Wasting and Metabolic Changes in the Era of HAART
At first glance, wasting syndrome -- an often chronic and sometimes life-threatening complication experienced by many people living with HIV and AIDS -- appears to be a thing of the past. Numerous reports from both clinical trials and large cohort studies have yielded some incredibly impressive news: HIV-infected patients on highly active antiretroviral therapy (HAART), especially those in the advanced stages of disease, are getting a second chance at life and good health. Undetectable viral loads and soaring T-cell counts aside, HIV-infected people are living longer, getting fewer opportunistic infections (OIs), and are experiencing robust increases in body weight. But do these much heralded reports of weight gain necessarily mean that wasting is no longer a problem?
Wasting Syndrome: A Primer
All too often, wasting syndrome is assumed to mean only one thing: weight loss. While the term wasting syndrome certainly does embody profound weight loss, it also means progressive loss of muscle mass with associated fatigue. Although the Centers for Disease Control has not altered its official definition of wasting to include decreases in muscle mass, numerous researchers and healthcare providers firmly believe that changes in muscle mass are equally, if not more, important than those seen in body weight. Unfortunately, much of the research generated thus far regarding the possible causes of and treatments for wasting have only used body weight as a measurement. Clinical trials are beginning to incorporate body mass measurements -- tests to measure body composition -- such as bio-electrical impedance analysis (BIA; see article) and dual-energy x-ray absorptiometry (DEXA).
There are, essentially, two different types of wasting. The first type reflects periods of rapid weight loss and muscle wasting. This type is most commonly found in people experiencing particular OIs, such as Mycobacterium avium complex (MAC) and tuberculosis. Given the proven benefits of HAART and prophylaxis, people living with HIV now stand a much better chance of either avoiding or recovering faster from an OI. This is certainly good news in terms of preventing one of the most common types of wasting (also referred to as cachexia). Patients who experience profound wasting as a result of an OI have an extremely difficult time regaining weight and muscle mass.
The second type reflects more gradual losses in both weight and muscle. Unlike the first type, which most often applies to patients with advanced HIV disease, gradual wasting can occur at any time and for any number of reasons and may be due to HIV infection itself. For starters, many people with HIV are simply not eating the right amounts or kinds of food, such as those high in protein and micronutrients (ie., certain vitamins and minerals). Some of the documented causes of this include: lack of nutritional knowledge; depression; economic hardship; impaired taste; nausea or vomiting (usually caused by adverse drug effects); and dietary restrictions, especially those surrounding multiple daily doses of certain antiretroviral drugs.
It is essential that people with HIV consume enough of the right kinds of food. Some studies have shown that, because HIV is a chronic infection, the body requires greater amounts of energy to consistently fuel itself. Even if viral load is being kept in check by HAART, additional energy is still required by the immune system to help build new cells and repair damaged tissues. Certain organs, such as the liver and kidneys, also require greater amounts of energy and certain micronutrients to efficiently process the relatively high levels of toxic therapies being consumed on a daily basis.
Malabsorption, a problem not uncommon among people with HIV, is another cause of gradual wasting. Foods that are swallowed require a great deal of processing by the gastrointestinal system (the gut) so that they can effectively be broken down into their most basic forms -- either protein (amino acids), fat (triglycerides and cholesterol), or sugar (glucose) -- and adequately absorbed by the intestine. Drug side effects, such as diarrhea and vomiting, can prevent food from staying in the gut long enough to be properly digested and absorbed. Diarrhea and vomiting may also be signs of an underlying infection or complication. Infections such as cryptosporidiosis and microsporidiiosis can both cause diarrhea and drastically impair the intestine's ability to absorb essential nutrients. Other infections and complications of the gut include CMV, lymphoma, and KS, all of which can impair digestive function and absorption without causing overt symptoms (ie., severe diarrhea).
There have been numerous reports of people on HAART who are experiencing significant improvements in their overall immune status and, as a result, are much less likely to develop an OI. Yet, it has not been adequately determined if, for example, 400 T-cells post-HAART are much better than 100 T-cells pre-HAART. It is still too early to throw caution to the wind; drug- or infection-induced symptoms such as diarrhea and weight loss should be brought to the attention of a healthcare provider immediately.
In recent years, a significant amount of research has focused on metabolic problems that can cause wasting. Metabolism -- an intricate system by which nutrients are either broken down (catabolism) for energy purposes or stored (anabolism) for later use -- has been shown to become highly irregular in people with HIV. More simply, metabolism is the body's utilization of energy from foods. To fuel its energy needs, the body first catabolizes glucose and lipids circulating in the blood ("free-floating" nutrients); amino acids are spared so that they can be used to build muscle mass and other substances such as enzymes and antibodies. If free-floating nutrients are used up and not adequately replaced, the body will then begin breaking down stored nutrients -- usually lipid and cholesterol deposits (fat mass) -- to keep up with its energy needs; stored amino acids, such as those in muscle, are spared during prolonged fasting and used as energy only as a last resort. In people with HIV, this entire process is often reversed. We know this because people with HIV often have elevated glucose levels and fat levels (hyperlipidemia) and, especially during an OI, have a negative nitrogen balance (a marker of muscle loss). While negative nitrogen balances are certainly a sign that muscle wasting is occurring, the connections between elevated glucose levels, lipid levels and muscle loss have not yet been fully determined. However they are characteristic of cachexia.
