Drug Mech: Antivirals

Viruses are obligate intracellular parasites (meaning they cannot survive on their own); their replication depends primarily on synthetic processes of the host cell.

• To be effective in treating viral infections, antiviral
• agents must either:
• 1) block viral entry into or viral exit from the host cell
• 2) inhibit viral replication inside the host cell

Human viral infection involves three stages:

• 1) Viral Entry: the virus has to get inside the cell
• 2) Viral Replication: the virus must replicate its genome
• 3) Viral Exit: the mature viral particles exit the cell to infect other cells

The antiviral drugs on the market target these three areas!

Viral replication consists of the following steps:

• 1) Adsorption to and penetration into susceptible host cells
• 2) Uncoating of viral nucleic acid
• 3) Synthesis of early regulatory proteins (e.g., nucleic acid polymerases)
• 4) Synthesis of RNA or DNA
• 5) Synthesis of late structural proteins
• 6) Assembly (maturation) of viral particles
• 7) Release from the cell

• There are three enzymes involved in viral replication:
• 1) Reverse Transcriptase
• 2) Integrase
• 3) Protease

• Note that Reverse Transcriptase has two catalytic (active) binding sites on it:
• 1) DNA polymerase catalytic site
• 2) RNase H catalytic site

• The steps involved in viral replication are as follows:
• 1) DNA polymerase catalytic site on Reverse Transcriptase enzyme: Build RNA/DNA double helix.
• 2) RNase H catalytic site on Reverse Transcriptase enzyme: cleave off RNA, therefore you have a single stranded DNA.
• 3) DNA polymerase catalytic site (again) on the Reverse Transcriptase enzyme: single-stranded. DNA is converted to double-stranded DNA
• 4) Integrase enzyme: clips 3' end and moves into nucleus with DNA and allows integration into host DNA.
• 5) Protease enzyme: clips pro-viral proteins from pro-viral mRNA, therefore uses clipped proteins to make the viral capsid, which then allows a mature viral DNA particle to go and infect other host cells.

• Acyclovir
• Valacyclovir
• Famciclovir
• Penciclovir
• Trifluridine
• Docosanol

• Ganciclovir
• Valganciclovir
• Cidofovir
• Foscarnet

• Zidovudine
• Didanosine
• Lamivudine
• Zalcitabine
• Stavudine
• Abacavir
• Emtricitabine

Tenofovir

• Nevirapine
• Delavirdine
• Efavirenz
• Etravirine

• Saquinavir
• Ritonavir
• Lopinavir
• Indinavir
• Nelfinavir
• Amprenavir
• Tipranavir
• Fosamprenavir
• Darunavir
• Atazanavir

Enfuvirtide

Maraviroc

Raltegravir

• Lamivudine
• Adefovir
• Interferon Alfa
• Pegylated Interferon Alfa
• Ribavirin
• Entecavir
• Telbivudine
• Tenofovir
• Emtricitabine

• Amantadine & Rimantadine
• Zanamivir & Oseltamivir

• Acyclovir
• Valacyclovir
• Famciclovir
• Penciclovir
• Trifluridine
• Docosanol

A nucleoside (with an s) consists of a nitrogenous base covalently attached to a (ribose or deoxyribose) sugar but without the phosphate group.

A nucleotide (with a t) consists of a nitrogenous base, a sugar, and a phosphate group. So, a nucleotide is a "nucleoside mono-phosphate."

The only difference between a nucleoside and a nucleotide is that the nucleotide contains one or more phosphates.

Acyclovir

Acyclovir is an acyclic guanosine derivative.

Recall guanosine is a nucleotide. Therefore acyclovir competes with guanosine triphosphate.

Acyclovir requires three phosphorylation steps for activation. It is converted first to the monophosphate derivative by viral thymidine kinase, and then to the diphosphate and triphosphate derivatives by the host’s cellular enzymes (human cell kinases).

1) Acyclovir first needs to be bioactivated via phosphorylation. The guanosine is added and then phosphorylated (a phosphate group is added). The first phosphorylation is by a viral kinase. The other two phosphorylations are by human kinases.

2) Acyclovir competes with guanosine triphosphate.

3) Acyclovir inhibits viral DNA synthesis.

Kinases phosphorylate

A polymerase is an enzyme whose central function is associated with polymers of nucleic acids, such as RNA and DNA.

The primary function of a polymerase is the polymerization of new DNA or RNA against an existing DNA or RNA template in the processes of replication and transcription.

