CHAPTER 8Antiviral Antimicrobics and Resistance

I. GENERAL CONSIDERATIONS

Events in the cell unique to viral replication are the target

DNA polymerase is often inhibited

II. SELECTED ANTIVIRAL AGENTS

A. Inhibitors of Attachment
  1. Antibody can bind to extracellular virus and prevent attachment
  2. Antibody is useful in prophylaxis, but has been minimally effective in treatment.
B. Inhibitors of Cell Penetration and Uncoating
  1. Amantadine and rimantadine are symmetrical amines, or acyclics, that inhibit early steps in replication
  2. Effective only against influenza A viruses, but sharply rising resistance rates now preclude their routine use.
a. Pharmacology and Toxicity
  1. Rimantadine is metabolized by the liver
  2. Amantadine is excreted by the kidney
C. Neuraminidase Inhibitors
  1. Oseltamivir and zanamivir are antivirals that selectively inhibit the neuraminidase of influenza A and B viruses
  2. Neuraminidase inhibitors are effective in treatment and prophylaxis of influenza A and B viruses
D. Inhibitors of Nucleic Acid Synthesis
a. Idoxuridine and Trifluorothymidine

1. Idoxuridine and trifluorothymidine block DNA synthesis

b. Acyclovir
  1. Acyclovir is effective against herpesviruses that induce thymidine kinase
  2. Inhibits viral DNA polymerase and terminates viral DNA chain growth

i. Pharmacology and Toxicity

  1. Oral form has low bioavailability but achieves concentrations in blood that inhibit HSV and to a lesser extent varicella-zoster virus (VZV)
  2. Intravenous acyclovir is used for serious HSV

ii. Treatment and Prophylaxis

1. Effective against herpes and zoster

c. Valacyclovir, Famciclovir, and Penciclovir
  1. Valacyclovir is a prodrug of acyclovir that is better absorbed and once absorbed, it becomes acyclovir
  2. After absorption Famciclovir is converted to penciclovir which is a competitive inhibitor of a guanosine triphosphate
d. Ganciclovir
  1. Ganciclovir does not require viral thymidine kinase for phosphorylation
  2. Neutropenia and thrombocytopenia limit use

i. Clinical Use

  1. Indicated for the treatment of active CMV infection in immunocompromised patients, but other herpesviruses are also susceptible

ii. Resistance

1. After several months of continuous ganciclovir therapy for treatment of CMV, between 5 and 10% of AIDS patients excrete resistant strains of CMV

2. In virtually all isolates, there is a mutation in the phosphorylating gene, and in a lesser number there may also be a mutation in the viral DNA

E. Inhibitor of Viral RNA Synthesis: Ribavirin

1. Ribavirin has several modes of action

2. Ribavirin is active against respiratory syncytial virus, Lassa fever virus, and hepatitis C

F. Inhibitors of HIV
a. Nucleoside Reverse Transcriptase Inhibitors

i. Azidothymidine (AZT)

1. A nucleoside analog of thymidine

2. HIV reverse transcriptase is more than 100 times more sensitive to AZT than is host cell DNA polymerase

3. The first useful treatment for HIV infection but now is recommended for use only in combination with other inhibitors of HIV replication

4. Resistance is associated with one or more mutations in the HIV reverse transcriptase gene

ii. Didanosine (ddI, dideoxyinosine) and zalcitabine (ddC, dideoxycytidine)

1. Nucleoside analogs that inhibit HIV replication

2. Serious adverse effects include peripheral neuropathy and pancreatitis

3. Used only in combination with one or two other anti-HIV drugs

iii. Stavudine (D4T)

1. Interferes with viral reverse transcriptase and also terminates the growth of the chain of viral nucleic acid.

2. Dose reduction is required for impaired renal function

iiii. Lamivudine (3TC)

1. 3TC suppresses development of AZT resistance

b. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

1. Compounds that are not nucleoside analogs but bind to essentially the same site on reverse transcriptase also inhibit HIV reverse transcriptase

2. Nevirapine, delavirdine, and efavirenz, have been evaluated alone or in combination with nucleosides

3. NNRTIs are often active against AZT-resistant strains

4. Rapid development of drug resistance occurs when NNRTIs are used alone

c. Protease Inhibitors

1. Protease inhibitors block viral-encoded proteases

2. Saquinavir, ritonavir, indinavir, and nelfinavir are potent protease inhibitors

3. Used in combination with other anti-HIV drugs

d. Inhibitor of viral entry – Maraviroc

e. Inhibitor of viral fusion– Enfuvirtide

f. Inhibitor of viral integration - Raltegravir

G. Nucleotide Analogs: Cidofovir

1. Mimic monophosphorylated nucleotides by having a phosphonate group attached to the molecule

2. Cidofovir inhibits viral DNA polymerase

3. Resistance can develop with mutations in the viral DNA polymerase

4. Cidofovir is approved for CMV retinitis, and disseminated adenovirus infections.

H. Other Antiviral Agents
a. Foscarnet

1. A pyrophosphate analog that inhibits viral DNA polymerase by blocking the pyrophosphate-binding site of the viral DNA polymerase

2. Used to treat patients with ganciclovir-resistant CMV and acyclovir-resistant HSV

b. Interferons

1. Recombinant DNA techniques allow large-scale production

2. Interferons inhibit viral protein synthesis

3. Interferon alpha is combined with ribavirin to treat chronic hepatitis C

c. Fomivirsen

1. A synthetic oligonucleotide, complementary to and presumably inhibiting a coding sequence in CMV

2. Approved for the local (intravitreal) therapy of CMV retinitis in patients who have failed other therapies

III. ANTIVIRAL RESISTANCE

A.Genetic alterations

1. Rate of viral replication. Higher rates of replication are associated with higher rates of spontaneous mutations.

2. Selective pressure of the drug. The selective pressure increases the probability of mutations to the point that virus replication is substantially reduced.

3. Rate of viral mutations. In general, single-stranded RNA viruses (eg, HIV, influenza) have more rapid rates of mutation than double-stranded DNA viruses (eg, herpesviruses).

4. Rates of mutation in differing viral genes. For example, within the herpesviruses, the genes for phosphorylating nucleosides (eg, UL97) are more susceptible to mutation than the viral DNA polymerase.

B. Detection of Resistance

1. Phenotypic resistance is detected by in vitro methods such as tissue culture

2. Genotypic methods are molecular detection of mutation by sequencing the viral gene or by restriction enzyme patterns.

3. Viral quantitation such as an increase in patient's viral burden despite treatment suggests development of resistant mutants