What are the adverse effects of nonnucleoside reverse transcriptase inhibitors (NNRTIs) in antiretroviral therapy of HIV infection?

Updated: Apr 18, 2019
  • Author: R Chris Rathbun, PharmD, BCPS (AQ-ID), AAHIVP; Chief Editor: John Bartlett, MD  more...
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Rash, which is the most common adverse effect associated with all NNRTIs, [8] usually develops within the first few weeks of therapy and resolves with continued treatment. [8, 28, 36] All NNRTIs except etravirine have the ability to cause some degree of hepatotoxicity. [28, 37] Delavirdine and efavirenz can increase transaminase levels, while nevirapine can cause severe toxicity, including hepatic necrosis in patients with CD4 counts that exceed 250 cells/µL. [8, 38]

Efavirenz causies CNS effects such as insomnia, vivid dreaming, dizziness, confusion, and hallucinations.  Rilpivirine is also associated with CNS effects such as insomnia, dizziness, vivid dreams, and headache but less commonly than efavirenz. [34]

Tolerance to efavirenz-related CNS adverse effects commonly occurs after several weeks of therapy. Bedtime administration and avoidance of food at the time of administration can minimize the intensity of adverse effects. CNS effects may persist in a small number of patients, requiring drug discontinuation. [8]

Gradual upward titration of efavirenz over 2 weeks can reduce neuropsychiatric symptoms and insomnia. In a randomized, double-blind, controlled trial of 114 patients, patients who received a full dose of 600 mg daily from day 1 had a higher incidence and severity of dizziness (66% vs 32.8%), hangover (45.8% vs 20.7%), impaired concentration (22.9% vs 8.9%), and hallucinations (6.1% vs 0%) during the first week, compared with patients who had gradual efavirenz titration to 600 mg daily by day 14. During week 2, the incidence of these aforementioned adverse events was similar in each group; however, severity was greater in the full-dose group. Virologic and immunologic efficacy was similar in both groups. [39]

A lower dose of efavirenz (400 mg) has also been evaluated as part of a fixed dose formulation with tenofovir DF and lamivudine and found to have comparable efficacy to efavirenz (600 mg)/tenofovir DF/emtricitabine after 96 weeks and fewer efavirenz-related adverse effects. [40]

Efavirenz use has been associated with an approximate two-fold higher risk for suicidality. This risk appears to be present with both early and chronic use. Increased risk for suicidality was observed in patients receiving psychoactive medications or with a psychiatric history, weighing less than 60 kg, and with injection drugs use. [41]

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