Bulletin of Experimental Treatments for AIDS, April, 1998
Liz Highleyman
Many different side effects are associated with the use of anti-HIV drugs. The occurrence of side effects plays a large role in adherence to drug regimens, which in turn can impact the development of drug resistance. Side effects such as nausea and diarrhea which affect drug absorption can also contribute to drug resistance.
A recent study by the University of California at San Francisco's Center for AIDS Prevention Studies found that concern about short-term and long-term side effects was one of the primary factors deterring people with HIV from starting combination anti-HIV therapy. Side effects may be especially feared by people in the early stages of HIV disease who feel well and are experiencing no symptoms. Such people must weigh the potential for keeping HIV in check with early treatment against the possibility of a reduction in their quality of life due to adverse drug effects.
The frequency and severity of side effects vary greatly from person to person. In some cases, side effects are worse when a drug is first started and may lessen over time. Side effects are often more frequent and more severe in people with advanced HIV disease who are more immunocompromised. Adverse events may be worse when drugs are used in combination due to interactions or additive effects (symptoms due to drug interactions are not discussed in this article; see "Protease Inhibitor Drug Interactions," BETA, September 1997).
Some people experience few or no side effects from anti-HIV medications. Furthermore, people with HIV are often able to manage side effects so that they can benefit from potent anti-HIV treatment while maintaining a good quality of life.
Basic information on the occurrence of drug side effects comes from clinical trials. Phase II trials are designed to assess drug safety. Phase III effectiveness trials include more participants and are more likely to uncover less common side effects. However, some side effects are not discovered until a drug has been approved and marketed, and is being used by many thousands of people.
Clinical trial researchers typically report the frequency of side effects experienced by users of a drug or combination regimen under study. If the occurrence of a side effect is, say, 20%, this means that 20% of the participants in a trial experienced the side effect, not that each participant experienced the side effect 20% of the time. People in a trial who are taking placebo, or mock therapy, also sometimes experience side effects, so researchers usually report the rates of adverse events in groups receiving therapy compared to the rates in groups receiving placebo. Pharmaceutical company package inserts generally include all the side effects that may have been associated with a drug, even those that occur rarely.
NOTE: In clinical trials, symptoms are graded on the basis of severity and frequency.
| Side Effect | Grade 1 | Grade 2 | Grade 3 | Grade 4 |
| Nausea | mild or transient; can maintain food intake | moderate discomfort; food intake decreased for less than 3 days | severe discomfort; minimal food intake for 3 or more days | hospitalization required |
| Fever | 100-101.5° F | 101.6-102.9° F | 103-105° F | above 105° F |
| Skin rash | redness, itchiness | maculopapular rash or dry desquamation | blister formation or moist desquamation or ulceration | exfoliative dermatitis; mucous membrane involvement; Stevens-Johnson syndrome; necrosis requiring surgery |
| Fatigue | < 25% decrease in normal activity | 25-50% decrease in normal activity | > 50% decrease in normal activity | unable to care for self |
Side effects may affect all systems of the body, and may range from serious toxicities that necessitate stopping a drug completely, to side effects that are not dangerous but may be uncomfortable or annoying and may interfere with daily life. Some of the most common types of adverse events associated with antiretroviral drugs are described below.
The most common side effects associated with anti-HIV drugs are those that affect the stomach and intestines. Abdominal cramps, nausea, vomiting and diarrhea often occur when taking certain drugs. Some people also experience constipation, "heartburn" (acid reflux) and intestinal gas. Gastrointestinal symptoms have been associated with all classes of antiretroviral drugs, but some drugs in a class are more likely to produce these side effects than others. For example, nelfinavir is more often associated with diarrhea than the other FDA-approved protease inhibitors. Symptoms may range from mild to severe, and may be intermittent or continuous. If vomiting or diarrhea is severe and prolonged, body chemistry may be disrupted, drugs may not be absorbed adequately and proper nutrition may be difficult to maintain.
