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# Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Drugs that wedge into a pocket of HIV-1 reverse transcriptase, away from the active site, and bend the enzyme so it stops copying the virus.

Updated 2026-11-01

## What they are

Allosteric inhibitors of HIV-1 reverse transcriptase: efavirenz, nevirapine, rilpivirine and doravirine. They need no intracellular activation and are inactive against HIV-2. Because resistance has risen, WHO no longer prefers them for first-line treatment.

## Mechanism of action

They bind a hydrophobic pocket in the p66 subunit of reverse transcriptase, near but outside the catalytic site. The shape change slows the enzyme non-competitively. Because the pocket is specific to HIV-1, a single mutation (for example K103N) can be enough to lose the older agents.

Target: Allosteric pocket of HIV-1 reverse transcriptase

## Key points

- Low genetic barrier: a single mutation can cause cross-resistance between efavirenz and nevirapine.
- Efavirenz: nervous system symptoms (dizziness, vivid dreams, insomnia) and psychiatric symptoms; inducer of CYP3A and CYP2B6.
- Nevirapine: severe hepatotoxicity and rash (Stevens-Johnson), mainly in the first weeks.
- Rilpivirine needs stomach acid; proton pump inhibitors are contraindicated.
- They are not active against HIV-2.

## Drugs in this class

- [**Efavirenz** A once-daily NNRTI used for years as first-line treatment. Typical effects are dizziness, vivid dreams and psychiatric… HIV-1 reverse transcriptase (NNRTI pocket)](https://durgical.com/en/pharmacology/efavirenz/)
- [**Nevirapine** An old, cheap NNRTI. It can cause hepatitis and severe skin reactions in the first weeks, more often in people with… HIV-1 reverse transcriptase (NNRTI pocket)](https://durgical.com/en/pharmacology/nevirapine/)
- [**Rilpivirine** A second-generation NNRTI. It is absorbed only with food and stomach acid; there is also a long-acting injectable form. HIV-1 reverse transcriptase (NNRTI pocket)](https://durgical.com/en/pharmacology/rilpivirine/)
- [**Doravirine** A newer NNRTI: taken with or without food, independent of stomach acid, with fewer nervous system and lipid effects… HIV-1 reverse transcriptase (NNRTI pocket)](https://durgical.com/en/pharmacology/doravirine/)

## Others in the class

- Etravirine

## Test yourself

Think of the answer, then tap the question to see it.

## How does the binding site of an NNRTI differ from that of an NRTI?

The NRTI enters the active site as a fake nucleotide; the NNRTI binds a nearby allosteric pocket and distorts the enzyme, with no need for phosphorylation.

## Why are NNRTIs useless against HIV-2?

The allosteric pocket they bind is specific to HIV-1 reverse transcriptase.

## What does a low genetic barrier mean for older NNRTIs?

That a single viral mutation (such as K103N) is enough to lose activity, often across the older class.

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Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed., ch. 64 (McGraw Hill, 2023); [ATCDDD - ATC/DDD Index](https://atcddd.fhi.no/atc_ddd_index/?code=J05AG) (WHO Collaborating Centre for Drug Statistics Methodology, 2026); [WHO recommends dolutegravir as preferred HIV treatment option in all populations](https://www.who.int/news/item/22-07-2019-who-recommends-dolutegravir-as-preferred-hiv-treatment-option-in-all-populations) (World Health Organization, 2019).

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