Metabolic Toxicities and HIV
In an energetic, post-ICAAC presentation, Frank Palella, M.D., urged people living with HIV and clinicians who work with them to put some of the adverse effects of antiretroviral treatment into a larger perspective. The point of departure for Dr. Palella's talk was the growing concern in the HIV community about metabolic toxicities and body-shape changes (sometimes called "body habitus changes") that, for many people, are associated with use of some antiretroviral (ARV) drugs.
Perhaps the most distressing concerns for many individuals arise from the visible, cosmetic changes that many begin to experience after starting highly active antiretroviral therapy (HAART). These changes include loss of facial fat, leading to the appearance of sunken cheeks; accumulation of fat around the waistline; buildup of fat at the back of the neck between the shoulder blades ("buffalo hump"); loss of fat in the arms and legs; and thickening of the neck. Although for many people, these changes in appearance can be quite stressful, they also represent just the tip of the iceberg of metabolic issues and other ARV treatment matters that HIV specialists are trying to address.
Today's wide-ranging debates about metabolic toxicities and body-shape changes, explained Dr. Palella, who is assistant professor of medicine at Northwestern University School of Medicine, are taking place in the context of another critical debate -- when to start HAART and what combination of drugs to start with. Earlier recommendations to start ARV therapy for almost everyone when the CD4 T-cell count reached 500 or to "hit early and hit hard" have now been replaced by more complex considerations of issues like possible long-term toxicities, quality of life, and so forth. Some HIV specialists are even recommending delaying the start of ARV therapy until the CD4 count reaches 200. Indeed, one reason for this recommendation is to avoid what some believe to be long-term toxicities of ARV treatment, such as metabolic abnormalities and body-shape changes.
Critical Data From HOPS
To help explain possible causes of lipid abnormalities and body-shape changes, as well as what they may imply for an individual's ARV therapy, Dr. Palella drew on the vast amount of data coming from the HIV Outpatient Study (HOPS). HOPS is a huge study of some 7,000 HIV patients at 10 key treatment centers across the United States. (The largest of the centers is at Chicago's Northwestern Memorial Hospital.) The study collects and analyzes data from these patients' specific treatment regimens, outcomes, adverse events, survival rates, and other information.*
The following are just some of the key issues that the HOPS data are helping Dr. Palella and other researchers address:
Using a variety of graphs and charts, Dr. Palella stressed that use of HAART, which began in early 1996 with the introduction of protease inhibitors (PIs), has a clear association with a dramatic drop in the number of deaths from HIV-related illnesses. In fact, for people who are able to take HAART, the number of deaths plunged by 90-95 percent. He also pointed out that during that same time the rates of illness due to pneumocystis carinii pneumonia, mycobacterium avium complex, and cytomegalovirus have also greatly declined. Furthermore, the HOPS data indicate that earlier initiation of ARV therapy is highly beneficial: People who began therapy with CD4 counts between 200 and 350 cells, as opposed to delaying therapy until below 200, had a five-times lower death rate. In addition, those who started therapy at between 350 and 500 CD4 cells had almost half the death rate as those who delayed starting therapy.
Dr. Palella urged that, for those wondering whether use of HAART is really a good idea, "we have to have a long memory, because prior to 1996 AIDS was the leading cause of death for men between the ages of 20 and 60 and the second leading cause of death for women. But today the death rate has been dramatically reduced. So, when talking about lipoatrophy and other metabolic effects -- even if we believe that adverse drug effects play a role -- we have to keep in mind what the alternative to not treating is."
Among the arguments in favor of starting ARV therapy at a higher CD4 count Dr. Palella pointed to the following:
Whether delaying therapy helps to avoid cumulative adverse events represents the "black hole that all of the lipid abnormality issues fall into," stated Palella. "This is because we do not have a complete understanding of the extent to which the drugs that we use in fact contribute to what are called 'drug-related adverse events.' "
Multiple Factors Linked to Fat Changes
After this explanation of how HOPS information clarifies the relationship between use of HAART and the drop in HIV-related death and disease, Dr. Palella focused on how careful analysis of HOPS, and other, data have begun to shed light on the host of factors that seem to be associated with the development of metabolic and body-shape problems with HIV infection.
First he sketched out some of the issues being addressed in trying to define lipodystrophy. Four general sets of abnormalities, which overlap with each other to varying degrees, come into play in any working definition of lipodystrophy:
Dr. Palella explained that these abnormalities can occur in different combinations in different individuals. For example, one person may experience high cholesterol and loss of facial fat, but none of the others. Another person may have insulin resistance and abdominal fat accumulation, while a third may experience some degree of all four types of abnormality.