Several anti-HIV drugs can cause skin rashes. Rashes are especially likely to occur in people taking the non-nucleoside reverse transcriptase inhibitors nevirapine and delavirdine and, to a lesser extent, efavirenz. Skin rashes may indicate an allergic or hypersensitivity reaction. A rash is often red in color, may be flat or raised, and may feature blisters or vesicles (fluid-filled bumps). A more severe rash may lead to exfoliation (shedding of the outer layers of skin and mucous membranes), ulcer formation and/or necrosis (localized tissue death). Some drugs (for example d4T and indinavir) have been associated with dry skin, while others can cause pruritis (itchiness). Certain drugs may increase photosensitivity (sensitivity to light), leading to rapid and severe sunburning.
In rare cases, a life-threatening condition called Stevens-Johnson syndrome may develop. Twenty cases have been reported in people taking regimens that contain nevirapine. The syndrome begins with a prodromal phase characterized by flu-like symptoms, fever, and muscle and joint pain, followed by a severe blistering rash affecting the skin and mucous membranes. A person who develops these symptoms should contact a physician or visit an emergency room immediately.
All antiretroviral drugs can cause side effects involving the liver. The liver processes drugs in the body, and can become overwhelmed if drug levels are high. Liver toxicity may be indicated by increased blood levels of the liver enzymes ALT and AST (measured as liver function tests) and/or by elevated alkaline phosphatase or bilirubin levels. Elevated bilirubin levels may lead to jaundice, a yellowing of the skin and whites of the eyes. Numerous physicians have reported increased liver enzyme levels in patients using anti-HIV drugs. More serious manifestations of liver toxicity include clinical hepatitis and long-term liver damage.
Side effects involving the liver may appear immediately after starting a new drug or up to 6 months later. Liver-related side effects are more common and more severe in people who have had viral hepatitis or who have pre-existing liver damage. Anyone with pre-existing liver problems should discuss them with their physician before starting anti-HIV treatment. Regular monitoring of liver function tests is recommended.
There have been reports of cases of severe drug-induced hepatitis in people taking protease inhibitors. In the March 29, 1997 issue of The Lancet, N. Brau and colleagues reported on 3 cases of severe liver inflammation in patients taking indinavir. One patient died and the other 2 recovered after they stopped taking the drug. However, according to indinavir manufacturer Merck and Company, there were no reported cases of severe hepatitis in over 2,000 participants in clinical trials of the drug, so this adverse event appears uncommon. J. Arribas and colleagues from Madrid, Spain reported at the 5th Conference on Retroviruses and Opportunistic Infections in February 1998 that 7% of their patients taking ritonavir (many of whom were co-infected with the hepatitis C virus) developed acute liver inflammation soon after starting the drug.
The pancreas is an abdominal organ that produces digestive enzymes. Some anti-HIV drugs have been associated with pancreatitis, an inflammation of the pancreas. Symptoms of pancreatitis may include abdominal pain, nausea, vomiting, constipation and jaundice. The condition has most often been associated with the use of ddI. People at more advanced stages of HIV disease and those with previous pancreas problems are at a higher risk for pancreatitis. Increased blood levels of the enzyme amylase may indicate damage to the pancreas. Severe pancreatitis can be fatal.
The kidneys are organs located near the lower back that filter the blood and produce urine. Kidney stones (nephrolithiasis) are accumulations of material such as minerals or drug crystals in the kidneys and urinary tract. Symptoms include severe pain in the back, flank or groin and, in some cases, blood in the urine. Kidney stones are particularly associated with the use of indinavir. The rate of kidney stone formation in people taking indinavir was about 4% in clinical trials, but more recent studies have shown rates as high as 12% (see "Research Notes," BETA, January 1998). To reduce the chance of developing kidney stones due to indinavir, drink at least 6-8 glasses of water each day. Merck and Company researchers recently reported results of a study that suggested that high-fat foods may lead to precipitation or settling of indinavir crystals in the kidneys.
Some people taking protease inhibitors may experience kidney damage. The June 1997 issue of AIDS reported on 3 patients taking standard doses of ritonavir plus saquinavir who experienced kidney-related adverse events. Warning signs of kidney toxicity include increased levels of creatinine in the blood and elevated levels of protein or glucose in the urine.
