Nucleoside reverse transcriptase inhibitors (NRTIs)

I. Introduction

Nucleoside reverse transcriptase inhibitors (NRTIs) are a foundational class of antiretroviral drugs primarily used in the treatment of Human Immunodeficiency Virus (HIV) infection and, to a lesser extent, Hepatitis B Virus (HBV) infection. They are considered the "backbone" of most antiretroviral therapy (ART) regimens. By targeting reverse transcriptase—an enzyme vital for retroviral replication—NRTIs interfere with viral reproduction, thereby reducing viral load and delaying disease progression.

These agents mimic naturally occurring nucleosides (the building blocks of DNA and RNA) but lack the 3′-OH group needed for forming phosphodiester bonds during DNA elongation. When incorporated into viral DNA, they act as chain terminators, halting further replication of viral genetic material.

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II. Mechanism of Action

NRTIs are prodrugs that require intracellular phosphorylation by host kinases to become active. After entering cells, they undergo sequential phosphorylation to their triphosphate forms, which then compete with endogenous nucleoside triphosphates for incorporation by HIV reverse transcriptase into the viral DNA. Once incorporated, they prevent the addition of further nucleotides due to the absence of a 3′-hydroxyl group, effectively terminating the DNA chain.

Key mechanisms include:

• Competitive inhibition of reverse transcriptase

• Chain termination upon incorporation into viral DNA

• Lack of proofreading by viral reverse transcriptase enhances NRTI efficacy

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III. NRTI Drugs and Their Characteristics

The major NRTIs currently in clinical use include:

1. Zidovudine (AZT)

• First approved antiretroviral drug (1987)

• Thymidine analog

• Adverse effects: Bone marrow suppression (anemia, neutropenia), headache, myopathy, lactic acidosis

2. Lamivudine (3TC)

• Cytidine analog

• Also active against HBV

• Well-tolerated, but resistance develops quickly with monotherapy

3. Emtricitabine (FTC)

• Cytidine analog, structurally similar to lamivudine

• Longer intracellular half-life than lamivudine

• Common in combination regimens (e.g., with tenofovir)

• Adverse effects: Skin hyperpigmentation, headache

4. Tenofovir disoproxil fumarate (TDF)

• Acyclic adenosine nucleotide analog (prodrug of tenofovir)

• Also active against HBV

• Adverse effects: Nephrotoxicity, bone mineral density loss, gastrointestinal intolerance

5. Tenofovir alafenamide (TAF)

• Newer prodrug of tenofovir

• Better intracellular delivery with lower systemic exposure than TDF

• Less renal and bone toxicity

6. Abacavir (ABC)

• Guanosine analog

• Not active against HBV

• Requires HLA-B*5701 screening due to risk of hypersensitivity reaction, which can be life-threatening

7. Didanosine (ddI)

• Adenosine analog

• Older drug, largely phased out due to toxicity

• Adverse effects: Pancreatitis, peripheral neuropathy, retinal changes

8. Stavudine (d4T)

• Thymidine analog

• High risk of mitochondrial toxicity

• No longer recommended due to adverse effects such as lactic acidosis, lipoatrophy, and pancreatitis

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IV. Approved Fixed-Dose Combinations Involving NRTIs

To improve adherence and therapeutic efficacy, many NRTIs are co-formulated with other antiretroviral agents:

• Truvada®: Tenofovir disoproxil fumarate + Emtricitabine

• Descovy®: Tenofovir alafenamide + Emtricitabine

• Epzicom® (Kivexa®): Abacavir + Lamivudine

• Combivir®: Zidovudine + Lamivudine

• Triumeq®: Abacavir + Lamivudine + Dolutegravir

• Biktarvy®: Tenofovir alafenamide + Emtricitabine + Bictegravir

• Atripla®: Tenofovir disoproxil + Emtricitabine + Efavirenz

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V. Clinical Applications

1. HIV Infection

• Backbone of combination antiretroviral therapy (cART)

• Always used in combination with drugs from other classes (NNRTIs, PIs, INSTIs)

• Typical regimens include two NRTIs + one integrase inhibitor or one NNRTI

2. Pre-exposure Prophylaxis (PrEP)

• Truvada (TDF + FTC) and Descovy (TAF + FTC) are approved for PrEP

• Used in high-risk individuals to prevent HIV acquisition

3. Post-exposure Prophylaxis (PEP)

• Used after potential exposure to HIV (e.g., occupational, sexual)

• Must begin within 72 hours of exposure

4. Prevention of Mother-to-Child Transmission

• Zidovudine is historically used during pregnancy, labor, and neonatal period

• Modern regimens now favor more tolerable agents such as tenofovir and lamivudine

5. Chronic Hepatitis B Infection

• Lamivudine, tenofovir (TDF and TAF), and entecavir (not an NRTI but a nucleoside analog) are used

• Long-term suppression of HBV replication reduces liver damage

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VI. Resistance Patterns and Considerations

HIV can develop mutations in reverse transcriptase that confer resistance to NRTIs.

