Metabolic Complications: A Look at the IAS Guidelines
It seems like the longer HIV/AIDS is around, the more complicated it gets. Truthfully, science is still learning exactly how HIV (not to mention the immune system!) works. Then there are the treatments for HIV. They work for a lot of people, but they have to be used in just the right combinations, in just the right way ... and they bring with them a whole other set of complications that have to be sorted out from the effects of HIV. On top of that, many people with HIV are living longer now -- they're getting older, and getting older has its own effects -- higher rates of heart disease, diabetes and elevated cholesterol, for example -- that have to be separated from those of HIV and those of the medications.
There's also all the lifestyle and family history stuff. Do you smoke or drink? Do you exercise? What are you eating? Do your parents have heart disease? All these kinds of things can also play a role in HIV ... and the treatments ... and aging. It's complicated.
Researchers are trying to sort through all of this, of course. At the top of their list is figuring out what's going on with what they usually call metabolic abnormalities or metabolic complications. This refers to the body shape changes that happen to many people -- arms and legs get skinny, middle section gets paunchy or thick, maybe a fatty lump between the shoulders or larger breasts. It also includes changes in the way the body handles sugars and fats, as well as bone disorders and disturbances that occur inside the cells and cause damage to the body.
At February's 10th Conference on Retroviruses and Opportunistic Infections (CROI), researchers from all over the world presented results from studies that looked at the many aspects of metabolic complications, from what's happening inside the cells of the body, to how common any one complication is, to possible treatments and interventions. In all, 51 posters and ten oral presentations addressed metabolic complications, including seven posters on the cardiovascular risks of antiretroviral therapy alone and 12 on the pathogenesis and mechanism of lipodystrophy.
Studies that look at metabolic complications are critical because all of these changes have been happening to people living with HIV, especially those who've been taking antiretrovirals since 1997 or so. They started to show up more often after people began using the combinations of medications we now refer to as HAART (Highly Active AntiRetroviral Therapy).
Since then, people have been asking the same questions about each of these complications: Am I likely to get this? Why is it happening? How is it happening? What can I do to stop it? Can I prevent it? So far, the answers to these questions have been, for the most part: "We're not exactly sure." In fact, some of the complications haven't even had a precise definition or standard of measurement. For example, facial lipoatrophy can be defined as a loss of fat in the face but there is no standard way to measure it. This makes it difficult for clinicians, researchers and people with HIV to be sure that they're all talking about the same thing when they use the term 'facial lipoatrophy' -- let alone figure out how to treat it.
People with HIV and their physicians have been trying things like switching HIV medications to stop or maybe even reverse the body shape changes or adding medications designed to lower the levels of fats in the blood (cholesterol and triglycerides). But we've largely been figuring it out as we go along. Now, for the first time, we have some guidance.
A group of twelve researchers and clinicians began meeting in May 2000 to create a set of recommendations for physicians about how to best manage metabolic complications for people living with HIV, especially those who are taking potent antiretrovirals. The group was made up of specialists in fields like endocrine and metabolic disorders, antiretroviral therapy, and patient care. They were chosen by the International AIDS Society-USA, a not-for-profit physician education organization.
The panel reviewed scientific studies and data presented at research conferences over the last five years. For each metabolic complication that has been identified so far, one or more members of the group reviewed the evidence, presented it to the larger group, and then wrote a draft summary and list of recommendations. The whole panel eventually decided on the final recommendations for the management of each metabolic complication. This document, "Management of Metabolic Complications Associated With Antiretroviral Therapy for HIV-1 Infection: Recommendations of an International AIDS Society-USA Panel," was published in the Journal of AIDS, Volume 31, Number 3, November 1, 2002.
The guidelines have a section on the following metabolic complications: insulin resistance and abnormal glucose homeostasis; lipid and lipoprotein metabolism abnormalities; body fat distribution abnormalities; lactic acidemia; and bone disease. Each section has three parts: background; recommendations for assessment and monitoring; and treatment.
