What to Know About Zidovudine (ZDV)

Zidovudine (ZDV) is an antiretroviral drug used in the treatment or prevention of human immunodeficiency virus, or HIV. It was, in fact, the very first drug approved to treat HIV back in 1987 and is still in use today. It was formerly called azidothymidine (AZT).

Marketed under the brand name Retrovir and others, ZDV is available as a generic and is also found in the fixed-dose combination drugs Combivir (zidovudine and lamivudine) and Trizivir (abacavir, zidovudine, and lamivudine).

While still important, ZDV is no longer used as a first-line treatment of HIV but rather in subsequent therapies when other treatments have failed. Part of the reason for this is that newer antiretroviral agents are less prone to drug resistance and are, therefore, better able to overcome drug-resistant strains of the virus.

Uses

Zidovudine is classified as a nucleoside reverse transcriptase-inhibitor (NRTI) and is used to either treat or prevent HIV infection. It can be used both in adults and children.

Treatment

ZDV works by blocking an enzyme called reverse transcriptase that the virus uses to translate its own single-stranded RNA into double-stranded DNA. By inserting its genetic coding into the nucleus of the host cell, HIV effectively "hijacks" the cell and turns it into an HIV-producing factory.

By blocking reverse transcriptase, ZDV halts the virus's ability to replicate. It doesn't "kill" HIV but rather prevents it from multiplying and infecting other cells. With that said, ZDV cannot suppress the virus on its own.

Prevention

ZDV can also be used to prevent HIV infection, either during pregnancy or when accidentally exposed to the virus. Although ZDV is less commonly used for these purposes today, it still has its place in resource-limited settings or when preferred drug agents are not available.

Zidovudine is sometimes used in the following preventive strategies:

Preventing Transmission During Pregnancy

In a landmark study published in 1993, ZDV was shown to reduce by 50% the risk of HIV transmission from a pregnant person to the fetus. When used in combination therapy, antiretrovirals can reverse the likelihood of transmission to as little as 2%.

While ZDV is less commonly used for this purpose today—supplanted by safer drugs with simpler dosing schedules—it still has its place as a last-minute infusion therapy in people with uncontrolled virus who are about to deliver their babies.

Post-Exposure Prophylaxis (PEP)

ZDV was also for many years as the backbone drug of post-exposure prophylaxis (PEP), a preventive strategy used for people accidentally exposed to HIV. The 28-day drug therapy is thought to reduce the risk of transmission if started within 24–48 hours after exposure.

Although zidovudine is still used for this purpose in parts of the developing world, newer drugs like Truvada (tenofovir + emtricitabine) have replaced it in the United States.

Other Uses

Although there are no specific guidelines in place, ZDV is sometimes used in combination therapy for people with HIV encephalopathy. Also known as AIDS dementia complex, this is a common complication of advanced HIV infection characterized by a significant loss of memory, cognitive function, judgment, and verbal fluency. 

Unlike some antiretroviral drugs, ZDV is better able to penetrate the blood-brain barrier that separates the brain from the rest of the body. By directly accessing brain tissues, ZDV may help slow the progression or alleviate the symptoms of this HIV-associated complication.

Before Taking

After HIV is diagnosed, additional tests will be performed to evaluate the status of your immune system and the degree of viral activity in your body. Doing so allows your healthcare provider to not only track your response to therapy but determine if other interventions are needed if your immune system is compromised.

The baseline tests include:

• CD4 count: The CD4 count is a blood test that measures the number of CD4 T-cell lymphocytes that HIV targets and destroys. The depletion of these white blood cells serves as a marker for your immune status. CD4 counts of 500 and above are considered "normal," while values below 500 indicate immunosuppression.
• Viral load: The HIV viral load measures the amount of virus in a sample of blood, the value of which can range from zero to the millions. With optimal antiretroviral therapy, the viral load should be undetectable (meaning below the detection level of current testing technologies).

