Patients with HIV infection and the clinicians caring for them have recently been expressing interest in the possible long-term effects of the potent anti-retrovirals currently in use. Reports of new-onset diabetes mellitus (increase in blood sugar), abnormal distribution of body fat, and hyperlipidemia (increase in cholesterol, decrease in HDL, increase in LDL and increase in triglycerides) occurring during treatment with protease inhibitors regimens have gained widespread attention. Little is known about why this happens, whether it's directly related to protease inhibitors, what to do about these new findings, and what the long-term health implications of these abnormalities are in the HIV-infected population.
What Is Hyperlipidemia-
Hyperlipidemia (increase in cholesterol and triglycerides) in individuals taking protease inhibitor therapy has been reported, sometimes to extreme levels, in excess of 1000 mg/dl. Hyperlipidemia was recognized as a complication of HIV disease prior to the era of protease inhibitors. Current reports indicate that elevated levels of triglycerides have occurred in individuals experiencing positive clinical and virologic response (decrease in viral load and increase in T-cells) to therapy.
What Is Cholesterol-
Cholesterol is a substance that is an essential part of cell membranes and a major part of brain and nerve cells. High concentrations are also found in the adrenal glands, where hormones are made. Cholesterol is an important part of bile acids and sex hormones. Triglycerides are used in the body mainly to provide energy for different metabolic processes.
Lipoproteins (LDL and HDL) are best known as the vehicle that help transport triglycerides and cholesterol throughout the blood stream. There are two types of lipoprotein; LDL which is low-density lipoprotein, (the bad cholesterol) and HDL which is high-density lipoprotein (the good cholesterol). LDL is released by the liver and is rich in triglycerides and cholesterol. LDL drops off triglycerides in fat and muscle cells. LDL transports triglycerides back to the liver and to the fat cells (adipose tissue). While all of this is going on, there is a scavenger called HDL which carries unwanted, excess cholesterol, partly from cell breakdown, back to the liver where the cholesterol might end up being excreted (in bile salts) or removed by receptors on the liver. This process helps rid the body of cholesterol and prevents lipid accumulation in the arterial wall. When the good cholesterol (HDL) is too low, then the bad cholesterol becomes too high and may lead to atherosclerosis (plaques in the arteries) which over the long term may lead to blockages that causes a heart attack or stroke.
What Can I Do to Lower My Cholesterol-
In general, the management of elevated triglycerides and cholesterol in HIV infected patients can follow established guidelines. First, it is important to start with a fasting (nothing to eat for 12 hours before having your blood drawn) measurement for your cholesterol and triglycerides so that an accurate baseline can be established. Dietary management includes decreasing your fat intake to less than 30% of your total caloric intake. Be aware of your intake of red meat, eggs, cheese, dairy products and alcohol. Ask your clinician to be referred for dietary evaluation, so that you can learn more about foods to avoid and how to decrease your fat intake.
Major factors that increase HDL are estrogen, exercise and loss of excess weight. HDL can be lowered by obesity, inactivity, cigarette smoking, progesterone-dominant oral contraceptives or hypertriglyceridemia. Fish oil has shown some promise, and can be found in health food stores. Lipid lowering agents can be used to control hyperlipidemia, if diet and exercise fail. More research needs to be done to address the long-term affects of abnormal lipid panels.
What Can I Do If Diet and Exercise Do Not Work-
In some cases, diet and exercise does not work and medications will need to be added to bring your cholesterol or triglycerides down to normal. Little information is known about the drug interactions between cholesterol/triglyceride lowering agents and protease inhibitors, but current studies looking at these drug interactions are in progress. Different drugs are used to lower cholesterol and triglycerides.
One class of drugs used to treat elevated cholesterol is known as bile acid sequestrants (e.g. cholestyramine and colestipol) are generally safe and are efficacious for lowering cholesterol, but may increase triglyceride levels. The most common side effects include constipation, bloating, gas and nausea. These drugs may interfere with absorption of your antivirals and therefore are not considered in the first line of medications because they can not be taken at the same time as antiretroviral medications.
Nicotinic acid (niacin) lowers total cholesterol and triglyceride levels and raises HDL cholesterol levels. Side effects include; flushing, itching of the skin, nausea and liver toxicity. In addition, increases in blood sugar can occur with nicotinic acid. The side effects and potential liver toxicity may limit the use of nicotinic acid in people on protease inhibitors.
Statins or the HMG-CoA reductase inhibitors (e.g. lovastatin, pravastatin, simvastatin, atorvastatin) are effective in lowering LDL cholesterol, but there is limited information on patients taking these drugs with protease inhibitors.
