Adverse Effects Associated with Antiretroviral Therapy
In recent years, excitement about the benefits of combination anti-HIV therapy has been tempered by a growing awareness of the problems that accompany the use of anti-HIV drugs. In addition to drug resistance and the difficulty of adhering to complex regimens, side effects associated with highly active antiretroviral therapy (HAART) have become a major concern.
Side effects due to anti-HIV drugs are not new. Since the late 1980s, the earliest drugs used to treat HIV infection -- AZT (Retrovir) and other nucleoside analogs, generally at higher doses than are currently used -- were associated with several adverse events including nausea, diarrhea, muscle disease (myopathy), and hematologic effects (e.g., bone marrow suppression leading to anemia and low white blood cell counts).
However, the most recently approved class of anti-HIV drugs -- the protease inhibitors -- has been associated with a new set of strange side effects including metabolic abnormalities and changes in body fat distribution. The magnitude and unusual nature of HAART-associated adverse effects have contributed to the current rethinking and debate about anti-HIV therapy. Indeed, these side effects are worrisome enough that some physicians are questioning the value of early treatment, and researchers have begun to explore new treatment strategies that allow for the use of fewer drugs for shorter periods.
However, some adverse effects are not discovered until a drug has been approved and marketed and is used by thousands of people, as was the case with the metabolic side effects associated with the protease inhibitors. Many anti-HIV drugs were granted accelerated approval by the U.S. Food and Drug Administration (FDA), and thus did not undergo the typical Phase IV (postmarket) testing. Pharmaceutical company package inserts are required to list adverse reactions that are seen during clinical trials.
The occurrence of side effects can vary dramatically among different people. Some people experience frequent and severe adverse reactions that necessitate dose reductions or discontinuation of treatment; others have side effects that are uncomfortable or annoying and can interfere with their daily quality of life; still others experience few or no adverse reactions. Although it is impossible to predict in advance who will experience side effects, adverse reactions do tend to be especially severe in people with advanced HIV disease.
It is important to note that many types of symptoms associated with use of anti-HIV drugs -- including peripheral neuropathy, gastrointestinal symptoms, mental symptoms, and certain metabolic changes -- are also found in people with HIV infection who are not taking anti-HIV therapy, especially those with later-stage disease and/or high viral loads. Sometimes it is difficult to determine whether a symptom is related to HIV infection or whether it is a drug side effect.
A 1998 study by the University of California at San Francisco's Center for AIDS Prevention Studies found that concern about side effects was one of the primary factors deterring people from starting HAART. The reduction in quality of life associated with some anti-HIV drugs is particularly troubling in people with early stage disease who feel well and are experiencing few or no symptoms related to HIV infection. Side effects can play a large role in discouraging adherence to therapy, which may in turn impact the development of drug resistance.
Several measures have proved helpful in managing gastrointestinal side effects. In many cases, the body adjusts to medications with continued use, and symptoms subside on their own. If a drug does not need to be taken on an empty stomach, taking it with food may help to reduce nausea and vomiting. A number of prescription antiemetic medications are available to help control nausea, including ondansetron (Zofran), lorazepam (Ativan), metoclopramide (Reglan), and prochlorperazine (Compazine); the latter two drugs should be used cautiously due to the risk of their own side effects, including movement disorders (tardive dyskinesia).
If the cause of diarrhea has been carefully evaluated and it is not related to an infection or another underlying condition (e.g., lactose intolerance), over-the-counter drugs such as loperamide (Imodium AD), attapulgite (Kaopectate), or psyllium derivatives (e.g., Metamucil), or stronger prescription drugs such as diphenoxylate (Lomotil) or pancrelipase (Ultrase), may help keep it under control. Calcium supplement tablets have been shown to alleviate diarrhea associated with nelfinavir; however, people should consult their physicians before taking supplemental calcium.
