HIV treatment has shown remarkable results starting in 1995 by lowering the death rate, decreasing hospitalizations and lengthening people's lives. But around 1997, following the respite from the years of AIDS despair, a new anxiety came to thousands of people who were doing better, surviving and resuming their lives. A similar, if not different look of AIDS had reappeared despite the use of effective anti-HIV drugs. Physicians began reporting metabolic problems and strange body shape changes in their HIV-positive patients. Media reports of the new syndrome appeared in newspapers. E-mail discussion lists led affected people to the Internet for support and advocacy. Researchers scrambled to find any clue. The new syndrome was as troubling as it was a big disenchantment for those who had survived AIDS. It appeared as if the honeymoon from the positive effects of HIV treatment were over.
At the time we did not know what was causing the metabolic changes, and hype fueled by fear of the unknown attributed every metabolic and fat redistribution issue to the protease inhibitors. Since 1997, we have learned that advanced HIV disease and monotherapy with NRTIs (nucleoside reverse transcriptase inhibitors) were also contributors to some of the metabolic changes that were beginning to appear in patients.
The metabolic disorders reported are a multitude of symptoms and irregularities that affect some but not all people with HIV. In order to best understand the benefits of HAART (highly active antiretroviral therapy) it may be useful to separate metabolic issues into two major categories in order to understand the subject. There are fat redistribution issues, and there are elevations in cholesterol/triglyceride levels and insulin resistance issues. For example, fat redistribution has long been attributed to some NRTIs and some PIs. It has also been documented in HIV-positive people who aren't on HAART. As far as we know, fat redistribution is unrelated to increases in blood levels of cholesterol and triglycerides. On the other hand, increased cholesterol and triglyceride levels also occur in HIV-negative individuals. However, certain drug combinations between PIs and NRTIs are recognized to increase triglyceride levels significantly, overlapping to create a metabolic syndrome in AIDS. We understand much more than we did five years ago when the first symptoms were reported, but prevalence, causation and treatment are still not fully understood. It's all very complicated.
It is important to look at how this syndrome emerged in order to get a clearer picture of what is happening. In and around 1997 people with AIDS began noticing a dramatic change in body shape, a look similar to wasting seen in the early years of the epidemic, despite the fact they were feeling healthy and had relative viral control. In some individuals the new "look" took several shapes -- thinning legs and arms and/or a gaunt facial look. We now refer to this condition -- loss of body fat -- as lipoatrophy. In other individuals, body fat was redistributed appearing as a weird paunch in the stomach and/or a disfiguring hump on the upper back. This condition is referred to as lipodystrophy. In addition, lipid levels, cholesterol and triglycerides, and glucose numbers were significantly out of range.
It was a difficult time for patients and doctors between 1995 and 1997. Some doctors were in denial about doing anything about these changes since anti-HIV drugs had been so effective, taking the attitude, "If it ain't broke, don't fix it." However, many doctors were often a part of the community they served and living with the dramatic improvements following 1995. Their concern about increases in lipids or fat distribution may have been tempered somewhat by a relief to finally see lives saved -- but not out of professional neglect. Treatment advocates felt an obvious reluctance by many pharmaceutical companies to conduct studies of their drugs, both approved in trials, because they did not want any bad light shed on them. Yet, it must be remembered that at the time a lot was unknown, and because neither morphologic nor metabolic changes were an issue when Phase IV trials were conducted, they were therefore not included in study protocols.
The HIV community mobilized as it had in the early years of AIDS by creating the Forum for Collaborative HIV Research, forming e-mail lists that provided a forum for people experiencing different manifestations of these metabolic complications and pressuring the pharmaceutical companies to begin looking at their own drugs to see if they were contributing to any metabolic problems. Most of the symptoms related to body fat redistribution are cosmetic and not serious at least in the short term. However, the body shape changes create a new look of AIDS that most of those affected find discomforting and stigmatizing. On the other hand, more evidence is showing the long-term effect of increases in lipids may be manifesting itself as heart disease, bone problems, and lactic acidosis. The need is becoming greater to find out what is happening and intervene before life-threatening conditions develop.
While guidelines have existed for lowering cholesterol and triglycerides in the general population, up until now there has been no HIV treatment guidance for physicians related to lipodystrophy and lipoatrophy besides the medical journals and conference abstracts. But now one of the results of collaboration in AIDS research is a new report compiled by the International AIDS Society U.S.A. (IAS), a 12-member panel of some of the leading researchers in the field. The guidelines were released in the Journal of Acquired Immune Deficiency Syndrome (Volume 31, No. 3) in November 2002. Visit www.iasusa.org for a copy.
