NNRTIs

I. Introduction

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a class of antiretroviral drugs used primarily in the treatment of human immunodeficiency virus type 1 (HIV-1). They are one of the three core drug classes that target the reverse transcriptase (RT) enzyme, which HIV uses to convert its RNA into DNA—a necessary step in viral replication. Unlike nucleoside reverse transcriptase inhibitors (NRTIs), which mimic nucleotides and terminate the DNA chain, NNRTIs work by non-competitively binding to a hydrophobic pocket of the reverse transcriptase enzyme, inducing conformational changes that inhibit its polymerase activity.

NNRTIs are HIV-1 specific and are not effective against HIV-2 due to structural differences in the RT enzyme. They are commonly used as part of combination antiretroviral therapy (cART) and are frequently included in fixed-dose combination formulations for better adherence and clinical outcomes.

---

II. Mechanism of Action

NNRTIs act by:

• Binding directly to a site adjacent to the active site of the HIV-1 reverse transcriptase enzyme

• This site is known as the NNRTI-binding pocket

• Binding causes allosteric inhibition (non-competitive), disrupting the enzyme's ability to convert viral RNA into DNA

This mechanism is distinct from NRTIs, which act as false substrates, being incorporated into the viral DNA chain and halting replication.

---

III. Approved NNRTIs

The NNRTI class includes several drugs approved by the FDA and other regulatory agencies:

Generic Name	Brand Name(s)	Generation	Approval Year
Nevirapine	Viramune®	First	1996
Delavirdine	Rescriptor®	First	1997 (withdrawn in 2023)
Efavirenz	Sustiva®	First	1998
Etravirine	Intelence®	Second	2008
Rilpivirine	Edurant®	Second	2011
Doravirine	Pifeltro®	Third	2018

Delavirdine has been withdrawn from many markets due to inferior efficacy, inconvenient dosing, and significant drug interactions.

---

IV. Generational Classification and Features

Generation	Drugs	Key Features
First	Nevirapine, Efavirenz	Lower genetic barrier, rapid resistance, CNS side effects (efavirenz)
Second	Etravirine, Rilpivirine	Better resistance profile, fewer side effects, higher selectivity
Third	Doravirine	Newest NNRTI, improved safety, high resistance threshold, fewer interactions

V. Pharmacokinetics

Drug	Half-life	Bioavailability	Route	Metabolism	Food Effect
Nevirapine	~25–30 hrs	High	Oral	Hepatic (CYP3A4)	No major effect
Efavirenz	~40–55 hrs	High	Oral	CYP2B6, CYP3A4	Take on empty stomach
Rilpivirine	~45 hrs	Moderate	Oral	CYP3A4	Must take with food
Etravirine	~40–55 hrs	Moderate	Oral	CYP3A4, 2C9, 2C19	Take after meals
Doravirine	~15 hrs	High	Oral	CYP3A4	No food restriction

NNRTIs are generally long-acting, allowing for once-daily dosing, except etravirine, which is given twice daily. Most are lipophilic, leading to wide tissue distribution, including the central nervous system (CNS).

---

VI. Clinical Uses

NNRTIs are prescribed as part of combination antiretroviral therapy (cART) for:

1. Treatment of HIV-1 infection in adults and children

2. First-line therapy (e.g., efavirenz and doravirine-based regimens)

3. Second-line or salvage therapy in patients with drug resistance (etravirine)

4. Fixed-dose combinations to simplify regimens

They are not effective against HIV-2.

---

VII. Fixed-Dose Combinations (FDCs)

NNRTI Component	Fixed-Dose Combination Product	Other Components
Efavirenz	Atripla®	Tenofovir DF + Emtricitabine
Rilpivirine	Complera® / Eviplera®	Tenofovir DF + Emtricitabine
Rilpivirine	Odefsey®	Tenofovir alafenamide + Emtricitabine
Doravirine	Delstrigo®	Tenofovir DF + Lamivudine

These combinations enable single-tablet regimens, improving adherence, convenience, and virologic suppression.

---

VIII. Resistance and Genetic Barrier

NNRTIs, particularly first-generation agents, have a low genetic barrier, meaning that a single point mutation can confer high-level resistance.

