Reviewed by: HU Medical Review Board | Last reviewed: 5/31/22

NNRTIs (non-nucleoside reverse transcriptase inhibitors) are a class of drugs used to suppress HIV in the body. When NNRTIs are used in combination with other HIV-fighting medications the treatment regimen is referred to as antiretroviral therapy (ART). 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 in order 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:

  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 backwards through this process to become DNA through a process called reverse transcription.

HIV carries around a special enzyme called reverse transcriptase, which allows it to move backwards from RNA to DNA and insert into the host cell’s DNA so that 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.1

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.

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. In order 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.

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 all the way through the reverse transcription process and into host DNA for further replication.2

Examples of NNRTIs

Common NNRTIs include, but are not limited to:

  • Doravirine (DOR)
  • Efavirenz (EFV)
  • Etravirine (ETR)
  • Nevirapine (NVP)
  • Rilpivirine (RPV)2,3

Things to note about NNRTIs

Certain NNRTI medications may carry their own specific risks. For example, some may increase an individual’s risk of liver problems, rash, or skin issues. Others may cause tingling in the hands and feet or changes in body fat. NNRTIs may also cause a condition called IRIS (immune reconstitution inflammatory syndrome). IRIS occurs when an individual’s immune system gets stronger after being weak and responds aggressively to previously hidden infections. This heightened response may make the person fighting the infection feel worse.

Some NNRTIs may impact mental health, nervous system functioning, and mood. Your doctor or healthcare provider will provide you with information on what issues you may be at risk for based on what NNRTI you are taking.4-8

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