Mitochondrial toxicity and NRTIs

Related Terms

Acquired immune deficiency syndrome, acquired immunodeficiency syndrome, antiretroviral therapy, ART, fusion inhibitors, HIV, HIV protease enzyme, human immunodeficiency syndrome, immune defense system, immune system, immunocompromised, immunodeficiency, infection, inhibitor, NNRTIs, non-nucleoside reverse transcriptase inhibitors, nucleotide reverse transcriptase inhibitors, opportunistic infections, polyprotein, protease, protease enzyme, reverse transcriptase inhibitors, virion, virus.

Background

Nucleoside reverse transcriptase inhibitors (NRTIs) are a class of antiretroviral drugs that are used to treat HIV patients. NRTIs, developed in 1987, were the first drugs designed to treat HIV. They serve as faulty DNA building blocks and once they are incorporated into the HIV DNA, the DNA chain cannot be completed. Therefore, the drugs prevent HIV from replicating inside a cell. NRTIs that have been approved by the U.S. Food and Drug Administration (FDA) include: Combivir?, Emtriva?, Epivir?, Epzicom?, Hivid?, Retrovir?, Trizivir?, Truvada?, Videx EC?, Videx?, Viread?, Zerit?, and Ziagen?.
Since HIV primarily targets the body's CD4 T-cells, which are white blood cells that help coordinate the immune system's response to infection and disease, HIV patients are vulnerable to opportunistic infections (OIs). Antiretrovirals are able to suppress HIV boosting the patient's immune system. They have also shown to dramatically decrease the progression of OIs. These drugs cannot cure HIV infection or AIDS.
HIV patients typically receive a combination of antiretroviral drugs because as the virus reproduces different strains emerge and some are resistant to certain drugs. This happens less often when patients adhere to their medication regimens. Therefore, highly active antiretroviral therapy (HAART), which is a combination of drugs from at least two different classes, is recommended.
Currently, the FDA has approved 28 antiretroviral drugs to treat HIV patients. These drugs fall into four major classes: fusion inhibitors, protein inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs).
Both NRTIs and NNRTIs disrupt the reverse transcription stage of the HIV lifecycle. During this stage, an HIV enzyme, called reverse transcriptase, converts the virus' RNA into DNA. NRTIs are made of faulty nucleotides (building blocks), which are used during this conversion. When the reverse transcriptase uses NRTIs, the HIV DNA is not generated correctly. This ultimately prevents the virus from replicating. NNRTIs attach to reverse transcriptase, preventing HIV from converting the HIV RNA into HIV DNA.

Author information

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

Bibliography

AIDSinfo. .
AIDSmap. .
HIV Medicine. .
Natural Standard: The Authority on Integrative Medicine. .
The Body: The Complete HIV/AIDS Resource. .
U.S. Food and Drug Administration. Drugs Use in the Treatment of HIV Infection. .

Function

Nucleoside reverse transcriptase inhibitors (NRTIs), also called nukes, are defective versions of the nucleic acids (building blocks) that HIV needs to replicate. Normally, the HIV enzyme called reverse transcriptase uses the nucleic acids inside the host cell to convert the viral RNA into DNA. When patients take NRTIs, HIV reverse transcriptase mistake the drugs for the real building blocks and uses them to produce defective DNA that cannot be incorporated into the host cell DNA.
Unlike the natural deoxynucleotides substrates, NRTIs do not have a 3'-hydroxyl group on the deoxyribose moiety (part of the DNA molecule that contains a five-carbon sugar). Consequently, once the medication has been incorporated into the viral DNA, the next dosynucleotide cannot form the 5'-3' phophodiester bond that is needed to complete the DNA chain. Therefore, NRTIs prevent HIV from replicating inside the host cells. This process is called chain termination, and NRTIs are classified as competitive substrate inhibitors.