Other standard blood tests will be performed, including a complete blood count (CBC) and liver function tests (LFTs), to determine if there are any abnormalities that may exclude or limit the use of ZDV.

Genetic Testing

The next step in formulating a treatment plan is to determine the genetic characteristics of your virus. This involves genetic resistance testing, a simple blood test that can identify the genetic structure (genotype) of your virus and the types of genetic mutations the virus has.

Based on the types and degrees of mutations, the lab can determine which antiretrovirals are most likely to "sidestep" these mutations and work most effectively.

In addition to genotyping the virus, the lab may also perform phenotypic tests to evaluate the characteristics of your virus. This involves exposing the virus to all available HIV drugs to see which ones work best.

Genetic resistance testing is recommended for both newly treated people and those for whom treatment is no longer working. Phenotypic testing may be ordered when there is treatment failure or a suboptimal response to therapy.

Precautions and Contraindications

ZDV can cause bone marrow suppression in some people. At the same time, because the drug is excreted mainly through the kidneys and, to a lesser degree, the liver, it can cause toxicity in people with kidney or liver dysfunction.

Although not contraindicated for use (not given as a reason not to use it), zidovudine should be taken with caution by anyone with the following conditions:

• Severe anemia
• Severe neutropenia
• Kidney disease
• Liver disease (including cirrhosis and hepatitis C)
• Myopathy (disorders affecting voluntary muscle control)

The only absolute contraindication to the use of ZDV is a known or suspected hypersensitive reaction to the drug, including a prior history of anaphylaxis, a potentially life-threatening allergic reaction, or Stevens-Johnson syndrome (SJS), a serious disorder of the skin and mucus membranes.

Other Drugs

There are four other NRTIs approved for use in the United States as well as five combination drugs that include one or two NRTIs:

• Combivir (zidovudine and lamivudine)
• Descovy (tenofovir alafenamide and emtricitabine)
• Emtriva (emtricitabine)
• Epivir (lamivudine)
• Epzicom (abacavir and lamivudine)
• Trizivir (abacavir, zidovudine, and lamivudine)
• Truvada (tenofovir disoproxil fumarate and emtricitabine)
• Viread (tenofovir disoproxil fumarate)
• Videx (didanosine)

Dosage

ZDV is available in pill, tablet, capsule, liquid, and intravenous (IV) formulations. The liquid formulation is used mainly in younger children but also in people who are unable to swallow pills. The IV formulation is primarily used to prevent transmission during pregnancy.

The dosage and strength vary by the formulation:

• Tablets: 300 mg (milligrams)
• Capsules: 100 mg
• Syrup: 10 mg/mL (milligrams per milliliter)
• IV infusion: 10 mg/mL in a 20 mg single-use vial

The recommended dose can also vary by age, body weight, and the aims of treatment.

Modifications

The ZDV dose may need to be adjusted or the treatment stopped in certain situations, including:

• Severe anemia or neutropenia: People who experience a drop of 25% or more from their baseline hemoglobin levels (a marker for anemia, the lack of healthy red blood cells) or 50% or more in their baseline granulocyte levels (a marker for neutropenia, or low neutrophil levels, which can lead to infection) may require an interruption or change of treatment.
• Kidney impairment: People on dialysis or with a creatinine clearance of less than 15 mL per minute should have the dosage adjusted to 100 mg every six to eight hours.

There are no recommended dose adjustments for people with liver impairment. Even so, liver enzymes should be routinely monitored to avoid hepatotoxicity (liver poisoning) and liver injury.

How to Take and Store

ZDV can be taken with or without food. The drug is relatively shelf-stable and can be stored at temperatures between 59 F–77 F (F15 C–25 C). It is best to keep the pills, capsules, or syrup in their original container, ideally in a cool, dark drawer or cabinet

While the drugs do not require refrigeration, they should not be stored on a sunny windowsill or in your glove compartment. Always check the expiration date, and discard any that have expired.

Side Effects

Side effects are common with all drugs. Many of those associated with ZDV tend to occur soon after treatment is started and gradually subside as your body gets used to treatment.

