In 1996, the HIV community was first introduced to highly active antiretroviral therapy, quickly shortened to HAART. The new medications that made so much difference were the protease inhibitors, or PIs. When used in combination with the older drugs, the nucleosides, they seemed to stop the virus in its tracks. We began to hear reports of skyrocketing T-cell counts, of viral loads diminishing to undetectable levels. By the following year the death rates had plummeted and we were convinced that there had been a miracle. Instead of preparing for death, people with HIV and AIDS were getting on with their lives. Spending down gave way to the Lazarus Syndrome.

Then we started getting the first clues that there might be a problem, an unwelcome side effect of the therapy. In June 1997, the Food and Drug Association issued a warning to doctors that there had been a mini-epidemic -- 83 reports of new cases or flare-ups of diabetes in patients on protease inhibitor therapy. Twenty-seven of these cases had necessitated hospitalization.

Then in March of 1998 we saw the first published reports of the body changes that have come to be known as lipodystrophy. One of the first and most obvious of these was an increase in abdominal fat. It goes by a lot of different names -- "Crix belly" and "protease paunch" are just two of the most common. This is not the kind of fat you can pinch, not a jelly belly. Instead it is fat that is wrapped around the internal organs, and it’s known as visceral or intraabdominal fat. According to endocrinologists, or hormone specialists, an overabundance of visceral fat is a marker, or warning sign, for various metabolic disorders. These include high blood lipids (fats) and glucose intolerance, both of which are known predecessors of diabetes and heart disease.

Another of the more visible features of lipodystrophy is what is commonly called buffalo hump, a thick pad of fat on the back where the neck meets the shoulders. There was an interesting study on buffalo hump done in California in 1998. The investigators wanted to see if people with HIV and AIDS who had buffalo hump also had Cushing's Syndrome, a condition that results from the overproduction of hormones from the adrenal glands located on the surface of each kidney that is also frequently characterized by the same fatty deposit. But Cushing's Syndrome also results in abnormalities in a blood component called cortisol, and in the HIV-positive patients the cortisol levels were normal. They did not have Cushing's Syndrome. Of further interest was the fact that only four of the eight HIV-positive people with buffalo humps who were being looked at were on protease inhibitors. The other four were taking antiretroviral therapy without PIs.

Besides intraabdominal obesity and buffalo humps, women have reported breast enlargement and a decrease in the size of their thighs. Men and women alike have reported loss of fat in the arms and legs and in the face.

But the visible manifestations were only part of the problem. Two Australian researchers found that people on PI therapy were also experiencing hyperlipidemia -- high total cholesterol, low HDL (high-density lipoproteins, the "good" cholesterol), and high LDL (low-density lipoproteins, the "bad" cholesterol), high triglycerides -- and new-onset hyperglycemia and diabetes. Of particular concern was the fact that each of these metabolic changes is an independent risk factor for cardiovascular disease.

These investigators thought the protease inhibitors might be the cause of both the visible and the metabolic changes of lipodystrophy. Their theory is that PIs bind to proteins in the body that resemble the protease enzyme in the T-cell but that cause changes in fat metabolism. In other words, the changes in your body may be due to the PIs acting in places other than T-cells. The Australians' theory has not been proved or disproved.

Dr. Donald Kotler, a world-famous AIDS researcher at New York City's St Luke's Hospital, is one who disputes the theory. He points to the fact that he and others have seen and documented body composition changes in HIV-positive people who were not taking protease inhibitors, like the four people with buffalo humps described above. Kotler, who has been working with people with HIV and AIDS for over fifteen years, recalls seeing patients with body fat changes in 1996, before the advent of protease inhibitors. Dr. Kotler sees the intraabdominal obesity and other body fat changes seen in people on HAART as the result of reduced viral loads and recovering immune systems, rather than as a direct effect of the protease inhibitors or other drugs.

Kotler likens HIV-related lipodystrophy to another lipodystrophy-like syndrome that occurs in people with chronic infections, which cause stress, which results in the manifestation of the syndrome. "Syndrome X" as it has been labeled includes fat redistribution and elevated blood levels of lipids and glucose. Kotler's thought is that the PIs uncover this underlying syndrome by dramatically lowering viral load and increasing T-cells.

