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Modifying antiretroviral therapy (ART)

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Also listed as: WAS
Related terms
Background
Author information
Bibliography
Acute toxicities
Chronic toxicities
Life-threatening toxicities
Co-existing medical conditions
Drug resistance

Related Terms
  • Antibodies, auto recessive, B-cells, bone marrow, bone marrow transplant, CBC, genetic disorder, immune system, immunodeficiency, inherited disorder, inherited immunodeficiency, leukocytes, leukemia, lymphoma, lymphocytes, malignancy, platelets, pneumonia, red blood cells, T-cells, thrombocytes, thrombocytopenia, tumor, WASP, white blood cells, Wiskott Aldrich syndrome, Wiskott-Aldrich syndrome protein, X-linked.

Background
  • Wiskott-Aldrich syndrome (WAS) is an inherited, immunodeficiency disorder that occurs almost exclusively in males. The recessive genetic disorder is caused by a mutation in the WAS (Wiskott-Aldrich syndrome) gene, which is an X-linked trait. The gene mutation leads to abnormalities in B- and T-lymphocytes (white blood cells), as well as blood platelet cells. In a healthy individual, the T-cells provide protection against viral and fungal infection, the B cells produce antibodies, and platelets are responsible for blood clotting to prevent blood loss after a blood vessel injury.
  • Individuals diagnosed with WAS suffer from recurrent infections, eczema and thrombocytopenia (low levels of platelets).
  • Before 1935, patients only lived an average of eight months. Today, patients usually live an average of eight years, according to a recent case study. The cause of death is usually attributed to extensive blood loss. However, cancer (especially leukemia) is common and often fatal among WAS patients.
  • The only possible cure for WAS is a bone marrow transplant. However, if a patient's family member is not a possible match for a bone marrow donation, patients may have to wait years for a potential donor. Other aggressive treatments may also increase a patient's life expectancy. For instance, one study found that patients who underwent splenectomy (removal of the spleen) lived to be more than 25 years old. The spleen may harbor too many platelets, and cause a decrease in the number of platelets in circulation. Antibiotics, antivirals, antifungals, chemotherapeutic agents, immunoglobulins and corticosteroids have also been used to relieve symptoms and treat infections and cancer associated with WAS.
  • Researchers estimate that about four people per one million live male births develop the disease in the United States.
  • The syndrome is named after Dr. Robert Anderson Aldrich, an American pediatrician who described the disease in a family of Dutch-Americans in 1954, and Dr Alfred Wiskott, a German pediatrician who discovered the syndrome in 1937. Wiskott described three brothers with a similar disease, whose sisters were unaffected.

Author information
  • This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography
  1. Binder V, Albert MH, Kabus M, et al. The genotype of the original Wiskott phenotype. N Engl J Med. 2006 Oct 26;355(17):1790-3.
  2. Jin Y, Mazza C, Christie JR, et al. Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation. Blood. 2004 Dec 15;104(13):4010-9. Epub 2004 Jul 29.
  3. Natural Standard: The Authority on Integrative Medicine. .
  4. St. Jude Children's Research Hospital. Inherited Immunodeficiencies: Wiskott-Aldrich Syndrome (WAS). .
  5. U.S. Immune Deficiency Foundation. The Wiskott Aldrich Syndrome. .

Acute toxicities
  • Some patients may experience immediate and short-term side effects, called acute toxicity, in response to antiretroviral therapy (ART). This type of reaction usually develops in less than 24 hours after ART is started. Common symptoms include nausea, vomiting, diarrhea, headache, and fatigue.
  • Although acute toxicities are usually not life threatening, the symptoms may interfere with a patient's quality of life and willingness to follow treatment plans.
  • Currently, there are no recommended guidelines for healthcare providers to manage acute toxicities in patients. In some cases, symptoms will resolve without any change in treatment. If acute toxicity can be attributed to a particular drug, or if more severe side effects such as rash, liver toxicity, or anemia (low levels of iron in the blood) occur, a healthcare provider may recommend switching to a different antiretroviral in the same drug class.