A variety of side effects involve the nervous system -- the body's system of sensory and motor nerves, the spinal cord and the brain. Peripheral neuropathy is damage to the peripheral nerves, most often in the feet and hands. Such nerve damage may lead to tingling, burning sensations, pain, numbness or weakness. The condition is most often associated with the use of ddC, ddI and d4T, but may also be due to nerve damage caused by HIV disease itself. Peripheral neuropathy may be especially severe if 2 or more drugs that can cause the symptom are used together. The condition typically subsides within a couple of months after drugs are stopped, but in some cases it may be permanent.
Paresthesias are unusual sensations such as prickling, tingling or numbness. Tingling around the mouth (circumoral paresthesia) is associated with the use of ritonavir and possibly amprenavir. Other neurological side effects may include headache, dizziness, confusion, and difficulties with speech or movement.
Various anti-HIV drugs have been associated with mental side effects including confusion, anxiety, paranoia and depression. People who already have mental symptoms may experience a worsening of their condition. It can be difficult to distinguish between drug side effects and symptoms due to pre-existing mental conditions, HIV-associated encephalopathy, or opportunistic infections such as toxoplasmosis or progressive multifocal leukoencephalopathy. Any change in mental status should be reported to a physician immediately.
Some drugs (including AZT and several anti-cancer drugs) can cause bone marrow toxicity. Damage to the bone marrow may lead to the loss of the ability to produce new blood cells. This can result in anemia (low red blood cell level), leukopenia (low leukocyte, or white blood cell level), neutropenia (low level of neutrophils, a type of immune cell) and thrombocytopenia (low level of platelets, which may lead to poor blood clotting).
Various anti-HIV drugs have been associated with other adverse events including fevers, chills, fatigue (unusual, prolonged tiredness) and insomnia (inability to sleep). Malaise is a general ill feeling often described as "flu-like." Certain side effects such as anorexia (loss of appetite), altered taste sensations and oral ulcers can affect the ability to eat. Myopathy is muscle weakness or degeneration, most often associated with AZT. Myalgia is pain in the muscles and arthralgia is pain in the joints. Cardiac side effects may include heart palpitations and loss of normal heart rhythm (arrhythmia).
Some people are unable to tolerate certain drugs and develop allergic or hypersensitivity reactions; such reactions seem to be more common in people with AIDS than among the population as a whole. Hypersensitivity reactions can range from a skin rash or swelling to life-threatening anaphylaxis characterized by difficulty breathing and a sharp decrease in blood pressure. Rare hypersensitivity reactions have been associated with several anti-HIV drugs, including protease inhibitors and the experimental nucleoside analog abacavir (see below). People taking sulfa drugs (for example, TMP-SMX to prevent Pneumocystis carinii pneumonia) may be especially at risk because protease inhibitors may affect the metabolism of sulfa drugs in the body, causing an intensification of common sulfa-related hypersensitivity reactions (see "Research Notes," BETA, January 1998).
According to a report from Glaxo Wellcome in December 1997, approximately 2-3% of participants in clinical trials of the experimental nucleoside analog abacavir (brand name Ziagen; also known as 1592) have experienced unusual hypersensitivity reactions. The reaction is characterized by increasing nausea, fever and flu-like symptoms, which may be followed by a generalized measles-like rash. Symptoms occurred several days to 4 weeks after starting abacavir. The symptoms subsided within a couple of days when the drug was stopped, but if abacavir was started again, reactions recurred within hours and were more severe, in some cases including high fever, low blood pressure and face/throat swelling; there has been at least 1 fatal reaction. People who experience systemic symptoms when taking abacavir should contact their physician immediately. Once they stop taking abacavir, they should not restart the drug.
Although many anti-HIV drugs can lead to a wide range of adverse events, certain drugs are most associated with specific side effects. Side effects that have been shown in clinical trials to be associated with specific drugs are shown in the table below.
