Pharmacology · Antiviral Pharmacology

NRTIs and NNRTIs

Reverse transcriptase inhibitors — mechanism, resistance, and clinical role

NRTIs are prodrugs that require intracellular phosphorylation to their active triphosphate forms — once incorporated into viral DNA by reverse transcriptase, their missing 3′-OH group causes obligate chain termination; plasma drug levels do not reflect intracellular active drug concentrations, and intracellular half-lives govern dosing intervals rather than plasma pharmacokinetics.
NNRTIs bind a hydrophobic allosteric pocket adjacent to but distinct from the RT active site, inducing a conformational change that slows catalysis — no phosphorylation is required, the pocket is absent in HIV-2 and human DNA polymerases (explaining their selectivity), and a single point mutation such as K103N can confer high-level resistance to first-generation agents efavirenz and nevirapine while leaving rilpivirine and doravirine fully active.
TDF and TAF are both tenofovir prodrugs targeting the same viral enzyme, but TAF delivers tenofovir preferentially to lymphocytes via a different intracellular activation pathway, reducing plasma tenofovir by approximately 10-fold and dramatically cutting the renal tubular and bone toxicity associated with TDF's OAT1-mediated proximal tubular accumulation.
Both FTC and 3TC are active against hepatitis B virus as well as HIV — in HIV/HBV co-infected patients, ART must include TDF or TAF plus FTC or 3TC, and abrupt discontinuation without a plan to maintain HBV suppression risks fatal hepatic decompensation from a rebound HBV flare; HBsAg testing before starting ART is therefore mandatory.
Resistance pathways for NRTIs are mechanistically distinct: M184V (selected by 3TC/FTC) increases RT fidelity and blocks incorporation of these analogues but paradoxically resensitizes RT to ZDV and TDF; thymidine analogue mutations (TAMs) selected by ZDV instead enhance pyrophosphorolysis to excise already-incorporated chain terminators; and the K65R mutation selected by TDF/TAF confers resistance to those agents while remaining largely incompatible with TAMs — the two pathways are mutually antagonistic.

Abbreviations: ART = antiretroviral therapy · NRTI = nucleoside/nucleotide RT inhibitor · NNRTI = non-nucleoside RT inhibitor · RT = reverse transcriptase · TAM = thymidine analogue mutation · HBV = hepatitis B virus · HSR = hypersensitivity reaction · OAT1 = organic anion transporter 1 · PPI = proton pump inhibitor · CYP = cytochrome P450

Mechanism Overview

NRTIs

Obligate Chain Termination

Prodrugs phosphorylated intracellularly to active triphosphate forms
Incorporated into viral DNA by RT in place of natural nucleotides
Lack 3′-OH group → chain elongation stops after incorporation
Plasma levels do NOT reflect intracellular active drug — intracellular half-lives govern dosing interval

NNRTIs

Allosteric Inhibition

Bind a hydrophobic pocket adjacent to (not at) the RT active site
No phosphorylation required — directly active as parent compound
Induce conformational change that slows RT catalysis
Active only against HIV-1 — pocket absent in HIV-2 RT and human DNA polymerases

Key NRTI Agents

Tenofovir Prodrugs

TDF / TAF

TDFHigh plasma tenofovir → OAT1-mediated proximal tubular accumulation → Fanconi syndrome risk; bone toxicity
TAFLymphocyte-targeted delivery → ~10× lower plasma tenofovir → far less renal and bone toxicity
Both active against HBV as well as HIV

Cytidine Analogues

FTC / 3TC

Emtricitabine (FTC) and lamivudine (3TC) — well tolerated cytidine analogues
FTC intracellular half-life ~39 hours, supporting once-daily dosing
Both active against HBV — abrupt discontinuation in HIV/HBV co-infection risks fatal HBV flare
Screen for HBsAg before starting ART in all patients

Carbocyclic Analogue

Abacavir (ABC)

Hepatic metabolism — no renal dose adjustment required
Fatal HSR in HLA-B*57:01 carriers (~5–8%) — screen before prescribing
Rechallenge after confirmed HSR is absolutely contraindicated — can be fatal
HLA-B*57:01 screening eliminates most clinical HSR events

HIV/HBV Co-infection Rule

Always include TDF or TAF plus FTC or 3TC in ART for HIV/HBV co-infected patients — these agents suppress both viruses simultaneously. Never discontinue either drug without a plan to maintain HBV suppression. Abrupt ART discontinuation in co-infected patients risks fatal hepatic decompensation from HBV reactivation flare. Baseline HBsAg testing is mandatory before ART initiation in all patients.