Side effects and mitochondrial toxicity

In general, most patients tolerate treatment with nucleoside reverse transcriptase inhibitors (NRTIs) well. Common side effects during the first weeks of treatment include fatigue, headache, and gastrointestinal problems, which range from mild abdominal discomfort to nausea, vomiting, and diarrhea.
However, NRTIs are capable of causing a wide variety of long-term side effects, including myelotoxicity (bone marrow suppression), lactic acidosis, polyneuropathy (nerve disorder that affects multiple nerves), and pancreatitis (inflamed pancreas).
Long-term side effects theorized to be related to mitochondrial toxicity were first described in 1999. Mitochondria are tiny organelles inside human cells that generate energy from fuels like glucose. When false nucleosides (NRTIs) enter the body's cells, the mitochondrial DNA may become damaged. Cells that have dysfunctional mitochondria die because they are unable to produce energy.
Fast-replicating cells (like those contained in bone marrow) may also be inhibited by NRTIs leading to blood disorders like anemia and neutropenia. Peripheral neuropathy and pancreatitis are also signs of mitochondrial toxicity.
Different NRTIs affect the mitochondria of different types of cells, which is why the side effects of the drugs are distinct from one another. For instance, stavudine is more toxic than abacavir.

Types of nrtis

Abacavir sulfate (Ziagen?):
Abacavir sulfate (Ziagen?), also known as ABC, was approved by the U.S. Food and Drug Administration (FDA) on December 17, 1998 to treat HIV in combination with other antiretrovirals in adults and children three months of age or older.
Abacavir sulfate is taken orally as a tablet liquid. The recommended dose of abacavir sulfate for adults is 300 milligrams twice a day. The recommended dose for children and adolescents three months to 16 years old is 8-300 milligrams/kilogram twice a day. Patients who have decreased liver function should take 10 milliliters twice a day of the liquid form of abacavir sulfate. Patients should tell their healthcare providers if they are taking any drugs (prescription or over-the-counter), herbs, or supplements because they may interact with antiretrovirals. Patients should take medications as prescribed by their doctors.
Abacavir sulfate has also been combined with other antiretroviral drugs in a single tablet. Abacavir, lamivudine, and zidovudine are available in a single tablet called Trizivir?, and abacavir and lamivudine are available in a single tablet called Epzicom?.
Patients should avoid abacavir sulfate if they have experienced an allergic reaction to the drug (Ziagen?, Epzicom?, or Trizivir?). There have been reports of severe allergic reactions to abacavir, which in some cases, has caused death. About five percent of patients experience severe allergic reactions. While this reaction typically occurs during the first six weeks of treatment, it may happen at any time. Patients should consult their healthcare providers if they experience skin rash or two or more of the following symptoms: sudden fever, severe tiredness or muscle aches, diarrhea, nausea, vomiting, stomach pain, sore throat, shortness of breath, cough, or myalgia (muscle pain).
Common side effects are often similar to symptoms of an allergic reaction and may include including nausea, vomiting, diarrhea, fever, chills, muscle aches, fatigue, headache, loss of appetite, trouble sleeping, changes in body fat distribution, high blood-sugar levels, worsening of depression (in patients who already suffer from depression), and severe abdominal or side pain.
Abacavir sulfate, like other NRTIs, may cause serious liver disease, which can be life threatening. This has been reported in patients who had liver disease and in those with no known history of liver disease.
Abacavir sulfate, lamivudine, zidovudine (Trizivir?):
Trizivir is a combination nucleoside reverse transcriptase inhibitor (NRTI) that contains abacavir sulfate (Ziagen?), lamivudine (Epivir?), and zidovudine (Retrovir?). All three drugs in this U.S. Food and Drug Administration (FDA) approved combination pill are NRTIs.
The recommended dose of Trizivir? is one tablet, which contains 300 milligrams of abacavir sulfate, 150 milligrams of lamivudine, and 300 milligrams of zidovudine, twice daily.
Patients who require different doses of abacavir, lamivudine, and/or zidovudine should not take Trizivir?. Individuals who have liver or kidney disorders, patients who weigh less than 88 pounds, and children should not take Trizivir? because serious side effects are likely to occur. Pregnant women and individuals who have blood disorders or an inflamed pancreas should consult their healthcare providers before taking Trizivir?. Patients should tell their healthcare providers if they are taking any drugs (prescription or over-the-counter), herbs, or supplements. Patients should take medications exactly as prescribed by their doctors.
