Important note: Information in this article was accurate in July 2000. The state of the art may have changed since the publication date.A standard lament at any meeting on HIV-related lipodystrophy concerns the lack of consensus on a case definition and even on whether these strange fat changes reflect one or two or more syndromes. Don't even mention the still uncertain gropings toward mechanisms. Attempts to get a handle on lipodystrophy can seem very much in the very-like-a-whale stage.
But is this humbling heterogeneity of opinion really so surprising? Not if one rewinds the AIDS history tape back sometime before 1998, before the profundity of this syndrome grew too great even for the lipodystrophy denialists. Back then, in the early and mid-90s, endocrinologists, gastroenterologists, and plain old AIDS docs busied themselves studying and disagreeing about definitions and mechanisms of another syndrome of debilitated body habitus--wasting.
Today, still in the throes of the lipodsytrophy crisis, these same specialists sometimes pause to reflect that those old wasting questions linger. Back-to-back symposia sponsored by Serono Laboratories near Phoenix on May 3 and 4 afforded one such opportunity for reflection.* At the first meeting attendees wrestled with that older, though no less fearsome foe, AIDS wasting. A day later, having resolved nothing, they leapt back into the ring to scrap with lipodystrophy.
*Mark Mascolini's attendance at this meeting was supported by funding from Serono Laboratories.
Like lipodystrophy, wasting has so far defied a categorical definition. Most agree, though, that the case definition proposed when the CDC made wasting an AIDS-defining condition in 1987 is too narrow. That definition stipulates a 10 percent weight loss along with diarrhea or chronic weakness and fever lasting at least 30 days but not caused by wasting.1 Phew! As Patrick Nemechek, DO, Bruce Polsky, MD, and Michael Gottlieb, MD, observe in their recent review of wasting, "This definition, useful for epidemiologic purposes, is of limited utility in practice since it does not address malnutrition and loss of BCM [body cell mass] or weight that may affect many patients."2
On top of that, research has demonstrated that only a 5 percent weight loss in people with HIV infection heralds progression and death.3 As a result, even though "we are still wrestling with case definitions for both classic wasting and fat distribution abnormalities," notes Kathleen Mulligan, PhD (University of California, San Francisco), "many of the more recent [wasting] intervention trials have required only a 5 percent weight loss to establish eligibility."4 Mulligan adds that some say the 5 percent loss must have happened in the past six months.
A breakout group at the May 3 wasting symposium proposed these simplified alternatives to define wasting:
Maybe, though, these fine discriminations approach hair splitting, suggested Donald Kotler, MD (St. Luke's-Roosevelt, New York). "You don't need BIA [bioelectic impedance analysis] to diagnose wasting," he noted. "All you need is a glance." But BIA can help gauge how body composition changes over time.
Already the reader who has not spent much time with the wasting literature lately begins to recall some of the complications. Barely 500 words into this article, and already we have BCM and BIA. How long can it be before we move on to LBM, BMI, and all the others? Not long at all. Indeed, the very next paragraph will begin bushwhacking through that thicket of abbreviated body measures.
Simple body weight (BW) is the easiest thing to chart, and experts urged seven years ago that regular weight measures are "essential data" in managing HIV infection.5 Yet many fear that clinicians aren't routinely telling patients to shed their shoes and jump on the scale (see note 6). Simple BW is important because rapid weight loss (more than 4 kg in fewer than four months) can signal acute infection, whereas slower weight loss (more than 4 kg in more than four months) may point to GI complications.7
Although research has linked body weight itself to HIV disease progression, falling BW remains only a crude harbinger of approaching morbidity. Mulligan leans toward body mass index (BMI) in her review4 and in an earlier survey written with Morris Schambelan, MD.7 It's pretty easy to figure:
What BMI gives you that weight alone doesn't, Mulligan and Schambelan explain, is a quick way to pit a person's current weight against population norms. Some suggest that people with any chronic disease and a BMI below 20 kg/m2 risk complications even if they haven't lost body weight.4 Nemechek and coauthors favor BCM as the best yardstick of body composition in people with HIV infection.2 Just what is BCM? It's not the same as lean body mass, LBM, the variable often construed as a surrogate of sleek muscle. LBM, say Nemechek et al, includes both BCM and something called "extracellular material" (EM). Notably, this extracellular material includes water. So a person with a nice gain in LBM may be carrying a load of extracellular water. BCM, on the other hand, includes only nonfat cells and the watery part of fat cells. Nemechek and colleagues sum it up this way2:
These authors argue that "BCM is the marker that best characterizes the degree of wasting in patients infected with HIV."2 Why? Because people with progressing disease can lose BCM and body fat in equal proportions, or they can lose BCM faster. "Malnutrition relates to loss of BCM," they write, and, "Since a relatively stable BW can mask underlying malnutrition, measurements of BCM are of prime importance in uncovering protein loss."2
And how does one measure BCM? BIA. So, OK, not everyone has a BIA machine in their office. But Mulligan and Schambelan reassure that measuring BIA isn't such a big deal. "The equipment is relatively inexpensive and portable," they say. "A measurement takes only approximately 10 minutes and involves no pain or discomfort for the patient."7 But it's not as easy as measuring weight or even figuring BMI. You, or someone you pay, has to stick the electrodes on in the right places, every time. And lack of predictive equations for BIA, Nemechek et al write, may lead to "variable results."2
Donald Kotler, for one, is doing something about that lack of predictive equations. If you want to know how important a BCM change may be in a person with HIV infection, he said at the wasting meeting, first you have to find out how much a normal population's BCM may drift over time. He tracked BW and BCM changes in 290 HIV-negative people for 12 months. In the six- to 12-month follow-up period, body weight changes (±11 percent) pretty much matched BCM changes (±10 percent) in this population. But earlier on, especially in the first three months of follow-up, BCM changes varied substantially more (up and down) than BW changes. That difference suggests, as Nemechek and colleagues argue, that BCM changes may tell a different story from simple weight changes, and they may tell that story sooner.