In the summer of 1999, still another theory on lipodystrophy made news. This one involves the nucleoside reverse transcriptase inhibitors (NRTIs, the AZT-type drugs). NRTIs are known to cause damage to the mitochondria of cells. The mitochondria are the powerhouses of our body's cells and are involved in both lipid and protein metabolism. The damage caused by NRTI-type drugs is called lactic acidosis. The physical symptoms include nausea, vomiting, abdominal pain, and hyperventilation. Mitochondrial damage is linked to damage to the heart muscle and kidneys, hepatitis, pancreatitis, and neuropathy.

This mitochondrial toxicity theory is based on the similarity between HIV-related lipodystrophy and another lipodystrophy syndrome called Multiple Symmetrical Lipomatosis. Also known as Madelung's disease, this syndrome also involves an abnormality in mitochondrial DNA. Only a minority of HIV-infected patients have this disease.

If that's not complicated enough, Kotler also reports in Medscape, an Internet research site, that over the past year investigators have begun to split their descriptions of the syndrome into lipoatrophy (fat wasting), fat accumulation (intraabdominal fat and buffalo hump), and mixed syndromes.

In January 2000 information was presented that suggested that PIs and NRTIs may promote body fat changes by different mechanisms. PIs are associated with abdominal fat accumulation and high blood fats. NRTIs are associated with lipoatrophy or fat wasting in the extremities and no elevations in blood fats.

It is now well accepted that hyperlipidemia is closely associated with PI use, although it may also be seen with Sustiva, which is a member of yet another class of drugs, the non-nucleoside reverse transcriptase inhibitors, or NNRTIs. The relationship between PI use and fat redistribution, however, is less clear. In fact, studies have documented fat redistribution in people with HIV and AIDS who have never been on PIs. Other studies show that the risk of fat accumulation appears to be related to PI use, while the risk of fat wasting in the extremities is associated with use of the NRTI d4T.

Another theory is that atrophy and accumulation can be attributed simply to total body fat, with heavier people more likely to demonstrate fat accumulation and thinner people more apt to develop fat wasting.

While investigators are still at odds regarding the cause of this syndrome affecting so many people on anti-HIV drug regimens, they are unanimous that the hyperlipidemia, glucose abnormalities, and visceral fat are linked to cardiovascular disease in the general population. And heart attacks and other coronary problems have been reported in individuals on HAART.

Dr. Carl Grunfeld, an endocrinologist from California, tried to assess the risk of developing heart disease on HAART compared with the risk of dying from AIDS-related causes in the absence of HAART. He found that the expected changes in cholesterol and triglyceride levels of people with HIV and AIDS on protease inhibitors resulted in a small average increase in the risk of heart disease, but that the benefit of treatment with PIs far outweighed the risk.

One other factor: According to a 1988 study, cardiac disease was a problem before PIs came along and was thought to be the cause of about 9 percent of HIV-related deaths. The reason is that opportunistic infections, and even the virus itself, can infect and damage the hearts of people with HIV and AIDS.

In addition, heart disease is a feature of aging, and the incidence of heart disease will naturally increase as people with HIV advance into their 50s. Other risk factors for heart disease, besides lipid levels, are family history of heart disease or diabetes, smoking, and sedentary lifestyle. Therefore, whether drug therapy is the direct cause of heart disease, it is something that HIV-infected individuals can anticipate as they get older along with the rest of the aging population. Lifestyle and dietary changes are recommended.

Donna Tinnerello is a dietitian specializing in HIV and nutrition in the community and at Cabrini Medical Center. She is past chairperson of Nutritionists In AIDS Care.

