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.

Common Types of Adverse Effects

Anti-HIV therapy affects the entire body, and the various drugs may cause adverse reactions in almost all organs and systems. This is not surprising, since the drugs often interfere with genetic and cellular processes that are common to both viruses and human cells. However, certain classes of drugs are more often associated with specific types of side effects; for example, some nucleoside analogs are associated with low blood cell counts and mitochondrial toxicity, some non-nucleoside reverse transcriptase inhibitors (NNRTIs) are associated with skin reactions, and long-term treatment, especially with regimens that include a protease inhibitor, is associated with increased blood fat levels and body fat redistribution. Some of the most common types of adverse events associated with antiretroviral drugs are described below.

Gastrointestinal Adverse Effects

The most common side effects associated with anti-HIV drugs are those that affect the stomach and intestines. Both nucleoside analog and protease inhibitor drugs frequently cause gastrointestinal side effects. Typical gastrointestinal side effects include diarrhea, nausea, vomiting, and abdominal cramps; intestinal gas (flatulence), acid reflux ("heartburn"), and constipation may also occur. Among the protease inhibitors, nelfinavir is the most common cause of diarrhea, although diarrhea associated with full-dose ritonavir tends to be more severe. Gastrointestinal side effects are not only unpleasant and detrimental to quality of life but can also interfere with the absorption of water, food, and medications, potentially leading to dehydration, disruptions in body chemistry, malnutrition, weight loss, and inadequate drug levels.

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, lorazepam, metoclopramide, and prochlorperazine; 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, attapulgite, or psyllium derivatives (e.g., Metamucil), or stronger prescription drugs such as diphenoxylate or pancrelipase, 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 have been shown to reduce nausea and have the added benefit of stimulating the appetite. For more information on managing nausea and diarrhea. With both vomiting and diarrhea, it is important to avoid dehydration and electrolyte imbalances. Balanced mixture of salt and sugar in water, can help prevent both problems.

Mental and Neurological Adverse Drug Effects

Many drug side effects involve the brain and nervous system. Peripheral neuropathy (damage to the peripheral nerves, most often in the hands and feet) is one of the most debilitating adverse effects of some nucleoside analog drugs, notably ddC (zalcitabine), ddI (didanosine), and d4T (stavudine). HIV infection itself may lead to neuropathy, but nerve damage in the hands happens more quickly when it occurs as a drug adverse effect.

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, desipramine, or antiseizure medications such as gabapentin. 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 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 is associated with unusual dreams and nightmares. Starting efavirenz with the anti-anxiety drug lorazepam may help prevent mental adverse effects, and these symptoms often subside or disappear over time with continued treatment.

Skin Adverse Drug Effects

Many drugs are known to cause skin reactions, and among the anti-HIV drugs, this is most likely to occur with the NNRTIs nevirapine, delavirdine, and efavirenz. A severe rash was reported in about 8% of people taking nevirapine in clinical trials. Abacavir can cause a potentially fatal hypersensitivity reaction, which may include a rash, in 3-5% of people who take the drug. Rashes are often red in color, may be flat or raised, are often itchy, and may feature blisters or vesicles (fluid-filled bumps); a blistering rash may be a sign of life-threatening Stevens-Johnson syndrome. 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 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 or hydroxyzine. 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.

Mild to moderate rash may be managed by symptomatic treatment with antihistamine and continuation of offending agent. Therapy should be discontinued if skin rash progresses to severe in nature accompanied by blisters, fever, conjunctivitis and edema. Any rash should be reported to a health-care provider, and people who develop these symptoms should be asked to contact their physicians or visit an emergency room immediately.

Liver Adverse Drug Effects

The liver processes most drugs and toxins in the body, and taking medications can adversely affect liver function. Liver damage may be indicated by elevated blood levels of the liver enzymes ALT (Alanine Transferase) and AST (Aspartate Transferase). Many different factors can lead to elevated liver enzyme levels, including several common drugs, viral hepatitis, and consumption of alcohol; people with HIV and their physicians should be concerned when levels reach the upper limits of normal in a person taking anti-HIV drugs. Liver damage may also lead to elevated levels of alkaline phosphatase or bilirubin (a pigment). Elevated bilirubin levels may result in jaundice, a condition characterized by yellowing of the skin and whites of the eyes, or by mental confusion in severe cases. Symptoms of liver toxicity may occur early or later in the course of therapy.

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.

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). All people taking HAART (Highly Active Antiretroviral Therapy) 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.

Pancreas Adverse Effects

The pancreas is an organ that produces digestive enzymes and sugar-regulating hormones. Some anti-HIV drugs, notably ddI, ddC, and 3TC have been associated with pancreatitis. 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.

Kidney Adverse Effects

The kidneys are organs located near the lower back that filter the blood and produce urine. Minerals and some drugs can crystallize and accumulate in the kidneys, leading to the formation of kidney stones (nephrolithiasis). Kidney stones were seen in nearly 10% of people taking indinavir in clinical trials. Symptoms of kidney stones include pain in the back, flank, or groin, and possibly blood in the urine. To reduce the risk of developing kidney stones when taking indinavir, drink at least 6-8 glasses of water each day.

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 dipivoxil (Experimental Anti-HIV drug) for 48 weeks. 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 drug was subsequently disapproved for marketing due to high levels of kidney toxicity. 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.

Hematological Adverse Effects

Some drugs including Zidovudine, trimethoprim/sulfamethoxazole (Co-trimoxazole), and several anticancer drugs can cause hematological, or blood-related, adverse effects. These drugs can damage the bone marrow, affecting its ability to produce new blood cells. Because all blood cells are produced in the bone marrow, bone marrow damage can lead to low red blood cell levels (anemia), which can result in fatigue and weakness; low white cell levels (leukopenia, neutropenia, or granulocytopenia), which can lead to reduced ability to fight infections; and low levels of platelets (thrombocytopenia), which can affect the blood's ability to clot. Zidovudine is associated with the most severe hematologic adverse effects and can cause decrease in both red and white blood cells. Other nucleoside analogs Zalcitabine, Didanosine, Stavudine, and Lamivudine can cause low white cell counts; abacavir is not associated with blood-related adverse effects.

Specific treatments for people experiencing bone marrow suppression are aimed at stimulating the precursor cells that produce various types of blood cells. Erythropoietin is used to stimulate the production of red blood cells. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor both stimulate white blood cell production.

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