Traditionally, it was thought that the natural course of HIV included a period of latency -- a time when the virus was inactive, often for years. This seemed to be a respite from the harsh effects that HIV can have on the body. But according to recent studies, this "latency period" may not be what it was originally thought to be -- in fact, HIV may have a greater impact on the body and immune system than we ever imagined.
Previously, it was assumed that the higher the CD4 count, the greater the level of protection. When CD4 counts were high, the risk for AIDS-defining opportunistic infections and other diseases was thought to be quite low, perhaps even nonexistent. But now we're seeing serious conditions like heart, liver, and kidney disease in people with higher CD4 counts. And we're also seeing more deaths in people whose CD4 counts are above 200. It appears that during this period of "latency" HIV is not silent, that CD4 levels may not indicate what is happening inside the body, and that inflammation may be affecting many organ systems. So the question is, how is this happening?
To answer this, we can look at the SMART study, one of the first to reveal this effect. In this study, people who stopped their HIV meds when their CD4 count rose above 350 had higher rates of AIDS-defining opportunistic infections and non-AIDS conditions, as compared with those who stayed on HIV therapy. They had higher amounts of virus in their blood, and those higher levels were associated with inflammation.
When the body fights invaders like viruses or bacteria, or repairs injured tissues, fluid and cells get transported to the site of injury. As the body heals, the cells can swell, get warm, and become sore. One theory is that as HIV chronically infects the body, cells and tissues are destroyed and then heal, activating the immune system. That leads to an overstimulated immune system that can become burned out or weakened. So, even though a lab result may show a high CD4 count, the amount of inflammation in the body may be causing damage on a cellular level. And that can lead to heart, liver, kidney disease, and greater levels of bone loss.
Evidence shows that while HIV medications may play a role, they are not the only culprit. During the SMART trial, when people who stopped their HIV meds restarted them, levels of inflammation decreased but never became normal. There remained a residual level of inflammation (shown by increased levels of IL-6 and D-dimer) and a greater number of cardiovascular events occurred, especially in people who started the study with undetectable viral loads. Why was this of concern? Because high levels of inflammation are thought to increase atherosclerosis (narrowing of the arteries) and heart disease even in people who don't have HIV. In the SMART trial, there were higher rates of heart, liver, and kidney disease among people with HIV at younger ages, even after controlling for differences in age and gender.
Research presented at the most recent Conference on Retroviruses and Opportunistic Infections in San Francisco provided further support of inflammation as a source of cardiovascular disease. In a study presented by Priscilla Hsue, the thickness of the carotid artery in the neck was measured by ultrasound among 285 people with HIV and compared with those of HIV-negative people. Among those with HIV, the carotid artery was significantly thicker, and lined with greater levels of plaque, placing them at greater risk for cardiovascular problems. In addition, they found the thicker arteries to be associated with high levels of a known inflammatory marker linked to heart disease called C-reactive protein. Another study found similar effects but found the artery thickness to be lower in people on HIV meds or with CD4 counts above 400. But it was never as low as in those who are HIV negative.
The first study also looked at how well the brachial artery could dilate, or widen, and whether it was becoming stiff due to inflammation. When they compared 98 people who were taking HIV meds with people who were HIV-negative, they found that even when HIV was well controlled with meds, the arteries were stiffer and not able to dilate in response to stress.
Increases in blood levels of several markers of inflammation have been linked with HIV disease. In addition to C-reactive protein, other markers such as interleukin-6, D-dimer, and TNF-alpha were also found to be elevated in people with HIV with thickened arteries. Higher levels of MCP-1 and RANTES are also seen in people with HIV, and can mean higher levels of protein in the urine, and kidney disease. The higher levels of inflammatory proteins seen in people with HIV (whether or not they are taking HIV meds) may suggest that HIV may be responsible for the heart, liver, and kidney disease that is seen at higher CD4 counts.
