Non-Nucleoside Reverse Transcriptase Inhibitor

Aka: Non-Nucleoside Reverse Transcriptase Inhibitor, NNRTI, Delavirdine, Rescriptor

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II. Precautions

  1. NNRTIs carry a high risk of induced HIV resistance
    1. Never use NNRTIs as monotherapy in HIV Infection

III. Mechanism

  1. NNRTIs have a completely different mechanism than nRTI (Nucleoside analogs)
  2. Like nRTIs, NNRTIs bind directly to reverse transcriptase
    1. Unlike Nucleosides, NNRTIs bind adjacent to the active polymerase site, distorting its active site
    2. NNRTI binding prevents RNA conversion to DNA

IV. Medications: First Generation

  1. Efavirenz (Sustiva, EFV)
  2. Nevirapine (Viramune, NVP)
  3. Delavirdine (Rescriptor)
    1. Released in U.S. in 1997 and among the original NNRTI agents
    2. Less potent than other NNRTIs (e.g. Efavirenz), and is no longer available in the U.S.

V. Medications: Second Generation

  1. Doravirine (Pifeltro)
    1. FDA approved in 2018
  2. Etravirine (Intelence)
    1. Approved in treatment experienced patients
  3. Rilpivirine (Endurant)
    1. FDA approved in 2011 for treatment-naive patients
    2. Available as oral agent and monthly IM Injection (as part of Cabenuva therapy)

VI. Adverse Effects

  1. Associated with significant Drug Reactions
    1. See specific agents
  2. Hyperlipidemia
  3. Rash is common (especially with Nevirapine)
    1. More common and more severe in women
    2. Reduced Incidence if starting slowly wth reduced dose over 2 weeks
    3. Prophylaxis not recommended (e.g. Corticosteroids)
      1. Antinori (2001) AIDS 15:1579-81 [PubMed]
    4. Switching to a different Drug Class may be needed
    5. May progress to Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, Erythema Multiforme
      1. Severe rash is especially more common with Etravirine and especially in women
  4. Neurologic Adverse Effects (esp. Efavirenz)
    1. Dizziness
    2. Headache
    3. Insomnia
    4. Difficulty concentrating
    5. Insomnia, Vivid dreams and Nightmares
    6. Hallucinations
  5. Hepatotoxicity
    1. Hepatotoxicity is a risk with most NNRTIs
  6. Hyperlipidemia
    1. Most common with Efavirenz and Etravirine
  7. QTc Prolongation
    1. Most significant with Efavirenz and Rilpivirine

VII. Drug Interactions

  1. Many potential Drug Interactions
    1. Most significant for the long list of interactions with Efavirenz and Etravirine
    2. See formal Drug Interaction applications
  2. Rifabutin
    1. Second generation NNRTIs require increased dose when concurrently taking Rifabutin
  3. Methadone
    1. Decreased Opioid effect with Nevirapine and Rilpivirine

VIII. References

  1. (2009) Treat Guidel Med Lett 7(78): 11-22 [PubMed]

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