Side Effects Reported for Specific Anti-HIV DrugsSide effects are listed from most to least common. Specific occurrence percentages are listed in parentheses where known; ranges reflect varying results from different studies. "Special concerns" side effects may not be common, but can be serious.
In addition to the more typical adverse events described above, a variety of unusual side effects have begun to appear in people taking combination anti-HIV therapy that includes protease inhibitors. Although these effects were not seen in initial clinical trials, anecdotal reports from physicians and people taking the drugs began to surface about a year ago. The 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) last September and the 5th Conference on Retroviruses and Opportunistic Infections (CROI) this past February both included several reports on these phenomena.
Most of the unusual side effects have to do with metabolic changes, and include diabetes, high blood levels of triglycerides (fats) and cholesterol, and body fat redistribution. These metabolic changes tend to occur a few months to a year or more after a person starts treatment -- thus the upsurge in reports of these effects last year, since triple combination therapy including protease inhibitors came into widespread use in 1996. Different research teams at CROI reported incidence rates of these side effects ranging from less than 5% to more than 60%.
Some people using each of the currently approved protease inhibitors have developed diabetes or less serious elevations in blood sugar levels (hyperglycemia), or have seen existing diabetes or hyperglycemia worsen. Several studies have shown evidence of insulin resistance in people taking combination therapy, a condition in which the bodyÕs cells do not respond normally to insulin.
In June 1997, the U.S. Food and Drug Administration (FDA) issued a warning letter to physicians indicating that the incidence of diabetes in people taking protease inhibitors appeared to be under 1%. However, some studies have suggested that the incidence rate is higher (see "Research Notes," BETA, January 1998). The warning signs of hyperglycemia and diabetes include increased thirst and hunger, unexplained weight loss, increased urination, fatigue and dry, itchy skin.
The FDA letter noted that the agency had received reports of 83 cases of diabetes in people taking protease inhibitors. Twenty-seven of these people required hospitalization and 6 cases were life-threatening. Diabetes occurred an average of 75 days after starting protease inhibitor therapy. FDA did not suggest that people stop taking anti-HIV drugs, but did recommend that physicians should monitor blood sugar levels.
There have been several reports of elevated blood triglyceride and cholesterol levels in people taking protease inhibitors. Before the advent of protease inhibitor therapy, people with HIV disease often had high triglyceride levels compared to HIV negative people, but not as high as the levels now being seen in people taking combination therapy. Also unusual is the appearance of high cholesterol levels in people taking the drugs; untreated people with HIV tend to have lower cholesterol levels than HIV negative people.
In the short term, high triglyceride levels can lead to pancreatitis. It is unknown what the long-term effects of elevated blood fat levels will be, although it is known that high triglyceride and cholesterol levels are associated with coronary artery disease, strokes and heart attacks. Physicians should regularly monitor blood triglyceride and cholesterol levels of people taking combination anti-HIV therapy.
Perhaps the most talked about side effect attributed to combination anti-HIV therapy is body fat redistribution, or lipodystrophy. These changes have been given several nicknames, including "crix belly," "protease paunch" and "buffalo hump." Typically fat is lost from the thighs, limbs and face, and accumulates in the trunk or at the base of the neck; often overall weight remains the same. K. Miller and colleagues at the National Institutes of Health reported at CROI that computed tomography (CAT) scans, which can visualize the internal soft tissues of the body, show increased fat within the body cavity, not just under the skin. Some people have reported that fat accumulation is accompanied by discomfort or a feeling of "tightness."
At CROI, David Cooper and colleagues from Sydney, Australia reported a 64% positive response when they asked patients taking protease inhibitors whether they had noticed any body shape changes. Fat redistribution appears to occur most often in people who are responding well virologically to anti-HIV treatment. The condition appears similar to Cushing's syndrome, which is caused by a high level of the adrenal hormone cortisol, although the people with HIV experiencing these symptoms typically do not have high cortisol levels.