Like many other chronic diseases, HIV and AIDS-related opportunistic infections put a tremendous amount of pressure on the body to rapidly expend energy. Because amino acids are much easier to convert into energy than lipids, the body begins catabolizing both free-floating and stored amino acids to fuel itself. In turn, muscle mass slowly becomes depleted while fat mass continues to accumulate. This is potentially dangerous, considering that muscle mass is necessary for survival.
How nutrient metabolism becomes altered in HIV-infected people is not entirely understood. While a number of studies have demonstrated a strong association between the severity of immune suppression and the likelihood of developing wasting, it is still not entirely clear whether or not immune system damage is an underlying cause of wasting. In its response to HIV and OIs, an abundance of hormone-like substances called cytokines are produced by cells to more effectively communicate with each other. While these cytokines play an important role in bolstering the immune response against an infection, prolonged and excessive amounts have been shown to result in significant problems. The cytokines interleukin-1 (IL-1), interferons (alpha, beta, and gamma), and tumor necrosis factor (TNF) have all been shown to induce the classic symptoms experienced during an illness. These include some that are prominent in HIV disease: fever, nausea, decreased appetite, fatigue, diarrhea, anemia, and confusion. Still it is not entirely clear whether or not hyperactivity of the immune system directly causes wasting or, more specifically, muscle loss.
Numerous studies have, however, implicated hormones and the immune system as likely culprits. Many people with HIV experience significant endocrine (hormonal) problems such as decreased production of both insulin-like growth factor (a precursor of growth hormone) and testosterone. Anabolic hormones such as these play a large role in promoting protein anabolism and muscle growth. Hypogonadism, or decreased testosterone production, is frequently reported in HIV-infected people; rates vary from 25% to 45%, depending on the stage of HIV disease. Possible causes of hypogonadism include testicular infections, drug side effects (particularly from ketaconazole, ganciclovir, and megestrol acetate), and elevations in cortisol levels (a hormone produced by the adrenal glands). No matter what the cause, low testosterone levels have been directly associated with fatigue, depression, decreased sex drive, and weight and muscle loss.
As the name syndrome implies, wasting is a multifactorial problem. One or all of the above mentioned problems can contribute to HIV-related wasting, sometimes gradually throughout the course of disease or sometimes rapidly in the presence of an OI. How each of these complications relate to each other and wasting is not entirely understood and are not likely to be worked out completely in the near future.
Given the numerous possible causes of wasting syndrome, it should come as no surprise that treatments for wasting are equally complex and, unfortunately, cannot be universally prescribed. No "standard of care" for wasting exists; in fact, there is little consensus regarding the best way to prevent and treat wasting, especially muscle loss. Yet, there are a number of treatment strategies that have been proven effective in terms of weight gain and, in some cases, muscle growth and maintenance.
First and foremost, dietary intervention is crucial for virtually all HIV-infected individuals suffering from mild to severe forms of weight loss. Forms of dietary interventions include nutritional counseling and oral nutritional supplementation. In terms of counseling, a registered dietitian can help identify weaknesses in an existing diet and make suggestions regarding dietary needs and how best to tailor them to meet individual tastes, schedules (ie., drug dosing schedules), and tolerances. Nutritional supplementation can also be extremely useful. A number of oral supplements -- including Ensure™, Sustacal™, Citrisource™, Resouce™, Jevity™, and Replete™ -- are widely available, but can be expensive. To meet individual dietary needs and/or restrictions, some are free of wheat, dairy (lactose), or other components that are frequently difficult to digest. Very few clinical trials of oral supplements , have focused on whether or not they can sustain weight in HIV-infected individuals (see CRIA News).
There are a number of treatments available to control symptoms, including drug side effects, that make eating undesirable. Drugs to control nausea and vomiting (antiemetics), diarrhea (antidiarrheals), and decreased appetite (appetite stimulants) are widely available. Treatments such as Marinol™ (gel-caps containing THC, the active ingredient in marijuana) and megestrol acetate (Megace™) have been shown to significantly increase appetite. However, as is the case with megestrol acetate, patients who do manage to achieve weight gain often do so in the form of fat, not muscle. In fact, megestrol acetate -- a synthetic form of the female hormone progesterone -- has been shown to decrease testosterone production in men.
Treating an active opportunistic infection, especially one that causes malabsorption, can halt and possibly reverse weight loss. Treatments for conditions such as MAC, TB, and intestinal diseases such as CMV and KS have been shown to be extremely effective and are often associated with increased weight. Unfortunately, there are no effective treatments for intestinal diseases such as cryptosporidiosis and microsporidiosis, however a number of recent reports have suggested that HAART may be extremely helpful in terms of boosting the immune response against these chronic infections and ultimately increasing weight. But, like appetite stimulants, treatments for OIs associated with weight gain usually contribute to fat accumulation, not muscle.
