What are the classes of antiretroviral drugs?

Antiretroviral therapy (ART) has transformed HIV from a fatal illness into a manageable chronic condition, with more than 17 million people receiving treatment worldwide in 2016. An essential component of this success is the use of different antiretroviral drug classes that target distinct stages of the HIV replication cycle. So, what are the classes of antiretroviral drugs and how do they work to suppress the virus?

Quick Summary

Antiretroviral drugs are categorized into distinct classes based on their mechanism of action, targeting specific steps of the HIV life cycle. These classes include reverse transcriptase inhibitors, integrase inhibitors, protease inhibitors, and entry inhibitors, used in combination therapy to effectively suppress viral replication.

Key Points

• Drug Classification: Antiretroviral drugs are sorted into classes based on which stage of the HIV life cycle they target, such as reverse transcription or viral entry.

• Combination Therapy: The standard treatment for HIV, known as cART, involves combining multiple drugs from different classes to maximize effectiveness and minimize drug resistance.

• Reverse Transcriptase Inhibitors: This category includes NRTIs (faulty DNA building blocks) and NNRTIs (non-competitive binders), both of which block the enzyme that converts viral RNA to DNA.

• Integrase Inhibitors: A highly effective class that prevents the integration of viral DNA into the host cell's genome, often forming the basis of first-line treatment regimens.

• Entry Inhibitors: A varied class that blocks HIV from entering host cells by targeting different steps like attachment to cell receptors (gp120, CCR5) or fusion of viral and cell membranes.

• Protease and Capsid Inhibitors: PIs prevent the maturation of new viral particles, while newer capsid inhibitors disrupt the viral protein shell at multiple stages, especially for drug-resistant HIV.

The HIV Life Cycle: The Basis for Antiretroviral Drug Classes

Human Immunodeficiency Virus (HIV) is a retrovirus that attacks and destroys the body's immune cells, primarily CD4+ T-cells. To effectively control the virus, antiretroviral drugs are designed to block different stages of its life cycle, from entry into a host cell to the assembly of new viral particles. Understanding this cycle is key to understanding how each class of drug works.

The Stages of the HIV Life Cycle

1. Binding and Fusion: The virus's outer envelope protein (gp120) attaches to the host CD4 receptor and a co-receptor (typically CCR5 or CXCR4), allowing the virus and cell membranes to fuse and the virus to enter.
2. Reverse Transcription: The enzyme reverse transcriptase converts the viral RNA into viral DNA.
3. Integration: The viral DNA is transported into the host cell's nucleus, and the integrase enzyme inserts it into the host cell's own DNA.
4. Replication: The infected cell uses its own machinery to create new viral proteins and long protein chains.
5. Assembly and Budding: The new viral proteins and RNA assemble into new, immature viral particles, which exit the host cell.
6. Maturation: The protease enzyme cuts the long viral protein chains into smaller, functional proteins, creating a mature, infectious virus.

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs/NtRTIs)

This class of drugs inhibits the reverse transcriptase enzyme, preventing it from converting viral RNA into DNA. NRTIs act as faulty building blocks for the viral DNA chain, leading to its termination and halting viral replication.

• Mechanism: Competitive inhibitors of reverse transcriptase.
• Examples: Abacavir, Emtricitabine, Lamivudine, Tenofovir.
• Role: Often form the backbone of a combination ART regimen.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Unlike NRTIs, NNRTIs do not act as decoy building blocks. Instead, they bind directly to the reverse transcriptase enzyme at a different site, causing a structural change that prevents it from functioning properly.

• Mechanism: Non-competitive inhibitors of reverse transcriptase.
• Examples: Doravirine, Efavirenz, Rilpivirine.
• Role: Used in combination with NRTIs to target reverse transcriptase from two different angles.

Integrase Strand Transfer Inhibitors (INSTIs)

INSTIs target the integrase enzyme, which HIV uses to insert its genetic material into the host cell's DNA. By blocking this step, INSTIs prevent the viral genetic information from being permanently incorporated into the host's genome.

• Mechanism: Blocks the strand transfer reaction catalyzed by integrase.
• Examples: Bictegravir, Dolutegravir, Raltegravir.
• Role: Often a core component of modern, first-line ART regimens due to high efficacy and tolerability.

Protease Inhibitors (PIs)

Protease is a viral enzyme that cuts long protein chains into smaller, functional pieces during the final maturation phase of the virus. PIs block this process, resulting in the assembly of immature, non-infectious viral particles.

• Mechanism: Competitively inhibit the HIV protease enzyme.
• Examples: Atazanavir, Darunavir, Lopinavir.
• Role: Effective against HIV that is resistant to other classes; often used with a 'booster' medication.

Entry Inhibitors

This is a diverse group of drugs that interfere with HIV's ability to enter a host cell. These can be further broken down into several sub-classes based on their precise mechanism of action.

• CCR5 Antagonists: Block the CCR5 co-receptor on the surface of immune cells, which prevents R5-tropic HIV strains from binding and entering. Requires a viral tropism test.
  • Example: Maraviroc.
• Fusion Inhibitors: Prevent the fusion of the viral envelope with the host cell membrane.
  • Example: Enfuvirtide.
• Attachment Inhibitors: Bind to the gp120 protein on the viral surface, blocking its attachment to the CD4 receptor.
  • Example: Fostemsavir.
• Post-Attachment Inhibitors: Bind directly to the CD4 receptor, inhibiting the conformational change required for the virus to enter.
  • Example: Ibalizumab.

