The Good, the Bad, and the Ugly
Managing drug-related side effects.
by Emily Bass

Fortune-tellers wanted: knowledge of HIV a plus. With protease inhibitors a mere four years old, it sometimes seems like a crystal ball is our best bet for forecasting long-term side effects. By now we know that highly active antiretroviral therapy, or HAART, has achieved miracles when it comes to extending the life span of people with HIV. But people on HAART have also taken a leap of faith: These potent drugs cause myriad side effects that affect everyone differently. For some healthy individuals, starting HIV therapy means feeling sicker, at least for a little while, than they were without drugs. While some problems may be mild or short-term, how serious are the long-term side effects of HAART?

Unfortunately, anecdotes are nearly all the information we've got about how these drugs are affecting major organs like the liver, kidney, and heart. But already the emerging picture is sobering. What small studies there are suggest that the average body takes quite a beating from anti-HIV medications. Check out the package insert for any HIV drug: Most include a laundry list of potential side effects. And since these drugs are taken in combination, there's a greater risk of toxicities caused by adverse drug interactions.

Common side effects that occur with anti-HIV drugs include fatigue, diarrhea, nausea, and rash, all of which may be manageable but still affect one's quality of life on a daily basis. More serious problems include hair loss, kidney stones, hepatitis, high cholesterol and other fat-related disorders that stress the heart, and nerve damage. Recently, at the Sixth Conference on Retroviruses and Opportunistic Infections in Chicago, new side effects were added to this list: Oral warts, loss of bone density (avascular necrosis), and other complications detailed below.

In many cases, longer lives are putting people at greater risk for developing side effects or illnesses associated with aging. While HAART regimens add years to people's lives, health concerns like cancer, diabetes, and heart disease that were once dismissed as irrelevant to HIV-positive people are coming to the fore. "We need to start asking questions about risk factors like smoking and drinking," says Minnesota HIV doctor Keith Henry. "It's a very different attitude from 'I don't want to take all your fun away because I just told you that you have AIDS.'" After seeing a few of his patients develop sudden cardiac problems last year, Henry warned that patients on HAART may be at higher risk for heart attack.

Here's a brief look at what we know so far about how HAART drugs affect several major organs and how to best manage a variety of side effects. Remember that regular exercise, good nutrition, a daily multivitamin, and other supplements can help counter long-term toxicities and may also help ease or prevent organ damage. (For a more complete list, see "Complementary Care" in the September issue of HIV Plus. Also check out the DAAIR website for holistic treatments at http://www.immunet.org.)

Heart and Blood
Call it the "X-Files." After nearly a year of focused research, HIV docs still aren't sure what causes "Buffalo Humps," "Crix Belly," or huge increases in breast size in some women. These dramatic and disfiguring changes of body size and shape have turned up in a growing number of people taking protease inhibitors, as well as with some of those taking other anti-HIV drugs. They are linked to a body fat-redistribution and metabolic disorder called lipodystrophy that resembles Syndrome X, a condition found in HIV-negative people. Other symptoms include skyrocketing levels of lipids and triglycerides (fats in the blood) and changes in blood-sugar tolerance that may lead to insulin resistance and diabetes. "I went from a size 7 to a size 16," says Eleanor Mitchell, a board member of New York's AIDS Treatment Data Network. "I didn't mind that as much as ending up in the emergency department two times a week feeling like I was having a heart attack." Mitchell developed angina and congestive heart failure after more than a year on Viracept and Combivir.

By now there have been many reports about lipodystrophy and considerable debate-but no agreement-on why it develops and how to treat it. The burning question is how much of a long-term health danger it poses. At the Chicago conference, a French study of 624 people found that after an average of 18 months on protease inhibitors, 78 percent had some evidence of metabolic disorder. In contrast, a Merck-sponsored study of its drug Crixivan found that after three years, only 19 percent of those on a Crix combo had developed metabolic problems (high triglyceride levels).

With such a mixed bag of data, experts are cautious about long-term forecasts. Instead, they stress the importance of paying attention to other warning signs. "There's research suggesting that the changes are not huge in terms of risk [on their own]," says Dr. Morris Schambelan, an endocrinologist at the University of California at San Francisco. "It's when you add in other risk factors like drinking, smoking, and a sedentary lifestyle that the risk becomes severe."