Because viral kinase is required for its initial phosphorylation, acyclovir is selectively activated and accumulates only in infected cells.

acyclovir triphosphate

Acyclovir triphosphate inhibits viral DNA synthesis by two mechanisms:

• 1) Competitive inhibition with deoxyGTP (Guanosine Triphosphate) for the viral DNA polymerase, resulting in binding to the DNA template as an irreversible complex.
• 2) Chain termination following incorporation into the viral DNA.

Resistance to acyclovir can develop in HSV or VZV through alteration (mutations) in either the viral thymidine kinase or the DNA polymerase.

Agents such as:

• foscarnet (antiviral for CMV)
• cidofovir (antiviral for CMV)
• trifluridine (antiviral for HSV & VZV)

do not require activation by viral thymidine kinase. As a result, they are active against the most prevalent acyclovir-resistant strains.

Acyclovir is generally well tolerated. Nausea, diarrhea, and headache have occasionally been reported.

Acyclovir is highly selective for infected human cells where the first enzyme for bioactivation can be found because it is provided by the virus (which is inside the cell, thus making the human cell "infected"). This is good because it lowers the toxicity of the drug.

• Ganciclovir
• Valganciclovir
• Cidofovir
• Foscarnet

Ganciclovir is an acyclic guanosine analog.

Its activity against CMV is up to 100 times greater than that of acyclovir.

The mechanisms of action are very similar, though.

Ganciclovir requires triphosphorylation for activation prior to inhibiting the viral DNA polymerase.

Initial phosphorylation is catalyzed by the viral protein kinase phosphotransferase UL97 in CMV-infected cells.

The other two phosphorylations are catalyzed by human cell kinases.

Ganciclovir triphosphate (the active form of the drug) competitively inhibits viral DNA polymerase and causes termination of viral DNA elongation.

1) Ganciclovir first needs to be bioactivated via triphosphorylation. The guanosine is added and then phosphorylated (a phosphate group is added). The first phosphorylation is by a viral kinase. The other two phosphorylations are by human kinases.

2) Ganciclovir competes with the natural substrate to inhibit the viral DNA polymerase.

3) Ganciclovir inhibits viral DNA synthesis.

1) Altered Viral Kinase: Mutations in UL97, resulting in decreased levels of the active triphosphorylated form of ganciclovir. Isolates with these mutations are not cross-resistant to cidofovir or foscarnet. In other words, cidofovir and foscarnet will still work, even when ganciclovir does not.

2) Altered DNA Polymerase: Mutations in UL54, resulting in a mutant DNA polymerase; these mutations occur less frequently.

Mutations in UL97, resulting in decreased levels of the active triphosphorylated form of ganciclovir. Isolates with these mutations are not cross-resistant to cidofovir or foscarnet. In other words, cidofovir and foscarnet will still work, even when ganciclovir does not.

Myelosuppression, particularly neutropenia (more common with IV than with oral administration)

Retinal detachment (in patients with CMV retinitis)

• Ganciclovir
• Valganciclovir
• Cidofovir
• Foscarnet

Cidofovir is a cytosine nucleotide analog.

Cidofovir is a cytosine analog.

Cidofovir is a nucleotide because it already has the phosphate group on it...it just needs two more phosphates to convert the drug to its active form.

Following phosphorylation, cidofovir acts both as a potent inhibitor of and as an alternative substrate for viral DNA polymerase, competitively inhibiting DNA synthesis and becoming incorporated into the viral DNA chain.

In contrast to ganciclovir, phosphorylation of cidofovir to the active diphosphate is independent of viral enzymes.

• Dose-dependent nephrotoxicity
• Decreased intraocular pressure

nephrotoxicity is dose dependent

• Ganciclovir
• Valganciclovir
• Cidofovir
• Foscarnet

• Foscarnet (phosphonoformic acid) is an inorganic
• pyrophosphate analog.

No...foscarnet is neither a nucleoside nor a nucleotide. Rather, it is just a phosphate.

Foscarnet inhibits viral DNA polymerase, RNA polymerase, and HIV reverse transcriptase directly, without requiring activation by phosphorylation.

• DNA polymerase
• RNA polymerase
• HIV reverse transcriptase

No...foscarnet will not compete with the natural substrate. Foscarnet does not compete. Rather, it is an inhibitor, not a competitor.

No...foscarnet does not require phosphorylation for activation.

Resistance to foscarnet in HSV and CMV is due to point mutations in the DNA polymerase gene and is associated with prolonged or repeated exposure to the drug. Mutations in the HIV-1 reverse transcriptase gene have also been reported.

In other words, Target Modification is taking place in resistance that alters where the drugs can bind.