Still, the starting point for any assessment of body changes in people with HIV infection should be "frequent documentation of BW," most seem to agree, "ideally at every visit."2
More is known about what causes wasting than about what causes lipodystrophy. But, as with lipodystrophy, it's sometimes hard to sort out the contributions of diverse factors. Cause number one for classic wasting, writes Mulligan, is "inadequate energy intake."4 But the reasons for not packing on calories can range from diarrhea (drug-induced and otherwise) to nausea, vomiting, esophageal complications, altered taste and smell, depression, poverty, and isolation. In other words, you name it. Beyond simple malabsorption, other causes of wasting include cytokine somersaults and metabolic deficits such as low quotients of testosterone or growth hormone.
The acute infections that define AIDS certainly slice pounds off people who suffer them. And when people recover from those bouts, their weight doesn't always bounce back to where it started. Then the next acute episode takes the weight down a few more notches, and so on. As a result the emergence of better therapies to treat opportunistic diseases, and of better antiretrovirals to prevent them, would seem the ideal one-two punch to send wasting reeling.
But things haven't always worked out that way. How come? The drugs sometimes hinder calorie cramming on their own. Clarithromycin, fluconazole, and ritonavir all may alter the sense of smell, and the list of AIDS drugs that can cause nausea, vomiting, or diarrhea is not brief.2 Mulligan observes that the metabolic effects of antiretrovirals may well cause body fat changes recently misclassified as wasting.4 "The expectation was that wasting would become a thing of the past with HAART," she said at the Serono wasting symposium. But that expectation remains unfulfilled.
To be sure, some studies of people beginning HAART regimens document weight gains. A study of people starting indinavir, for example, recorded weight gains in 56 percent of 214 individuals who had at least a 5 percent drop in their usual body weight before treatment.8 And the gains correlated significantly with CD4+ and viral load changes. But because such early studies of HAART's effect on wasting lacked body composition measures, Mulligan notes,4 they couldn't exclude the possibility that fat accounted for much of this weight gain. Indeed, another study suggested exactly that.9
Nemechek and coauthors observe that no placebo-controlled trial has ever verified a link between HAART and weight gain. And two preliminary reports10,11 dispute the earlier association between weight changes and viral load.8 Another non-peer-reviewed study found that "aggressive HAART" didn't stop weight loss in 24 percent of treated individuals and that one third with HAART-induced viral load drops still lost BCM.12
Just how do these portents of persistent wasting add up in larger populations? At the Phoenix meeting, Mulligan cited a Boston cohort study being published by Christine Wanke, MD, and colleagues13 that documented wasting in 34 percent of 469 individuals. More than half were taking a HAART regimen when they met the wasting criteria.
The CDC's index of AIDS indicator conditions shows little slippage in recent wasting numbers. In 1993, Mulligan said, the CDC attributed 10 percent of AIDS cases to wasting. In 1998, a couple years into the HAART age, that number stood at 8 percent. In the large Johns Hopkins cohort, wasting jumped from tenth on the list of AIDS conditions in 1994 to sixth in 1998.14 Because rates of most other AIDS events have withered in the past few years, those numbers don't mean that wasting is on the upswing, but they do suggest it's holding steady. "It is increasingly apparent," Mulligan concludes, "that not every patient with wasting gains weight or lean tissue upon initiation of HAART."4
Surely, though, the multitiered cloverleaf of cellular trafficking during HIV treatment only figures to get more knotted as researchers train their impedance analyzers and DEXA scanners on the unsuspecting adipocytes of infected people. Sorting out what's simple wasting, what's lipodystrophy, and what's something else won't be easy, as a study by German researchers makes clear.15 This analysis encompassed two cross-sectional studies of 247 people in 1996 and 266 people in 1997, plus a longitudinal study of 111 people from these cohorts who began treatment with a protease inhibitor.
Depending on how the investigators defined malnutrition, they figured that its prevalence sank by 30 to 50 percent during the two study years. In the longitudinal study, total body weight increased and fat mass decreased (P < 0.001). But among people with apparent fat redistribution, 21 percent gained more intracellular water than people without fat redistribution, a change that could account for body weight gains in this subset.
In a prospective study these same investigators found that a BIA measure called phase angle independently predicts HIV disease progression and death in people taking HAART, Mulligan reported at the wasting symposium. But Achim Schwenk, the lead author, sought to play down the import of the finding because, he told Mulligan, "No one has ever seen a phase angle walking down the street."
If wasting remains a threat, even to some people taking otherwise effective HAART, can clinicians turn to new therapies that shore up this potential breach? Sadly, no. Although some research continues to seek new remedies for AIDS wasting, no new products have received the FDA's blessing since recombinant human growth hormone (rhGH, Serostim), megestrol acetate (Megace), and dronabinol (Marinol) passed muster.
