What Are NNRTIs In Antiretroviral Therapy for HIV Infection?

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are one of the classes of drugs that form part of the antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection. The first NNRTI drug was introduced in 1996, and since then this drug class has been an integral part of HIV treatment.

Antiretroviral therapy is a treatment regimen for HIV infection, with a combination of three or more drug classes that stop virus replication in different ways. An NNRTI drug is usually one of the drugs used in the combination when antiretroviral therapy is first initiated after diagnosis of HIV infection.

HIV infection is caused by a virus that infects and weakens the human immune system. HIV specifically targets the T-cell, which is a type of lymphocyte that develops in the thymus gland and is an integral part of the immune system. The virus enters the T-cell and uses its cell machinery to replicate itself, destroying the host cell in the process.

Untreated HIV can progress to acquired immune deficiency syndrome (AIDS), a late stage of HIV infection when the body’s immunity is so compromised it cannot fight infections effectively. HIV infection has no cure, and the patient must be on a lifelong regimen of antiretroviral therapy to manage the infection and prevent its transmission.

HIV is a minute virus particle with a single strand of genetic matter known as RNA. In its RNA form, the virus cannot enter the nucleus of the T-cell or use the cell machinery for its replication. The virus releases and uses a special enzyme known as reverse transcriptase to convert its RNA into DNA that can enter the nucleus.

The NNRTI drug binds to the reverse transcriptase enzyme, altering its structure and inhibiting its function in the transcription of RNA into DNA. NNRTIs are effective in controlling HIV infection, particularly the newer formulations, which are able to bind with even resistant viral mutations to some extent.

Both nucleoside and non-nucleoside reverse transcriptase inhibitors work at the same stage of the viral replication cycle, when the viral RNA converts itself into DNA using reverse transcriptase enzyme.

The nucleoside transcriptase inhibitors (NRTIs), have a nucleoside that is structurally similar to the T-cell DNA’s nucleoside. Mimicking the T-cell enables the NRTIs to integrate with the T-cell DNA and stop the production of viral DNA proteins.

The non-nucleoside transcriptase inhibitors do not get into the cell nucleus or interfere with the DNA. NNRTIs bind directly to the HIV’s reverse transcriptase enzyme and inhibit its activity.

NNRTIs have a relatively higher potential for drug-on-drug interactions in patients taking other medications for co-existing conditions. Major side effects of NNRTIs include:

• Rash
• Headache
• Liver toxicity
• Neuropsychiatric symptoms such as
  • Insomnia
  • Hallucinations
  • Suicidal thoughts

Most of the side effects resolve after a few weeks of therapy. Gradual increase of dosage helps in reducing some of the side effects.

Following are the FDA-approved individual NNRTIs that are currently part of antiretroviral therapy for HIV infection; common side effects are listed.

Delavirdine (Rescriptor)

Available as tablets, but not used as a part of initial therapy, and rarely used even as second-line treatment because of its low efficacy in comparison with other NNRTIs.

Side effects include:

• Rash
• Headache
• Nausea
• Fatigue
• Liver toxicity

Efavirenz (Sustiva)

Available as tablets and capsules, taken on empty stomach to reduce the intensity of side effects.

Side effects include: 

• Rash
• Central nervous system effects such as
  • Sleepiness
  • Vivid dreams
  • Confusion
  • Visual hallucinations
  • Suicidal thoughts (higher risk in patients with psychiatric history or on psychoactive medications)
• Hyperlipidemia (high levels of blood fats)

Etravirine (Intelence)

Available as tablets and approved only for antiretroviral treatment–experienced patients with drug resistance.

Side effects include:

• Rash
• Nausea

Nevirapine (Viramune, Viramune XR)

Available as tablets and suspension.

Side effects include:

• Rash
• Hepatitis

Rilpivirine (Edurant)

Available as tablets.

Side effects include:

• Depressive disorders
• Insomnia
• Headache
• Rash

Doravirine (Pifeltro)

Available as tablets. May lose efficacy if given with certain antibiotic drugs that boost a particular enzyme in the body, known as CYP3A4, and lead to HIV drug resistance.

Side effects include:

• Immune reconstitution syndrome: Development of inflammatory symptoms caused by the response of the immune system that has recovered with antiretroviral therapy, which starts attacking other pre-existing, latent bacterial or viral infections. These symptoms usually resolve in a few weeks:
  • Nausea
  • Headache
  • dizziness