Point mutations, which is the mechanism of resistance seen with foscarnet, are associated with prolonged or repeated exposure to the drug.

• Nephrotoxicity
• Anemia
• CNS toxicity (headache, hallucinations, seizures)

Antiretroviral therapy

• regular virus: makes DNA from RNA (like human cells do)
• retrovirus: makes RNA from DNA (exact opposite of a regular virus)

A large number of antiretroviral drugs are available for the treatment of HIV-1 infection.

Monotherapy with any one agent should be avoided because of the need for maximal potency to inhibit viral replication and to avoid premature development of resistance.

A combination of drugs (Highly Active Antiretroviral Therapy; HAART) is usually effective in reducing plasma HIV RNA levels and in gradually increasing CD4 cell counts, particularly in antiretroviral-naive patients.

Optimization of adherence, tolerability, and convenience is also important in selecting the antiretroviral drugs for therapy.

HAART therapy consists of at least three antiviral drugs.

Given that many patients will experience at least one treatment failure, close monitoring of viral load and CD4 cell counts and the use of drug resistance testing are critical to trigger appropriate changes in therapy.

• viral load
• CD4 cell count
• drug resistance testing

• Zidovudine
• Didanosine
• Lamivudine
• Zalcitabine
• Stavudine
• Abacavir
• Emtricitabine

Yes...nucleosides compete for the catalytic site and then inhibit. NRTIs fall into this category, and are therefore nucleosides.

Yes...NRTIs are considered prodrugs because they need to be bioactivated. Each one of the NRTIs requires intracytoplasmic activation by phosphorylation to the triphosphate form. Phosphorylation of the NRTIs is catalyzed by human cell kinases.

• The reverse transcriptase enzyme has two active (catalytic) sites:
• 1) The RNase H (RNA-cleaving) active site
• 2) The DNA polymerase (DNA-synthesizing) active site

Both activities (RNA-cleaving and DNA-synthesizing) are needed to reverse-transcribe HIV’s RNA-based genomic material into DNA.

NRTIs bind to the DNA polymerase catalytic site of the reverse transcriptase enzyme. As a result, they competitively inhibit the DNA polymerase activity of the enzyme and can also be incorporated into the growing viral DNA chain to cause termination.

Yes...both activities (RNA-cleaving and DNA-synthesizing) are needed to reverse-transcribe HIV’s RNA-based genomic material into DNA.

NRTIs bind to the DNA polymerase catalytic site of the reverse transcriptase enzyme.

Yes...NRTIs bind to the DNA polymerase catalytic site of the reverse transcriptase enzyme. As a result, they competitively inhibit the DNA polymerase activity of the enzyme and can also be incorporated into the growing viral DNA chain to cause termination.

Each one of the NRTIs requires intracytoplasmic activation by phosphorylation to the triphosphate form. Phosphorylation of the NRTIs is catalyzed by human cell kinases.

No...NRTIs are catalyzed by human cell kinases.

Resistance to the NRTIs is caused by viral mutations.

Cross-resistance between the NRTIs has been demonstrated. Recall that a mutation in the DNA polymerase will cause resistance. Because all the NRTIs bind to the same site on the DNA polymerase, there is 100% cross resistance because if one can't bind, none can bind....all because they have the same binding site.

Lactic acidemia and severe hepatomegaly have been reported with the use of the NRTIs, alone or in combination with other antiretroviral drugs.

Zidovudine (Azidothymidine; AZT)

Zidovudine is a deoxythymidine analog.

It has been shown to decrease the rate of clinical disease progression and prolong survival in HIV-infected individuals.

When administered during pregnancy, during labor, and to the neonate, zidovudine has also been shown to reduce the rate of vertical (mother-to-newborn) transmission of HIV.

Vertical transmission is when an HIV-positive mother passes the virus onto the newborn.

There is a 30% decrease of preventing transmission from the HIV transmission from mom to the neonate. It's not a lot, but it's better than nothing.

As with other NRTIs, viral resistance to AZT may limit its clinical efficacy.

High-level resistance to AZT is generally seen in strains with three or more mutations.

Withdrawal of AZT exposure may permit the reversion of AZT-resistant HIV-1 isolates to the susceptible wild-type phenotype.

Withdrawal of AZT exposure may permit the reversion of AZT-resistant HIV-1 isolates to the susceptible wild-type phenotype.

Myelosuppression (resulting in anemia or neutropenia) is the most common adverse effect of AZT.

Tenofovir

Tenofovir is an acyclic nucleoside phosphonate (nucleotide) analog of adenosine.