Investigators continue to study rhGH, hoping to find a more targeted regimen and to validate its effect in children, and other workers continue to appraise the potential merits of testosterone replacement and anabolic steroids, with or without exercise. Although there are no dazzling advances to report, a few recent studies showed the merits of testosterone replacement in wasting men with low levels of that hormone. Arguments continue over the value of steroids. Serono scientists have begun to nose out other agents that address wasting, but these compounds are far from clinical trials.16
Short of drug therapy, improving nutrition is an obvious starting point that may involve psychological referral or the help of a nutritionist or social worker. Mulligan and Schambelan offer a concise review of nutritional support in their online article,7 and Nemechek and colleagues consider a few more recent studies.2 These authors add that cigarette smoking, which suppresses appetite, should be discouraged.
Aside from rhGH, the other products licensed to treat AIDS wasting are both appetite stimulants, megestrol acetate and dronabinol. Megestrol acetate helped people with wasting put on pounds, but almost all of them from fat. "Although increases in body fat in this setting may not be intrinsically harmful," Mulligan and Schambelan note, "there is no correlation between body fat content and survival."7 Because megestrol acetate lowers testosterone levels, researchers tried boosting its effect by giving it with replacement testosterone. But even this tactic failed to beef up lean body mass.17
Dronabinol, the active ingredient of marijuana, may give people the munchies, but it doesn't help them add avoirdupois. A randomized placebo-controlled double-blind trial showed no significant weight gain in the dronabinol arm,18 and coupling dronabinol with megestrol acetate didn't work either.19 Most experts agree that these appetite stimulants have, at best, an adjunctive role in the management of wasting. Nemechek and coauthors write that "they may be valuable when combined with agents that promote gain of" lean body mass.2
Much has been made of the potential for testosterone and its derivatives--anabolic steroids--in helping wasted people muscle up. Their biggest advantage would be that they cost a whole lot less than rhGH. But although the most recent studies turned up some positive results, questions remain, especially about anabolic steroids. The rationale for using these agents is that 30 to 50 percent of HIV-positive people may be hypogonadal,20 and that resulting low testosterone levels correlate with body cell mass loss.21 But Nemechek and coauthors cite another study indicating that fewer than 13 percent of people with wasting fall short in testosterone tallies.22
The most promising anabolic steroid studies involve oxandrolone (Oxandrin) and nandrolone decanoate (Deca Durabolin). A randomized double-blind trial compared oxandrolone at 20 mg/day with placebo in 24 eugonadal HIV-positive men taking 100 mg of testosterone weekly to suppress endogenous testosterone production.23 Everyone also enrolled in a progressive resistance exercise program. The men had endured an average 9 percent loss in body weight before the study began. Although both groups gained weight, lean body mass, and strength, the oxandrolone group gained significantly more lean body mass and strength. Another placebo-controlled study also documented weight gains with oxandrolone, this time at a dose of 15 mg/day for 16 weeks, in men whose body weight had dropped more than 10 percent.24 Muscle strength again improved with oxandrolone.
An open-label trial of nandrolone decanoate, at a dose of 100 mg/mL every two weeks for 16 weeks, increased weight (mean 0.14 kg/week, P < 0.05), lean body mass (mean 3 kg by anthropometry, P < 0.005), and quality of life in 24 people whose body weight had dropped 5 to 15 percent.25 A placebo-controlled study of 100 mg/mL of nandrolone weekly for 12 weeks corroborated weight gain with this agent (3.9 pounds, P = 0.04),26 but study participants were eugonadal and had not lost weight before the study.
In an editorial accompanying the oxandrolone-exercise study,23 Adrian Sandra Dobs, MD (Johns Hopkins) urges caution.27 A limitation of the study, she notes, is the lack of an exercise-only control arm. But, more to the point, Dobs just doesn't think oxandrolone and other anabolic steroids have been studied long enough in enough people. "At this time," she counsels, "it is still reasonable to take a conservative approach" when considering steroids for wasting.
Dobs also spelled out the long list of side effects that may accompany androgenic steroids: "virilization, irregular menses, and hirsutism in women and testicular atrophy and infertility in men."27 Add to that premature epiphyseal closure in teenagers, lowered levels of high-density lipoprotein ("good") cholesterol, cardiomyopathy, hypercoagulation, tendon tears, hepatocellular carcinoma, psychiatric disorders, and sudden death. Still, Dobs allows, these side effects "may be acceptable risks in selected patients with advanced illness and muscle wasting, especially if other measures have failed."27
In their review Nemechek and colleagues yield even less ground. Because testosterone analogs in general "show varied efficacy in improving nutritional status, may carry risks for hepatic toxic effects, and have not been extensively evaluated in women," they write, "physiologic replacement doses should be used only for men who are wasting if either free or total testosterone levels are subnormal or in the low normal range."2
What about straight testosterone replacement? In three studies it helped HIV-positive men with low testosterone levels gain lean body mass. The most recent study of this strategy, a double-blind trial, randomized 61 HIV-positive men with low testosterone readings and at least a 5 percent weight loss to four arms: 100 mg of testosterone enanthate per week intramuscularly with no exercise, placebo with no exercise, placebo plus resistance exercise, or testosterone plus resistance exercise.28
After 16 weeks men in the testosterone-only and exercise-only arms had significant weight gains (2.6 kg, P < 0.001; and 2.2 kg, P = 0.02), but, oddly, men in the testosterone-plus-exercise group did not (0.7 kg, P = 0.08). Average lean body mass jumped by 2.3 kg in the testosterone-only group (P = 0.004) and by 2.6 kg in the testosterone-plus-exercise group (P < 0.001). Overall, these researchers concluded that testosterone plus exercise did not yield greater gains than either intervention alone.
