What Are NRTIs in Antiretroviral Therapy For HIV Infection?

Nucleoside reverse transcriptase inhibitors (NRTIs) are one of the seven classes of drugs developed to treat human immunodeficiency virus (HIV) infection. NRTIs were the first drugs developed to manage HIV infection and remain a mainstay of antiretroviral therapy (ART) combinations.

HIV infection is caused by a virus that attacks the T-cells of the human immune system. This results in progressive weakening of the immune system leading to acquired immune deficiency syndrome (AIDS), when the body is no longer able to fight infection effectively. HIV has no cure and can only be controlled by lifelong medication.

Antiretroviral therapy is a treatment regimen for HIV infection, usually with a combination of three or more classes of drugs. Each drug targets the virus in different ways at different phases of its life cycle. Typically, two of the drugs in the combination are NRTIs.

One of the stages in the viral life cycle is the release of an enzyme known as reverse transcriptase. HIV is an RNA virus, and the reverse transcriptase enzyme is essential to convert the RNA into DNA in order to enter the host cell’s nucleus and integrate viral DNA with the host DNA.

Once the viral DNA integrates with the host DNA, it makes long protein chains, which break up and become new viral particles (virions). The nucleoside reverse transcriptase inhibitors work by interfering with the process of protein chain formation.

A nucleoside is a base molecule in the DNA of all living cells. The NRTIs mimic the T-cell’s nucleoside structure, get incorporated into the infected DNA, and stop the viral DNA from adding further protein subunits to the chain. Without elongation of the DNA chain, the virus cannot progress to the next phase of replication.

The HIV may gradually mutate and become resistant to the administered NRTI, in which case a patient may have to try alternate NRTIs. An HIV patient undergoes regular tests to check for drug resistance and side effects.

NRTIs are first metabolized by the mitochondria in the cell before they can work on the virus. Mitochondria play an important role in metabolism and conversion of food energy into energy that the body uses. 

• NRTIs may cause mitochondrial toxicity leading to conditions that include
• Lactic acidosis (excessive buildup of lactic acid)
• Pancreatitis (inflammation of pancreas)
• Hepatic steatosis (fatty liver)
• Peripheral neuropathy (pain, numbness, tingling and weakness from nerve damage)
• Lipoatrophy (localized loss of fat tissue)

Many of the common side effects like headache, nausea, vomiting and stomach upset may resolve as the body gets used to the drug. The drug is eliminated by the kidneys, and people with renal impairment must be cautious about dosage. 

Following are the FDA-approved individual NRTIs that are currently part of antiretroviral therapy for HIV infection:

Abacavir (Ziagen)

Available as tablet or oral solution.

Side effects include hypersensitivity reactions such as:

• Fever
• Rash
• Nausea
• Vomiting
• Diarrhea
• Malaise
• Shortness of breath
• Cough
• Pharyngitis

People positive for the HLA-B 5791 gene have the highest risk for hypersensitivity.

Didanosine (Videx, Videx EC)

Available as delayed release capsule and powder form for solution.

Side effects include:

• Peripheral neuropathy
• Pancreatitis
• Lactic acidosis
• Nausea

Emtricitabine (Emtriva)

Available as capsule and oral solution.

Side effects include:

• Minimal toxicity
• Hyperpigmentation (skin darkening)
• Potential worsening of hepatitis in people with hepatitis B upon discontinuation of the drug
• Lactic acidosis

Lamivudine (Epivir)

Available as tablet and oral solution.

Side effects include:

• Minimal toxicity
• Potential worsening of hepatitis in people with hepatitis B upon discontinuation of the drug
• Lactic acidosis
• Pancreatitis
• Hepatitis

Stavudine (Zerit)

Available as capsule and oral solution.

Side effects include:

• Peripheral neuropathy
• Pancreatitis
• Lactic acidosis
• Lipoatrophy
• Hyperlipidemia (high amount of blood fats)

Tenofovir disoproxil fumarate (DF) (Viread)

Available as tablets and oral powder.

Side effects include:

• Nausea
• Vomiting
• Diarrhea
• Headache
• Asthenia (abnormal weakness and lack of energy)
• Renal insufficiency
• Bone mineral density loss

Tenofovir alafenamide AF (Vemlidy)

Available as tablets.

Side effects include:

• Nausea
• Abdominal pain
• Fatigue
• Headache
• Back pain
• Cough

Zidovudine (Retrovir)

Available as tablets, capsules, oral and intravenous solutions.

Side effects include:

• Nausea
• Vomiting
• Headache
• Asthenia
• Anemia
• Neutropenia (low neutrophil white cells in blood)