It requires activation by phosphorylation to the triphosphate form. Phosphorylation of tenofovir is catalyzed by human cell kinases.

No. Phosphorylation of tenofovir is catalyzed by human cell kinases.

Like the NRTIs, tenofovir competitively inhibits the DNA polymerase activity of the HIV reverse transcriptase enzyme and causes chain termination following its incorporation into viral DNA.

Cross-resistance between tenofovir (Nucleotide Reverse Transcriptase Inhibitor) and the NRTIs (Nucleoside Reverse Transcriptase Inhibitors) have been reported. Recall they have the same active site.

GI upset is the most common side effect of tenofovir. As with the NRTIs, lactic acidosis and hepatomegaly may occur.

• Nevirapine
• Delavirdine
• Efavirenz
• Etravirine

Non-nucleoside Reverse Transcriptase Inhibitor

The NNRTIs bind directly to sites on the HIV-1 reverse transcriptase, resulting in inhibition of RNA- and DNA-dependent DNA polymerase activities.

Although both NNRTIs and NRTIs inhibit the same enzyme, they work differently.

• NNRTIs
• - bind directly to the reverse transcriptase enzyme
• - don't require phosphorylation for activation
• - don't compete with natural substrates

• NRTIs
• - don't bind directly to reverse transcriptase enzyme
• - require phosphorylation for activation
• - compete with the natural substrate

The binding sites for the NNRTIs are near to but distinct from the binding site for the NRTIs (i.e., they are near to the DNA polymerase catalytic site of the enzyme). Binding of the NNRTIs blocks the DNA polymerase activity by disrupting the DNA polymerase catalytic site of the enzyme.

Binding of the NNRTIs blocks the DNA polymerase activity by disrupting the DNA polymerase catalytic site of the enzyme.

Unlike the NRTIs, the NNRTIs do not compete with nucleoside triphosphates and do not require phosphorylation to be active.

Unlike the NRTIs, the NNRTIs do not compete with nucleoside triphosphates and do not require phosphorylation to be active.

Resistance to a NNRTI is rapid with monotherapy, so combination therapy is suggested.

Resistance to a NNRTI is rapid with monotherapy and is associated with specific viral mutations.

There is no cross-resistance between the NNRTIs and the NRTIs or the protease inhibitors.

Nevirapine, a NNRTI, is used mainly as a component of a combination antiretroviral regimen.

Nevirapine is extensively metabolized by CYP3A4 in the liver (ie, it is a substrate for CYP3A4).

• It is also an inducer of CYP3A metabolism (drug
• interactions).

• Severe and life-threatening skin rashes, including toxic epidermal necrolysis, have occurred during nevirapine therapy; in such cases,
• nevirapine therapy should be discontinued.

• Fulminant (sudden and severe enough to be life threatening) hepatitis may occur within the
• first 6 weeks of initiation of therapy; serial monitoring of liver function tests is recommended.

• Saquinavir
• Ritonavir
• Lopinavir
• Indinavir
• Nelfinavir
• Amprenavir
• Tipranavir
• Fosamprenavir
• Darunavir
• Atazanavir

During the later stages of the HIV growth cycle, the Gag and Gag-Pol gene products are translated into polyproteins and then become immature budding particles.

The protease enzyme is responsible for cleaving these precursor molecules to produce the final structural proteins of the mature virion core.

Recall that the protease enzyme is like the scissors....it cuts off the virus when mature so it can go infect other cells. In other words, the protease enzyme converts non-infectious immature viral particles into mature viral particles by cleaving polyproteins (which the virus needs to mature) into smaller functional proteins.

Protease inhibitors inhibit this protease enzyme, which inhibits the mature virus.

The protease inhibitors prevent cleavage of the Gag-Pol polyprotein by inhibiting the protease enzyme.

Inhibition of the protease enzyme results in the production of immature, noninfectious viral particles.

• Specific genotypic mutations that confer viral
• resistance to the protease inhibitors are common.

As a result, monotherapy is contraindicated. (In other words, protease inhibitors are always used in combination).

Cross-resistance among the protease inhibitors exists and appears to require a minimum of four substitutions in the gene.

• A syndrome called lipodystrophy is characterized by redistribution and accumulation of body fat that includes:
• central obesity
• dorsocervical fat enlargement
• breast enlargement

• Other toxicities include:
• increases in triglyceride levels
• increase in LDL levels
• glucose intolerance
• insulin resistance

These abnormalities appear to be particularly associated with the use of the protease inhibitors; the cause is not yet known.