More or less, the guidelines lay it out like this: here's what we've learned; here's what we can do; and here's what we need to find out. It's clear that some complications are better understood than others. The guidelines provide useful and much needed help, but also remind us of the work that remains to be done so that people with HIV may live long, healthy lives with the current antiretroviral medications. Here's a summary of the guidelines' contents.
Background: Diabetes, including the conditions that lead up to it -- insulin resistance and glucose intolerance -- was not particularly common in people with HIV before the advent of HAART. Now as many as 40% of people who use a protease inhibitor as part of their antiretroviral combination will develop insulin resistance and, as a result, have impaired glucose tolerance. This means that their bodies need more and more insulin, a hormone produced by the pancreas, to break down sugar, or glucose, in the blood. Eventually, if the pancreas can't produce enough insulin or the insulin can't break the sugar down properly, the level of glucose gets too high. This is called glucose intolerance. Other complications, including heart disease, may be influenced by glucose intolerance and insulin resistance.
It isn't known whether insulin resistance brought on by antiretroviral medications carries the same risk of heart disease and other complications as it does in people without HIV. However, there is concern that this risk may be higher for people taking protease inhibitors who have other risk factors for diabetes, including being overweight or having a family history of diabetes.
Recommendations: People starting an antiretroviral regimen that includes a protease inhibitor should have their glucose levels checked before starting the medication, three to six months after starting, and at least once a year thereafter. There is some evidence to suggest that it may be best to avoid the use of a protease inhibitor in people whose glucose is too high to begin with or who have relatives with diabetes.
Treatment: There isn't enough data from studies of people with HIV to know for certain what to do or which treatment is best for people with high blood sugar levels. Most of the recommendations in the guidelines are based on data from people without HIV infection and on the opinions of specialists. Losing weight if overweight, eating a balanced diet, and exercising are recommended for everyone, particularly for those with glucose intolerance.
If medications are needed to improve insulin sensitivity, the preference is for metformin (Glucophage) or others in a group of medications called thiazolidinediones, such as pioglitazone (Actos) or rosiglitazone (Avandia). However, these drugs require some caution. Metformin, for example, may cause a condition called lactic acidemia, and the thiazolidinediones can cause liver problems. Drugs are not recommended if there is evidence of insulin resistance but glucose levels are normal.
Background: Two kinds of fats, or lipids, in the blood -- cholesterol and triglycerides -- are the focus of the guidelines. These are the lipids that can eventually lead to heart disease if they get too high and stay high. Before HAART, people with HIV didn't usually live long enough to worry about heart disease. Then combination therapy with protease inhibitors came along and it eventually became clear that the very drugs that were making it possible for people to imagine a future were increasing their risk for that other killer, heart disease, by increasing their lipid levels.
All protease inhibitors are not created equal when it comes to the extent to which each one affects levels of cholesterol and triglycerides in the blood, but the bottom line is the same. They increase both LDL (low density lipoprotein) cholesterol and triglycerides -- the two most dangerous lipids for the arteries and, therefore, the heart.
While protease inhibitors seem to have the most profound effect on lipid levels, drugs from the other classes of antiretrovirals have also been implicated. There is also the suggestion that a person's genetic predisposition may influence the risk of developing lipid problems.
So far, it's been hard to assess the extent of risk caused by antiretroviral use for future heart disease. Retrospective studies, those that look back at people's medical histories, include too many unknown variables to provide a clear picture, while prospective studies, those that look forward with the intent of finding answers to a specific question, haven't gone on long enough yet to provide useful findings. The prospective study that may provide the most complete data so far is the D:A:D study, which was presented at CROI.
The D:A:D (Data on the Adverse Effects of Drugs) study looked at 23,468 people from around the world, comparing those on three-drug antiretroviral therapy (including a protease inhibitor and/or a non-nucleoside) to those who had not taken any antiretrovirals. The study ran from July 1999 to April 2001, with follow-up in August 2002. The researchers used a mathematical model to figure out the risk of myocardial infarction (heart attack) while on HAART for up to seven years. After adjusting for other risk factors, the researchers found that the risk and the incidence of myocardial infarction increased the longer a person was exposed to antiretrovirals. The risk did not become apparent until after a year on antiretroviral therapy.