Side effects may include pale skin, unusual tiredness or weakness, fever, chills, sore throat, headache, muscle soreness, nausea, vomiting, loss of appetite, trouble sleeping, changes in body fat distribution, high blood-sugar levels, worsening of depression (in patients who already suffer from depression), severe abdominal or side pain, ear discharge of swelling, ulcers or white spots on the lips or inside of the mouth, swollen skin, and painful spots on the neck, armpit, or groin. Serious side effects include severe abdominal or stomach pain, skin rash, feeling of fullness, nausea, tingling, burning, numbness, and pain in the extremities.
Individuals who have experienced serious allergic reactions to abacavir should not take Trizivir?. An allergic reaction typically occurs during the first six weeks of treatment, but may happen at any time. Patients should consult their healthcare providers if they develop a skin rash or experience two or more of the following symptoms: sudden fever, severe tiredness or muscle aches, diarrhea, nausea, vomiting, stomach pain, sore throat, shortness of breath, cough, or myalgia (muscle pain).
Trizivir?, like other NRTIs, may cause fatal lactic acidosis and liver disease, as well as blood problems or muscle weakness. Patients who experience digestive system problems, joint or muscle pain and weakness, tingling hands or feet, headache, dizziness, and fatigue should consult their healthcare providers.
Abacavir sulfate, lamivudine (Epzicom?):
Epzicom? is a combination of two NRTIs - abacavir sulfate (Ziagen?) and lamivudine (Epivir?). The U.S. Food and Drug Administration (FDA) approved the drug on August 2, 2004 for the treatment of HIV infection in adults.
The recommended daily dose of Epzicom? is one tablet, which contains 600 milligrams of abacavir sulfate and 300 milligrams of lamivudine. Patients who require different doses of abacavir sulfate and/or lamivudine should not take Epzicom?.
There have been reports of severe allergic reactions to abacavir; in some cases it has caused death. Allergic reactions typically occur during the first six weeks of treatment, but may happen at any time. Patients should consult their healthcare provider if they develop a skin rash or experience two or more of the following symptoms: sudden fever, severe tiredness or muscle aches, diarrhea, nausea, vomiting, stomach pain, sore throat, shortness of breath, cough, or myalgia (muscle pain).
Some of the most common side effects are nausea, vomiting, diarrhea, fever, chills, muscle aches, extreme tiredness, skin rash, headache, loss of appetite, trouble sleeping, changes in body fat distribution, high blood-sugar levels, and worsening of depression (in patients who already suffer from depression). Serious side effects include severe abdominal or stomach pain, feeling of fullness, tingling, burning, numbness, pain in the extremities, and vomiting. Other less serious side effects may include ear discharge or swelling, reddening of the skin, swollen or warm skin, neck pain, groin pain, armpit pain as well as sores, ulcers or white spots on lips or inside the mouth.
Individuals who have experienced a serious allergic reaction to abacavir should not take Epzicom?. There have been reports of severe allergic reactions, which in some cases, have been fatal. Patients should consult their healthcare providers if they develop a skin rash or two or more of the following symptoms: sudden fever, severe tiredness or muscles aches, diarrhea, nausea, vomiting, stomach pain, sore throat, shortness of breath, cough, or myalgia (muscle pain). Individuals who have liver disease or poor kidney function should avoid Epzicom?. Patients should inform their healthcare providers if they are taking any drugs (prescription or over-the-counter), herbs, or supplements. Patients should take medications exactly as prescribed.
Epzicom?, like all NRTIs, may cause fatal lactic acidosis and liver disease, as well as muscle weakness or blood disorders. Patients who experience digestive system problems, joint or muscle pain and weakness, headache, dizziness, tingling hands or feet, and/or unusual tiredness should consult their healthcare providers.
Didanosine (Videx?, Videx EC?):
Didanosine (Videx?), also known as ddI, was approved by the U.S. Food and Drug Administration (FDA) on October 9, 1991. The FDA approved enteric-coated didanosine (Videx EC?) on October 31, 2000. Both are approved for use with other antiretrovirals to treat HIV in adults and children.