A six-month placebo-controlled trial of testosterone enanthate (300 mg intramuscularly every three weeks), followed by a six-month open-label phase in which everyone got testosterone, documented the benefit of long-term treatment in 51 hypogonadal HIV-positive men with weight loss.29 People originally randomized to the placebo arm added an average 1.9 kg of lean body mass after the crossover (P = 0.03), whereas men who got testosterone shots for all 12 months ended up with a 3.7-kg gain, significantly more than in the other group (P = 0.05). During the double-blind phase of this study, the men getting testosterone also gained more fat-free mass (P = 0.036) and muscle mass (P = 0.005) than men taking placebo.30
A placebo-controlled study of Androderm, the testosterone patch, in 41 HIV-positive men with low testosterone levels found that 12 weeks of treatment yielded significant gains in lean body mass (1.3 kg, P = 0.02) and fat-free mass (1.4 kg, P = 0.02) measured by DEXA.31 People in the placebo arm enjoyed no such gains.
Because of findings like these, Nemechek and coauthors recommend measuring free and total testosterone yearly in HIV-positive people.2 If body cell mass falls below 35 percent of body weight in men or below 30 percent in women, and if testosterone levels are low, they recommend testosterone replacement. If body cell mass continues to slide after four to eight weeks, they recommend 6 mg of rhGH daily for 12 weeks.
Schambelan, Mulligan, and colleagues established the efficacy of rhGH in people with AIDS wasting in a 178-person placebo-controlled trial using 0.1 mg/kg daily for 12 weeks.32 That study documented significant gains in weight, lean body mass, and strength, along with a significant loss of body fat among people randomized to take growth hormone. Arthralgias, myalgia, puffiness, and diarrhea generally responded to dose reductions.
Michael Mooney and other treatment advocates who focus on wasting remain notably dubious about rhGH as a wasting remedy, principally because gains in lean body mass--a key outcome measure in rhGH studies (and in testosterone and steroid studies as well)--"does not necessarily indicate that there is an increase in skeletal muscle tissue, functional strength or physical performance."33 Earlier this year Mooney wrote to the FDA, asking the agency to forbid companies from making "statements about LBM without qualifying exactly what LBM means" because "LBM does not equal skeletal muscle."33
This is the same point Nemechek and coauthors make about lean body mass (see "What to measure and when" above). But preliminary results of an open-label study of rhGH in people with excess adipose tissue did chart a significant increase in skeletal muscle in 24 people after 12 weeks of treatment with 6 mg daily (P = 0.03, see page 209). If these results hold true in larger groups, including people with wasting, they would appear to address Mooney's concern.
Certainly, Nemechek, Polsky, and Gottlieb are convinced by the data in hand that rhGH can play a substantial role in treating AIDS wasting. They outline a strategy for shorter courses of rhGH that could trim the bill for this expensive drug.2 It works like this:
At the May 3 wasting symposium, Nick Paton, MD (Communicable Disease Center, Singapore) suggested another approach to more focused use of rhGH. Because weight loss tracks closely with acute opportunistic infections, he and coworkers in two London hospitals conducted a double-blind placebo-controlled trial of rhGH targeted to acute episodes. These investigators managed to recruit 20 individuals in whom Pneumocystis carinii pneumonia, cytomegaloviral GI disease, or a bacterial infection had been diagnosed within 48 hours. Everyone got standard OI treatment plus intensive nutritional support. Nine got rhGH and 11 got placebo. The average CD4+ count measured 30 cells/mm3 in both groups.
Six weeks later, people in the rhGH group enjoyed a significant gain in fat-free mass and a significant drop in fat mass (P < 0.05), whereas those in the placebo group had no significant change in these measures. Body cell mass improved with rhGH, but not significantly. Grip strength decreased slightly in the placebo group while increasing in the rhGH group, but this difference wasn't significant either. On a quality-of-life measure, both groups improved, and side effect rates were similar with rhGH and placebo.
Paton proposed that this strategy may make sense because it could stop weight loss in its tracks during acute infections and so obviate later wasting interventions, when lost pounds can be harder to restore and more rounds of rhGH may be needed. But he warned that the strategy should be considered only with a heavy dose of caution, since research recently showed increased mortality among critically ill patients receiving growth hormone.34 One symposium attendee suggested that mortality finding would keep him from giving rhGH to a person with an acute infection. It's hard to tell whether that person will become critically ill, he argued, and so confront a higher risk of death with rhGH.
Another attempt to control wasting earlier comes in an ongoing open-label study of rhGH in people with moderate wasting, defined as 5 percent weight loss in the prior 12 months or a 3 to 5 percent drop in body cell mass. The trial aims to enroll 225 people who will take the standard dose of 0.1 mg/kg daily. Ross Pettit (Serono Laboratories) unveiled early results at the wasting symposium. So far 24 people have completed treatment, 22 of whom were taking a protease inhibitor. Fasting cholesterol dropped an average 17 mg/dL, while HDL cholesterol rose and LDL cholesterol fell. Both AST and ALT decreased during rhGH treatment. Weight and fat-free mass increased.