Hardened fat deposits may accumulate around the midriff or midsection ("protease paunch"). H. Rosenberg and colleagues from Cornell University Medical College reported at CROI that 7% of a group of older patients taking protease inhibitors (median age 38 years old) experienced abdominal fat increases. Fat may also accumulate on the upper back below the neck ("buffalo hump"). Peter Ruane, MD, reported at ICAAC on 3 male patients taking indinavir who developed fatty deposits below the base of the neck. V. Roth and colleagues reported at CROI on 7 patients taking 1 of the 4 approved protease inhibitors who developed "buffalo hump."
Fat redistribution has been associated with all 4 approved protease inhibitors. There have also been reports of fat redistribution in people taking anti-HIV regimens that do not include a protease inhibitor. Stephen Deeks, MD, of San Francisco General Hospital (SFGH), noted during a February 5th BETA LIVE! teleconference that cases of "buffalo hump" were seen 3-4 years ago at SFGH prior to the protease inhibitor era. He pointed out that all people reported to have the condition -- both the earlier SFGH patients and those described in case studies presented at CROI -- were taking 3TC.
Physicians and researchers do not know whether these changes are a side effect of protease inhibitor drugs, a consequence of the drugs' effect on the immune system, a manifestation of HIV disease itself or something else entirely.
Although the metabolic changes experienced by people taking anti-HIV therapy appear similar in many cases to changes caused by certain hormonal imbalances, studies show that people with HIV who experience these symptoms usually do not have abnormal levels of hormones (except for testosterone deficiency in some cases).
Many of the body's metabolic processes are regulated by the liver, and metabolic changes may be related to toxic effects on the liver due to extended use of certain anti-HIV drugs. Carr and colleagues reported at CROI that certain chemicals important for proper metabolism -- including a LDL cholesterol receptor -- resemble a portion of the HIV protease enzyme and may be targeted by protease inhibitor drugs, possibly resulting in metabolic dysfunction.
Some believe that the new side effects may be related to HIV disease status rather than to anti-HIV drugs themselves. For example, wasting syndrome was reported long before the advent of protease inhibitors, and some have attributed the weight gains now being seen to the fact that potent anti-HIV drugs are holding HIV disease in check and allowing the body to regain weight; however, this hypothesis does not explain weight gain confined to specific areas of the body.
Metabolic side effects are more commonly seen in older people with HIV. Dawn Averitt of Project Inform suggests that as people with HIV are living longer they may be succumbing to changes such as abdominal weight gain ("beer belly"), diabetes and high cholesterol that plague the aging HIV negative population as well. However, the side effects now being seen are more exaggerated and develop more rapidly than normal age-related changes.
It is not yet clear what the best course is for people on anti-HIV therapy who are experiencing metabolic changes. Last summer, Lisa Capaldini, MD, told AIDS Treatment News that the metabolic side effects being seen in people taking combination therapy "do not seem to be causing any short-term risk." On the other hand, Mary Romeyn, MD, counters that it cannot be assumed that such a risk is not present. It is not known what, if any, dangers are posed by long-term anti-HIV therapy. However, it is known that high triglyceride and cholesterol levels are associated with increased risk of coronary artery disease and heart attack, and that sustained high glucose levels can lead to a variety of complications.
It may be that the benefits of keeping HIV in check outweigh the long-term dangers of combination therapy. People with HIV and their physicians must balance overall benefits against overall risks. People who are concerned about metabolic side effects should not stop or change drugs without consulting their physician, since doing so may encourage drug resistance and may make future anti-HIV therapy less effective. Research on this issue will continue as patients continue to take anti-HIV drugs for longer periods.
The occurrence of adverse drug events is highly individualized. While some people experience many side effects, others experience few or none. Several steps can be taken to reduce the occurrence of side effects or ameliorate the symptoms of toxicity.
Physicians should inform patients about possible drug side effects so that they are not taken by surprise. However, patients should also be aware that many people do not experience adverse events. Believing that side effects are inevitable may increase the chance of their occurrence, in part due to fear and anxiety.
People with HIV should report all side effects -- even those that seem minor -- to their healthcare provider. Do not attempt to adjust drug doses or change medications without consulting a physician. The likelihood of drug interactions and the possibility of developing drug-resistant HIV make it important to seek expert advice.