Dietary changes, such as eating several small meals or snacks throughout the day and reducing consumption of fats, dairy products, and spicy foods, may help control nausea and diarrhea. Many people find alternative therapies beneficial, including acupuncture, wrist acupressure, and herbal remedies. Mint and ginger can relieve nausea, and acidophilus capsules may help control diarrhea. Marijuana and its synthetic derivative dronabinol (Marinol) have been shown to reduce nausea and have the added benefit of stimulating the appetite. For more information on managing nausea and diarrhea, see "Nausea and Vomiting" (BETA, June 1997) and "Diarrhea" (BETA, June 1997). With both vomiting and diarrhea, it is important to avoid dehydration and electrolyte imbalances. Balanced sports drinks such as Gatorade, or a mixture of salt and sugar in water, can help prevent both problems.
Peripheral nerve damage is characterized by tingling, burning, pain, numbness, and/or weakness. Some people have described the feeling as being similar to wearing thick gloves or socks. Symptoms usually subside a month or two after stopping the drugs, but in some cases nerve damage may be permanent. The chances of permanent nerve damage may be lessened if drugs are discontinued as soon as symptoms of neuropathy emerge. The symptoms of drug-induced peripheral neuropathy may be reduced by taking certain antidepressant drugs such as amitriptyline (Elavil), desipramine (Norpramin), or antiseizure medications such as gabapentin (Neurontin). Experimental nerve growth factor has also shown benefits. Other relief measures include acupuncture, massage, soaking the hands or feet in cool water, and avoiding tight gloves or footwear.
Paresthesias are unusual sensations such as prickling, tingling, or numbness. Tingling around the mouth (circumoral paresthesia) is associated with the protease inhibitors amprenavir (Agenerase) and ritonavir.
Anti-HIV drugs can also affect the brain, leading to symptoms such as headache, dizziness, mental confusion, and inability to concentrate -- although these symptoms may also be due to HIV itself. Some drugs affect the mood, resulting in depression or anxiety. Several anti-HIV drugs are known to cause either insomnia or drowsiness, and efavirenz (Sustiva) is associated with unusual dreams and nightmares. Starting efavirenz with the anti-anxiety drug lorazepam may help prevent mental side effects, and these symptoms often subside or disappear over time with continued treatment.
At the 14th Annual Medical Management of AIDS Conference in December 1999, Toby Maurer, M.D., of San Francisco General Hospital described a skin condition that may be a newly recognized side effect of HAART: a red, flat or bumpy, possibly itchy rash that begins shortly after starting an anti-HIV drug regimen and lasts for about a month. Anti-HIV drugs may also cause more severe skin reactions characterized by shedding of the outer layers of skin and/or mucous membranes (exfoliation).
Some drugs, notably indinavir (Crixivan) and d4T, have been associated with dry skin, while others can cause itchiness (pruritis); itchiness should not be ignored, since it can be a sign of liver dysfunction. Skin rashes and itchiness can often be treated with oral antihistamines such as diphenhydramine (Benadryl) or hydroxyzine (Atarax). Certain drugs, including some antibiotics, can increase sensitivity to light (photosensitivity), leading to rapid and severe sunburn; persons taking these drugs should avoid the sun or wear protective clothing and use a strong sunscreen.
Some anti-HIV drugs -- notably nevirapine and delavirdine -- can cause an unusual, life-threatening reaction called Stevens-Johnson syndrome. The syndrome begins with flu-like symptoms, fever, and muscle and joint pains, followed by a severe blistering rash affecting the skin and mucous membranes. Any rash should be reported to a health-care provider, and people who develop these symptoms should contact their physicians or visit an emergency room immediately.
Elevated liver enzymes have been reported in people taking all three currently approved classes of anti-HIV drugs. Cases of more severe liver damage (drug-induced hepatitis), including liver failure, have been reported in people taking the protease inhibitors indinavir and ritonavir, and the NNRTI drug nevirapine. Mark Sulkowski, M.D., and colleagues from Johns Hopkins University reported in the January 5, 2000 issue of the Journal of the American Medical Association that after six months of various HAART regimens, some 10% of people in their study experienced liver damage severe enough to warrant stopping anti-HIV therapy; half of these cases occurred in people taking ritonavir.