Chronic toxicities
  • General: Some serious side effects may develop months to years after antiretroviral therapy (ART) is started. This is called chronic toxicity. Common signs and symptoms of chronic toxicity may include changes in body fat distribution, increased lipid (fat) levels in the blood, and changes in glucose metabolism. Changes in glucose metabolism may lead to the onset or worsening of diabetes.
  • In many cases, these symptoms may be caused by more than one antiretroviral, making it difficult for healthcare providers to properly treat the condition. Certain drugs are more likely to cause chronic toxicities than others. If a patient with chronic toxicity is taking drugs that are known to cause toxicities, these drugs are substituted first.
  • Dyslipidemia: Dyslipidemia, which is abnormal levels of lipids (fat) in the blood, is a sign of chronic toxicity. Most patients with dyslipidemia experience no symptoms, which often allows the condition to progress to heart disease.
  • Protease inhibitors usually cause this condition. Patients react differently to different types of protease inhibitors. Certain protease inhibitors are more likely to cause dyslipidemia in some patients. Switching to a different protease inhibitor has been shown to be an effective treatment for dyslipidemia.
  • Nucleoside reverse transcriptase inhibitors (NRTIs), especially stavudine (Zerit®), have also been shown to cause dyslipidemia. Some NRTIs are more likely to cause dyslipidemia than others. Several studies suggest that taking an NRTI called tenofovir (Viread®) in place of stavudine is an effective treatment.
  • Lipodystrophy: Lipodystrophy, which causes fat to accumulate or atrophy (shrink) in certain areas of the body, is also a sign of chronic toxicity. The condition is most likely to occur 18 months after therapy is started.
  • Protease inhibitors, including amprenavir (Agenerase®), tipranavir (Aptivus®), indinavir (Crixivan®), saquinavir mesylate (Invirase®), lopinavir/ritonavir (Kaletra®), fosamprenavir calcium (Lexiva®), ritonavir (Norvir®), darunavir (Prezista®), atazanavir sulfate (Reyataz®), and nelfinavir mesylate (Viracept®), have been shown to cause lipodystrophy in HIV patients.
  • Patients who take nucleoside reverse transcriptase inhibitors, such as stavudine (Zerit®), in combination with protease inhibitors have an increased risk of developing lipodystrophy, compared to patients who only take protease inhibitors.
  • It is believed that substituting one protease inhibitor for another will only worsen the condition. Therefore, patients with lipodystrophy should discontinue treatment with protease inhibitors after consulting their healthcare providers. Researchers are currently investigating alternative treatment plans for patients who develop lipodystrophy.
  • Insulin resistance: Insulin resistance is a sign of chronic toxicity. This condition can lead to the development or worsening of diabetes. Common symptoms include fatigue, bloating, weight gain, depression, and dark patches of skin.
  • The protease inhibitor called indinavir (Crixivan®) has been shown to cause decreased insulin sensitivity in HIV patients. According to laboratory studies, other protease inhibitors may also cause insulin resistance in HIV patients.
  • Some protease inhibitors are more likely to cause insulin resistance than others. If a patient who is taking a protease inhibitor develops insulin resistance, a different protease inhibitor may be taken instead. Protease inhibitors, including abacavir (Ziagen®), as well as two non-nucleoside reverse transcriptase inhibitors called efavirenz (Sustiva®) and nevirapine (Viramune®), have been shown to be effective substitutes for protease inhibitors that cause insulin resistance. There is insufficient evidence as to whether the protease inhibitor called atazanavir (Reyataz®) is an effective substitute for other protease inhibitors.

Life-threatening toxicities
  • General: Life-threatening toxicities, which are rare, are treated with alternative antiretroviral therapy regimens. Once a patient develops a serious toxic reaction to a drug, that medication should not be taken again in the future.
  • Lactic acidosis: Lactic acidosis is another potentially fatal toxic reaction to antiretroviral therapy. Lactic acidosis occurs when a waste product of glucose, called lactic acid, builds up in the body tissues. If left untreated, this condition can lead to acidosis, which describes increased acidity of the blood. Symptoms may include weight loss, fatigue, general feeling of discomfort, nausea, vomiting, abdominal pain, and shortness of breath.
  • This condition has been reported with all nucleoside reverse transcriptase inhibitors, especially stavudine (Zerit®) and didanosine (Videx®). According to retrospective data, either of these drugs can be substituted with another nucleoside reverse transcriptase inhibitor that is less likely to cause lactic acidosis, such as abacavir (Ziagen®), lamivudine (Epivir®), or tenofovir (Viread®).
  • Skin conditions: Serious skin conditions, such as Stevens-Johnson syndrome (SJS), indicate severe toxicity that may be fatal. These conditions are potentially life threatening because, in severe cases, the lesions can cause significant scarring of the involved organs, which often leads to loss of function of the organ systems. Common symptoms include extensive shedding of the skin, reddening of the skin, inflammation of the skin, blisters, open sores, and dead skin. Skin lesions may occur anywhere on the body, but they are most common on the soles of the feet, palms of the hands, and back of the hands. Clusters of outbreaks generally last about two to four weeks.
  • Skin conditions, such as SJS, are most likely to occur in patients who are taking non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as delavirdine (Rescriptor®), efavirenz (Sustiva®), or nevirapine (Viramune®).