Treatment
In Chicago, a handful of small, uncontrolled clinical trials offered ideas but no decisive answers about treating HAART-related lipid disorders. Metformin, an anti-diabetes drug, lowers triglyceride levels and decreases insulin resistance but can cause or worsen kidney problems. Metformin also causes weight loss, which may or may not be due to the loss of excess fat. Another experimental lipid-lowering drug, troglitazone, can impair liver function and should be used with caution. Meanwhile, a recommended National Cholesterol Education Program regimen of diet, exercise, and lipid-lowering drugs like gemfibrozil and atorvastatin (Lipitor) was effective in less than 50 percent of patients and may increase the risk of eye problems (myopathy). Atorvastatin and other cholesterol-lowering drugs in the "statin" family interact with other anti-HIV drugs and should be used with caution. Changing to a non-protease regimen may be another option, but this doesn't always reverse the changes in body size and may not be as effective against HIV.

Other treatments for fat disorders include use of human growth hormone (hGH) like Serono's Serostim, now covered by Medicaid. The current recommended dose of Serostim may also be higher than necessary for those with lower body weight, some of whom have reported nasty side effects. Tip: It may be possible to mix lower doses-and stretch this pricey liquid-by mixing Serostim with Abbott's bacteriostatic water, say treatment advocates. Oxandrin, a 17-alkylated steroid, can also work to treat wasting but should be used with caution since it can stress the liver and increase LDL, the "bad kind" of cholesterol.

Kidneys
The kidneys are two small, ingeniously designed organs that collect and filter fluids from the blood-up to 47 gallons a day-3.2 pints of which leave the body as urine. When a kidney starts to filter less, it's called "renal insufficiency." Many common drugs, like antibiotics and anti-inflammatory drugs, aren't friendly to the kidneys (an effect called "nephrotoxic"). Crixivan, for instance, can lead to a buildup of drug crystals and kidney stones that block nephrons, the kidney's slender filtration tubes. Preveon is linked to a serious kidney disorder called Fanconi's syndrome.

Studies have shown that the average Crixivan regimen is enough to tax the kidneys, sometimes severely. A New England Journal of Medicine report this February cited two cases of kidney failure, or renal atrophy, in men who'd taken Crixivan for 18 or more months. A French study of severe toxicities linked protease inhibitors to at least 12 cases of kidney stones. In a study of women, about one quarter of the participants developed kidney problems after a year on protease inhibitors. Experts caution that kidney problems can't be predicted solely on the basis of the drugs in your medicine cabinet. Many people, particularly African Americans and IV drug users, experience HIV-related kidney failure as the disease progresses.

Whether these kidney problems will increase over time is an open question. "Are there cumulative risks? I wish we knew," says Paul Klotman, Chief of Nephrology at Mount Sinai Medical Center in New York. "The main issue with some of the newer drugs like adefovir [more commonly known as Preveon]," he continues, "is whether or not the 60 percent of people who don't get problems in the first six months will develop them over the long term." Experts note it's important to balance the risk versus benefit of these drugs: HAART therapy may also be protective, limiting viral damage to the kidneys.

Treatment
Steroids and angiotensin-converting enzyme blockers have all shown some activity in reducing or reversing kidney damage. Not all damage is reversible, so prevention is key. Drinking lots and lots of fluids-think up to eight liters a day-can help flush out drug crystals that can block the the kidneys and develop into kidney stones. You can also track kidney function with regular checkups at your doctor's office (get a urinalysis and check blood levels of creatinine and bicarbonate). Elevated levels of uric acid (hyperuricemia) can also be a sign of kidney trouble, as can aches and pains in the joints, back, and flank, urination at night (nocturia), foamy or bloody urine, and swelling of the legs or eyelids.

Dropping doses can also help. New research suggests that a Norvir-Crixivan combo (400 mg each, twice a day) reduces kidney problems without sacri- ficing drug potency. In March, Gilead Sciences announced that halving the recommended doses of Preveon to 60 milligrams a day might be an effective option that's easier on the kidneys.

Peripheral Nervous System
Wheelchairs, stumbling, and painful walking are just a few of the things you don't see in the outdoorsy, athlete-packed ads for anti-HIV drugs. But they're an unfortunate part of reality for people with nerve damage, or neuropathy, caused by HIV or medication. Numbness, tingling, and loss of feeling in the hands and feet are some of the most common symptoms. When it comes to anti-HIV drugs, the culprits are the "d" drugs-ddI, d4T, and ddC-all of which can cause or exacerbate neuropathy, especially when used for long periods of time. Hydroxyurea can also cause nerve problems.

"If you follow trends over more than 10 years, it looks like the incidence of neuropathy is going up," says Dr. David Simpson, director of neurological AIDS research at Mt. Sinai. That's because most people with HIV face a triple threat when it comes to nerve damage: First, the virus itself; second, anti-HIV drugs that are toxic, and third, though rare, HIV drug-related insulin resistance, or diabetes. "If a patient has neuropathy, look at the glucose levels," suggests Simpson, who has found that many doctors misdiagnose neuropathy, which can be spotted with a history of neurological symptoms, including a simple ankle reflex check. Neuropathy risk also increases with age and low CD4 T-cell counts.