Capsid Inhibitors

Capsid inhibitors are a newer class of antiretrovirals that interfere with the HIV capsid, the protective protein shell around the virus's genetic material. They work at multiple stages of the viral life cycle by disrupting the formation and breakdown of the capsid.

• Mechanism: Interfere with capsid function, disrupting viral replication.
• Example: Lenacapavir.
• Role: Often used for treatment-experienced patients with multidrug-resistant HIV.

Combination Antiretroviral Therapy (cART)

Effective HIV treatment relies on a regimen of multiple drugs from different classes, a strategy known as combination antiretroviral therapy (cART). Using drugs with different mechanisms of action significantly reduces the risk of drug resistance and more effectively suppresses the virus. Current guidelines often recommend regimens combining an INSTI with two NRTIs.

Comparison of Antiretroviral Drug Classes

Drug Class	Mechanism of Action	Target	Examples	Common Use	Potential Resistance
NRTIs/NtRTIs	Inhibit reverse transcriptase by acting as faulty DNA blocks, terminating chain synthesis.	Reverse Transcriptase Enzyme	Abacavir, Emtricitabine, Tenofovir	Backbone of most regimens.	Mutations in the reverse transcriptase gene.
NNRTIs	Inhibit reverse transcriptase by binding directly to the enzyme at a non-active site, causing conformational change.	Reverse Transcriptase Enzyme	Doravirine, Efavirenz, Rilpivirine	Combination with NRTIs.	Single amino acid mutations can cause high-level resistance.
INSTIs	Block the integrase enzyme, preventing viral DNA from integrating into the host cell's DNA.	Integrase Enzyme	Bictegravir, Dolutegravir, Raltegravir	Recommended for first-line therapy.	Mutations in the integrase gene.
PIs	Block the protease enzyme, preventing the maturation of new viral particles into infectious forms.	Protease Enzyme	Atazanavir, Darunavir, Lopinavir	Effective against resistant strains.	Multiple mutations in the protease gene.
Entry Inhibitors	Prevent HIV from entering the host cell by blocking attachment or fusion.	Host cell receptors (CD4, CCR5) or viral proteins (gp120, gp41)	Maraviroc, Enfuvirtide, Fostemsavir	Treatment-experienced patients; specific resistance patterns.	Mutations allow virus to bypass the block.
Capsid Inhibitors	Interfere with the HIV capsid, the protective protein shell, disrupting viral replication at multiple stages.	Viral Capsid	Lenacapavir	Heavily treatment-experienced patients.	Resistance mutations within the capsid gene.

Conclusion

Antiretroviral drugs represent a cornerstone of modern HIV management, and their classification based on their mechanism of action is fundamental to effective treatment. The diverse classes, including NRTIs, NNRTIs, INSTIs, PIs, and Entry and Capsid inhibitors, each target a unique stage of the virus's life cycle. The standard of care, cART, combines multiple drugs from these classes to achieve maximum viral suppression and prevent the emergence of drug resistance. Continued research and development of new classes and regimens ensure that people with HIV can live long, healthy lives with reduced risk of complications and transmission. For detailed, up-to-date treatment guidelines, consult a reliable resource like the US Department of Health and Human Services guidelines. https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/whats-new-and-updates

Frequently Asked Questions

Why is combination therapy (cART) necessary for treating HIV?

Combination therapy is necessary because it targets the virus at multiple stages of its life cycle, which makes it much harder for HIV to mutate and develop resistance to the drugs. This approach leads to higher efficacy and better viral suppression than using a single drug.

What is the primary difference between NRTIs and NNRTIs?

Both NRTIs and NNRTIs target the reverse transcriptase enzyme, but they do so differently. NRTIs are faulty nucleoside analogues that are incorporated into the viral DNA chain, causing it to terminate. NNRTIs bind to a different, non-active site on the enzyme, causing a conformational change that prevents it from functioning.

How do entry inhibitors prevent HIV infection?

Entry inhibitors are a broad class that block HIV from entering the host cell. They can prevent attachment to cell receptors (like CD4 or CCR5) or block the fusion of the viral and cellular membranes.

When might a capsid inhibitor be used in HIV treatment?

Capsid inhibitors, such as lenacapavir, are a newer class of antiretrovirals often used for heavily treatment-experienced patients who have multidrug-resistant HIV. They work by interfering with the viral capsid at multiple stages of the viral life cycle.

Are there side effects associated with antiretroviral drugs?

Yes, like all medications, antiretroviral drugs can have side effects. Common side effects can include nausea, diarrhea, fatigue, and headache, though newer regimens are generally more tolerable and have fewer adverse effects than older ones.

What are integrase inhibitors, and why are they important?

Integrase inhibitors (INSTIs) block the HIV enzyme integrase, which is required to insert the viral DNA into the host cell's DNA. They are a crucial component of modern HIV therapy due to their high efficacy, favorable tolerability, and a high barrier to resistance.

How do protease inhibitors contribute to HIV treatment?

Protease inhibitors block the protease enzyme that HIV uses to cut viral protein chains into smaller, functional pieces. This results in the production of immature, non-infectious viral particles that cannot spread to new cells.

What is viral tropism testing, and why is it sometimes necessary?

Viral tropism testing determines which co-receptor (CCR5 or CXCR4) an HIV strain uses to enter host cells. This test is necessary before prescribing a CCR5 antagonist, like maraviroc, as these drugs are only effective against CCR5-tropic strains of the virus.