another treatment strategy being tested calls for adding a highly effective newgeneration drug to a conventional regimen to intensify pressure on the virus and push down HIV replication to levels well below what is currently considered “undetectable.” Whether this approach can prevent production of residual HIV or toxic HIV fragments that disturb the immune system is uncertain, and new types of drugs and assays may have to be developed to determine whether there is ongoing immune damage despite viral control. The ultimate goal of this research is to permanently eradicate HIV from the body.

The consensus on when to begin HIV treatment is now shifting toward starting treatment earlier during infection, when CD4 counts are higher. As evidence increasingly suggests that any period of uncontrolled HIV replication is harmful— even if there are no apparent outward signs or symptoms—then medical opinion may eventually abandon the CD4 test and decide that HIV treatment should begin as soon as the virus is diagnosed. A large clinical trial that compares starting therapy using current guidelines with starting therapy much sooner also plans to look at the signs and chemical markers of premature aging. This trial, a follow-up to the trial that first illuminated the premature aging problem, should provide some important answers about the risks of letting HIV go untreated.

If the damage done during the first few days and weeks of HIV infection has lifelong impact, then it will be difficult to treat, short of finding a way to repair the injury. Most people are unaware that they have become infected, and even if they experience symptoms of acute infection, it may be too late to repair the devastated immune cell population. More research is needed to understand these early events, but one “experiment in nature” may help illuminate what is going on. Clinical trials are being conducted to investigate the possibility of preventing HIV-negative people at high risk for infection from acquiring the virus by giving them antiretroviral medications before they are exposed. The idea is that the drugs may stop an infection from taking root—hence the name of the concept, preexposure prophylaxis, or PREP. But since no treatment is perfect, some people using PREP will inevitably become infected despite having the drugs in their bodies. This has already happened at least once, with the provocative apparent result that, even though the infection was not blocked, the intensity of the initial impact of HIV may have been blunted by the drugs and the individual’s subsequent viral levels seem to be partially controlled. A follow-up study of this individual and others may lead to an important understanding of what HIV is doing in the body during those crucial early days after infection.

One unsolved barrier to understanding the subtle effects of HIV on aging is that any treatment that reverses premature senescence will take a lifetime to prove. While inflammation is strongly suspected as a factor in shortening the life spans of people with HIV, there is as yet no conclusive link and no easy-to-use laboratory marker that can indicate when a treatment has had a beneficial impact. The tests explored by immunologists to date represent a plethora of unvalidated markers determined by procedures that vary from lab to lab. So far, no “smoking gun” better than the CD4 count has been proven, and CD4 counts are only very general indicators of immune capacity; we need to understand what is happening well before CD4 counts begin to drop.

Premature aging is a growing concern among people with HIV and their doctors. The factors that may be responsible are not well understood. While some studies are being done, the basic scientific research that could explain the underlying mechanisms is fragmented and underfunded. Though the prospect of premature aging may seem of secondary concern in a disease that only a dozen years ago produced nearly inevitable early death, discovering whether there is a link between inflammation and the premature degradation of the mind and body is of interest to all.

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