American Foundation for AIDS Research, March 2001
Emily Bass

At the 8th Conference on Retroviruses and Opportunistic Infections, there were few breakthroughs for scientists bent on unscrambling the causes of lipodystrophy, bone disease and other metabolic changes. Although the underlying causes are poorly understood, it is clear that these abnormalities are some of the most important consequences of long-term use of highly active antiretroviral therapy (HAART).

In a discussion entitled "Issues in Metabolic Complications: Controversy or Consensus," Australian metabolics expert Andrew Carr rattled off unanswered questions (session 64, unnumbered state-of-the-art summary): "I think we don't truly know the breadth of mitochondrial disease spectrum, we don't know when lactate should be measured. ... Is the association between lactate and toxicity causal? Will lactic acidemia [high lactic acid levels] result in bone fractures and chronic liver disease? We don't really know what causes osteonecrosis [bone tissue death] and, with a few exceptions, I don't think we've been looking hard enough."

(Lactic acid is the end-product of oxygen-independent cellular energy production. Elevated levels are a sign of dysfunction in the mitochondria, the small, semi-autonomous organelles in cells that oxidize sugar to yield carbon dioxide, water and energy. Nucleoside analogs can impair mitochondria reproduction and function)

Carr's talk reflects the fact that metabolic disorders remain, in many ways, an unbreakable code. Scientists have picked up potentially important signals, such as changes in levels of lactate and bone mineral density, but they are still unable to decipher their meanings and causes.

One of the confounding problems is that some of observed changes in body fat and blood chemistry are part of aging, and not due to HIV. Drug choices, HIV, age and gender are all part of the body's messages, which may differ from one person to the next. The challenge is to pick up the most useful signals for predicting and managing these toxicities, and tune out the background noise.

University of Pittsburgh researcher Lawrence Kingsley presented a review (slide presentation 538) of data from the decade-old Multicenter AIDS Cohort Study (MACS). It provided a window onto one of the most basic problems: defining lipodystrophy, the syndrome of changes that include central body fat accumulation (in abdomen or breasts), subcutaneous fat loss and changes in blood chemistry. 868 HIV-infected and uninfected MACS participants were surveyed and tested for an array of symptoms, including body fat redistribution and changes in lipid levels and blood chemistry. This cross-sectional analysis was designed to provide a snapshot of trends in the cohort, and to pinpoint specific symptoms that could be used to narrow and improve the definitions of lipodystrophy.

The study results underscored the fuzziness of the current definition. Depending on which question was asked, rates of lipodystrophy in HIV-positive and -negative men varied widely. HIV-positive and -negative men reported similar rates of fat accumulation in the abdomen (35% versus 26%, respectively). The most precise information - i.e. the clearest distinction between HIV-positive and -negative participants - came from a question that asked about a combination of fat depletion in the peripheral parts of the body plus central fat accumulation. The prevalence of combined moderate to severe changes was 20% among HIV-positive men and less than 1% in HIV-negative participants. Combined moderate to severe changes also were infrequent in HIV-positive members receiving no treatment (2%) and in those receiving just one or two antiretroviral drugs (8%).

The MACS data also identified an interesting trend: the prevalence of lipodystrophy among men on protease inhibitors (PIs) rose dramatically during the first two years of PI-use, but plateaued thereafter. It is unclear whether this was a result of how the data were collected or whether there is actually an increased risk of metabolic complications during the first two years. It has been a common impression that if someone gets through the first two years without lipodystrophy they may be "home-free," and such relief has made it easier for patients to deal with growing adherence issues.

Rising Lactic Acid Levels

In the past two years, researchers have pinpointed lactic acid in the blood as a sign and symptom of drug toxicities. Elevations in lactate appear connected to specific body fat changes, like peripheral fat loss (lipoatrophy), as well as to peripheral neuropathy and severe liver toxicities. However, elevations in lactate can also be harmless - and researchers are still struggling to decide how to use and interpret information about this substance.

Studies have shown that 8% to 21% of patients on nucleoside analogs, such as ddI, d4T and AZT, experience elevated levels of lactate in the blood. In his symposium talk, Andrew Carr took pains to distinguish lactic acidemia, a term which refers to any elevation, from lactic acidosis, which has a more specific diagnosis. Hyperlactemia is yet another term used to describe any elevations. Lactic acidemia is more common among people with HIV. Symptoms of acidemia can include everything from fatigue and gastrointestinal symptoms to muscle aches, nausea and changes in breathing and heart rhythms, as well as the more severe consequences of liver toxicity and peripheral neuropathy.

Elevations may not causes symptoms at all, said Carr, who does not believe that routine screening is a helpful tool for managing side effects. He did recommend screening in a number of cases, including for individuals with symptoms of acidemia, liver dysfunction, lipoatrophy, bone fracture, osteopenia (moderate bone mineral loss), pregnancy, patients restarting nucleoside analogs after symptomatic acidemia, and perinatal exposure to nucleoside analogs followed by post-natal neurological illness. He offered a chart (see below) mapping out treatment decisions for different lactate levels.