The report suggests recommendations that are meant to help guide physicians into the management and diagnosis of the complications. Before the guidelines so much of the syndrome was misunderstood and baffling to many in the HIV arena. Now there is more understanding as to the cause of lipodystrophy, even though the panelists admit the syndrome is far from being completely understood. They recommend the best that can be done today is to monitor people on antiretroviral therapy and diagnose correctly, treat with lipid lowering agents in some cases, and switch or at worst, stop antiviral drugs if risks outweigh the benefits. There is also data that shows the risk of heart disease in HIV-positive and HIV-negative individuals to be comparable even though race, cigarette smoking, and other factors may lead one to expect a significantly higher risk in HIV-positive people.
The IAS Guidelines report helps to understand metabolic complications by breaking them down into categories and then presenting the medical background, recommendations for assessment and monitoring, and the known therapy that may help treat the symptoms.
In HIV, metformin was looked at in small studies and appeared to help reduce insulin levels, waist circumference, blood pressure and risk of heart disease. Thiazolidinediones increase insulin sensitivity in people with HIV with documented insulin resistance and increased blood lipids. However, the guidelines urge care in side effects related to these drugs. In the absence of more treatments, the IAS guidelines suggest a balanced diet and regular exercise for everyone regardless of HIV status. Also, people with HIV who are overweight are urged to lose weight since obesity is a contributing risk factor for diabetes.
Years of medical research has shown that heart disease is probably the most serious effect of elevated lipid levels. In HIV-negative individuals, age, family history, gender, smoking, diabetes, hypertension and menopausal status among women are factors associated with increased risk of cardiovascular disease. Therefore, the same risks and preventative efforts such as stopping smoking and watching weight are also recommended for people with HIV. Lifestyle adjustments with diet changes and exercise also make sense. Lipid-lowering agents are showing good results thus far for those with severe lipid problems, though they often do not reduce the levels to normal. Longitudinal studies looking at heart disease have not been performed in HIV since it is a relatively new disease. It may be a while before we can associate anti-HIV drugs with heart disease. Since it is not something we can wait for studies to discern, it makes sense to follow good heart disease prevention efforts anyway. However, for those with a prior history of elevated lipid levels or a family history of heart disease, switching from a protease inhibitor-containing regimen should be considered if it is an option.
Another life-threatening concern is pancreatitis, which can be forewarned by monitoring triglyceride levels. Again, the IAS guidelines will help direct the physician to the best treatment option for the individual patient.
Other host factors have been characterized to be associated with fat distribution abnormalities. Older age, baseline or change in body mass index, duration of HIV infection, effectiveness of drug therapy, immune restoration with drug therapy, and white race have been documented. One of the cruelties of body fat redistribution in HIV are that women are more likely to see fat gain while men experience more fat loss.
Unfortunately, like a broken record in these guidelines, the underlying cause of fat redistribution has not yet been identified and that is why definitive treatment remains elusive. Possible therapies are listed in the guidelines but should be considered in the context of other metabolic abnormalities in each individual. Switching or stopping anti-HIV drugs has thus far not shown to be effective in reversal of fat gain, however some improvement in lipoatrophy was seen in one study that switched Ziagen (abacavir) or Retrovir (AZT) for Zerit (d4T, stauvidine). Mitochondria are microscopic cellular organs that control cell life and are the source of cellular energy. Studies show they become damaged by certain nucleoside analogs. We know that Zerit causes mitochondria damage that may eventually trigger events that cause fat redistribution. Mitochondria damage may also be the cause of drug-related nerve damage and other symptoms.
Metformin, testosterone, human growth hormone and the thiazolidinediones may improve fat gain but there are complexities with each therapy. As with lipid abnormalities, diet and exercise remain areas of intervention also under investigation. In the "body fat redistribution" scenario much more work needs to be done to discern what is going on and how to treat. Body shape changes are a tangible, visible malady that signify HIV infection and therefore can further stigmatize people with HIV.
Since there is no treatment at all for facial wasting, one dramatic Band-Aid approach is utilizing different types of implants. Few studies have been performed with implants such as New-Fill, and even fewer qualified plastic surgeons are trained to perform them in people with HIV. The procedures are expensive and require many treatments over time. Implants may, however, be the only recourse for those who are severely affected.
For people co-infected with hepatitis C and being treated with ribavirin, there is a greater risk for elevated lactate in the blood. There is no current treatment for lowering lactic acid other than interruption of anti-HIV drugs, and by the time the syndrome is reversed it may be too late to simply stop therapy. Various complementary therapies have shown limited success in other mitochondrial diseases.