The D:A:D study did not assess the relative risk of individual antiretrovirals. Notably, smoking and prior cardiovascular disease were associated more with myocardial infarction than was the use of antiretroviral therapy.
The authors of the D:A:D study noted that the risk of heart attack remains extremely low (126 incidents over the 21 months of observation, or less than 0.5% of all patients). They emphasized what is true for most aspects of HIV therapy -- any potential risk must be balanced with the possible benefits of suppressive antiretroviral therapy.
Recommendations: There isn't enough data from studies of people with HIV to know for certain how to monitor and treat lipid abnormalities. Also, it isn't known whether high lipid levels resulting from HIV itself or antiretroviral use carry the same risk of heart disease as in people who are HIV-negative. As with glucose levels, the guidelines suggest that people should have their lipid levels checked before beginning an antiretroviral regimen, three to six months after starting, and at least once a year after that. People who already have high lipids or risk factors for heart disease, or those with a family history should avoid protease inhibitors if possible.
When deciding whether and how to treat elevated lipids, the guidelines recommend that the decision include consideration of any other risk factors that a person might have. How old? Smoker? Diabetic? Family history of heart disease? High blood pressure? Menopausal? The decision should ultimately be made with all of these things in mind as well as how well the individual's HIV is under control.
Treatment: With no good clinical trials that establish the best treatment for elevated lipids due to antiretroviral use, the panel included in its review of evidence some data from studies of people not HIV-infected, as well as the opinion of experts.
When possible, the guidelines recommend a switch from a protease inhibitor to a non-nucleoside-based (particularly Viramune [nevirapine]) or triple nucleoside antiretroviral regimen. The guidelines are clear, however, that antiretrovirals that might increase lipids should not be withheld from someone who is not able to switch from a protease inhibitor to a non-nucleoside-based or a triple nucleoside regimen.
As an example of how quickly things change, it's likely that the suggestion to switch to a triple nucleoside regimen will be removed when the IAS guidelines are updated. In March, the AIDS Clinical Trials Group (ACTG) stopped the triple nucleoside arm of a study that was comparing three different combinations in people who had never taken antiretrovirals before. People who were taking just three nucleosides -- AZT, Epivir (3TC) and Ziagen (abacavir) in the form of Trizivir -- had viral loads that went above 200 sooner and more often than those who were taking Sustiva (efavirenz), a non-nucleoside, with either Trizivir or AZT and Epivir. The triple nucleoside regimen just didn't work anywhere near as well.
There are no good clinical trial results that suggest whether changes in diet can affect lipid levels in people with HIV. Therefore, the guidelines' recommendations are the same as those for all people trying to control their lipid levels -- a diet that is limited in fats, losing weight if overweight, increasing physical activity, and decreasing alcohol consumption. Interestingly, the guidelines do not reference smoking, even though it is frequently cited as a risk factor for heart disease.
If switching the antiretroviral regimen is not an option and lifestyle changes don't work, the guidelines suggest the use of medications to lower lipid levels. They lay out which particular drugs are best to use -- pravastatin (Pravachol) or atorvastatin (Lipitor) to lower cholesterol and gemfibrozil (Lopid) or fenofibrate (Tricor) to lower triglycerides -- the particular lipid levels at which they should be used, and potential drug interactions. The long-term effects of using lipid-lowering drugs for the treatment of lipids that are increased from antiretrovirals are not known.
Background: This category of metabolic complications includes things like an accumulation of fat in the trunk of the body, a loss of fat in the arms, legs, face, and/or butt, and the lump of fat that some people get on their upper backs, called buffalo hump. Sometimes people get painful nodules of fat under the skin that look like tumors, called lipomas.
These body shape changes as a group are sometimes referred to as lipodystrophy, which just means that the body isn't breaking down and processing fats properly. It's been difficult to know just how many people with HIV experience changes in the way fat is distributed around their bodies -- there hasn't been a good definition, which makes it hard to diagnose with any consistency. Estimates of body fat redistribution are as high as 50% in people who are on antiretrovirals.
