Reviewed by: HU Medical Review Board | Last reviewed: May 2024 | Last updated: May 2024

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a class of drugs used to suppress HIV in the body. When NNRTIs are used along with other HIV-fighting drugs, the treatment regimen is referred to as antiretroviral therapy (ART).1

NNRTIs act on the reverse transcription portion of the HIV life cycle, where the virus transforms itself from RNA to DNA inside human host cells to carry out the rest of its replication process.

HIV life cycle

Viruses, like HIV, need human host cells to replicate. They cannot multiply on their own without human cells. When HIV particles, called virions, enter the body after a transmission event, the next main steps of the HIV lifecycle are as follows:2

  1. Binding
  2. Fusion
  3. Reverse transcription
  4. Integration
  5. Replication
  6. Assembly
  7. Budding1

Figure 1. NNRTIs target reverse transcription in the HIV life cycle

NRTIs target reverse transcription in the CD4 Cell in the HIV life cycle

The first two steps of the life cycle focus on HIV getting into a human CD4 cell, or T cell, which is its target cell. Once inside, it needs to disassemble itself and begin the replication process. Normally in our cells, our body converts the information in our DNA to RNA (also called transcription) and then RNA to proteins. DNA and RNA are both forms of genetic material. The HIV virus is able to go backward through this process to become DNA through a process called reverse transcription.2

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HIV carries around a special enzyme called reverse transcriptase, which allows it to move backward from RNA to DNA and insert into the host cell’s DNA so it can continue to be replicated in its original form with the rest of our normal DNA. This special property of HIV is why it is classified as a retrovirus.2

Once HIV replicates itself, it can then reassemble into new virion particles that get released out of the cell and back into the bloodstream, to infect new CD4 cells.2

How do NNRTIs work?

The purpose of NNRTIs is to stop the reverse transcription process. Normally, HIV uses its reverse transcriptase enzyme to build a strand of DNA from its original RNA form. To do this, it uses genetic building blocks called nucleosides that come from the host cell. These nucleosides are strung together one at a time, like beads on a string, to create the final DNA product. NNRTIs bind to the reverse transcriptase enzyme itself to stop the DNA-building process.1

When an NNRTI binds to reverse transcriptase, the enzyme is unable to attach more nucleosides to the chain. This prevents the DNA strand from being formed, preventing HIV RNA from making it through the reverse transcription process and into host DNA for further replication.1

Examples of NNRTIs

NNRTIs approved to treat HIV include:1,3-6

  • Edurant® (rilpivirine hydrochloride)
  • Intelence® (etravirine)
  • Pifeltro® (doravirine)
  • Viramune® (nevirapine)

What are the possible side effects of NNRTIs?

The most common side effects of NNRTIs include:3-6

  • Rash
  • Headache
  • Trouble sleeping (insomnia)
  • Depression
  • Nausea, vomiting
  • Tiredness
  • Abdominal pain
  • Dizziness

These are not all the possible side effects of NNRTI drugs. Talk to your doctor about what to expect when taking an NNRTI medicine. You also should call your doctor if you have any changes that concern you when taking an NNRTI medicine.

Other things to know

Before starting treatment with an NNRTI, tell your doctor if you:3-6

  • Have or have had hepatitis or other problems with your liver
  • Receive dialysis
  • Have mental health issues
  • Are pregnant, planning to become pregnant, or breastfeeding

NNRTI drugs can interact with other medicines and cause serious side effects. Before beginning treatment for HIV, tell your doctor about all your health conditions and any other drugs, vitamins, or supplements you take. This includes over-the-counter drugs.

Treatment results and side effects can vary from person to person. This treatment information is not meant to replace professional medical advice. Talk to your doctor about what to expect before starting and while taking any treatment.