Also see parts one, two and four.

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.

Diabetes, Insulin Resistance and Impaired Glucose Tolerance

Insulin resistance and impaired glucose tolerance -- both indications of diabetes, are the first category in the IAS guidelines. Insulin resistance is when the body's cells are not as sensitive to the affects of insulin -- it takes more and more insulin for sugar to be transported into the cells of the body [>200 u/day for one week as opposed to 30-50 u/day]. This taxes the pancreas, which ultimately wears out. Eventually, more insulin is required to the point that what the pancreas can produce is insufficient to get the job done. Impaired glucose tolerance is when the body doesn't use insulin efficiently or doesn't produce enough insulin, resulting in excess levels of sugar in the blood. And as we all know, too much sugar causes all sorts of problems. Both are indications of diabetes. It is still unknown how many people with HIV and insulin resistance will go on to develop diabetes. We know in HIV-negative people that insulin resistance is related to increased risk of heart complications, but whether the same risk holds true for people with HIV is still not established. Before anti-HIV drugs, insulin resistance, glucose intolerance and diabetes were rarely seen in HIV-positive individuals. However, studies show 40% of people with HIV on a regimen containing a protease inhibitor will have increased glucose levels. There are clues as to the potential mechanisms of the effect of protease inhibitors on insulin resistance, but nothing hard and fast. Comparative studies need to be done to tease out this problem. One recommendation is for physicians to determine whether their patients have had abnormal fasting glucose levels and/or have a history of diabetes in their families, before starting them on a protease inhibitor. Research has also shown that nucleoside analogs cause a fat breakdown called lipolysis that can contribute to insulin resistance, so all HIV drug classes are suspected.

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.

Lipid Abnormalities

Lipid abnormalities, changes in important fat molecules in the blood called cholesterol and triglyceride, are covered extensively in the IAS guidelines. Two types of elevated lipids seen in HIV are low-density lipo-protein (LDL) and triglycerides, both of which are related to heart disease, although currently very minimal evidence links elevated triglycerides to heart disease. High-density lipoprotein (HDL) is actually necessary to transport lipids from the blood to tissues in the body. HDL is sometimes lowered by use of antiretrovirals. Before HAART many people with HIV had lowered levels of cholesterol, then known as a positive thing. But now, protease inhibitors have been associated with increases in LDL cholesterol and triglycerides. Genetic factors may also have some influence. While a powerful protease inhibitor, ritonavir (Norvir) has the worst effect on lipid levels in studies thus far, the guidelines admit there is not yet enough information to rule out the role of other antiretrovirals. For instance, emerging data links both Zerit (d4T) and Sustiva (efavirenz) with increases in cholesterol levels. As with insulin resistance, it is not at all clear what the mechanism is for increased lipid abnormalities with antiretrovirals. These are important and ongoing research questions given the growing AIDS pharmacopoeia we are faced with, and the general lack of long-term, in-depth analysis of drugs by pharmaceutical companies.

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.

Body Fat Redistribution

Body fat redistribution is seen in 40% to 50% of people with HIV. When talking about body fat redistribution we mean a fat gain in the trunk and breast and/or a fat loss in the face, buttocks, arms and legs. We are also referring to buffalo hump, an increase of fat on the upper back and neck, and lipomas, individual fat nodules that are not necessarily symmetrical. The redistribution is seen at various levels and in different combinations in different populations. In HIV it has been difficult to ascertain just how many people are experiencing these body fat changes because of the variability in reporting. When body fat changes were first reported they were referred to as "Crix belly" because Crixivan was the most widely used protease inhibitor at the time. But in fact body fat changes were seen before the advent of protease inhibitors so it cannot be certain that Crixivan or any other protease inhibitor is the sole cause. On the contrary, there is a new study by Carl Grunfeld from the San Francisco Veterans Hospital claiming that there is no difference in trunk size when comparing HIV-positives to HIV-negatives. But the study has caused great debate since we have witnessed that this is a glaring problem in people with HIV. There is no definitive anti-HIV drug that has been related to body fat redistribution. The IAS Guidelines suggest there is an association with nucleoside analogs, and maybe acceleration with an added protease inhibitor. Surely, combinations including the two drug classes were widely used when the syndrome was first recognized.

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.

Lactic Acidosis

Lactic acidosis consists of elevated levels of lactate in the blood. It is a serious, mostly fatal condition that has been seen in HIV. The IAS guidelines say that it is only reported in 1.5% to 2.5% of people with HIV on therapy but mortality is 80%. Symptoms include fatigue, weight loss, nausea, abdominal pain, difficulty breathing, and irregular heartbeat. There are no differences regarding gender, race or ethnicity as once suspected, although pregnant women may be at higher risk. There is an association with six months or greater use of antiretroviral therapies. Once again, mitochondria damage is implicated as the underlying factor for lactic acidosis.

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.

Bone Disease

One peculiar area related to metabolic dysfunction is bone disease. Many people with HIV are having hip replacement surgery, a serious procedure typically seen in the elderly. Since 1980, osteonecrosis (bone death because of inadequate blood circulation) has been reported in people with HIV, but with widespread use of potent antiretroviral therapy, a discernible increase has been noted. One survey showed 4.4% of people having scans had necrosis of the hip. The condition is also related to corticosteroid use and elevated lipid levels, but has not been associated with anti-HIV therapies thus far. On the other hand, osteoporosis, a demineralization in the bone, was rarely seen before antiretroviral use. The guidelines show osteopenia (bone mineral depletion) in 22% to 50% and osteoporosis in 3% to 21% of those receiving a protease inhibitor containing regimen. Studies to show which anti-HIV drugs are most responsible for bone disorders need to be performed. It is still not clear what is happening with bone disease, so the IAS guidelines do not suggest routine screening. Adequate intake of calcium and vitamin D is recommended to all people with HIV as well as appropriate weight-bearing exercise.

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.