Several factors seem to be involved in this condition, including whether people are on potent antiretroviral therapy, how long they've been on it, how the medications have worked against the virus, and which specific medications they've been taking. There is a link between the nucleoside analogs and the loss of fat, for example, and a suggestion that protease inhibitors are linked more closely to fat accumulation. The non-nucleosides don't appear to be involved in the development of these particular conditions.
There are likely other factors, too. A person's age, sex, race and other individual factors may be part of what determines whether body shape changes occur. Exactly what is happening in the body to lead to these conditions and the way it happens is not known.
Recommendations: The ideal way to find out if there are changes in the distribution of body fat is to take an image of the body with a CT (computed tomography) scan or an MRI (magnetic resonance imaging). The problem is, these tests are very expensive and aren't available to a lot of people. A cheaper and less complicated way to assess changes is to do various body measurements. However, it is very difficult to ensure that any two people measuring the same patient would get the same results or even that the same person would measure a patient exactly the same way on different occasions. It is also hard to detect subtle changes with measurements like these.
It is no surprise, then, that the guidelines say that no specific technique for routinely assessing or monitoring body shape changes can be recommended at this time. No one test is specific enough, sensitive enough and predictable enough.
Treatment: In the absence of other metabolic complications, like elevated lipids, there is no agreement about whether to even try to treat body fat changes. Although many ways to address fat distribution abnormalities are being studied, none have been proven to work or approved for these conditions. Given that so many things seem to be happening at the same time, and there are potentially many different factors at play, the guidelines suggest it is unlikely that a single drug or intervention will address all the aspects of fat redistribution.
There have been studies looking at whether switching antiretroviral drugs might reverse some of the fat redistribution problems. So far, it looks like taking away the protease inhibitor -- thought to be a factor in fat accumulation -- does not help. However, replacing Zerit (d4T) with Retrovir (AZT) or Ziagen (abacavir) may increase fat in the extremities in people who have lost fat there, although the changes won't necessarily look significant to the eye.
A study presented at CROI switched 61 people who were experiencing fat redistribution while taking combinations that included nucleoside analogs to a combination with no nucleoside analogs -- the non-nucleoside Sustiva (efavirenz) and the protease inhibitor Crixivan (indinavir), boosted by Norvir (ritonavir). After almost one year on the new combination, the study participants experienced significant improvement in lipoatrophy but increased central fat accumulation.
The guidelines report diet and exercise as possible therapies and suggest that exercise, especially, might be useful for combating fat accumulation in the trunk. Resistance exercise, like weight lifting, has been found to help decrease fat and increase muscle mass. No special diets have been found to be helpful, but any diet that results in fast weight loss is not desirable because it can speed up the loss of muscle tissue. The guidelines suggest a healthy diet.
Some hormone interventions have been studied a little, but the guidelines do not recommend them at this time. Growth hormone (Serostim) may reduce central fat accumulation, for example, but the best doses haven't been established and there are potential negative side effects, including glucose intolerance, insulin resistance, and fluid accumulation in the extremities.
Based on what's known, testosterone replacement may benefit some HIV-positive men with low levels of the hormone and increased fat in the trunk. The guidelines don't recommend this as a therapy, however, because there aren't yet any results from studies looking at its use in men with HIV and fat distribution abnormalities.
Some drugs, like rosiglitazone (Avandia) and pioglitazone (Actos), have been studied but have not shown consistent evidence of improvement of fat redistribution. Triglyceride and cholesterol levels increased in one study of rosiglitazone. More studies are ongoing, but the guidelines do not recommend the use of these drugs based on currently available data.
Although not discussed in the IAS guidelines, many researchers are paying considerable attention to surgical and cosmetic interventions for changes in body fat distribution. The results of several such studies were presented at CROI. Two studies from France looked at the use of polylactic acid (New-Fill) for severe fat loss in the face.