Adverse drug reactions affecting the liver are more likely in people who have chronic hepatitis B or C, or other types of preexisting liver damage (for instance due to heavy alcohol use). Just over half of the participants in Dr. Sulkowski's study had chronic viral hepatitis in addition to HIV; these people were nearly four times as likely to develop severe liver toxicity associated with anti-HIV drugs. According to Dr. Sulkowski, "Ritonavir was far and away the most toxic drug. If you have a choice, it may be prudent in a patient with hepatitis C to avoid using ritonavir if you can." All people taking HAART should have liver function tests done every month for the first three months after starting a new drug regimen and, if normal, every three to six months thereafter.
Symptoms of pancreatitis may include abdominal pain, nausea, vomiting, constipation, and jaundice. People at more advanced stages of HIV disease and those with previous pancreas problems are at a higher risk for pancreatitis, as are those who have a history of heavy alcohol consumption. Pancreatitis is also associated with elevated levels of blood triglycerides and other fats, which are often seen in people taking protease inhibitors. Increased blood levels of the enzyme amylase may indicate damage to the pancreas, and people taking HAART should have their amylase levels monitored if they are experiencing symptoms that suggest pancreatitis. Severe pancreatitis can be fatal.
In addition to kidney stones, anti-HIV drugs may also cause kidney toxicity. In one study, a form of kidney damage called proximal renal tubular dysfunction occurred in 32% of persons taking adefovir (Preveon) for 48 weeks (see "Selected Highlights from the 12th World AIDS Conference," BETA, October 1998). This condition, which resembles Fanconi's syndrome, can be life-threatening, causing low phosphate and high creatinine levels and can potentially lead to acute kidney failure. The high level of toxicity is one reason the FDA declined to approve the drug last November. Warning signs of kidney toxicity include increased levels of creatinine in the blood and protein or glucose in the urine; people taking HAART should have these levels checked every three to six months.
Specific treatments for people experiencing bone marrow suppression are aimed at stimulating the precursor cells that produce various types of blood cells. Erythropoietin (Epogen, Procrit) is used to stimulate the production of red blood cells. Granulocyte colony-stimulating factor (filgrastim or Neupogen) and granulocyte-macrophage colony-stimulating factor (sargramostim or Leukine) both stimulate white blood cell production.
Researchers still do not understand what causes these symptoms -- although there are several theories -- or even whether they are side effects of HAART, an outcome of the body's altered immune response, or a manifestation of long-term HIV infection itself. The symptoms have been seen in a number of people with HIV who are not taking protease inhibitors (see "Selected Highlights from the 6th Conference on Retroviruses and Opportunistic Infections," BETA, April 1999).
One recent theory involves mitochondrial toxicity. Mitochondria are organelles in cells that produce energy by metabolizing fat and sugar byproducts. Mitochondrial toxicity is signaled by elevated blood levels of lactate (hyperlactatemia or lactic acidosis) and can be associated with muscle damage, neuropathy, pancreatitis, liver failure, and fatty growths (lipomas). Mitochondrial toxicity is a known side effect of nucleoside analog drugs. For a detailed discussion of metabolic abnormalities and body fat changes in people taking HAART, see "Body Fat Changes: More than Lipodystrophy" (BETA, January 1999) and "HAART Attack: Metabolic Disorders During Long-Term Antiretroviral Therapy" (BETA, April 1999).
The warning signs of hyperglycemia and diabetes include increased thirst and hunger, unexplained weight loss, increased urination, nocturnal diarrhea, fatigue, and dry, itchy skin. In a July 1997 warning about cases of hyperglycemia and diabetes associated with combination anti-HIV therapy, the FDA recommended that physicians should monitor the blood sugar levels of their patients taking HAART every month for the first three months, and then every three to six months, unless symptoms suggest more frequent monitoring.