Clinical trials have begun to look at drug interactions with protease inhibitors and cholesterol lowering agents. Side effects from HMG-CoA can include increases in liver enzymes. These drugs are generally taken once a day, usually with the evening meal since, most cholesterol synthesis takes place in the evening. These medications should be started at the lowest dose and titrated up gradually, monitoring liver enzymes closely.
Fibric acids (gemfibrozil) work best on triglycerides. It is generally used when triglycerides are extremely high (above 100 mg/d1). There are some preliminary reports using gemfibrozil in people with HIV infection on protease inhibitors and it appears to be relatively safe. However, fibric acids do not appear to lower cholesterol and raise HDL as well as HMG-CoA reductase inhibitors. Replacing estrogen in women who are post-menopausal can help to lower LDL and raise HDL; estrogen has been found to be a naturally occurring (the body makes it) cardiovascular protecting agent.
Abnormal Fat Distribution
Several terms have been used to describe various alterations in body fat distribution, including "protease paunch", "Crix belly", "buffalo hump", and peripheral lipodystrophy. Some of these abnormal findings were observed before the use of protease inhibitors, raising the possibility that a factor other than protease inhibitors themselves may be involved.
Abnormal collection of fat in the back of the neck and upper back (called a buffalo hump) has been associated with protease treatment, but also reported in some patients not on a protease inhibitor. In multiple instances, the fatty nature of the accumulations has been confirmed by imaging procedures or surgical pathology. Surgical excision or liposuction has been tried but recurrences have been reported.
Increases in triglycerides have also been reported with this visceral fat deposition. In some patients with abnormal fat redistribution, abnormalities in insulin response have been noted (so-called insulin resistance). It is not yet known whether changes in insulin levels are somehow involved in the changes in fat redistribution. Loss of fat in the extremities has also been reported. Studies collecting objective measures of body composition, using dual-energy x-ray absorp-tiometry (DEXA scanning) and MRIs (magnetic resonance imaging) along with measurements of the chest, abdomen, hips, thigh, hip-to-waist ratio, and BIA are currently being collected for analyzing.
High Blood Sugar
Hyperglycemia is an elevation in blood sugar. The first report of protease inhibitor associated hyperglycemia (high blood sugar, also known as diabetes) was in June 1997. Reports of hyperglycemia have occurred with all of the protease inhibitors, but may occur in some more often than others. However, this side effect continues to remain an uncommon complication of protease inhibitors occurring in approximately 4% of all those patients taking these drugs. The mechanism of this hyperglycemia is not clearly understood, but there seems to be a positive response to diet and medications.
Patients who have developed new onset diabetes have been responding well to antiretroviral treatment when hyperglycemia develops. There have been a few reports of patients who have developed hyperglycemia during treatment with protease, who stopped their protease inhibitors, but continued their nucleosides and had a spontaneous resolution of their high blood sugar. But this is not true for all patients who have stopped using their protease inhibitors.
Diet modification (changing the way you eat) is the first line of treatment for mild increases in blood sugar. In those patients whose blood sugar cannot be controlled with diet and exercise, a hypoglycemic medication should be added. In extreme situations, insulin may need to be added to control otherwise uncontrollable blood sugars. The potential benefits of sustained suppression of viral replication obtained with a protease inhibitor based anti-retroviral regimen generally outweighs the potential for complications in patients where their hyperglycemia is controlled.
Definitive data linking protease inhibitor therapy to most of these metabolic abnormalities are accumulating, but there are still many unanswered questions. These abnormalities may be caused by:
- or protease inhibitor therapy may amplify pre-existing metabolic disorders
- or these metabolic disorders may be a direct effect of protease inhibitor medications.
In people who develop these changes while responding to a protease inhibitor regimen, the recommendation is not to change your therapy, until more information can be collected. The potential risks of developing therapy induced changes in glucose metabolism, blood lipids, and body composition needs to be addressed in prospective clinical trials. More women should also be studied to identify any gender-specific differences. Protease inhibitor containing regimens should be compared to non-protease inhibitor therapies to evaluate a potential difference. Long-term cardiovascular risks must be evaluated in the context of prolonged survival. Finally, we need to understand how these newly reported complications affects our patients and their HIV disease in order to develop rational treatment and prophylaxis for metabolic abnormalities. Your fasting lipids should be monitored frequently and a good low fat diet and regular exercise should be encouraged.
||Desirable blood cholesterol|
||Borderline high blood cholesterol|
||High Density Lipoprotein (HDL, good cholesterol)|