• Recall lipodystrophy is the redistribution of fat on the body. There are two types:
• 1) lipohypertrophy (accumulation of fat)
• 2) lipoatrophy (loss of fat)

• 1) lipodystrophy is caused just by protease inhibitors
• 2) lipodystrophy is caused by protease inhibitors and HAART combination
• 3) lipodystrophy is caused by protease inhibitors, HAART combination and the HIV infection itself

Tesamorelin (Egrifta®), a growth hormone-releasing factor administered as a once-daily injection, was approved by the FDA for the treatment of lipodystrophy in patients receiving antiretroviral therapy.

Yes. Recall protease inhibitors will cause diabetes-like symptoms, such as glucose intolerance and insulin resistance. Therefore, protease inhibitors cause changes in lipid and carbohydrate metabolism.

A molecule on which an enzyme acts.

All protease inhibitors are substrates for CYP3A4 in the liver (ie, they are metabolized by CYP3A4 in the liver). As a result, there is a great potential for drug-drug interactions.

In addition, protease inhibitors are CYP3A4 inhibitors as well. Consequently, these agents can cause decreased clearance and increased plasma levels of other substrate drugs. Protease inhibitors should not be administered concurrently with agents that are extensively metabolized by CYP3A4.

Ritonavir

• Saquinavir
• Ritonavir
• Lopinavir
• Indinavir
• Nelfinavir
• Amprenavir
• Tipranavir
• Fosamprenavir
• Darunavir
• Atazanavir

Ritonavir is an inhibitor of HIV-1 and HIV-2 proteases.

Since ritonavir is an inhibitor of CYP3A4, concurrent administration of ritonavir with other protease inhibitors results in increased plasma levels of these agents because it decreases the rate of metabolism of these drugs (there will be no enzyme to degrade them with ritonavir inhibiting the CYP3A4 enzyme).

• These pharmacokinetic interactions between ritonavir and other protease inhibitors have been exploited to permit:
• more convenient dosing (ie, improve patient compliance)
• improve tolerability
• enhance efficacy

• For example, administration of saquinavir
• in combination with a low (subtherapeutic) dose of ritonavir has allowed clinicians to decrease the frequency of saquinavir dosing and resulted in improved antiviral efficacy of saquinavir and decreased GI side effects that are typically associated with saquinavir therapy.

In this combination, the subtherapeutic dose of ritonavir inhibits the CYP3A4-mediated metabolism of saquinavir, thereby resulting in increased exposure (blood levels) to saquinavir.

The high saquinavir plasma levels that are produced by this combination maintain potent viral suppression as well as provide a pharmacologic barrier to the emergence of resistance.

Other examples of the use of ritonavir in a combination with another protease inhibitor are the lopinavir/ritonavir and the tipranavir/ritonavir combinations.

Ritonavir is the most potent CYP3A4 inhibitor.

PI boosting, which stands for "Protease Inhibitor Boosting" is a unique trick used by practitioners in fighting the HIV virus. Rather than directly inhibit the protease enzymes, CYP3A4 inhibitors, like Ritonavir can be used to boost plasma levels of other protease inhibitors, which in essence, makes the effect of protease inhibitors stronger.

Blocking the liver enzyme that metabolizes drugs (CYP3A4) would enhance the protease inhibitors plasma levels because the protease inhibitors won't be degraded as quickly by the CYP3A4 enzyme.

Enfuvirtide (T-20)

In terms of viral replication, fusion is a pre-requisite for viral entry.

Fusion is when the viral envelope melts into the cell membrane. It begins with binding of glycoproteins gp 41 located in the viral envelope.

Enfuvirtide is a synthetic 36-amino-acid peptide.

Of interest, this drug was developed in North Carolina.

Enfuvirtide is administered subcutaneously, in combination with other antiretroviral agents, in patients with persistent HIV-1 replication despite ongoing therapy.

Enfuvirtide is administered subcutaneously, in combination with other antiretroviral agents, in patients with persistent HIV-1 replication despite ongoing therapy.

Enfuvirtide is administered subcutaneously, in combination with other antiretroviral agents, in patients with persistent HIV-1 replication despite ongoing therapy.

Enfuvirtide is a fusion inhibitor that blocks entry of the virus into the cell. It binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for the fusion of the viral and cellular membranes.

Viral resistance to enfuvirtide can occur and it is being investigated.

There is no cross-resistance between enfuvirtide and the other currently available antiretroviral drug classes.

The most common side effects of enfuvirtide therapy are local injection site reactions. Hypersensitivity reactions of varying severity may occur and recur on rechallenge.

Maraviroc

CCR5 are co-receptors on CD4 lymphocytes (the cells that HIV attacks) that the virus needs to enter the cell.