Others may develop over time and become increasingly intolerable or severe. To avoid this, let your healthcare provider know if you experience any unusual symptoms after starting ZDV or combination drugs containing ZDV.

Common

ZDV is known to cause gastrointestinal and whole-body side effects in as many as 60% of people soon after starting treatment. These tend to be transient (passing quickly) and resolve after several days or weeks. Some people experience no side effects at all.

The most common side effects affecting over 5% of users include (by order of frequency):

• Headache
• Malaise (not feeling well)
• Nausea
• Loss of appetite
• Vomiting
• Weakness
• Constipation

Insomnia and acid reflux (heartburn) may also occur, although they are less common.

Severe

Some people may experience side effects as a result of the prolonged use of ZDV. These may be due to the onset of bone marrow suppression or the loss of kidney or liver function.

With ongoing use, ZDV can also affect mitochondria (structures within cells that generate energy), leading to abnormal changes in metabolism, muscle, fat, and nerve signals.

Seriouse effects of ZDV therapy may include:

• Severe anemia: Symptoms include extreme fatigue, weakness, paleness, chest pain, rapid heartbeat, light-headedness, and shortness of breath.
• Severe neutropenia: Symptoms include fever, chills, profuse sweating, abdominal pain, diarrhea, mouth sores, cough, and shortness of breath.
• Hepatomegaly (enlarged liver): Symptoms include fatigue, weakness, abdominal pain, nausea, vomiting, and jaundice (a yellowing of the skin and whites of eyes due to high bilirubin pigments in blood).
• Myopathy: Myopathy is a condition caused by mitochondrial damage that can cause muscular symptoms, including weakness, pain, stiffness, rigidity, cramping, and atrophy (wasting).
• Lipodystrophy: Lipodystrophy is the abnormal redistribution of body fat mainly affecting the face, buttocks, abdomen, breast, and upper back (also caused by mitochondrial damage).
• Lactic acidosis: The abnormal build-up of lactic acid, lactic acidosis is caused by mitochondrial disruption and can lead to fatigue, cramping, diarrhea, rapid heart rate, confusion, trouble swallowing, and, in severe cases, shock and death.

Warnings and Interactions

There are risks associated with any drug, With ZDV, there is a black box warning advising consumers about the risk of severe anemia, neutropenia, and myopathy as well as potentially fatal cases of lactic acidosis and hepatomegaly.

With respect to pregnancy, the benefits of ZDV are typically seen to outweigh the risks. Even so, animal studies have shown a potential for fetal harm (although small), and there are no well-controlled studies in humans.

However the drug is used, it is important to speak with your healthcare provider about the benefits and risks to make a more informed choice.

Drug Interactions

There are certain drugs that can interact with ZDV, either by increasing or decreasing the concentration of one or the other drug in the blood. Decreased levels can reduce the effectiveness of a drug, while increased levels can raise the risk of side effects. Other interactions can activate ZDV's toxic effects.

To overcome this, a dose adjustment or drug substitution may be needed. In other cases, the doses may need to be separated by several hours.

Among the drugs known to interact with ZDV are:

• Benemid (probenecid): Used to treat gout
• Cytovene (ganciclovir): Used to treat cytomegalovirus (CMV)
• Valproic acid: Used to treat seizures and bipolar disorder
• Diflucan (fluconazole): Used to treat fungal infections
• Dilantin (phenytoin): Used to treat seizures
• Lipodox (doxorubicin): A chemotherapy drug
• Mepron (atovaquone): Used to treat pneumocystis carinii pneumonia (PCP)
• Methadone: Used to treat opioid use disorder
• Multiferon (interferon alfa): Used to treat hepatitis and cancer
• Norvir (ritonavir): Used to treat HIV
• Ribavirin: Used to treat respiratory syncytial virus (RSV) and hepatitis C
• Rifadin (rifampin): Used to treat tuberculosis
• Viracept (nelfinavir): Used to treat HIV