Antiviral Medications and Therapy Basics

Antiviral Drugs

• Antiviral drugs target viral enzymes or structures crucial for replication.
• These drugs are available for viruses causing significant morbidity and mortality.
• Developing antiviral drugs is challenging as they need to inhibit viral replication without harming host cells.

Overview of Viral Infections

• Common viral infections include encephalitis/meningitis (JC virus, measles, LCM virus, arbovirus, rabies), pharyngitis (adenovirus, Epstein-Barr virus, cytomegalovirus), cardiovascular (Coxsackie B virus, Hepatitis A, B, C, D, E), skin infections (varicella-zoster virus, HHV-6, smallpox, molluscum contagiosum, HPV, parvovirus B19, rubella, measles, Coxsackie A virus).
• Additional categories include Sexually transmitted diseases (Herpes simplex type 2, HPV, HIV), Eye infections (Herpes simplex virus, adenovirus, cytomegalovirus), Parotitis (Mumps), Pneumonia (influenza virus, types A and B, parainfluenza virus, respiratory syncytial virus, adenovirus, SARS CoV), Myelitis (Poliovirus, HTLV-I), Gastroenteritis (adenovirus, rotavirus, norovirus, astrovirus, coronavirus), and Pancreatitis (Coxsackie B virus).

Learning Objectives

• Factors hindering antiviral drug development
• Specific targets for antiviral drugs, particularly against Herpes viruses
• HAART (highly active antiretroviral therapy) in HIV infections
• Advantages of combination therapies in HIV treatment over monotherapy
• Neuraminidase inhibitors for influenza infections
• Interferon therapy for hepatitis C

Problems in Developing Antiviral Agents

• Selectivity: Viruses have unique structures, and mutations can change antigen proteins.
• Toxicity: Viruses rely on host cell functions for infection, reproduction, and release. Effective antiviral agents must inhibit the virus without being harmful to the host's cells.

Targets for Antiviral Agents

• Structures/enzymes crucial for viral replication (DNA-dependent DNA polymerase, RNA-dependent RNA polymerase, RNA-dependent DNA polymerase, Integrase, Protease, Neuraminidase)
• Key steps in Viral Replication (Attachment & Penetration of virus into host cell, Uncoating of virus, Synthesis of new viral components by host cell, Assembly of components into new virus, release of virus from host cell)

HIV Virus structure

• gp120 (docking glycoprotein)
• gp41 (transmembrane glycoprotein)
• RNA
• Capsid
• Matrix
• Lipid Membrane

Antiretroviral drugs (ART)

• Nucleoside reverse transcriptase inhibitors (Zidovudine)
• Non-nucleoside reverse transcriptase inhibitors (Nevirapine)
• Protease inhibitors (Indinavir)
• Integrase inhibitors (Raltegravir)
• Chemokine receptor antagonists (Maraviroc)
• HIV fusion inhibitor (Enfuvirtide)

HAART (Highly Active Antiretroviral Therapy)

• The standard HIV treatment involves a combination of at least three drugs (2 NRTIs, 1 or 2 Pls).
• Goals of HAART include:
  • Suppressing HIV viral load (<50 copies/mL).
  • Reducing viral resistance.
  • Restoring/preserving immune function (CD4 count >200 cells/mm³).
  • Reducing mortality and morbidity rates among HIV infected individuals.
  • Improving quality of life.
  • Preventing HIV transmission

HAART (WHO Guidelines)

• Initiate ART if CD4 cell count is ≤500 cells/mL for individuals with severe/advanced HIV disease, or CD4 count is ≤350 cells/cu mm, or with active TB, HBV co-infection (with severe chronic liver disease), pregnant and breastfeeding women.

Herpes Simplex Viruses (HSV)

• HSV-1: Oral herpes
• HSV-2: Genital herpes

Antiviral Therapy for Herpes Viruses

• Acyclovir, Famciclovir: These drugs compete with guanosine triphosphate to inhibit DNA polymerase.
• Uses: Herpes simplex and varicella-zoster infections

Anti Influenza drugs

• Neuraminidase inhibitors (Influenza A&B): Oseltamivir, Zanamivir
• Amantadine and Rimantadine (used only in Influenza A): Inhibit uncoating & assembly of influenza A virus.

Interferons

• Types: α, β, γ
• Mechanism: Inhibits viral replication (preventing viral penetration, assembly/release, translate viral mRNA into viral proteins).
• Uses: Chronic hepatitis B & C.
• PegIFNα-2a & 2b are superior to conventional IFN.