Diabetes can often be controlled with diet modification and, if necessary, oral glucose-lowering medication such as glipizide (Glucotrol), glyburide (Micronase), metformin (Glucophage), pioglitazone (Actos), repaglinide (Prandin), and rosiglitazone (Avandia); another antidiabetes drug, troglitazone (Rezulin), was taken off the market by the FDA in March because it can cause liver toxicity. It appears that these drugs are effective in people with drug-induced diabetes; however, their long-term interactions with anti-HIV drugs are unknown.
Physicians should carefully monitor the blood fat and cholesterol levels of people taking combination anti-HIV therapy. Mary Romeyn, M.D., an HIV physician in San Francisco, suggests annual monitoring of cholesterol and fasting triglyceride levels, with additional tests one month after a new drug is added to a regimen and more frequent monitoring of persons whose levels are elevated on the first test. Several studies suggest that blood lipid levels return to normal when protease inhibitors are discontinued.
High triglyceride and cholesterol levels can be treated with diet modifications and oral medications. Medications used to treat high triglyceride levels include niacin, gemfibrozil (Lopid), and probucol (Lorelco). Drugs used to reduce cholesterol levels include atorvastatin (Lipitor), lovastatin (Mevacor), pravastatin (Pravachol), and simvastatin (Zocor). Studies are just beginning on the use of triglyceride- and cholesterol-lowering drugs in people with HIV taking HAART (see "Conference Coverage" in this issue of BETA).
Because the statin drugs are metabolized by the same liver enzymes as the protease inhibitors, they may further strain the liver and can interact dangerously with anti-HIV drugs; atorvastatin has been reported to drastically reduce blood levels of saquinavir (Fortovase). Because of this, many physicians avoid using atorvastatin, lovastatin, or simvastatin in people taking HAART. Due to the possibility of liver toxicity, liver function tests should be monitored every four to six weeks. In addition, because of the risk of muscle inflammation (myositis), creatine phosphokinase levels should also be monitored.
Elevated blood fats may not be the only factor predisposing people taking HAART to heart disease. At the 7th Conference on Retroviruses and Opportunistic Infections (CROI) in January/February 2000, James Sosman, M.D., and colleagues from the University of Wisconsin reported that protease inhibitors can affect the endothelium, or blood vessel linings. Speaking at a meeting of the American Heart Association last fall, Dr. Sosman noted, "We need to be taking the long-term cardiac care of HIV patients who are using protease inhibitors more seriously."
Also at the 7th CROI, D.L. Johnson and colleagues reported that protease inhibitor therapy was associated with an increase in systolic blood pressure, another risk factor for cardiovascular disease. Jack Stapleton, M.D., and colleagues from the University of Iowa College of Medicine has reported on several cases of deep vein thrombosis (blood clotting) or pulmonary embolism (blockage of blood vessels in the lung by a migrating piece of clotted blood) in persons taking combination regimens that included indinavir, nelfinavir, ritonavir, or saquinavir.
In addition to medications that lower blood fats and cholesterol, common sense measures such as diet modification (reducing the consumption of foods high in sugar, fats, and cholesterol), aerobic exercise, and smoking cessation are likely to be as beneficial in reducing heart disease for HIV positive people as they are for HIV negative people.
Body fat changes have been associated with all of the approved protease inhibitors except amprenavir; such changes have also been associated with viral suppression in some people with long-term HIV infection who have not taken protease inhibitors. In some studies, body fat redistribution has improved in some but not all people after changing or discontinuing the protease inhibitor in the person's drug regimen. Several studies have shown that body fat changes appear most often in persons who are responding well to treatment that is reducing their viral load.
Currently no methods for medically managing body fat changes are universally accepted. However, Ramon Torres, M.D., of St. Vincent's Medical Center, Donald Kotler, M.D., of St. Luke's-Roosevelt Hospital, and other researchers have reported that fat accumulation in the neck and abdomen decreased in persons taking recombinant human growth hormone (Serostim). Bernard Bihari, M.D., a New York physician who frequently champions alternative therapies for HIV, has reported that the narcotic antagonist naltrexone (Revia) appears to have a protective effect against peripheral fat loss. Some people have resorted to surgical procedures such as liposuction or fat resection to remove excess fat from around the neck and from the abdomen, and implants to fill out sunken cheeks. However, liposuction is risky and appears temporary, since excess fat may return if HAART is continued.