Didanosine is available as a chewable tablet, enteric-coated capsule, liquid, and powder. Didanosine is taken orally without food. The powder form of didanosine is mixed with at least one ounce of water before it is swallowed. Didanosine should be taken on an empty stomach, at least 30 minutes before or two hours after eating. This helps ensure that the drug is absorbed in the gastrointestinal tract. The tablet, liquid, and powder forms contain an antacid "buffer," which prevents the stomach acid from breaking down the drug before it is absorbed. The capsule form contains small, coated beads that allow the medicine to pass through the stomach and then dissolve in the intestine where it is absorbed.
Recommended doses of the drug depend on the patient's weight and form of the drug. Adults who weigh 132 pounds or more typically take 200 milligrams twice daily (tablets), 250 milligrams twice daily (powder), or 400 milligrams once daily (capsules). Adults who weigh less than 132 pounds typically take 125 milligrams twice daily (tablets), 167 milligrams twice daily (powder), or 250 milligrams once daily (capsules). The recommended dose for children varies depending on their age, weight, and form of the drug. Patients should take medications exactly as prescribed.
Individuals who have liver or kidney disease, inflammation of the pancreas, or gout should consult their healthcare providers before taking didanosine. Patients should tell their healthcare providers if they are taking any drugs (prescription or over-the-counter), herbs, or supplements because they may interact with antiretrovirals.
Side effects may include pancreatitis (which may cause nausea, severe stomach pain, or vomiting), enlarged liver, lactic acidosis (which may cause fatigue, stomach discomfort, feeling cold, dizziness, lightheadedness, and irregular heartbeat), vision problems, and tingling or pain in the hands or feet.
Other less serious side effects may include diarrhea, headache, dizziness, anxiety, difficulty sleeping, and skin rash.
Emtricitabine (Emtriva?):
The U.S. Food and Drug Administration (FDA) approved emtricitabine capsules on July 2, 2003 for use with other antiretrovirals drugs to treat HIV in adults. The FDA approved emtricitabine oral solution on September 28, 2005 for use with other antiretrovirals to treat HIV in patients older than three months of age.
The recommended dose for adults is 200 milligrams (capsule) or 24 milliliters (oral solution) once daily. The recommended daily dose for children depends on age and weight. Children who weigh more than 72.8 pounds and who can swallow capsules typically take 200 milligrams in capsule form once daily. Individuals (adults and children) who have decreased kidney function may need to take emtricitabine less than once a day. Researchers are currently conducting studies to determine whether different doses are effective in elderly patients. Patients should take medications exactly as prescribed. Patients should inform their healthcare providers if they are taking any drugs (prescription or over-the-counter), herbs, or supplements.
Serious side effects include nausea, vomiting, abdominal pain, fatigue, loss of appetite, weight loss, and difficulty breathing. Other less serious side effects include headache, diarrhea, nausea, rash, and skin discoloration.
Emtricitabine, tenofovir disoproxil fumarate (Truvada?):
Truvada? consists of two NRTIs - emtricitabine (Emtriva?) and tenofovir disoproxil fumarate (Viread?).
The U.S. Food and Drug Administration (FDA) approved Truvada? on August 2, 2004 for use with other antiretrovirals to treat HIV in adults. Emtricitabine and tenofovir disoproxil fumarate have each been FDA approved for the treatment of HIV infection in adults and children.
Adults typically take one emtricitabine/tenofovir disoproxil fumarate tablet a day, which contains 200 milligrams of emtricitabine and 300 milligrams of tenofovir disoproxil fumarate). Patients who need a different dose of emtricitabine and/or tenofovir disoproxil fumarate should not take Truvada?.
Precautions and side effects are similar to those for emtricitabine and tenofovir disoproxil fumarate separately. Patients who have advanced kidney disease should not take emtricitabine/tenofovir disoproxil fumarate. Patients should tell their healthcare providers if they are taking any drugs (prescription or over-the-counter), herbs, or supplements because they may interact with antiretrovirals. Patients should take medications exactly as prescribed.
Serious side effects may include fatal lactic acidosis and liver disease, as well as muscle weakness, blood disorders, kidney failure, pancreatitis, vomiting, abdominal pain, decreased appetite, weight loss, cramping, and difficulty breathing. Patients who experience gastrointestinal problems, joint or muscle pain, pain or tingling in the hands or feet, headache, dizziness, and/or fatigue should consult their healthcare providers.
Lamivudine (Epivir?):