With some drugs, side effects may be worse when a drug is first started and may lessen over time. In such cases, a person may be able to "wait through" the worst of the symptoms if he or she knows they will subside. For some drugs, a desensitization protocol can be used, in which a small amount of a drug is given at first and the dose is gradually increased; dose escalation is routinely used for nevirapine, ritonavir and the sulfa drugs.
Specific measures can be taken to manage different types of symptoms. If a drug does not need to be taken on an empty stomach, taking it with food may help to reduce nausea and vomiting. Various prescription antiemetic drugs including prochlorperazine (Compazine), metoclopramide (Reglan) and odansetron (Zofran) can alleviate nausea; however, these drugs may cause their own side effects. Acupuncture, wrist pressure and herbal remedies (for example, mint and ginger) have been used to alleviate nausea. In addition, many people have reported an anti-nausea effect from marijuana or its synthetic derivative dronabinol (Marinol); marijuana also may stimulate the appetite of people experiencing loss of appetite as a drug side effect. For more information, see "Nausea and Vomiting," BETA, June 1997.
Drug-related diarrhea may be controlled by over-the-counter antidiarrhea drugs such as loperamide (Imodium AD), attapulgite (Kaopectate) and Pepto Bismol, bulking agents such as Metamucil, or stronger prescription drugs including diphenoxylate (Lomotil). Alternative therapies for diarrhea include acidophilus capsules, herbs and acupuncture. Dietary measures may include reducing consumption of dairy products, sugar, fat and caffeine. For more suggestions, see "Diarrhea," BETA, June 1997.
With both vomiting and diarrhea, it is important to avoid dehydration and electrolyte imbalances. Sports drinks such as Gatorade, or a mixture of 1 teaspoon of salt and 4 teaspoons of sugar in a liter of water, can help prevent both problems.
Skin rashes and itchiness can often be treated with oral antihistamines such as diphenhydramine (Benadryl) or hydroxyzine (Atarax). Topical corticosteroids may also be beneficial, but should not be used with certain anti-HIV drugs. Avoiding the sun or using a strong sunscreen can help prevent skin damage due to photosensitivity reactions.
The symptoms of drug-induced peripheral neuropathy may be reduced by antidepressant drugs such as amitriptyline (Elavil) or desipramine (Norpramin). Other measures include acupuncture, massage, avoiding tight gloves or footwear and soaking the feet in cool water.
Specific treatments are available for people experiencing bone marrow suppression. Erythropoietin (Epogen) can help rebuild the level of red blood cells. Low levels of certain white blood cells can be treated with granulocyte colony-stimulating factor (Neupogen).
With regard to metabolic side effects, it is too soon to know what measures might be useful. Diabetes can usually be controlled with oral glucose-lowering medication or with insulin injections. High triglyeride and cholesterol levels can be treated by diet modification or with oral medications such as gemfibrozil (Lopid) or clofibrate (Atromid). However, these medications have not been studied for controlling high blood glucose or fat levels associated with anti-HIV drugs, and they may cause additional strain on the liver and kidneys. Common-sense measures such as exercise and smoking cessation may reduce the risk of heart disease in people with high blood fat levels. Testosterone and other hormone levels should be monitored, since they may affect glucose and fat metabolism.
In some cases, side effects cannot be sufficiently managed to allow an acceptable quality of life. In such cases, it may be possible to adjust drug dosages or to switch to other medications that provide similar benefits with fewer side effects. Tailoring drug treatments is a highly individualized process, and some people may better tolerate drugs that cause unacceptable side effects in others.
People have been using anti-HIV drugs for at most 10 years, and usually for far shorter periods. It is not known what long-term side effects may develop in people taking combination therapy over the course of most of their lifetime. Recent reports regarding metabolic effects associated with drug therapy are cause for concern, and more research on long-term side effects is urgently needed. It is also important to study new drug formulations, dosing schedules and delivery systems that allow for maximum therapeutic benefit while maintaining a high quality of life for people with HIV.
Liz Highleyman is Assistant Editor of BETA.
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