In poster 625, Dutch researcher Kees Brinkman, one of the original researchers to look at lactic acidosis offered his assessment of the use of lactate tests: "obscure." Although there is a clear link between elevated lactate levels and use of nucleoside analogs, Brinkman and his colleagues found that levels fluctuated from one test to the next, making it difficult to use these results for individual treatment decisions.

To complicate matters, traditional liver function tests do not help predict lactate-related hepatitis. "One very important take-home message is that liver enzymes are not that abnormal [in patients who develop acidemia-related hepatitis]," said Carr, who has seen fatal cases in individuals with grade 3 (moderately elevated) blood levels of these enzymes. "Will chronic nucleoside-induced acidemia lead to increased or accelerated chronic liver disease?" he asked. "I don't think anyone's starting to look at that."

Bruce Brew (St. Vincent's Hospital, Australia) gave a somewhat contradictory presentation (slide presentation 9) that suggested lactate levels may be a useful tool for distinguishing between neuropathy caused by specific drugs, particularly nucleoside-analogs, and neuropathy caused by HIV itself. In a small study, he looked at the link between lactate levels, neuropathy and nucleoside analog use. He found that 13 out of 15 patients who had neuropathy and were taking d4T also had elevated lactate levels. When they stopped taking d4T, the neuropathy went away and the lactate levels returned to normal. Out of six patients who appeared to have HIV-related neuropathy, only one had elevated lactate. If Brew's findings are borne out, then elevated lactate levels could provide clues about whether stopping nucleoside analogs will help ease neuropathy symptoms. However, further studies are needed to determine whether or not the link between lactate and peripheral neuropathy is tight: although neuropathy resolved itself when the drug was stopped, the lactate levels may not have been the source of the problem.

Researchers are also scrambling to link drugs with specific toxicities. Several studies, including two presented at the Retrovirus Conference (posters 624 and (625) fingered d4T as a prime offender in elevating lactate levels. These, in turn, may be linked with specific aspects of lipodystrophy, or lipoatrophy, in particular.

French researcher Veronique Joly presented a prospective, randomized trial (slide presentation 539) tracked the emergence of metabolic dysfunction in a cohort already enrolled in a study of d4T/3TC/indinavir versus AZT/3TC/indinavir. All of the participants in the trial had a treatment history that included AZT and either ddI, ddC or both. All were protease-inhibitor naïve and had never taken d4T or 3TC. A lipodystrophy assessment conducted after 30 months on therapy found that all patients in the d4T arm had significantly more fat loss in the face, arms and legs than those in the 3TC arm. Ninety-six out of the 150 trial volunteers were included, and the study was unblinded: doctors knew which patients were taking d4T when the body fat measurements were made. These factors could have biased the results.

The data nonetheless are an important warning, both about the additional toxicities of d4T and about possible gender-specific side effect of the drug. In Joly's paper, women were at significantly higher risk for lipoatrophy than men. There have also been other reports suggesting that there may be a gender-specific effect with this drug. Last winter, the FDA issued an alert about the deaths of three pregnant women who had been taking d4T as part of a combination regimen. Further studies are needed to determine the severity and cause of the side effects in women.

Bone Disease

Over the past two years, bone disease has come onto the horizon as a long-term effect of HIV, HAART or both. The primary conditions are osteoporosis, the loss of bone mass and micro-scale changes in the skeleton that can increase risk of fractures; and osteopenia, which refers to bone-thinning that can precede severe osteoporosis. Both of these conditions are characterized by loss of bone mineral density (BMD). BMD is measured by dual-energy x-ray absorptiometry, or DEXA tests.

The role of HAART in general and certain particular drugs in BMD remains unconfirmed. Michael Wang (Washington University School of Medicine) looked at whether different protease inhibitors have different effects on bone mineral density (slide presentation 541). In this experiment, indinavir (Crixivan) inhibited bone nodule formation by targeting bone-building cells called osteoblasts. Ritonavir (Norvir) had the opposite effect. It appeared to stop the activity of osteoclasts, the group of cells that resorbs bone tissue and acts to balance osteoblast activity. Both drugs were evaluated in cell tissue cultures and in mice.

These results, though preliminary, are "clearly very reminiscent of different protease inhibitor effects on lipid and glucose metabolism," remarked Andrew Carr, who added, "We need to start thinking about class effects. We also need to distinguish between different drugs in a class."

In an interview, New York metabolics expert Donald Kotler (St. Lukes-Roosevelt Hospital) cautioned against fingering PIs as the sole cause. "I don't rule out protease inhibitor effects. But I think there's multiple effects," he said, adding that the important question is, "Where is the calcium going?" Kotler pointed out that bone is more subject to breakdown in acidic environments, and that people with chronically-elevated lactate levels might be more prone to osteopenia. Backing this up, a study by Andrew Carr's group (poster 631) found an association between lactic acidemia and spinal osteopenia in men. Kotler suggested that one intervention might be to reduce the acidity of the bone environment by administering bicarbonate. A possible alternative is to use biphosphanate (the anti-osteoporosis drug alendronate) to reduce bone resorption by osteoclasts.