Treating metabolic disorders associated with wasting has been a large focus of research over the past few years. In particular, results from clinical trials of anabolic therapies have suggested that certain agents -- including testosterone, growth hormone, oxandrolone, nandrolone, and oxymethalone -- can significantly increase muscle mass in HIV-infected people with wasting. Interestingly, weight gain as opposed to muscle mass does not appear to be a significant benefit of anabolic steroids and might be best used in combination with appetite stimulants and/or nutritional supplements to boost weight.
In terms of treating immune system disorders, promising results have been seen using the drug thalidomide -- once banned because of its ability to cause birth defects in pregnant women taking the drug -- which apparently reduces levels of the inflammatory cytokine tumor necrosis factor. Yet, the most promising therapy in terms of stabilizing the immune system has been HAART. By drastically reducing the amount of virus circulating in the body, HAART allows the immune system to recover from the onslaught of HIV. In fact, a large number of studies have demonstrated that patients on HAART, especially those with wasting, are gaining weight while on therapy. At first, this weight gain was heralded as a significant triumph. As of recent, however, many researchers, healthcare providers, and patients have begun to wonder what much of the weight gain is really all about.
Lipodystrophy: A New Type of Wasting?
Little less than a year ago, reports began to surface that people on HAART were experiencing significant increases in weight... and waist size. Over time, the number of reports increased and were classified as a distinct syndrome associated with HAART. Along with fat mass accumulation around the waist, the syndrome was also characterized by the loss of the layer of fat under the skin, making veins seem to protrude; wasting of the face and limbs; narrowing thighs; breast enlargement in women; and the accumulation of fat between the shoulder blades. The syndrome, now dubbed lipodystrophy, has become one of the most closely watched manifestations in people with HIV. While numerous researchers and clinicians have directly associated the lipodystrophy with protease inhibitor therapy, some experts argue that the syndrome is associated with the biological consequences of HAART, not the drugs themselves.
Cases of lipodystrophy have now been reported among people taking any of the four approved protease inhibitors. Although lipodystrophy's early nickname was "Crix belly" (after Crixivan™), it is now clear that it is not specific to one drug. In fact, there have been a number of reports of lipodystrophy occurring among HIV-infected patients taking non-protease inhibitor-based HAART combinations.
Estimates of the proportion of people who develop lipodystrophy while on HAART have ranged from 11% to 64%. While the obvious discrepancy in this range is highly suspect, it is important to note that some researchers only reported cases in which body changes were physically apparent, while others used scans (ie., MRI, DEXA, CT scan) to measure very subtle body changes. In light of these varying study methods and results, further research into the epidemiology of this syndrome is warranted.
Many people on HAART are also experiencing metabolic complications such as elevated glucose levels and glucose intolerance, hyperlipidemia, hypertension, along with mild elevations in cortisol secretion and hypogonadism, all of which have been associated with body composition changes in HIV-infected patients. Yet, many people on HAART have only specific metabolic complications sometimes in the presence of body composition changes and sometimes without. In turn, there is not even consensus on exactly what HIV-related lipodystrophy includes; a case definition of the syndrome does not exist.
Research into the this syndrome is still in its infancy. Preliminary results from one study have demonstrated that protease inhibitors can have a direct effect on fat metabolism. However, some researchers are not convinced that protease inhibitors are necessarily to blame. According to Dr. Donald Kotler, CRIA Vice President and a researcher at St. Luke's Roosevelt Hospital, the major weaknesses in the protease inhibitor argument are that: 1) Some HIV-infected patients with lipodystrophy are not taking protease inhibitors; 2) A similar syndrome was seen in the past -- although more rarely; and 3) A similar syndrome exists in HIV-uninfected subjects. Lipodystrophy has been found in patients with diabetes mellitus, Cushing's syndrome, and other chronic diseases. As with these other diseases, HIV-related lipodystrophy is associated with body composition changes in both men and women, glucose intolerance, hyperlipidemia, hypertension, elevations in cortisol secretion, and decreased testosterone levels. A common thread in the syndromes seen in both HIV-positive patients on HAART and HIV-negative patients with other diseases, may be the presence of a "chronic stress response;" even in the presence of therapy intended to control certain aspects of the disease, the metabolic system remains highly dysfunctional. The similarities in syndromes are worrisome, since the syndrome in HIV negative patients is associated with accelerated cardiovascular disease, stroke, and osteoporosis.
To date, virtually no anti-wasting/weight loss therapy has shown to be effective in terms of halting or reversing lipodystrophy. Clinical trials are currently being conducted to study possible treatments (ig., growth hormone) for lipodystrophy, including one at CRIA. Anecdotal reports regarding the efficacy of anabolic compounds, anti-inflammatory drugs (ie., prednisone), and various alternative treatments (non-pharmaceutical compounds such as alpha-lipoic acid) have suggested that therapeutic intervention may be helpful.
Tim Horn is the Executive Editor of the PRN Notebook_, published by the Physicians' Research Network, and is a member of the Treatment Action Group (TAG)._