As early as 1996, reports began to appear of diabetic problems occurring in some patients who were taking protease inhibitors, so the concern about metabolic abnormalities in HIV treatment is not new. Because virtually all HAART regimens at that time contained at least one PI, that class of drugs was thought to be the most likely cause of the abnormalities. With a variety of failed efforts to explain what the association could be, Dr. Palella said, "attention shifted to the nucleoside analog class of drugs (Zerit, Retrovir, Videx, Epivir, Combivir, etc.), and that is where it has stayed for the last couple of years, especially when talking about fat atrophy."
Now that analysis of a variety of factors associated with different manifestations of metabolic abnormalities has become available, for example from the HOPS data, some things have become clearer. "While some drugs themselves might account for certain aspects of these problems, especially the association of blood lipid abnormalities with use of protease inhibitors, a close association of one drug and the development of one of these abnormalities does not imply that there is any association with development of any of the other abnormalities."
Dr. Palella went on to explain that HOPS investigators looked at data from about 1,100 patients in the study to try to uncover two things:
HOPS investigators identified the following associations:
The two medications most associated with these abnormalities were Crixivan and Zerit. However, Dr. Palella stressed that real accountability for the occurrence of the problems could not be assigned to either drug because these were the most commonly used medications among that group, with more than 85 percent of them being treated with Zerit. He compared this situation to "walking into a room full of dark-skinned people who are all HIV-positive and saying that they're positive because they're dark-skinned. Of course, you can't say that, because the real reason is that these just happen to be the people that you're looking at now."
Another later analysis of HOPS data found an association between an individual's CD4 nadir (the lowest level that her or his count had reached) and the development of facial fat loss. This analysis found that the lower a person's CD4 count got, the higher the likelihood of developing sunken cheeks or skinny limbs. Furthermore, the risk was even higher for someone whose CD4 count was low and stayed low.
Although other studies have since agreed with the HOPS findings, this analysis was the first real confirmation that there are other factors besides drug treatments that are associated with the development of fat loss and fat gain, and possibly with other metabolic abnormalities. "If we were to make up a laundry list of lipodystrophy, metabolic disorders, and things that might be associated with them, over the last couple of years we've gone from focusing on drugs in general -- and sometimes even on specific classes of drugs -- to focusing on the bigger picture: duration of infection, severity of disease, age, degree of immune reconstitution, and possibly gender and race."
Where Does Mitochondrial Toxicity Fit In?
Dr. Palella also touched on another issue that often comes up in the context of discussions of HIV-related metabolic and lipid disorders -- mitochondrial toxicity. (Mitochondria are tiny structures inside certain types of cells. One of the main responsibilities of mitochondria is to help convert foods into energy that the body can use.) Some studies have indicated that use of ARV therapy can damage mitochondria. One possible result of such damage is higher than normal levels of lactate in the blood. (Lactate is a byproduct of the use of sugar by muscles during exercise.) When lactate levels reach a critically high level, a condition called lactic acidosis can result, with a variety of symptoms that may include nausea, vomiting, abdominal pain, and difficulty breathing. In a very small number of cases, patients have experienced a severe weakening of muscles in the legs and arms.
While the results of lactic acidosis can be extremely severe when they do occur, Dr. Palella cautioned that too many people with HIV and physicians have come to think of mitochondrial toxicity, high lactate levels, and body-shape changes as all part of the same problem. He went on to stress that no carefully designed studies to date have been able to confirm that any connection at all exists between damage to mitochondria and changes in lipid levels or fat distribution. He further cautioned that, although ARV therapies may or may not be involved in any one of these abnormalities, no data have yet been able to confirm that any one drug or class of drugs is clearly linked to the development of specific metabolic abnormalities.
No Retreat on Treatment Progress
To drive home his core message that patients and providers alike should keep their attention more on the larger context of HIV treatment, rather than on possible adverse events, Dr. Palella suggested an analogy: "If we were talking about a cancer, like small-cell carcinoma of the lung, and we had combination chemotherapy that could result in durable remission -- with more than 90 percent reduction of death rates -- but the therapy had to be continued for many years. And if we found some metabolic abnormalities that may or may not be due in part to use of the drugs, would that ever be considered justification for delaying or modifying what is known to be life-saving therapy? Absolutely not. We should never think that withholding therapy for anybody at risk for HIV disease progression is something that is admissible. Especially since the majority of metabolic changes described here, like high cholesterol, insulin resistance, and high triglycerides, are treatable. People who are taking ARV therapy are living their lives, holding down jobs, raising families, and so on. Therapy is saving lives that we could not save a decade ago, and I don't want to go back to that time again."
Steve McGuire is a Chicago-based writer and consultant specializing in medicine, public policy, and non-profit issues.
* Much of the credit for analyzing the HOPS data belongs to Kenneth Lichtenstein, M.D., of the University of Colorado, who is one of the lead HOPS investigators.
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