Lipodystrophy is newer, curiouser, and more confusing than wasting. Yet it already seems more familiar. That's probably because--after a brief bout of denial--many researchers, clinicians, and even journalists have focused feverishly on this problem, perhaps encouraging reactions where there should be none. According to Project Inform's Ben Cheng, who spoke at the May 4 Serono symposium, ballooning concern over lipodsytrophy has led some infected people to delay treatment and others to switch away from protease inhibitors even if they have no symptoms of fat changes. Cheng has the clear impression of a "growing sense of panic and disappointment with new anti-HIV therapies."
Meanwhile, people who study this syndrome are far less certain than wasting experts about what causes it, what to do about it, and even what to call it. At the Phoenix symposium David Cooper, MD, DSc (who first offered a thorough account of these problems with Andrew Carr, MD, at St. Vincent's in Sydney) stuck with his favored rubric, lipodystrophy, because it broadly refers to fat abnormalities. Julian Falutz, MD (Montreal General Hospital) has proposed HAL, for HAART-associated lipodystrophy, while Serono's Norma Muurahainen, MD, PhD, suggests HARS, for HIV-associated adipose redistribution syndrome. But she allowed that some may prefer HAMS, for HIV-associated adipose maldistribution syndrome.
These adventures in philology clearly reflect the larger problem of crafting a case definition for lipodystrophy35 or deciding whether it's one or several syndromes. Inevitably, at least one speaker per meeting tries to squirm out of this lexicographic bind by invoking US Supreme Court Justice Potter Stewart's famous formula for pornography--"I shall not today attempt further to define [pornography] . . . but I know it when I see it."36
However, as Julian Falutz amply demonstrated, for lipodystrophy it ain't necessarily so. A day earlier Donald Kotler could get away with the claim that you can diagnose wasting with "a glance." With just a few slides, Falutz showed that even a long, hard look may sometimes fail to diagnose lipodystrophy. One slide showed the face of a perfectly normal looking--even handsome--man who complained to Falutz that his "sunken" cheeks signaled lipodystrophy. Falutz thought not. Another slide profiled a second man's paunch, which the man identified as central adiposity and Falutz described as a mere portent of advancing age. But a month or so later, this same man's facial fat all but disappeared.
When it comes to diagnosis, such borderline cases may be exceptional, but they show that Justice Stewart's dictum doesn't apply to lipodystrophy. By and large, though, David Cooper reported, clinicians' physical diagnoses in the Australian cohort study correlated closely with DEXA scan results. But the story's different when questions of symptom reversal arise. In such cases, Cooper said, Australian DEXA results showed that people with lipoatrophy often claimed improvement when none exists or even when the atrophy worsens. Julian Falutz offered an example in slides of a patient's posterior before and after that person switched from a PI regimen. The patient perceived a return toward normal gluteal reserves, but the two slides looked identical.
Distinguishing signs of lipodystrophy from innocent age-related change is difficult enough, but it pales before the challenge of construing the scope of the syndrome. This problem is no mere semantic squabble, as Christine Wanke, MD (Tufts University, Boston) suggested. Wanke placed herself squarely in the camp of the splitters--those who see multiple syndrome components. She counts four: central fat deposition, peripheral fat wasting, lipid elevations, and insulin resistance. If Wanke's right, the implications are irksome. "It is likely that the etiologies of the four components of lipodystrophy will be distinct but interrelated," she foretold. "It is equally likely that therapies for lipodystrophy will need to be directed at each of the four individual components as well."
Within the next year or two, though, clinicians should have a better idea of the extent of lipodystrophy in HIV-positive people and, with luck, may even be able to talk the same language when discussing it. Two studies now under way will help.
The first is the case definition project spearheaded by David Cooper. Clinicians at 40 sites in Europe, Australia, North America, South America, and Asia will collect detailed data on 800 persons and shoot it all to the survey's statistical nerve center via Web-based forms.
The second effort, the Fat Redistribution and Metabolism (FRAM) study, is a cross-sectional survey of 1200 randomly selected HIV-positive persons from 16 US sites, who will be compared with 300 seronegative people in an ongoing heart disease and weight study. Principal investigator Carl Grunfeld, MD, PhD (University of California, San Francisco) explained that the goals are to estimate the prevalence of distinct abnormalities, define their association, and "determine the cofactors of these syndromes." A tall order indeed.
A strong point of the Serono lipodystrophy symposium was the gallery of thoughtful speakers who considered management of the metabolic side effects that accompany antiretroviral therapy. Coincidentally, shortly after the meeting the Adult ACTG Cardiovascular Disease Focus Group issued its "Preliminary Guidelines for the Evaluation and Management of Dyslipidemia in HIV-Infected Adults Receiving Antiretroviral Therapy," which are online at the ACTG Web site.38 At this early date in the lipodystrophy era, everyone cautions that most management advice rests on inference, intuition, and common sense, not on data. But this is not the first time HIV docs have had to make treatment decisions without the benefit of a lengthy randomized double-blind placebo-controlled trial.