If the infection uses only CCR5, we call it a "tropic" infection. For example, a strain that uses only CCR5 would be called: CCR5-tropic HIV-1 detectable disease.

In other words, HIV uses one of two co-receptors known as Chemokine Receptor 5 (CCR5) and Chemokine Receptor 4 (CXCR4) to enter human CD4 cells of the immune system and infect them.

In general, viruses that use CCR5 predominate in early disease; as CD4 cell counts decline in more advanced disease, patients begin to harbor viruses that use CXCR4 for cell entry.

Patients with HIV that preferentially uses CCR5 are classified as having CCR5-tropic disease.

An HIV infection that uses more than CCR5 would be called a "dual" or "mixed tropism" infection. For instance, some strains use both CCR5 and CXCR4.

Maraviroc is a new anti-HIV drug approved by the FDA in August 2007.

It is indicated for use in combination with other antiretroviral drugs to treat adults with CCR5-tropic HIV-1-detectable disease.

It is indicated for use in combination with other antiretroviral drugs to treat adults with CCR5-tropic HIV-1-detectable disease.

No. Maraviroc has been approved for adult use only.

Unlike other antiretroviral drugs that inhibit viral proteins, maraviroc targets host CD4 T cells.

Maraviroc binds to and blocks CCR5 on CD4 cells. As a result, it is able to block the entry of HIV into CD4 cells and prevent the infection.

Maraviroc is effective only in patients with CCR5-tropic disease; it is ineffective against HIV that uses both receptors (dual/mixed tropism) or that preferentially uses CXCR4 for cell entry (CXCR4-tropic disease).

Patients must undergo a screening test to determine the tropism of their HIV infection (CCR5, CXCR4, or dual-tropic) before initiating treatment with maraviroc.

However, the test (Trofile®) may fail to detect the presence of small numbers (<0.3%) of the CXCR4-tropic virus, which would proliferate and cause maraviroc to fail. The Trofile test will work 100% of the time as long as the CXCR-4 virus affects at least 0.3% of the viral population.

Treatment with maraviroc has been associated with an increased incidence of hepatotoxicity (it has a boxed warning for potential hepatotoxicity). Symptoms of a systemic allergic reaction may occur before hepatotoxicity develops.

Treatment with maraviroc has also been associated with cardiovascular events such as myocardial ischemia and infarction and postural hypotension. It should be used with caution in patients with increased risk of cardiovascular disease.

• Treatment with maraviroc may increase a patient’s
• risk of developing infections and malignancy.

Treatment with maraviroc has been associated with an increased incidence of hepatotoxicity (it has a boxed warning for potential hepatotoxicity). Symptoms of a systemic allergic reaction may occur before hepatotoxicity develops.

• Treatment with maraviroc has been associated with
• cardiovascular events such as myocardial ischemia and infarction and postural hypotension.

It should be used with caution in patients with increased risk of cardiovascular disease.

Yes. Treatment with maraviroc may increase a patient’s risk of developing infections and malignancy.

Raltegravir

Raltegravir is the first in a new class of oral HIV drugs called HIV-1 integrase strand transfer inhibitors (InSTIs).

orally

It is approved for use in combination therapy for treatment-experienced adults infected with HIV-1 strains that are resistant to multiple antiretroviral agents.

No. It is approved for use in combination therapy for treatment-experienced adults infected with HIV-1 strains that are resistant to multiple antiretroviral agents.

No. Raltegravir has only been approved for adult use only.

Raltegravir is active against HIV strains that are resistant to other antiretroviral drugs.

In essence, Raltegravir attacks the enzyme that integrates viral DNA into the cell DNA:

HIV-1 integrase catalyzes an important step in the process of inserting viral DNA into the host cell genome.

Raltegravir inhibits the integrase enzyme, preventing viral DNA from integrating with cellular DNA.

Target Modification Viral resistance to raltegravir has occurred due to mutations in the integrase enzyme.

Raltegravir has different target than other drugs, so there is no cross resistance with NRTIs, Tonofovir and other drugs. That is why Raltegravir is used in resistant strains of HIV.

Think muscle malfunctions with Raltegravir toxicities!