NRTI Toxicity

Class Effect

Mitochondrial Toxicity — pol-gamma Inhibition

Risk ranking: ZDV > ABC >> TDF / FTC / 3TC / TAF
Manifestations: lactic acidosis (most severe), hepatic steatosis, peripheral neuropathy, lipoatrophy
ZDV also causes anemia and neutropenia from bone marrow suppression — distinct from mitochondrial toxicity
Stavudine and didanosine had highest risk — no longer used in clinical practice

TDF-Specific

Nephrotoxicity — Fanconi Syndrome

OAT1 transporter concentrates TDF in proximal tubular cells → mitochondrial injury
Fanconi syndrome: glucosuria without hyperglycemia, phosphaturia, proteinuria
Risk increased by concurrent ritonavir or cobicistat — both inhibit tubular efflux
TAF avoids this: plasma tenofovir ~10× lower; tubular exposure minimal

NRTI Resistance Mechanisms

Discrimination Pathway

Discrimination Mutations

M184V (3TC/FTC)High-level resistance to both selecting agents; increases RT fidelity — paradoxically resensitizes to ZDV and TDF
K65R (TDF/ABC)Resistance to TDF, TAF, ABC; preserves ZDV susceptibility
M184V and K65R are mutually antagonistic — K65R suppresses the TAM pathway

Excision Pathway

Thymidine Analogue Mutations (TAMs)

Selected by ZDV — enhance RT pyrophosphorolysis to remove incorporated chain-terminating NRTI
Six canonical TAMs: M41L, D67N, K70R, L210W, T215F/Y, K219Q/E
Multiple TAMs = broad NRTI cross-resistance across the class
TAM and K65R pathways are largely mutually exclusive — competing evolutionary pressures

NNRTI Agents

First Generation

Efavirenz

CYP3A4 and CYP2B6 inducer — reduces levels of many co-administered drugs
CNS toxicity: vivid dreams, dizziness, depression — often improves over weeks but can persist
Reduces methadone by 50–60% → opioid withdrawal; lowers oral contraceptive levels
K103N confers high-level resistance; avoid in psychiatric illness and methadone patients

Second Generation

Rilpivirine

CYP3A4 substrate only — no induction; fewer drug interactions than efavirenz
Must take with a substantial meal — absorption fails without food
PPIs absolutely contraindicated — suppress gastric acid all day, preventing adequate absorption regardless of timing
Contraindicated when VL >100,000 copies/mL or CD4 <200 cells/μL at initiation
K103N does NOT cause resistance — active against this common transmitted mutation

Second Generation

Doravirine

CYP3A4 substrate only — no induction; excellent CNS tolerability compared to efavirenz
Active against K103N and E138K — covers common transmitted NNRTI mutations
No food requirement — flexible dosing
Rifampin reduces doravirine AUC by ~88% — contraindicated combination
Good option when efavirenz CNS toxicity or drug interactions are a concern

Critical NNRTI Drug Interactions

Efavirenz + Methadone — Dangerous Interaction

Efavirenz reduces methadone plasma concentrations by 50–60% through induction of CYP3A4 and CYP2B6. Opioid withdrawal typically begins within 1–2 weeks of starting efavirenz and can be severe. Coordinate with the methadone prescriber before initiating any efavirenz-containing regimen. An INSTI-based regimen is strongly preferred in all patients on methadone maintenance therapy.

Rilpivirine — Acid Suppression Is Contraindicated

PPIs are absolutely contraindicated with rilpivirine — they suppress gastric acid throughout the entire day and prevent adequate rilpivirine absorption regardless of the timing of administration. H2 blockers may be used if taken at least 12 hours before or at least 4 hours after rilpivirine. Antacids must be separated by at least 2 hours before or 4 hours after rilpivirine.

Transmitted Resistance and NNRTI Selection

K103N is present in approximately 2–8% of newly diagnosed treatment-naive patients in the U.S. This single mutation confers high-level resistance to efavirenz and nevirapine but does not affect rilpivirine or doravirine. Baseline genotypic resistance testing is required before selecting any NNRTI — patients with K103N who receive efavirenz will have virologic failure. Patients with multiple NNRTI resistance mutations should receive an INSTI-based regimen instead.

Suggested References

Author / Source	Title	Publication
Katzung BG, ed.	Basic and Clinical Pharmacology, 15th ed. — Chapter 49: Antiviral Agents	McGraw-Hill; 2021
Brunton L, Knollmann B, Hilal-Dandan R, eds.	Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed. — Chapter 55: Antiretroviral Agents and Treatment of HIV Infection	McGraw-Hill; 2023
Cihlar T, Ray AS	Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine	Antiviral Res. 2010
Mallal S et al.	HLA-B*5701 screening for hypersensitivity to abacavir	N Engl J Med. 2008
de Bethune MP	Non-nucleoside reverse transcriptase inhibitors: discovery, development, and use	Antiviral Res. 2010
Clutter DS et al.	HIV-1 drug resistance and resistance testing	Infect Genet Evol. 2016
DHHS Panel	Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV	AIDSinfo.nih.gov