The potential long-term cardiovascular risk of PI-provoked lipid elevations has aroused great concern and inspired serious study. While awaiting those study results, what should clinicians be doing? First, proposed Ariane Marelli, MD (McGill University, Montreal), they should be evaluating HIV-positive people for cardiovascular risk. That means the traditional history and physical, laboratory testing including a fasting lipid profile, and electrocardiography in selected individuals. "Second," she proposed, "we must proceed to risk stratification and further testing in moderate-risk groups and referral when necessary in high-risk groups." And if guidelines indicate a need for treatment, they should be followed, she advised.
That's pretty much what the ACTG's Cardiovascular Disease Focus Group says too, starting with nondrug therapies for people at lower risk of coronary heart disease (CHD). But because many people taking antiretrovirals may have "only minimally increased risk . . . it may be preferable to delay drug therapy in those individuals until more is established regarding the safety and efficacy of drug treatment in this population."38
Not a whole lot is established yet, said Judith Aberg, MD (Washington University, St. Louis), the focus group's representative at the Phoenix symposium. "Clinicians have begun treating HIV-infected patients with lipid-lowering agents in the absence of concrete data demonstrating safety and efficacy of therapeutic agents," she noted. But Aberg was hardly scolding colleagues: she routinely uses lipid lowerers herself.
So how do you size up a person's CHD risk? Here's what the ACTG suggests:
When should high lipids be treated? Aberg and her ACTG colleagues suggest that the LDL-based recommendations of the National Cholesterol Education Program are a good place to start39 (Table 1). Aside from the LDL guidelines, the ACTG panel recommends diet, exercise, or both for people whose serum triglycerides top 200 mg/dL. Antilipidemics "should probably be considered" for people without other risk factors whose triglycerides exceed 1000 mg/dL. Drug treatment may be appropriate for people who have had pancreatitis and triglyceride levels above 500 mg/dL. The panel suggests combining drug and nondrug therapies if triglycerides soar beyond 2000 mg/dL.
Both statins and fibrates may play a role in treating antiretroviral-associated dyslipidemia, says the ACTG focus group (Table 2). But some statins may create more problems than they solve because they share the metabolic pathway favored by PIs. The ACTG experts warn clinicians to stay away from lovastatin and simvastatin. Fluvastatin shouldn't be given to people taking nelfinavir. Cerivastatin, the newest drug in this group, may prove the least likely to interact with PIs, but the studies haven't been done yet. Early work suggests that atorvastatin and pravastatin have minimal interactions with protease drugs, according to the ACTG group.
But at the symposium Aberg registered some concern about atorvastatin because of reported interactions with ritonavir plus saquinavir. A study that should conclude by the end of the year, she said, will evaluate atorvastatin given with indinavir and efavirenz. Clinicians who prescribe atorvastatin with PIs now should expect higher levels of the statin, so Aberg recommended starting with 10 mg and titrating up, watching carefully for signs of rhabdomyolysis. Because PIs have minimal effects on pravastatin levels, though, she suggested starting with the full 40-mg dose of that drug, which was the dose used in studies confirming pravastatin's clinical efficacy. But Aberg finds herself using fenofibrate more than either of these statins, because it's a once-a-day drug and because fibrates are considered the first choice for isolated hypertriglyceridemia (Table 2), which is common in her practice.
How about avoiding lipid drugs altogether by swapping the PI for a nonnucleoside or abacavir? One could write ad taedium on this topic, and some have,40 but the ACTG panel dispatched the issue without much fuss. Switching to abacavir or nevirapine appears to improve lipid profiles, the panel notes, while preliminary studies suggest efavirenz doesn't share that asset. Of course switching makes sense only for people without nonnucleoside experience or a lengthy history of nucleoside use. For people with less antiretroviral experience, clinicians will have to balance "the risks of new treatment-related toxicities and the possibility of virologic relapse when switching from a PI-based regimen" against "the risks of potential drug interactions and new treatment-related toxicities from lipid-lowering agents added to PI-based regimens.38
People who endure only moderate lipid gains with PIs may not have to make that choice between antilipid agents and switching to a non-PI combo. They may get by with diet or exercise. Alas, even less is known about how well these (usually safe) strategies work than is known about PI-sparing tactics. Christine Wanke acknowledged that concern over dietary interventions at the Serono symposium, and she added another as well: "If we are going to try to be involved in diet for our patients," she counseled, "it's absolutely crucial to have a dietitian involved and not to be relying on our own medical misunderstanding of the nutritional world."
Then again, top chefs of "the nutritional world" have concocted some pretty questionable stews of their own, Wanke noted, beginning with the low-fat, high-carbohydrate diet. It looked great on paper, but the low-fat/high-carb recipe turned out to "a very counterproductive diet" because it lowers HDL cholesterol while raising triglycerides, postprandial lipidemia, postprandial hyperglycemia, and postprandial hyperinsulinemia. Sounds like you'd do better at Dunkin' DoNuts, though you might not feel as virtuous. And, perversely, low-fat diets may end up making people fatter, because stinting on dietary fats leaves them hungry and they gobble nonfats to make up.
So what's a dieter to do? The answer may be what Wanke labeled a low-glycemic index diet. The glycemic index of a carbohydrate measures how fast that carbohydrate gets digested and absorbed, and how fast it's transformed into glucose. Low-glycemic index foods are digested, absorbed, and transformed more slowly. Wanke stopped short of listing examples of such foods. (That's where the dietitian comes in.)