The first study followed 50 patients for two years after their initial polylactic acid injections. They received injections every two weeks for six weeks, for a total of four sets of injections. The benefits of New-Fill included clear, observable aesthetic improvement and better quality of life.
In the other study, 40 patients received New-Fill injections twice, 15 days apart, and were evaluated after each injection and periodically up to six months later. In this case, patients reported no significant improvement in quality of life, although there was clear visual improvement measured photographically. Neither study reported any serious side effects.
Background: Lactic acidemia, sometimes called lactic acidosis, means an elevated level of lactic acid in the blood. The symptoms include fatigue, weight loss, nausea, abdominal pain, difficulty breathing and heart rhythm disturbances. There may also be abnormalities in the liver, although symptoms of liver abnormalities are much harder to identify. Lactic acidemia can come on suddenly or slowly, sometimes without any symptoms at all.
It is linked to the use of nucleoside analogs, especially with treatment lasting longer than six months. While all aspects of lactic acidemia are not understood, it is thought to be the result of damage that occurs inside the cells, involving the mitochondria, the cells' energy source.
There are no good data regarding the incidence of lactic acidemia by gender, race, or age, although pregnant women may be at higher risk.
Recommendations: There is no way to predict who will get lactic acidemia, or when. Mild acidemia does not seem to predict more severe acidemia. The guidelines do not recommend routine screening in the absence of symptoms. If symptoms do occur, lactate levels should be measured and, if elevated, confirmed by a second test.
Treatment: There are no substantial clinical trial results that evaluate interventions for lactic acidemia in people with HIV. Other than stopping any nucleosides, no proven interventions exist for lactic acidemia. Vitamins B-1 (thiamine), B-2 (riboflavin), C, E and K, coenzyme Q10 and L-carnitine have been used with some success to treat lactic acidemia in genetic mitochondrial diseases, but there are no data supporting their role in treating this condition when it's caused by nucleoside analogs.
Background: The death of bone tissue, what's called osteonecrosis, has been associated with HIV since at least the late 1980s. However, it appears to have become more frequent since the widespread use of HAART. Generally, the bone dies because there isn't sufficient blood circulation. It most often affects bones in the hip area, but it may involve other areas, like the shoulder and wrist. Osteonecrosis has been linked to elevated lipids and the use of steroids, but not the use of any specific antiretroviral medications.
Osteoporosis, a decrease in bone mineral density that can cause bone fractures, was rarely seen in HIV before the use of antiretrovirals. As with osteonecrosis, the incidence of osteoporosis has also increased with the widespread use of HAART. It may be associated with the use of protease inhibitors, but the link to specific antiretrovirals isn't well established. Exactly how and why it happens are also not understood. Thankfully, bone fractures in people with HIV are rare.
Recommendations: The guidelines do not recommend routine screening for bone disorders.
Treatment: The only effective therapy for symptomatic osteonecrosis is surgical joint replacement and resection of the involved bone. It is recommended that everyone have an adequate intake of calcium and vitamin D, ideally through diet, and do weight-bearing exercise, like walking or yoga.
There are a few unfortunate themes that run through the IAS guidelines. One of them is expressed as something like "the precise mechanisms are not known" or "the pathophysiologic basis is unknown." The other one is, basically, "Few studies have been completed to guide the optimal monitoring and treatment." In other words, we don't know exactly what's going on, and we often don't know quite what to do about it.
Maybe these still rather mysterious metabolic complications are by-products of the accelerated approval of antiretroviral drugs -- getting drugs out faster to save people's lives requires the forfeiture of knowing all the side effects that they might cause once they've been used for a few years. Or they may just add to an already complicated disease process further complicated by treatment.
In the end, it doesn't much matter. "Am I likely to get this?" "Why is it happening?" "How is it happening?" "What can I do to stop it?" "Can I prevent it?" These are the questions that really matter. The numerous studies presented at CROI looking at metabolic complications attest to the serious attention that research is devoting to these questions. Time -- but hopefully not too much more time -- will give us some answers.
Heidi M. Nass is an HIV-positive community advocate based in Madison, Wisconsin.
This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.