Co-existing medical conditions
  • Pregnancy: Patients who were/are taking antiretroviral medication before becoming pregnant should talk to their healthcare providers to determine the safest and most effective treatments. In general, efavirenz (Sustiva®), stavudine (Zerit®), hydroxyurea (Droxia® or Hydrea®), and the oral liquid formulation of amprenavir (Agenerase®) should not be taken during pregnancy because they may cause harm to the fetus.
  • Combination antiretroviral therapy with zidovudine (Retrovir®) and other antiretrovirals is the standard treatment to prevent the HIV-infected pregnant woman from passing the virus on to her baby. Zidovudine is considered the most effective antiretroviral at preventing HIV transmission from mother to child. Treatment begins after the first trimester (14-34 weeks into pregnancy), when the fetus is less susceptible to harmful side effects of the drug. The exact combination and dosage varies among patients depending on their overall health and severity of their HIV infections. The newborn typically receives zidovudine by mouth every six hours for six weeks after birth.
  • Zidovudine may also be prescribed alone to prevent transmission from an HIV-infected pregnant woman to her baby. However, taking the drug alone is typically less effective at reducing the viral load than combination therapy with other antiretrovirals. Taking only one antiretroviral also increases the mother's risk of developing drug resistance. Once drug resistance occurs, the particular drug can no longer suppress the virus, even if it is taken in the future. This treatment is usually administered after 28 weeks of pregnancy in women who have low levels of HIV in the blood and who are concerned about the side effects antiretrovirals may have on the baby. A single dose of nevirapine and zidovudine is then taken during labor.
  • Liver disorders: Since the liver breaks down antiretroviral drugs, patients with liver disease may have a difficult time tolerating treatment. In general, patients with liver disease take lower doses of antiretrovirals. Patients with liver disease should consult their healthcare providers to determine the safest and most effective treatment.
  • Drug interactions: Because HIV infects and destroys immune cells, HIV patients have an increased risk of developing infections. However, the standard medications or doses used to treat these infections may not be safe for HIV patients because they may interact with antiretrovirals.
  • For instance, rifabutin (Mycobutin®) is often used to treat tuberculosis in patients who do not have HIV. However, this drug should not be used to treat HIV patients who are taking the protease inhibitor saquinavir (Invirase®) or the non-nucleoside reverse transcriptase inhibitor delavirdine (Rescriptor®) because there is an increased risk of serious side effects, such as uveitis (inflammation of the inner eye). Instead, HIV patients take a combination of isoniazid (Nydrazid®), rifampin (Rifadin®, Rimactane®), ethambutol (Myambutol®), and pyrazinamide.
  • Many other types of medications, herbs, and supplements may interact with ART medications. Therefore, patients should consult their healthcare providers and pharmacists before taking any other drugs (prescription or over-the-counter), herbs, or supplements.

Drug resistance
  • In order for anti-HIV drugs to work correctly, they must be taken exactly as prescribed. Skipping doses or not taking the medications correctly can cause the amount of an antiretroviral drug to decrease in the bloodstream. If the drug level becomes too low, HIV can begin reproducing more quickly. The faster HIV reproduces, the more mutations occur, including those that may be resistant to drugs.
  • According to several studies, HIV patients must be more than 95% adherent to their treatment regimens in order for them to remain effective. This means that missing more than one dose a month could decrease the drug's ability to treat HIV.
  • Once a patient becomes resistant to a drug, the medication is no longer effective, even if it is taken in the future. Patients who become resistant to a drug typically replace that drug with another medication from the same class. However, if a patient becomes resistant to a non-nucleoside reverse transcriptase inhibitor (NNRTI), he/she may also be resistant to other drugs within the same class. As a result, patients may have fewer treatment options.
  • Healthcare providers evaluate the effectiveness of treatments by measuring the patient's CD4 cell count. These immune cells are the primary targets of HIV. Healthy individuals have a CD4 cell count between 600 and 1,200 cells per microliter of blood. HIV patients have less than 600 cells per microliter of blood. A patient progresses to AIDS (acquired immune deficiency syndrome) when his/her CD4 cell count is less than 200 cells per microliter of blood. If an adequate CD4 cell count is maintained, the likelihood of the virus mutating into resistant strains, as well as the risk of infection, is decreased.

Copyright © 2011 Natural Standard (www.naturalstandard.com)


The information in this monograph is intended for informational purposes only, and is meant to help users better understand health concerns. Information is based on review of scientific research data, historical practice patterns, and clinical experience. This information should not be interpreted as specific medical advice. Users should consult with a qualified healthcare provider for specific questions regarding therapies, diagnosis and/or health conditions, prior to making therapeutic decisions.

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