Some of these adverse reactions affect the whole body, including fever, chills, and malaise, a general "flu-like" feeling. Fatigue, an unusual, prolonged tiredness, has been reported in people taking any of the three approved classes of anti-HIV drugs. Some side effects such as loss of appetite (anorexia) and altered taste sensations (associated with both protease inhibitors and nucleoside analogs) can affect the ability to eat and thus lead to weight loss. Muscle damage (myopathy) may occur with AZT. Some drugs are also associated with muscle and joint pain (myalgia and arthralgia, respectively). Adverse cardiac effects (other than those associated with elevated blood fat levels, as described above) may include heart palpitations and loss of normal heart rhythm (arrhythmia).
Recently there have been reports of several new side effects associated with HAART regimens, ranging from gout to ingrown toenails. At the 7th CROI, Amy Colson, M.D., and colleagues from Brigham and Women's Hospital in Boston reported that sexual dysfunction (erectile difficulties or loss of libido) was three times more likely to occur in men taking protease inhibitors than in men not taking these drugs. Fifty-two out of 274 HIV positive men first reported sexual dysfunction after starting a protease inhibitor. The researchers noted that the approval of sildenafil (Viagra) in the spring of 1998 may have increased the number of men seeking treatment for erectile dysfunction; sildenafil should be used cautiously by men taking protease inhibitors due to the potential for drug interaction.
Avascular necrosis of the hip bones was first reported at the Interscience Conference on Antimicrobial Agents and Chemotherapy in September 1998. At the 7th CROI, Pablo Tebas, M.D., and colleagues from Washington University in St. Louis reported that 50% of 64 participants taking protease inhibitors in one study experienced osteopenia (mild-to-moderate bone mineral loss) and 21% experienced osteoporosis (severe bone loss), compared to 6% of those not taking the drugs; men were twice as likely as women to experience osteoporosis, an interesting finding because among HIV negative people, osteoporosis is most likely to affect postmenopausal women.
Jennifer Hoy, M.D., of Alfred Hospital in Melbourne, Australia, and colleagues reported that 28% of 80 participants in her study experienced osteopenia and 9% experienced osteoporosis. It is not yet clear why anti-HIV drugs might cause these symptoms or what is the best way to manage them, although there may be a role for periodic bone density scans.
Some 3-5% of people who take abacavir, the most recently approved nucleoside analog, experience a severe hypersensitivity reaction characterized by nausea, fever, fatigue, and flu-like symptoms, which may be followed by a generalized measles-like rash; in January, abacavir manufacturer Glaxo Wellcome added sore throat, cough, and shortness of breath to the list of symptoms that may signal a hypersensitivity reaction. Although symptoms typically subside when the drug is stopped, an even more severe, potentially fatal, reaction may occur if abacavir is restarted. People who experience these symptoms when taking abacavir should contact their physicians or an emergency room immediately; once they stop taking abacavir, they should not restart the drug.
People with HIV should report all side effects, even those that seem minor, to a health-care provider. If an adverse reaction is severe -- such as a blistering rash, a high fever, or the symptoms of an abacavir hypersensitivity reaction -- see a provider or go to an emergency room immediately.
Sometimes adverse reactions are related to the additive effects and interactions that result when drugs are used in combination. In some cases, adverse reactions are most severe when a drug is first started and may lessen over time if a person can wait them out. With some drugs, side effects can be controlled by starting with small doses that are gradually increased. This type of desensitization protocol is often used for nevirapine, ritonavir, and sulfa drugs used to treat certain opportunistic infections.