Unfortunately, the IAS guidelines provide little earth shattering or new information. It is clear there is still a lot of ambiguity about HIV metabolic complications and that is frustrating for many who are living with the syndrome, tired of waiting for answers. Despite the frustration, it is also clear that incremental progress is being made. Many studies are underway and more are planned to tease out the incidence, causes, treatments of and risk factors for metabolic complications. One thing is for sure: As people live longer with HIV there will be more problems with long-term side effects, aging and the issues of a broken immune system. Metabolic complications highlight the fact that while we have potent therapies for slowing progression of HIV, the drugs we have are deficient, and disease progression remains a mystery. We simply must do better. Researchers and pharmaceutical companies need to continue to explore new ways to control HIV and better yet, find ways to bolster and improve the immune system.
The guidelines are geared to help the physician help his or her patients. However, each person must be treated as an individual with the guidelines as a frame of reference. Every patient will have his or her own unique situation. The guidelines can assist by providing the needed resources for monitoring and diagnosis on an individual basis.
At the Barcelona International AIDS Conference a person living with AIDS having suffered from the effects of metabolic complications spoke out in one session. He was a long-term survivor and had suffered side effects and many serious health set-backs. He said, "It is a cruel irony that 5% of those PWAs worldwide who have access to drugs are ambivalent about them because of the side effects, the medicalization of our bodies, and the uncertainty of the long term impact." Many people on anti-HIV drugs are frightened by the future of life-long therapy. They may even go on drug holidays or stop completely. People who are newly diagnosed see the "look" of people on anti-HIV drugs and delay or refuse to start them. Either scenario poses a serious public health conundrum for care providers and patients alike.
It seems a long time since the days of AIDS wasting, when people with HIV mirrored the look of Holocaust victims. Then anti-HIV drugs brought us the "Lazurus effect" -- seemingly reversing the effect of AIDS. Even with so many unanswered questions, it is obvious that the benefits of treatment outweigh the risks. More prospective studies need to be done in order to find the reasons behind metabolic complications, so that living with HIV can be completely manageable.
My Lipo LifeAs a dancer, I used to spend every day in front of a mirror perfecting my craft. I became familiar with the way my body moved and I worked hard to maintain my physique. Dancers have to look their best because their bodies are their canvas and the mirror is simply one of their tools.
My goal was always to look as good as I could, but when I look at myself today after retiring from dance 13 years ago, I see the look of AIDS. It's an upsetting feeling seeing myself virtually deformed by anti-HIV drugs. Vanity aside, I admit that much of what I see is the aging process, that which everyone has to deal with. But now, as a person living with AIDS for 13 years -- as long as my ballet career -- I am also coping with the effects of antiretroviral drugs.
Admittedly, along with my will to fight AIDS, the drugs have kept me alive but at the same time I am cursed by their side effects. I have had to pay a price for survival. That price is the craggy faced, pot-bellied look I see in the mirror on a daily basis.
You see the effect of AIDS drugs all around. Those misshapen bodies -- flat butts and deep crevassed faces. It's the look of AIDS in the HAART (highly active antiretroviral therapy) era. Yet, many of us are thriving despite the look. AIDS should have taken us a long time ago. Some say it's a double-edged sword. A risk versus benefit. Unfortunately, we are faced with the dilemma of "the look" if we want to survive.
I first noticed a bloated belly about six years ago. I thought it was positive as I had only just recovered from severe weight loss with AIDS wasting. A big belly was as Martha Stewart says, "a good thing." Little did I know that I was experiencing a new phenomenon, wholly misunderstood by researchers and doctors. Lipodystrophy had set in before my very eyes. The effects were so blatant that I was actually asked by a noted AIDS metabolic researcher to be his "poster boy" for one of his lipodystrophy talks.
I began using human growth hormone to treat the bloated belly and it worked fairly well. But when I would visit family or friends after months being away, they would confide in me that I looked "bad." I realized I looked a lot like I had years ago when I was sick with AIDS wasting, but mostly I felt pretty damn good.
It's tough these days maintaining my health and my body with a fragile immune system and a virus that refuses to die. And I am constantly aware of the way people stare a little longer, curious as to know what's wrong. I guess I'll have to live with the rudeness. It is totally frustrating to know there is little I can do for my wasted face. Facial implants, the current Band-Aid, are out of the question because of the high cost, and insurance refuses to cover "cosmetic" surgery, which is actually reconstructive surgery to reverse the effects of drugs and disease.
So, I fight for more promising AIDS therapies with fewer side effects. I will force myself to cope with "the look" and just be thankful I am still alive. At least I have lived long enough to be called a long-term survivor and look in the mirror. -- Matt Sharp