The low-glycemic index diet Wanke outlined would include about 1 to 1.5 g of protein per kilogram of body weight and would be about 35 to 40 percent fat, predominantly as omega 3 or omega 6 fatty acids--fish oils. But Wanke conceded that it's hard to get enough omega 3 and 6 in your diet "unless you're some kind of marine life form."
If the low-glycemic index diet works for people with HIV infection (and Wanke said if because it's not been studied yet), it could reduce insulin resistance and so decrease both weight and central fat. The diet's fat component "should be able to decrease fat biosynthesis and decrease blood triglycerides." And if all those ifs come true, starting the diet early in the course of HIV infection may "prevent or modulate the severity" of metabolic derangements in infected people and so, perhaps, ward off fat abnormalities.
But the diet has a possible downside too. Because so many HIV-positive people absorb carbohydrates poorly--48 percent in Boston's Nutrition for Healthy Living Cohort--the low glycemic index diet "might end up causing more complications than we could prevent," said Wanke. Clearly, clinicians will want to wait for the study before ringing up the dietitian and working on that list of low-glycemic index foods.
Exercise is nearly always a safe intervention, said Abby Shevitz, MD (Tufts University, Boston), even though exercise does juice up the immune system. But that activating effect rarely boosts HIV plasma load, Shevitz found in a study published last year.40The qualifier rarely reflects her finding that three people with undetectable viral loads did have measurable blips with a 15-minute "bout of acute exercise." Viral loads went nowhere when 23 people with detectable viremia exercised.
Shevitz recommended mixed aerobic and strength training for HIV-positive people. The aerobics can increase cardiovascular fitness, trim the risk of coronary artery disease, improve LDL and HDL profiles, banish abdominal fat, and increase insulin-dependent glucose uptake by muscle. Pumping iron does none of that, but it can increase lean body mass and fat mass in people with wasting, increase lean mass and decrease fat in people without wasting, and improve overall physical functioning. And, by and by, it makes you stronger.
What can exercise do for people with lipodystrophy? In a study of 10 HIV-positive men with self-reported gains in abdominal girth, Shevitz's colleagues used DEXA scans to show that that a 16-week supervised program of aerobic and strength training decreased total body fat 2.1 percent (P < 0.01), most of it trunk fat (P < 0.03).42 But the exercise didn't affect overall weight, lean mass, or bone mineral density.
Shevitz stressed that an effective exercise program like this depends on a sound and steady diet. "If participants in exercise programs . . . increase their [food] intake," she said, "they're likely not to see the kind of changes that we saw."
Another potential antiretroviral side effect--not broached by the ACTG Cardiovascular Disease Focus Group, but addressed by the high-glycemic index diet and by exercise as well--is insulin resistance. Diabetes isn't the only reason clinicians should worry about insulin resistance and hyperinsulinemia, said Steven Grinspoon, MD (Massachusetts General Hospital). Fasting hyperinsulinemia may seem "just a number," he suggested, but "the company it keeps" is unsavory. Time and again, hyperinsulinemia turns up with hyperlipidemia, truncal adiposity, and hypertension, a "constellation of findings" that forebodes heart disease in HIV-negative people and may do so as well in seropositive people with lipodystrophy. But it's also possible that hyperinsulinemia itself, independently of its ill-starred allies, inflates the risk of coronary artery disease. Grinspoon cited research showing that high insulin levels can raise the risk of thrombosis.
A problem with several studies of insulin and glucose in people with lipodystrophy, Grinspoon noted, is that the investigators measured the wrong thing: fasting glucose. His study of 71 people with lipodystrophy, matched with controls for age and body mass index, showed no difference between the groups in fasting glucose. But 35 percent of people with lipodystrophy had impaired glucose tolerance, compared with 5 percent of controls. The glucose challenge test also diagnosed diabetes in 7 percent in the lipodystrophy group. He recommended that assay for everyone with HIV-related lipodystrophy.
Diabetes should be treated with standard interventions if diagnosed in HIV-positive people, Grinspoon said, but how to treat people with impaired glucose tolerance and hyperinsulinemia is not so clear. Grinspoon proposed that, "given the known risk of hyperinsulinemia in non-HIV-infected patients, patients with HIV infection and hyperinsulinemia may benefit from . . . insulin-sensitizing agents." Still, he cautioned, that remains a hypothesis only now being tested.
Sulfonylureas, oral antiglycemic agents, are not useful for people with hyperinsulinemia, Grinspoon advised, because "they stimulate production of insulin without increasing insulin sensitivity. But insulin production is already extremely increased" in this population. And insulin itself "is not particularly useful for insulin resistance in the early stages." Insulin-sensitizing agents such as metformin and the glitazones could be "better alternatives" because they can increase insulin sensitivity. And because metformin and glitazones act by different mechanisms, combining them "may prove particularly useful in the HIV lipodystrophy syndrome." The ACTG has begun a double-blind placebo-controlled trial of metformin and rosiglitazone alone and combined for HIV-positive people with hyperinsulinemia. The combination has already proved effective in HIV-negative individuals, Grinspoon said, without increasing side effect rates.43
If diet or exercise fails to correct HIV-linked lipid or insulin insults, the medications discussed in the preceding sections may help. But what happens if diet or exercise fails to remedy the body shape changes of lipodystrophy? Cecilia Shikuma, MD (University of Hawaii) outlined a new ACTG study that addresses this problem, a randomized placebo-controlled study of a transdermal testosterone, AndroGel, for HIV-positive men with mild to moderately reduced serum testosterone and abdominal obesity. A substudy of ACTG 384 will appraise metabolic and body composition changes in people randomized to a nelfinavir regimen or an efavirenz regimen. And the metformin-rosiglitazone study mentioned by Steven Grinspoon will chart those drugs' effects on visceral fat.