• Increases in the following have occurred in raltegravir’s clinical trials, but cause and effect are not clear:
• 1) serum creatine kinase (Clinically, creatine kinase is assayed in blood tests as a marker of myocardial infarction (heart attack), rhabdomyolysis (severe muscle breakdown), muscular dystrophy, the autoimmune myositides and in acute renal failure),
• 2) myopathy (muscle fibers do not function right)
• 3) rhabdomyolysis (Rhabdomyolysis is the breakdown of muscle fibers resulting in the release of muscle fiber contents (myoglobin) into the bloodstream)

• Lamivudine
• Adefovir
• Interferon Alfa
• Pegylated Interferon Alfa
• Ribavirin
• Entecavir
• Telbivudine
• Tenofovir
• Emtricitabine

• The prevalence of infections caused by hepatitis B
• virus (HBV) and hepatitis C virus (HCV) is very high worldwide.

The morbidity (the rate of incidence of disease) and mortality (the rate of deaths associated with the disease) associated with these infections reflect a great and critical need for improved anti-hepatitis therapies.

Similar to the antiretroviral therapy, available anti-hepatitis therapy is suppressive rather than curative.

Like tenofovir, adefovir is a nucleotide analog of adenosine monophosphate.

Adefovir has been approved for the treatment of HBV infection.

• Studies have shown that adefovir therapy results in significant suppression of HBV replication
• and improvement in liver histology and fibrosis.

However, serum HBV DNA reappeared following cessation of therapy.

1) Adefovir is phosphorylated by cellular kinases to the active diphosphate metabolite.

2) Following activation, it competitively inhibits HBV DNA polymerase

3) Adefovir then inserts itself via incorporation into the viral DNA

4) This inhibition results in chain termination

Yes. Adefovir is similar to tenofavir...it must be phosphorylated to become activated.

No. Adefovir is phosphorylated by cellular kinases (not viral kinases) to the active phosphorylated form with two phosphate groups.

Yes. Adefovir competitively inhibits HBV DNA polymerase.

Once Adefovir has incorporated itself into viral DNA, it causes chain termination which will inhibit the virus.

Adefovir therapy is associated with a dose dependent nephrotoxicity. The risk of nephrotoxicity may rise in patients with preexisting renal dysfunction or in those treated for longer durations.

• As with the antiretroviral nucleoside analogs (NRTIs) the following can occur:
• 1) lactic acidosis (Lactic acidosis is when lactic acid builds ups in the bloodstream faster than it can be removed. Lactic acid is produced when oxygen levels in the body drop.)
• 2) severe hepatomegaly may occur. (An enlarged liver).

Adefovir therapy is associated with a dose dependent nephrotoxicity.

The risk of nephrotoxicity may rise in patients with preexisting renal dysfunction or in those treated for longer durations.

As with the antiretroviral nucleoside analogs (NRTIs) the following can occur:

• 1) lactic acidosis (Lactic acidosis is when lactic acid builds ups in the bloodstream faster than it can be removed. Lactic acid is produced when oxygen levels in the body drop.)
• 2) severe hepatomegaly may occur. (An enlarged liver).

Interferons (IFNs) are a group of cytokines. They are endogenous proteins that exert complex antiviral, immunomodulatory, and antiproliferative activities through cellular metabolic processes involving the synthesis of both RNA and protein.

Interferon alfa preparations are available for the treatment of both HBV and HCV infections; they are administered SC or IM.

• Recall that cytokines:
• 1) bind to a cytokine receptor
• 2) activate JAK-STAT signal transduction pathway which produces anti-viral proteins like cytokines
• 3) cytokines can then inhibit different steps in the viral mechanism of action

Interferon alfa can be used alone for HBV and HCV, or it is also used in combination with Ribaviron.

Pegylated interferon alfa preparations (where a linear or branched polyethylene glycol (PEG) moiety is attached to the interferon molecule by a covalent bond) are available.

• In comparison with the nonpegylated interferon alfa preparations, the pegylated products have:
• 1) substantially longer half-lives
• 2) slower clearance
• 3) steadier serum concentrations

All of these things allow for less frequent dosing.

Interferons (IFNs) are a group of cytokines. They are endogenous proteins that exert complex antiviral, immunomodulatory, and antiproliferative activities through cellular metabolic processes involving the synthesis of both RNA and protein.

They bind to specific membrane receptors (cytokine receptors) on the cell surface and initiate a series of intracellular events that include enzyme induction, suppression of cell proliferation, immunomodulatory activities, and inhibition of viral replication.

Following binding to specific cellular receptors (cytokine receptors), IFNs activate the JAK-STAT signal-transduction pathway and lead to the nuclear translocation of a cellular protein complex that binds to genes containing an IFN-specific response element. This leads to the synthesis of over 24 antiviral proteins that contribute to viral resistance mediated at different stages of viral penetration.