The picture may be most severe in vertically infected children who experience viral and treatment-effects on their bones as they are in formation. An Italian study (latebreaker slide presentation LB9) looked at HAART, HIV and bone mineral content in children. Out of 40 vertically infected children, 35 were treated and five were untreated. The researchers found that HAART-treated children had significantly lower BMD than untreated children, and that both groups had lower BMD than their HIV-negative counterparts. BMD was even lower in the six HAART-treated children with lipodystrophy, although the difference was not significant. Presenter Alessandra Vigano, Chair of Pediatrics at the University of Milan, attributed the findings to an increased rate of bone turnover, based on measures of markers of bone formation found in the blood. More studies are needed, Vigano said, to determine whether HAART-treated and HIV-infected children face "a life-long risk of osteoporosis."

Another new study (latebreaker slide presentation LB 8), presented by Steven Arpadi from the St. Lukes-Roosevelt team, also found decreasing bone mineral content as children with HIV got older. It did not, however, find a link with HAART.

Several abstracts did not show a direct HAART-bone disease link in adults. Cross-sectional studies by Donald Kotler (poster 627) and two Spanish groups (posters 626 and 629) connected osteopenia with HIV infection, but did not specifically with use of antiretrovirals. Other contributing factors may include aspects of the immune response to HIV infection, particularly cytokine release and CD4+ T-cell activation.

Changes in BMD pose problems for monitoring and treatment. At present, DEXA tests are not routinely recommended for HIV-positive individuals. Two posters (posters 627 and 638) looked at patients receiving human growth hormone and oxandrolone, a synthetic anabolic steroid. Neither intervention effected BMD.

Lipids and Heart Disease

Harvard researcher Steven Grinspoon provided an overview of current research on lipids, lipodystrophy and body fat changes (session 64, unnumbered state-of-the-art lecture). Like Andrew Carr, he urged clinicians to use correct definitions and diagnostic parameters. In particular, Grinspoon noted that the fasting glucose lab test is "most likely to be normal" in individuals with lipodystrophy. The 75-gram glucose challenge, which measures how well glucose is taken up into the muscle and fat, is far more likely to reveal underlying metabolic problems, Grinspoon said.

Grinspoon reviewed data from a Harvard study comparing various parameters in HIV-positive and -negative groups. Eight to nine percent of the HIV-positive group had glucose levels in the range of diabetes versus .5% in the general population; for impaired glucose tolerance, the figures were 35% and 5%, respectively. The HIV-positive group also had significantly more elevated cholesterol.

Here, one burning question is whether these changes in blood chemistry will translate into increased risk of heart disease for HAART-treated individuals. "Traditional" markers, like lipid levels, are often elevated in individuals on HAART and "portend potentially increased cardiovascular risk," warned Grinspoon. He also cited studies showing increased rates of premature carotid lesions and reduced vascular distensibility (a measure of how much blood vessels expand) in HIV-positive individuals. These are also indications of risk for coronary artery disease and might supplement traditional markers. At present, Grinspoon said, there's still no evidence linking these factors with coronary disease in HIV patients. The story is "still emerging."

It may be too early yet to see the full effect on increased coronary artery disease on the development of myocardial infarction (heart attack). Still, major new chapters in the story came from a study of more than 4,500 HIV positive members of Kaiser Permanente health maintenance organization in Northern California (poster 655) and by a French hospital database study of nearly 20,000 HIV-positive men (poster 657). In the California study, PI use did not increase risk of heart disease, but people with HIV did have a higher rate of coronary artery disease compared with the general population. Study investigators concluded, "HIV-infected patients with classic risk factors [for heart disease] need better risk management." The French study, in contrast, found an increased risk of myocardial infarction with duration of PI exposure. The numbers of in the French study were relatively small: 54 case out of nearly 20,000 men.

As with bone disease, there are no proven treatments for HAART- and HIV-associated changes in blood chemistry. Genes, diet, exercise, smoking and aging all contribute to heart disease risk among the general public; and these factors will certainly play a determining role in HIV-positive individuals, too. Australian researcher John Miller presented a 12-week study (poster 540) of the effects of a low fat diet, with or without gemfibrozil, a drug that lowers fats called triglycerides in the blood. Changing diet did not affect triglycerides, cholesterol, glucose, or insulin levels. Gemfibrozil had a slight, but not significant effect. The drug is not a solution to this complex problem, though may help a little - "It's not gangbuster," summed up Dr. Grinspoon.

There is general agreement that lowering lipids through a combination of diet, exercise and/or drugs is a necessary intervention. An upcoming study will look at the use of other agents, including the diabetes drugs metformin and rozyglitizone, on blood chemistry.

Ultimately, the clearest message at the conference was the SOS sounded again and again by presenters and attendees: As difficult as they are to decode, metabolic problems must not be ignored. As Carr said at the end of his symposium speech, "We have little idea how to treat toxicities but we should still look. If we don't - if we deny that these problems are there - patients won't take their drugs. If we understand why these toxicities are there, we will get better drugs."

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