HAART to Heart Talk

Dr Manuel Morlote is a cardiologist at Cabrini Medical Center in New York City. A teaching attending physician at the hospital, Dr. Morlote treats people with HIV and AIDS both in the hospital and in his private practice. The author sat down with Dr. Morlote recently to talk about cardiovascular risk factors and how to prevent heart disease in people on HAART. DONNA TINNERELLO: The new syndrome -- lipodystrophy -- has both providers and the community worried. On the one hand, people on HAART have so far survived a life-threatening disease, one that took the lives of so many people before the new drugs came along. But now we have a new set of problems. In the general population, the metabolic changes that are part of the syndrome are clear risk factors for cardiovascular disease. Left untreated, they can lead to myocardial infarctions and strokes. And they may be caused by the very medications that have rescued the people who are experiencing them from AIDS-related complications. We have heard very little from cardiologists; we need your expertise. People with HIV and AIDS on HAART have very high levels of triglycerides. A normal triglyceride level is 40–150mg/dl. Triglycerides above 1000mg/dl can cause pancreatitis. Is there a connection between high triglycerides and heart disease? What is the treatment? MANUEL MORLOTE: This question remains unanswered at this time. However, there is speculation, and it is reasonable to initiate lifestyle changes when triglyceride levels go above 200mg/dl. Lifestyle changes are the backbone of treatment for high triglycerides. The primary treatment is body weight control. In addition, I recommend a low-fat, low-cholesterol diet with careful attention to avoiding excess carbohydrates, regular exercise, smoking cessation, and restricted alcohol use. Regarding medications: Drugs like gemfibrozil/Lopid are safely used for the treatment of HIV-related high triglycerides. Other medications, including nicotinic acid [a B vitamin derivative], are effective treatment, but the risk of causing glucose intolerance [poor blood sugar control], particularly in people on PI therapy, makes it a bad choice. DT: People with HIV and AIDS who are on HAART often have high total cholesterol, high low-density lipoprotein [LDL] levels, and very low high-density lipoprotein [HDL] levels. What are the cardiovascular implications of this lipid profile? How would you treat? MM: The implications are those of atherosclerotic cardiovascular disease. These include myocardial infarctions [heart attacks], strokes, peripheral vascular disease [PVD, a disease of the arteries and veins of the extremities that causes the blockage of blood flow], and coronary heart disease [CHD, myocardial damage due to damaged arteries that interrupts blood flow to and from the heart]. The treatment guidelines are from the National Cholesterol Education Program. Although they are not specific to HIV, they represent a reasonable starting point. They include lifestyle changes, particularly giving up smoking and initiating a regular exercise program, along with diet changes and drug therapy. DT: Can you talk about the program's dietary recommendations? I know that they are considered the standard of care and that they are being used successfully by HIV-treating dietitians across the country in dealing with the metabolic complications of drug therapy. MM: It is a two-step program, and it is progressive. The Step 1 diet is lower in fat and cholesterol than the usual American diet. Those who are already eating a Step 1 diet and who still need to lower their cholesterol advance to Step 2. Obviously this can be quite complicated and requires guidance from a qualified health professional. In the Step 1 diet, 8 to 10 percent of the day's total calories come from saturated fat, such as whole-milk dairy products, red meat, etc., and 30 percent or less of total calories come from fat of any kind. In addition, the diet contains less than 300 mg of cholesterol per day, and daily sodium intake is limited to 2,400 mg. After that, the person needs to consume sufficient calories to achieve or maintain a healthy weight and to reduce blood cholesterol levels. In Step 2, the proportion of the day's total calories that come from saturated fat is reduced to 7 percent, while the amount that comes from fat of any kind stays at 30 percent. The amount of dietary cholesterol is reduced to 200 mg per day, and the sodium limit stays at 2,400 mg. And again, the person must eat sufficient calories for healthy weight and lowered blood cholesterol levels. DT: What about drug treatments? MM: The HMG-COA reductase inhibitors, or "statins," are used to treat abnormal cholesterol levels. Each drug of this class has the suffix "statin" in its generic name, e.g., lovastatin, pravastatin, atorvastatin. Statins are the first-line drug therapy because of evidence of their beneficial effects. In people who have never had heart disease, they are preventive, while in people with previous heart disease, they prevent further damage and protect against future strokes and heart attacks. These are the best drugs to normalize blood lipids and thus prevent new or recurring heart disease. DT: Antiviral therapy for people with HIV and AIDS often includes protease inhibitors. In general, there are a lot of drugs that cannot be used in combination with PIs because both use the same enzyme system. Protease inhibitors use what is called