Treatment
Neuropathy can be a serious stumbling block to staying on HIV medication. "I have one patient with undetectable viral levels whose neuropathy is so bad, he's crippled," says New York AIDS doc Howard Grossman. For now, Grossman has taken his patient off the "d" drugs and is using the experimental immune-booster IL-2 in hopes that his patient's bolstered immune system will fight the virus while his nerves recover. Unfortunately, IL-2 can also be a tough drug to take. Of course, such extreme solutions aren't an option for everyone. More research is needed to identify candidate treatments for reversing nerve damage. Right now, Genentech's recombinant nerve growth factor (r-NGF), is a promising agent in development. Clinical r-NGF trials have been encouraging, but Genentech is reportedly not pursuing HIV-related approval of its drug.

Other neuropathy treatments provide partial symptomatic relief. Anti-depressants like amitriptyline and nortriptyline can work in some patients. Lamotrigine is a promising new anti-convulsant that may require dose elevation. Other experimental strategies include using mexiletine (heart medicine) and prouridine. Painkillers can also help and may be used liberally, although some opiates can be addictive. Herbal remedies, physical exercise, and acupuncture may also help: Several doctors recommend a combo of calcium (500 mg twice a day), magnesium (250 mg twice a day), and vitamin B-6, which should be used with caution since high doses can damage peripheral nerves (dose range: 25-50 mg twice a day). Doses may vary, so check with your doctor. One promising, relatively nontoxic treatment is the lidocaine, or Lidoderm, patch.

Liver
The liver is a powerhouse organ responsible for, among other things, breaking down nutrients, vitamins, and drugs, and getting rid of toxic substances such as alcohol. Like the kidneys, the liver is dealt a double blow by HIV (the virus enters liver cells at a very early phase of infection) and the drugs that treat it. Liver problems are common with many prescription drugs. At the Chicago conference, a French study showed that liver toxicity was the leading cause of hospitalization in people taking protease inhibitors, occurring in 32 out of 168 patients. A recent British study found severe liver disease in eight out of 200 patients who began or switched to HAART.

In many of these cases, liver disease is linked to co-infection with hepatitis B and C, which carries a high risk of liver cirrhosis and cancer. "What I'm seeing is people with undetectable viral loads doing their best to adhere, and then liver disease gets the best of them," says Mardge Cohen, a lead investigator at the Chicago site of the federal Women's Interagency Health Study. Various studies estimate hepatitis C is present in 9 percent to 30 percent of people with HIV. Some HAART combos can cause a flare-up of pre-existing hepatitis; in other cases these flare-ups are the first sign of hepatitis infection. Doctors say it's possible to "treat through" these flares, which can be quite severe.

Can people with underlying liver disease remain on anti-HIV drugs for many years? It may be a challenge. A small study recently reported that 13 percent of participants co-infected with hepatitis C and HIV were unable to remain on HAART. A German study found that blood levels of those taking Norvir were twice as high in individuals co-infected with hep C and HIV, suggesting that doses may need to be modified in this group.

Will HAART itself poison the liver over time? While we don't have concrete data, experts are sounding the alarm about the potential compli- cations of long-term management of hepatitis and HIV. "Unpublished data indicates that, other than AIDS, the leading cause of death for people living with HIV is liver disease," says liver expert Doug Dieterich. "It's likely that this will increase over time." As with the kidneys, however, it's important to balance that risk against the benefit of HIV drugs, which quell HIV infection in the liver.

Treatment
Early diagnosis of hepatitis may be a crucial tool for avoiding or minimizing liver complications. A blood test at your doctor's office can help you track liver function with liver enzyme tests. Most specialists recommend using highly sensitive polymerase chain reaction (PCR) blood tests for hepatitis C if an antibody test comes back negative. Alpha-interferon and ribavirin (prescribed together as Schering-Plough's Rebetron) are the two most common treatments for hepatitis C. The anti-HIV drug Preveon works against hepatitis B but stresses the kidneys, so talk to your doctor about the risks and benefits of using it. 3TC is also active against hepatitis B (see "HIV-Related Illnesses," page 31). Research is also under way using pegylated interferon, which requires weekly dosing. Meanwhile, milk thistle herb, dandelion root, and thioctic acid/ALA alpha-lipoic acid are among the nutritional supplements that support liver function.

When it comes to drug-related liver toxicity, Crixivan and Norvir appear to be the worst offenders. While Crix liver problems often emerge within the first month of treatment, Norvir toxicity develops after six to nine months, says Dieterich. Nucleoside analog drugs also cause lactic acidosis, a rare but serious condition marked by nausea, vomiting, and shortness of breath.