Lamivudine (Epivir?), also known as 3TC, was approved by the U.S. Food and Drug Administration (FDA) on November 17, 1995 for use in combination with other antiretrovirals for the treatment of HIV in adults and in children older than three months. Lamivudine has also been used to prevent people (especially healthcare workers) from acquiring HIV infection after being accidentally exposed to the virus. However, this treatment practice has not received FDA approval.
Lamivudine is also used in many NRTI combination pills. Lamivudine and zidovudine are combined in a tablet called Combivir?, lamivudine and abacavir sulfate in a tablet called Epzicom?, and lamivudine is also combined with abacavir sulfate and zidovudine in a tablet called Trizivir?.
Lamivudine is also available as a lower-dose liquid and tablet (Epivir-HBV?) for the treatment of hepatitis B virus (HBV) infection. This medication is designed for individuals who only have HBV infection. Epivir-HBV? is not recommended for patients who have both HBV and HIV infections.
Lamivudine is available as a liquid and tablet. Adults typically take 300 milligrams of lamivudine once a day or 150 milligrams twice daily. Children ages three months to 16 years typically take 4-150 milligrams/kilogram twice daily. Patients should tell their healthcare providers if they have kidney disorders because they may require different doses. Patients should take medications exactly as prescribed. Patients should inform their healthcare providers if they are taking any drugs (prescription or over-the-counter), herbs or supplements because they may interact with antiretrovirals.
Serious side effects may include severe abdominal or stomach pain, feeling of fullness, nausea, tingling, burning, numbness, pain in the extremities, and vomiting. Other less serious side effects may include ear discharge or swelling, reddening of the skin, swollen or warm skin, pain under the arm, neck pain, groin pain, as well as sores, ulcers or white spots on lips or inside the mouth.
Lamivudine/zidovudine (Combivir?):
Lamivudine/zidovudine (Combivir?) is a combination tablet made from two NRTIs - lamivudine (Epivir?) and zidovudine (Retrovir?). The U.S Food and Drug Administration (FDA) approved lamivudine/zidovudine on September 27, 1997 for use with other antiretrovirals for the treatment of HIV in adults and in children older than 12 years.
Patients who are 12 years old and older typically take one tablet, which contains 150 milligrams of lamivudine and 300 milligrams of zidovudine, twice daily. Patients who need different doses of lamivudine and/or zidovudine than are contained in the combination product should not take Combivir?.
Precautions and side effects of lamivudine/zidovudine are similar to those for each of the antiretrovirals separately. Children younger than 12 years old should not take lamivudine/zidovudine. Individuals who have blood disorders, kidney disease, liver disease, or pancreatitis may require alternative doses and should consult their healthcare providers before taking the drug. Patients should tell their healthcare providers if they are taking any drugs (prescription or over-the-counter), herbs, or supplements because they may interact with antiretrovirals. Patients should take their medications exactly as prescribed.
Serious side effects may include burning, tingling or pain in hands or feet, chills, ear swelling or discharge, nose or throat problems, fever, muscle aches, nausea, pale skin, severe stomach pain, skin rash, fatigue, vomiting, or jaundice (yellowing of the eyes or skin). Other less serious side effects may include cough, diarrhea, mild stomach cramps, dizziness, headache, loss of appetite, or trouble sleeping.
Stavudine (Zerit?):
The U.S. Food and Drug Administration (FDA) approved stavudine, also known as d4T, on June 24, 1994 for the treatment of HIV in adults and children with other antiretrovirals. Stavudine has also been used to prevent individuals, especially healthcare workers, from contracting HIV after being accidentally exposed to the virus. However, this practice has not been FDA approved.
The recommended dose depends on the patient's body weight. Patients who weigh 132 pounds or more typically take 40 milligrams of stavudine twice daily. Patients who weigh less than 132 pounds typically take 30 milligrams twice a day. Doses are generally taken every 12 hours. Pediatric doses depend on the patient's weight. Patients should tell their healthcare providers if they have kidney disease, liver disease, or pancreatitis because they may need to take lower doses. Patients should tell their healthcare providers if they are taking any drugs (prescription or over-the-counter), herbs, or supplements because they may interact with antiretrovirals. Patients should always take medications exactly as prescribed.
Serious side effects may include joint or muscle pain, nausea, severe stomach pain, fever, skin rash, vomiting or burning numbness, and/or pain or tingling in the hands or feet. Other less serious side effects may include chills, fever, diarrhea, headache, loss of appetite, weight loss, mild stomach pain, change in body fat distribution, trouble sleeping, or fatigue.