the p450 enzyme system. When the PIs were first introduced, we soon learned that various classes of drugs -- including antihistamines, antibiotics, and antacids -- also use this enzyme system. This means that taking these drugs together could either decrease or increase the level of PI in the blood. This is always a consideration when any drug is prescribed together with the PIs. When doctors prescribe the PIs, they have to take a really hard look at all the drugs the patient is taking and make the necessary adjustments to ensure that he or she has the right amount of PI in the blood to keep the virus in check. If the drug levels fall below the acceptable level in the blood, the virus is free to replicate. Thus a lot of drugs interact badly with PIs because of this common enzyme system. Are you aware of any of the standard drugs used to manage blood lipids that might fall into this category? What drugs, if any, would you prescribe? MM: Drug therapy for patients receiving PIs is problematic. Lovastatin, brand name Mevacor, and simvastatin, brand name Zocor, are extensively metabolized and are likely to be toxic when combined with the PIs. This problem may be less severe with pravastatin, which is sold as Provachol, making it the safest to use with PIs. There are minimal changes when pravastatin is taken together with ritonavir and saquinavir. With all the statin drugs, muscle toxicity is a major concern. Patients must be made aware of possible symptoms and monitored frequently by their healthcare providers. DT: Many of our patients on HAART are becoming diabetic, mostly with type 2 diabetes, which usually occurs in middle age and is associated with a family history of the disease and with obesity. In this type of diabetes, blood glucose levels are elevated, not because the pancreas is failing to make insulin -- the hormone that controls the amount of sugar in the blood -- but because the insulin receptors on the cells that normally let the body utilize the blood sugar are faulty and do not allow the glucose into the cell. This is usually treated with oral hypoglycemic agents rather than insulin. Some people think it might also be insulin resistance, although insulin resistance is usually not associated with diabetes. Insulin resistance refers to the amount of insulin the body has to put out to maintain normal blood sugar levels. It is not so obvious, because blood sugar levels are normal. It is usually not associated with diabetes or glucose intolerance. Insulin resistance implies that the pancreas has to supply an increased amount of insulin to maintain normal blood sugars. This one is not often diagnosed, and long-term consequences are not clear. What are the cardiovascular risk factors most common in type 2 diabetes? What is the treatment? MM: Whether high insulin levels are an independent risk factor for heart disease is a matter of controversy. But the risk for coronary heart disease is two to four times greater among diabetics than among the general population. Diabetics have a very high risk of developing blood vessel blockages, and these can lead to heart attacks and strokes. What is remarkable is that the coronary heart disease death rate in diabetics does not differ significantly depending upon whether there is a prior history of heart attack. Because of this, it is suggested that all patients with type 2 diabetes should receive risk interventions as aggressive as those given to patients with established coronary heart disease. I always advise lifestyle modifications -- exercise, quitting smoking. In addition I stress strict blood sugar control. Diabetics should also monitor fasting blood fats [blood fat levels after twelve hours without food]. Diabetics should be encouraged to follow the NCEP guidelines because of their increased risk for cardiovascular complications. We also recommend that diabetics pay attention to the type of carbohydrates they consume. For the best outcome, the diet should be low in concentrated sweets -- simple sugars like candies, sweetened desserts, regular sodas, etc. -- and refined carbohydrates such as white bread, rice, and pasta. The more complex whole grains such as brown rice and whole-grain bread and pasta are recommended, as they tend to release their carbohydrates more slowly and require less insulin to process. DT: Can you describe Syndrome X [see above]? What causes it in the general population? How would you treat the whole person with Syndrome X? MM: The metabolic Syndrome X, first described in 1988, includes insulin resistance, glucose intolerance, compensatory hyperinsulinemia, elevated triglycerides, glucose intolerance, decreased HDL, and hypertension. Several other characteristics have been added since then -- smaller denser LDL, high uric acid levels, and protein in the urine. The hypothesis is that insulin resistance plays a major role in the development of these changes and that this clustering of abnormalities poses an increased risk for CHD. No causal relationship, however, has yet been established between insulin resistance and CHD. Treatment should be that described above for diabetes, with careful attention to controlling blood sugars, blood fats, and blood pressure, with lifestyle and dietary changes.

An HIVer's Guide to Metabolic Complications More on Metabolic Complications

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This article was provided by Body Positive. It is a part of the publication Body Positive.