Key Resistance Mutations:

Mutation	Impacted Drugs	Notes
K103N	Efavirenz, Nevirapine	Most common; does not affect etravirine or doravirine
Y181C	Nevirapine, Delavirdine	Reduces susceptibility to rilpivirine
E138K	Rilpivirine	Common in virologic failure
V106A/M	Broad NNRTI resistance	May affect efavirenz and nevirapine
G190A/S	Multiple NNRTIs	High-level resistance

Etravirine and doravirine retain activity against many viruses with common NNRTI mutations, providing salvage options in treatment-experienced patients.

---

IX. Adverse Effects

Drug	Common Side Effects	Serious Adverse Effects
Nevirapine	Rash, fever	Hepatotoxicity, Stevens-Johnson Syndrome
Efavirenz	Dizziness, vivid dreams, depression	Suicidality, CNS toxicity
Etravirine	Rash, nausea	Hypersensitivity reactions
Rilpivirine	Depression, insomnia	QT prolongation at high doses
Doravirine	Well-tolerated	Minimal CNS effects

Rash and hepatotoxicity are class effects, most severe with nevirapine. Efavirenz is notable for CNS side effects (dizziness, sleep disturbances, hallucinations). Doravirine shows the most favorable tolerability in its class.

---

X. Drug Interactions

Most NNRTIs are substrates and/or inducers/inhibitors of cytochrome P450 enzymes, especially CYP3A4.

Interacting Class	Effect	Notes
Rifampin, Rifabutin	↓ NNRTI levels (except efavirenz partially)	Avoid or adjust
Anticonvulsants (phenytoin)	↓ NNRTI levels	Avoid or monitor
Azole antifungals	↑ NNRTI levels (esp. rilpivirine)	Monitor for toxicity
Methadone	Efavirenz may ↓ methadone	Monitor withdrawal symptoms
PPIs	↓ Rilpivirine absorption	Contraindicated with rilpivirine
Antacids	Separate dosing with rilpivirine	≥2 hours before or 4 hours after

Doravirine has a better drug interaction profile, making it preferable in polypharmacy patients.

---

XI. Contraindications and Cautions

Absolute Contraindications:

• Rilpivirine: With proton pump inhibitors due to pH-dependent absorption

• Nevirapine: Initiating in women with CD4 >250 or men >400 due to hepatotoxicity risk

Use with caution in:

• Psychiatric illness: Efavirenz may exacerbate

• Hepatic impairment: All NNRTIs are hepatically metabolized

• Pregnancy: Efavirenz historically avoided in first trimester (now considered safer); rilpivirine and doravirine preferred

---

XII. NNRTIs in Special Populations

Population	Preferred Agents	Notes
Pregnancy	Rilpivirine, Efavirenz	Efavirenz now considered safe
Pediatrics	Efavirenz (≥3 years), Nevirapine	Dosing by weight
Renal disease	All NNRTIs safe (not renally cleared)	Adjust other components in combinations
Hepatic disease	Monitor LFTs	Avoid nevirapine in severe liver disease

XIII. Summary of NNRTI Characteristics

Drug	Dosing	Common Use	Unique Notes
Nevirapine	BID	Developing countries	High hepatotoxicity risk
Efavirenz	QD	First-line in resource-limited settings	CNS toxicity
Etravirine	BID	Salvage therapy	High barrier to resistance
Rilpivirine	QD (with food)	First-line or switch regimens	Avoid with PPIs, needs acidic stomach
Doravirine	QD	Modern first-line	Fewest interactions, favorable profile

XIV. Clinical Guidelines and Recommendations

1. WHO Guidelines (2023)

• NNRTI-based regimens (especially efavirenz) are being replaced with integrase strand transfer inhibitors (INSTIs) like dolutegravir as first-line.

• NNRTIs remain valuable in resource-limited settings or for switch therapy.

2. DHHS Guidelines (USA)

• Efavirenz and rilpivirine are alternative options to integrase-based regimens

• Doravirine considered for treatment-naïve and switch therapy in stable patients

• Etravirine used in treatment-experienced patients with NNRTI resistance

---

XV. Future Directions and Research

• Long-acting NNRTIs: e.g., rilpivirine injectable formulation in Cabenuva® (with cabotegravir) for monthly dosing

• Development of new NNRTIs: with improved resistance profile and bioavailability

• Dual therapy: NNRTIs paired with integrase inhibitors or NRTIs for simplification