Classification of Antiretrovirus Drugs

Human Immunodeficiency Virus (HIV) infection is a chronic, life-threatening condition that requires lifelong treatment. Antiretroviral drugs are used to manage HIV infection by suppressing viral replication and improving immune function. These drugs are used in combinations as part of antiretroviral therapy (ART) to prevent resistance and reduce the risk of disease progression.

This blog from Pharmacy Freak provides a comprehensive classification of antiretroviral drugs, their uses, drug of choice highlights, and key side effects, with academic references from KDT, Sparsh Gupta, and Goodman & Gilman.

what is Antiretrovirus Drug?

Antiretroviral drugs are agents that inhibit various stages of the HIV life cycle. They do not eliminate the virus completely but prevent its replication, thus slowing disease progression and reducing transmission.

Antiretroviral Drug Classification (KD Tripathi)

• Nucleoside reverse transcriptase inhibitors (NRTIs): Zidovudine, Didanosine, Stavudine, Lamivudine, Abacavir, Emtricitabine, Tenofovir
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs): Nevirapine, Efavirenz, Delavirdine
• Protease inhibitors (PIs): Ritonavir, Atazanavir, Indinavir, Nelfinavir, Saquinavir, Amprenavir, Lopinavir
• Entry inhibitor: Enfuvirtide
• CCR-5 receptor inhibitor: Maraviroc
• Integrase inhibitor: Raltegravir

Classification(General)

Antiretroviral drugs are classified into the following classes based on their mechanism of action:

1. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
   Mechanism: Inhibit reverse transcriptase enzyme by acting as false substrates, preventing DNA synthesis
   Examples: Zidovudine (AZT), Lamivudine (3TC), Tenofovir, Abacavir, Emtricitabine
   Use: Backbone of ART regimen: Zidovudine is also used for post-exposure prophylaxis (PEP)
2. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
   Mechanism: Bind to a different site on reverse transcriptase and inhibit its function non-competitively
   Examples: Nevirapine, Efavirenz, Delavirdine, Etravirine
   Use: Combined with NRTIs in ART regimens
3. Protease Inhibitors (PIs)
   Mechanism: Inhibit viral protease enzyme, preventing maturation of viral proteins
   Examples: Ritonavir, Lopinavir, Indinavir, Atazanavir, Darunavir
   Use: Used with a pharmacokinetic booster like Ritonavir or Cobicistat
   Note: Ritonavir is often used at low doses to boost other PIs
4. Integrase Strand Transfer Inhibitors (INSTIs)
   Mechanism: Inhibit HIV integrase enzyme, blocking integration of viral DNA into host genome
   Examples: Raltegravir, Elvitegravir, Dolutegravir
   Use: Preferred first-line agents due to high potency and low resistance
5. Fusion Inhibitors
   Mechanism: Inhibit fusion of the viral envelope with the host cell membrane
   Example: Enfuvirtide
   Use: Reserved for resistant cases due to cost and injection route
6. CCR5 Antagonists (Entry Inhibitors)
   Mechanism: Block CCR5 coreceptor on CD4 cells, preventing viral entry
   Example: Maraviroc
   Use: Used when HIV tropism test confirms CCR5-tropic virus
7. Pharmacokinetic Enhancers (Boosters)
   Mechanism: Inhibit CYP3A enzymes to increase plasma concentration of co-administered drugs
   Examples: Ritonavir, Cobicistat

Uses

Antiretroviral drugs are used in the following clinical scenarios:

• First-line treatment of HIV (as per WHO and NACO guidelines)
• Prevention of mother-to-child transmission (PMTCT)
• Post-exposure prophylaxis (PEP)
• Pre-exposure prophylaxis (PrEP) in high-risk individuals
• Treatment of drug-resistant HIV
• Occupational exposure (e.g., needle stick injuries)

Drug of Choice Highlights

• HIV first-line therapy (adult) – Tenofovir + Lamivudine + Dolutegravir (TLD regimen)
• PMTCT – Zidovudine + Lamivudine + Nevirapine
• PEP – Tenofovir + Lamivudine + Dolutegravir for 28 days
• PrEP – Tenofovir + Emtricitabine (daily)
• HIV in children – Abacavir + Lamivudine + Lopinavir/ritonavir
• HIV with tuberculosis – Avoid Efavirenz due to interaction with Rifampin; prefer Dolutegravir-based regimen

Side Effects

• NRTIs – Lactic acidosis, hepatic steatosis, lipodystrophy
• Zidovudine – Anemia, neutropenia
• Abacavir – Hypersensitivity (check for HLA-B*5701)
• NNRTIs – Rash, hepatotoxicity, CNS effects (Efavirenz)
• PIs – Hyperlipidemia, lipodystrophy, insulin resistance, kidney stones (Indinavir)– Insomnia, headache, rare hypersensitivity
• Enfuvirtide – Injection site reactions
• Maraviroc – Hepatotoxicity, orthostatic hypotension
• Ritonavir – GI intolerance, drug interactions (CYP3A4 inhibitor)

Updated Clinical Pearls

• Tenofovir and Dolutegravir are currently the most preferred drugs in HIV management due to high efficacy and low resistance.
• Dolutegravir has a high genetic barrier to resistance and is part of most first-line regimens globally.
• Efavirenz is avoided in psychiatric illness and pregnancy (especially first trimester).
• Zidovudine is still used in PMTCT and PEP due to availability and familiarity.
• All ART regimens should be monitored for viral load suppression and CD4 count recovery.

References

1. Tripathi KD. Essentials of Medical Pharmacology. 7th ed. New Delhi: Jaypee Brothers Medical Publishers; 2013. p. 848–861.
2. Gupta S, Garg A. Review of Pharmacology. 15th ed. New Delhi: Jaypee Brothers Medical Publishers; 2023. p. 278–283.
3. Brunton LL, Chabner BA, Knollmann BC, editors. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill Education; 2011. p. 1269–1287.