Tenofovir disoproxil fumarate (Viread?):
The U.S. Food and Drug Administration (FDA) approved tenofovir disoproxil fumarate (Viread?), also known as tenofovir DF, on October 26, 2001 for the treatment of HIV in adults in combination with other antiretrovirals.
Adults typically take 300 milligrams of tenofovir DF once daily. Patients who have kidney disorders should tell their healthcare providers because they may require lower or less frequent doses. Patients should tell their healthcare providers if they are taking any drugs (prescription or over-the-counter), herbs, or supplements because they may interact with antiretrovirals. Patients should always take medications exactly as prescribed.
Serious side effects may include liver or kidney failure and pancreatitis. Symptoms of these side effects may include abdominal pain, decreased appetite, diarrhea, rapid breathing, general feeling of discomfort, muscle pain or cramping, nausea, shortness of breath, fatigue, and vomiting.
Other less serious side effects may include abdominal discomfort, diarrhea, dizziness, gas, headache, and rash.
Zalcitabine (Hivid?):
Zalcitabine (Hivid?), also known as ddC, was approved by the U.S. Food and Drug Administration (FDA) on June 19, 1992 for the treatment of HIV in adults and children in combination with other antiretrovirals. Currently, zalcitabine is not recommended for patients who are taking antiretrovirals for the first time because serious side effects may occur.
Adults typically take 0.75 milligrams of zalcitabine every eight hours. Patients should tell their healthcare providers if they have kidney disease because they may need to take lower or less frequent doses. Researchers are currently conducting studies to determine whether the drug can be taken twice a day.
Patients should tell their healthcare providers if they are taking any drugs (prescription or over-the-counter), herbs, or supplements because they may interact with antiretrovirals. Patients should take medications as prescribed by their doctors.
Patients who have a history of pancreatitis (inflamed pancreas) or nerve pain should only take zalcitabine when there are no other alternative treatment options. Patients who are taking the anti-infective drug pentamidine (commonly used to treat Pneumocystis carinii pneumonia, now called Pneumocystis jiroveci pneumonia) should not take zalcitabine because it may cause fatal pancreatitis.
Serious side effects may include severe inflammation of the pancreas (which may be fatal), peripheral neuropathy (nerve disorder), or liver damage. Symptoms of peripheral neuropathy typically develop within a few months of treatment and may worsen over time if the drug is not discontinued. Symptoms of peripheral neuropathy may include burning, numbness, or tingling in the hands or feet. Symptoms of pancreas damage may include stomach pain, nausea, and vomiting. Individuals who experience symptoms of serious side effects should consult their healthcare providers.
Other less serious side effects may include headache, stomach upset, sores in the mouth or throat, skin rash, and tiredness.
Zidovudine (Retrovir?):
Zidovudine (Retrovir?), also known as AZT or ZDV, was approved by the U.S. Food and Drug Administration (FDA) on March 19, 1987 for the treatment of HIV infection in adults and in children three months of age or older. It is also approved for use in pregnant women who are infected with HIV. This drug is used to prevent pregnant women from transmitting the virus to their babies during pregnancy and birth. Newborns then receive the drug for the first six weeks of life. Zidovudine has also been used to prevent healthcare workers from contracting HIV after accidental exposure to the virus, although this practice is not FDA approved.
Adults typically take 600 milligrams of zidovudine a day. This can be taken as either 300 milligrams twice daily or 200 milligrams three times daily. Children six weeks to 12 years old receive 160 milligrams/meter squared every eight hours (480 milligrams/meter squared/day, up to 200 milligrams every eight hours). Pregnant women who are at least 14 weeks pregnant typically receive 100 milligrams five times daily until the start of labor. Intravenous zidovudine should be administered during labor and delivery. Within 12 hours after birth, the newborn is given zidovudine every six hours until they are six weeks old. The exact dose of the drug depends on the infant's weight. Patients should take medications exactly as prescribed by their doctors.
Patients should tell their healthcare providers if they are taking any drugs (prescription or over-the-counter), herbs, or supplements because they may interact with antiretrovirals. Side effects may include pale skin, fatigue, fever, chills, sore throat, headache, muscle soreness, and nausea.