The big question is whether increased inflammation affects the lifespan of people with HIV. Early studies suggest it could be linked to all causes of death among people with HIV. A study by Kalayjian explored the link between inflammatory markers and AIDS deaths. In the study, people who had never taken HIV medications started medications during the trial. Those who later developed AIDS or died during the study had their inflammatory markers measured (specifically TNF, IL-6, CD27, and CD40). The researchers found that there were higher levels of all these markers in people who developed a new AIDS-defining illness or who died before they started HIV meds. Levels of TNF, CD27, and CD40 were higher before HIV treatment was started in people who later developed an AIDS-defining cancer or who died. This occurred about a year after they started HIV meds, even though most of them had undetectable viral loads and CD4 counts above 200. So it would appear that inflammation may be causing damage early in the course of HIV disease, despite lower viral loads and higher CD4 counts, and that it may play a role in both HIV-related cancers and death.
HIV may also lead to premature aging. In one study, vasodilation, or the blood flow, of people with HIV seemed to look like that of HIV-negative people who were 10 to 15 years older. Another study found the blood vessels of people with HIV appear to be similar to those of HIV-negative people who are 25 years older. The T cells of people with HIV look like those of people without HIV who are 32 years older -- while the median age of HIV patients in one study was 56, their T cells looked like those of patients who were 88. (The people with HIV had fewer CD8 cells, specifically those with CD28 and CD56 markers.) Further, people living with HIV for 8 to 12 years were 15 times more likely to be frail as compared with their HIV-negative peers. And the thymus gland, which helps T cells to mature, appears smaller in people with HIV.
All of these findings indicate that HIV seems to be linked with diseases normally seen at older ages, and that chronic HIV infection may create a state of premature aging and inflammation. If this is the case, what can be done to protect people with HIV from these serious non-AIDS conditions?
The short answer is that we're not sure. One idea was to try Valcyte, a drug that reduces levels of cytomegalovirus (CMV), which was thought to lead to inflammation in people who had both CMV and HIV. But in one small trial, it didn't reduce the levels of residual inflammation. ACTG 5256 studied Selzentry, a new HIV receptor blocker, to see if adding it to people's standard HIV meds could lower inflammation. Inflammatory markers did go down, but the study couldn't tell whether this led to fewer cardiovascular events or higher CD4 counts. The "Jupiter" study (done in HIV-negative individuals) found that when people who had low LDL cholesterol but high C-reactive protein took the anti-cholesterol drug Crestor, they had 44% fewer cardiovascular events. But some studies have shown the opposite. We need further studies combining Selzentry with statins like Crestor to see if that could lower the markers of chronic inflammation and actually improve the health of people with HIV.
Several groups are looking at whether intensifying treatment by using more than the current standard of three HIV medications may reduce chronic inflammation. Some researchers have started to look at whether immune suppressants like prednisone, hydroxyurea, cyclosporine, and mycolic acid could help. Others are looking at medications like Renagel or colustrum supplements to keep microorganisms from leaving the gut and spreading inflammation throughout the body. Still others are looking at using chloroquine, a medication used for malaria. Common over-the-counter medications like Motrin and Aleve are also being tested for their ability to reduce chronic HIV inflammation.
In addition, some researchers are studying whether the thymus can be stimulated to produce more T cells. Clinical trials are planned of Serostim, a human growth hormone, and Sirolimus, an antirejection drug used in transplant patients, to see if they can reduce inflammation by bringing more CD4 cells onto the scene. Researchers at the French-based biotech Cytheris have studied IL-7 to see if it can increase CD4 counts in order to lower inflammation. IL-6 has also been further explored in clinical studies. And yet another group is looking at an immune-based therapy called Esbriet.
Some studies in rats and dogs have found that reducing the number of calories eaten may slow the aging process. A drug called resveratrol, which may have the same effect as calorie restriction, is being studied. Also, as we age a part of our chromosomes known as telomeres have been found to shorten, so researchers are looking into whether telomerase activators might slow the aging process in people with HIV. Finally, other groups are looking at vitamin D and omega-3 fatty acids as a way to slow the premature aging process seen in HIV.
It will take more studies before we know how to prevent heart, liver, and kidney disease in people with HIV. But one thing seems clear: HIV isn't sitting silently during its "latency period." Indeed, it is quite active, leaving a significant imprint on the body's immune and inflammatory systems.
Donna M. Kaminski is a fourth-year medical student at UMDNJ-SOM, and ACRIA's former Associate Director of Treatment Education.