Common resistance mutations:

• M184V: Confers high-level resistance to lamivudine and emtricitabine; increases susceptibility to zidovudine

• K65R: Reduces susceptibility to tenofovir, abacavir, and didanosine

• Thymidine analog mutations (TAMs): Confer cross-resistance to zidovudine and stavudine

• L74V: Associated with abacavir and didanosine resistance

Resistance testing is critical before initiating or modifying therapy, especially in cases of treatment failure.

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VII. Pharmacokinetics

• Oral bioavailability: Most NRTIs have good absorption

• Metabolism: Most undergo renal elimination, except abacavir (hepatic)

• Half-life: Intracellular half-lives are more relevant than plasma half-lives

• Dosing considerations: Renal function adjustments required for tenofovir, lamivudine, and emtricitabine

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VIII. Adverse Effects and Toxicities

NRTIs are generally well tolerated but may cause:

1. Mitochondrial Toxicity

• Due to inhibition of mitochondrial DNA polymerase γ

• Manifestations: Lactic acidosis, hepatic steatosis, peripheral neuropathy, pancreatitis, lipodystrophy

2. Bone and Renal Toxicity

• Mainly with TDF

• TAF has a better renal and bone safety profile

3. Hypersensitivity Reaction

• Abacavir: Requires HLA-B*5701 testing

• Symptoms: Fever, rash, gastrointestinal and respiratory symptoms; re-challenge is contraindicated

4. Hematological Effects

• Zidovudine: Causes anemia and neutropenia, especially in advanced HIV

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IX. Drug-Drug Interactions

NRTIs generally have fewer drug-drug interactions compared to NNRTIs or protease inhibitors, as they are not extensively metabolized by the cytochrome P450 (CYP) enzyme system.

However, key interactions include:

• Tenofovir + Nephrotoxic Drugs: Additive renal toxicity (e.g., aminoglycosides, NSAIDs)

• Didanosine + Tenofovir: Increased didanosine toxicity (pancreatitis, lactic acidosis)

• Abacavir + Alcohol: Alcohol can increase abacavir levels via hepatic competition

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X. Special Populations

1. Pregnancy

• Preferred NRTIs: Tenofovir (TDF), Lamivudine, Emtricitabine

• Zidovudine used historically, but newer regimens preferred due to tolerability

2. Renal Impairment

• Adjust dose for TDF, lamivudine, emtricitabine

• TAF preferred due to lower renal clearance

3. Pediatrics

• Many NRTIs are approved for children

• Zidovudine used in neonatal prophylaxis

4. Hepatitis B Coinfection

• Tenofovir and lamivudine active against both HIV and HBV

• Discontinuation may cause HBV flare

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XI. Comparison Between TDF and TAF

Feature	TDF	TAF
Intracellular activation	Requires plasma hydrolysis	Activated in lymphoid cells
Bone and kidney toxicity	Higher risk	Lower risk
Systemic tenofovir levels	High	Low
Co-formulation	With efavirenz (Atripla), FTC (Truvada)	With FTC (Descovy), bictegravir (Biktarvy)

XII. Future Directions and Research

1. Long-acting NRTI formulations

   • Investigated for improved adherence and convenience

2. Dual therapy regimens

   • Reducing toxicity by using fewer drugs (e.g., dolutegravir + lamivudine)

3. NRTIs in HIV cure research

   • Studied for latency reversal and impact on viral reservoirs

4. Nanotechnology-based NRTI delivery

   • Targeted and sustained release systems for ART

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XIII. Summary of Common NRTIs

Generic Name	Brand Name(s)	Analog Type	Key Notes
Zidovudine (AZT)	Retrovir	Thymidine	Bone marrow suppression
Lamivudine (3TC)	Epivir	Cytidine	HBV activity
Emtricitabine (FTC)	Emtriva	Cytidine	Long half-life
Tenofovir DF	Viread	Adenosine	Renal & bone effects
Tenofovir AF	Vemlidy	Adenosine	Better safety profile
Abacavir (ABC)	Ziagen	Guanosine	HLA-B*5701 testing
Didanosine (ddI)	Videx	Adenosine	Pancreatitis risk
Stavudine (d4T)	Zerit	Thymidine	Obsolete due to toxicity