In some cases, side effects cannot be managed well enough to allow an acceptable quality of life. Since different people react differently to different drugs -- and because some drugs in each class are associated with more side effects than others -- it may be possible to adjust drug dosages or to switch to other medications that provide similar benefits with fewer side effects. For example, among the nucleoside analogs, 3TC is associated with few side effects, and hypersensitivity reactions due to abacavir are uncommon. People with HIV and their physicians should try to devise individualized treatment regimens that provide the greatest benefit with the fewest possible side effects. However, people with HIV should not attempt to adjust doses or change medications on their own without consulting a physician; the likelihood of drug interactions and the possibility of developing drug-resistant HIV when drugs are stopped make it important to seek expert advice.
Reports of adverse metabolic effects associated with protease inhibitors are cause for concern; indeed, some researchers have begun to question the value of early treatment for asymptomatic people with HIV and to explore new treatment strategies. In the words of Keith Henry, "The major goal of HIV therapy is to maintain the long-term health of the patient while avoiding drug-related toxicity and preserving viable future treatment options . . . Early, aggressive therapy often prematurely exposes patients to risks for medication-related side effects and resistance. A more cautious, patient-focused, long-term approach to therapy would help foster studies of alternate strategies, such as delayed initiation of therapy, protease-sparing therapy, class-sparing therapy, planned drug interruptions, switches in therapy, and immune-based therapy. It is time for clinicians to rethink their approach to the treatment of HIV infection."
Planned drug interruptions, also known as structured treatment interruption (STI), is currently a hot topic among researchers who hope that periodically stopping anti-HIV drugs will stimulate the immune system and give patients a break from side effects. To date, small studies in a few patients suggest that STI may be feasible. Researchers have cautioned, however, that this approach is "still highly experimental and unproven." Short, careful, periodic treatment interruptions may one day allow HIV to be treated more like cancer. Cancer chemotherapy can be extremely unpleasant, resulting in nausea, vomiting, hair loss, blood deficiencies, and other symptoms. Yet, as Jay Levy, M.D., has noted, "No cancer patient takes three or four chemotherapeutic drugs for a lifetime." (For more information on STI in this issue of BETA, see "Structured Treatment Interruption" and "HIV Persists Despite HAART".)
The debate about anti-HIV drug side effects and treatment strategies made its way into the popular press this past winter. Journalist Celia Farber in Gear magazine and medical columnist Nicholas Regush on the ABC News Web site both wrote scathing commentaries on side effects associated with HAART, what Regush called, "a drug-induced nightmare of unprecedented magnitude." He continued, "[People taking HAART] develop dangerously high cholesterol and diabetes. Some of them have suffered gross deformities . . . A name more worthy of the toxic effects listed on the drug labels would be 'medical poisons.'"
Farber and Regush were countered in a widely distributed article by AIDS treatment activists Tim Horn and Linda Grinberg. In the words of Horn and Grinberg, both themselves HIV positive, "A handful of case reports confirming heart attacks among people receiving HAART cannot be compared to the devastation of the '80s and early '90s as we faced the loss of our loved ones to untreatable AIDS-related infections and our own mortality.Yes, fat redistribution is horrific and these miraculous drugs may leave us wanting. But, let us not deny our history, nor forget our past. Let us not forget the macabre horror of witnessing the wasted, KS-riddled shells of almost an entire generation slowly going blind or mad, struck down in their prime. Let us not forget the grim reality that AIDS is more lethal than any drug and that death is never pretty."
For many people, the benefits of keeping HIV in check will outweigh the immediate negative side effects and long-term risks of combination anti-HIV therapy. Others, especially those with early stage HIV infection who have few or no disease-related symptoms, may decide that maintaining a good current quality of life is more important to them. Each person with HIV and his or her physicians must balance the overall benefits against the overall risks.
Indeed, the most recent revision of the Department of Health and Human Service's Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, updated in February, categorizes drugs as "preferred" on the basis of pill burden, dosing frequency, toxicity, and other considerations, not just their ability to suppress viral load. According to the panel that prepared the guidelines, "Physicians and patients must weigh the risks and benefits of starting antiretroviral therapy and make individualized and informed decisions."
Related BETA Article: Side Effects Reported with Approved Anti-HIV Drugs
Liz Highleyman is a freelance medical writer.
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This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.