(RITA!)HIV Treatment Alerts - February 2001
Fehmida Visnegarwala, MD - Baylor College of Medicine

There is growing emphasis on long-term toxicities with the use of highly active antiretroviral therapy (HAART). A total of 8 conference sessions were devoted to these issues. The following metabolic complications are now associated with the use of HAART: dyslipidemia (abnormal blood levels of fats like cholesterol and triglycerides), lipodystrophy (fat wasting and accumulation in different parts of the body), insulin resistance, new-onset diabetes, retinoid (vitamin A) changes, lactic acidosis, and sexual dysfunction. To this growing list, disorders of bone metabolism (osteopenia, osteoporosis and osteonecrosis) have now been added.

What are these disorders of bone metabolism?

Every normal person reaches a maximum bone mass by age 30. A constant remodeling of bone occurs that is a normal process of aging. When bone resorption (breaking down) exceeds bone formation, there is a net loss of bone, which is called osteopenia when mild, and osteoporosis when severe. Osteoporosis causes a dramatically increased risk of bone fractures. The bone mineral density is measured with DEXA or CT scans. Among HIV-infected individuals, osteopenia has been reported in as many as 20% to 50% of patients, a rate much higher than in the general population. The cause of these effects may be the drugs or the virus itself. For example, one study at the conference showed evidence for osteopenia in the absence of HAART. There is some laboratory evidence that protease inhibitors (PIs) may have a negative effect on bone metabolism. At this time there is no definite link between the use of HAART and the development of osteopenia or osteoporosis, but prospective studies are being done. Ways to decrease the risk of osteoporosis are advised. These include stopping smoking, exercising regularly, treating hypogonadism, and increasing calcium intake.

Avascular necrosis or osteonecrosis may be on the rise among the HIV-infected population. Osteonecrosis is bone death due to decreased blood supply. This syndrome is unrelated to osteopenia. In contrast to osteopenia, there has been a clear increased incidence of osteonecrosis in the HAART era, more than 20 times the risk as compared to the general population. The condition most commonly occurs in weight-bearing joints like the hip and involves severe pain. One report links the condition to the use of anabolic steroids. A diagnosis of osteonecrosis is confirmed by CT scan or MRI. The treatment is pain management and possibly surgical replacement of the hip.

Lactic Acidosis

Lactic acid is a normal product of the body's processing of sugar for energy. Asymptomatic lactic acidosis (excess lactic acid production) is found in up to one third of patients receiving anti-HIV drugs called nucleoside reverse transcriptase inhibitors (NRTIs). There is no recommendation for regular monitoring of lactic acid levels. These levels should be measured for unexplained fatigue, abdominal pain, shortness of breath, hepatitis, peripheral neuropathy, osteopenia, and pregnancy. In one presentation at the conference, an Australian group used lactic acid levels to distinguish between drug-associated, recent onset peripheral neuropathy and neuropathy caused by HIV itself.

It is important to remember that lactic acidosis (levels greater than 10) can be rapidly fatal if unrecognized. If levels are greater than 10, all NRTIs should be stopped and the patient should be hospitalized (with any underlying infection treated). Supportive care should be given along with intravenous L-Carnitine (1000 mg three times daily) and Vitamin B6, which also may help. The reason for lactic acid buildup may be drug toxicity to mitochondria (energy producing centers in cells) but this is not definite yet. Another possibility is a fatty liver, which may decrease the clearance of lactic acid from the body.

Management of patients with lipodystrophy: what's new?

Overall, there was surprisingly little information on the management of lipodystrophy. In patients taking PIs, a small study from Australia showed minimal benefit with a drug called gemfibrozil to reduce triglyceride levels and no changes in levels of other lipids or insulin. Some studies where PIs were switched for other drugs showed improvement in blood lipid levels and insulin resistance, but little change in the symptoms of lipodystrophy. Improvements in fat wasting using a new class of drugs called insulin sensitizers require further studies. Another study found that lipoatrophy (loss of fat in the face, arms, or legs) is more common among HIV-infected men than among uninfected men. On the other hand, fat accumulation in the belly was roughly the same between the 2 groups. In other words, at least some of the changes in body shape are the result of age or inactivity, and not necessarily HIV or its treatment.

Do PIs increase the cardiovascular risks?

This has been a million dollar question and 2 large studies presented at the conference tried to answer it. The first report was from a French group who looked at the hospital records of 19,795 men exposed to PIs. The cohort was divided in 3 groups based on the number of months of PI exposure. The rates of myocardial infarctions (heart attacks) were compared to HIV negative individuals. They found a direct relationship between months of PI exposure and the rate of myocardial infarction. As compared to the general population, those with PI exposures of less than 18 months, 18 to 29 months, and greater than 30 months had 1, 2, and 3 times higher risk of myocardial infarction. The second report was from Kaiser Permanente, in California, comparing 4541 HIV-infected persons to HIV-negative persons. Even though the rate of coronary events was 2 times higher in the HIV-infected individuals compared to the HIV-negative group, there was no increased risk noted with the use of PIs. Obviously, more studies are needed to find a definite answer.

In view of the long-term toxicities of HAART combined with the prospect of life-long treatment, we now have more questions than answers. The HIV epidemic is moving into minority populations who are already at a higher cardiovascular risk. While we await more data on the long-term management of patients on HAART, every patient who begins taking PIs should be given intensive education for how to reduce cardiovascular risks. It is possible that beginning PIs increases a patient's cardiovascular risk category, and it is the patient's right to know that.

DEFINITIONS

Asymptomatic: showing no symptoms or signs of disease.

Cardiovascular: relating to heart and blood vessels.

Coronary: relating to the heart.

Hypogonadism: decreased production of sex hormones, particularly in males.

Lactic acidosis: accumulation of lactic acid in the body.

Peripheral neuropathy: degeneration of peripheral nerves (such as those in the arms and legs) resulting in muscle weakness, pain, and numbness.

Prospective: studying or following patients from the present time into the future.

Toxicities: poisonous or damaging effects on the body.

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Copyright © 2001 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org

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