Three prospective noncontrolled studies show that rhGH can improve or reverse some physical signs of lipodystrophy, but in two studies it had little effect on accompanying lipid and insulin aberrations. All three studies delineate the disadvantage of this approach--the fat abnormalities reappear soon after this expensive treatment stops. But one of those studies suggests that a maintenance rhGH regimen will preserve the gains of full-dose treatment, and an ongoing trial is appraising that tactic.
The first two studies--both of them published--evaluated 5 to 6 mg of rhGH daily in 20 people with lipodystrophy. Ramon Torres, MD (Bentley-Salick Medical Practice, New York) and colleagues gave 5 to 6 mg daily to 10 people with fat maldistribution for one month to two years.44 Nine had truncal adiposity and six had buffalo hump. Both abnormalities improved with treatment, sometimes resolving entirely. Notably, one person with buffalo hump had to lower the dose of rhGH because of carpal tunnel syndrome, and the fat deposit disappeared with the reduced dose. But when people stopped taking rhGH--one because an insurer quit paying after four months--the fat changes recurred.
BIA detected "no consistent changes in body weight and total body fat," but six people with serial BIA had a mean 1.8 percent gain in fat-free mass. Lipid levels did not improve. Nor did signs of peripheral wasting in these people. Side effects included "worsening or onset of hyperglycemia" in one, facial swelling in one, and carpal tunnel syndrome and arthalgias or myalgias in two each.
Christine Wanke and coworkers at Tufts and Beth Israel Deaconess gave another 10 people with self-reported lipodystrophy 6 mg of rhGH daily for 12 weeks.45 Body mass index, percent fat (measured by BIA and by anthropometry), waist-to-hip ratio, and thigh circumference all improved significantly. The thigh improvement (from a mean 49.1 cm at baseline to 51.8 cm, P = 0.01) suggests--unlike Torres' study--that rhGH can improve peripheral wasting. But midarm circumference did not improve significantly in Wanke's group. Nor did lean body mass, percent lean mass, or body fat, all measured by BIA. Like Torres, Wanke recorded no improvement in metabolic measures--glucose, triglycerides, or cholesterol.
Three people had "significant" side effects--severe myalgia, hand swelling, and elevated glucose and hemoglobin A1C. The first two individuals continued taking rhGH at 6 mg every other day instead of daily and completed the 12-week course. Seven people continued treatment on this alternate-day schedule after the first 12 weeks, and they maintained their body shape improvements.
Wanke's little case series is also interesting because five of the 10 people reported that they exercised at least 30 minutes daily at least three times a week. Fasting triglycerides and cholesterol were "only moderately abnormal" in these exercisers, but their self-reported and confirmed lipodystrophy shows that exercise will not ward off or reverse unwanted fat swings in everyone. Because three people were taking replacement testosterone or oxandrolone, Wanke observed that those agents "may not provide protection" from fat redistribution in some people and may not be effective treatment either.
The third rhGH study, reported at the Phoenix meeting by Ellen Engelson, EdD (St. Luke's-Roosevelt, New York), is the first to show (by whole-body magnetic resonance imaging) that this agent builds skeletal muscle in people with lipodystrophy. The 30 people she studied all had excess adipose tissue, and 10 also had peripheral fat wasting. They took the 6-mg daily dose for 24 weeks, twice as long as usual, followed by a 12-week washout. Then they resumed treatment at 2 mg daily.
Engelson reported results on 24 people treated for the first 12 weeks. These people gained an average 3 percent skeletal muscle--the lean meat that provides a stricter measure of improvement than lean body mass (P = 0.03). Trunk fat also melted through 24 weeks, an improvement just a hair short of statistical significance (P = 0.052). Engelson's cohort also differed from Torres' and Wanke's in that total cholesterol fell significantly, from 225 to 201 mg/dL (P < 0.01). But fasting insulin increased with treatment in these already hyperinsulinemic people. As noted earlier, preliminary results of an rhGH wasting study included improvements in fasting cholesterol, HDL, and LDL (see More Focused Use of rhGH?).
Side effects were common among the people Engelson studied, only one of whom completed 24 weeks of treatment with no complaints. Twenty-one had stiffness or myalgia, 17 had fluid retention, and 10 had tingling in the hands or feet. Tolerability should improve with the 2-mg dose used in the second phase of the trial. Whether that dose proves effective is the crucial question. During the washout, Engelson reported, abdominal fat returned to its pretreatment levels. So all three studies show that, unless people can afford to keep taking rhGH continuously--and can escape or tolerate side effects while doing so--a lower maintenance dose will be essential for success.
Mark Mascolini writes about HIV infection (mailmark@ptd.net).
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35. Since Andrew Carr and David Cooper opened everyone's eyes to the extent of this syndrome, and since they favor the term lipodystrophy, and since no one has made a compelling case against that term, this article will use it.
36. Jacobellis v. Ohio, 378 U.S. 184 (Stewart J., concurring)(June 22, 1964).
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