A major effect of IFN-induced antiviral proteins is inhibition of viral protein synthesis for many viruses. A given virus may be inhibited at several steps, and the principal inhibitory effect differs among virus families.

Remember the general idea of the picture below: interferon alfa will lead to anti-viral proteins expressed which will inhibit several steps in the viral mechanism of action. The predominant effect varies from one virus to another, but in most viruses, the anti-viral proteins inhibit step #2 below, which is translation.

Certain viruses are able to resist the antiviral effects of IFNs by blocking production or activity of selected IFN-inducible antiviral proteins.

For example, resistance to IFN therapy in HCV infections is attributed to a number of mechanisms including inhibition of the IFN-induced protein kinase.

Yes. In addition to their direct antiviral effects, IFNs are also able to modify the immune response to viral infections.

The GOOD: For example, IFN-induced expression of MHC antigens (major histocompatibility antigens) may contribute to the antiviral actions of IFNs by enhancing the lytic effects of cytotoxic T-lymphocytes.

The BAD: Conversely, IFNs may mediate some of the systemic symptoms associated with viral infections and contribute to immunologically mediated tissue damage in certain viral diseases.

• Common side effects include a flu-like syndrome within 6 hours after dosing that tends to resolve
• upon continued administration.

Other potential adverse effects include: thrombocytopenia, hypotension, and severe neuropsychiatric side effects.

Common side effects include a flu-like syndrome within 6 hours after dosing that tends to resolveupon continued administration. Therefore, just continue on with therapy.

• There are many contraindications to interferon
• therapy, including:
• psychosis
• severe depression
• symptomatic heart disease
• uncontrolled seizures

Alfa interferons are abortifacient in primates and should not be administered during pregnancy.

It is a guanosine analog that requires intracellular activation. It is phosphorylated by host cell enzymes to the active triphosphate.

Yes. Ribavirin must be phosphorylated by the host cell enzymes to the active triphosphate form.

Ribavirin is used in combination with interferon alfa for the treatment of HCV infection.

Because Ribavirin is used in combination with interferon alfa for the treatment of HCV, they won't put you on Ribavirin combination unless the single therapy doesn't work.

Its mechanism of action has not been fully elucidated. However, it appears to be involved in the following:

• 1) It interferes with the synthesis of guanosine triphosphate.
• 2) It inhibits capping of viral mRNA.
• 3) It inhibits viral RNA-dependent RNA polymerase.

• 1) It interferes with the synthesis of guanosine triphosphate.
• 2) It inhibits capping of viral mRNA.
• 3) It inhibits viral RNA-dependent RNA polymerase.

Dose-dependent hemolytic anemia and depression.

Dose-dependent hemolytic anemia and depression.

It is contraindicated during pregnancy (it is teratogenic in animals and mutagenic in mammalian cells).

• Amantadine & Rimantadine
• Zanamivir & Oseltamivir

Amantadine & Rimantadine

Amantadine (Symmetrel®) and its derivative rimantadine (Flumadine®) are cyclic amines.

• Rimantadine is four to ten times more active than
• amantadine in vitro.

Recall in vitro means not in a living organism, but in a controlled environment, like a test tube.

Influenza type A. However, resistance of influenza A virus to both agents has increased substantially in recent years.

Amantadine and rimantadine inhibit the uncoating of the viral RNA of influenza A virus within infected host cells, thus preventing its replication. For some influenza A strains, they also inhibit viral assembly.

The primary target for both agents is the M2 protein within the viral membrane, which makes these two agents highly specific against influenza A virus (influenza B virus contains a different protein in its membrane).

By binding to and inhibiting the function of the M2 protein (an ion channel), these drugs are able to inhibit the acid-mediated dissociation of the viral ribonucleoprotein complex early in viral replication (i.e., inhibiting viral uncoating) and alter hemagglutinin processing (by inducing conformational changes in hemagglutinin during its intracellular transport) later in replication (i.e., inhibiting viral assembly).

Remember, the virus cannot replicate unless the coat is removed in the genome. That is why inhibiting viral uncoating will block the virus from replicating.

The primary target for both agents is the M2 protein within the viral membrane, which makes these two agents highly specific against influenza A virus (influenza B virus contains a different protein in its membrane).

• inhibit viral uncoating
• inhibit viral assembly (in some selected strains)

Yes. The primary target for both agents is the M2 protein within the viral membrane, which makes these two agents highly specific against influenza A virus (influenza B virus contains a different protein in its membrane).

Resistance of influenza A virus to both agents has increased substantially in recent years, to the point that this combination is currently not recommended for use.

Yes. Resistance, caused by mutation, rapidly develops in treated patients. Transmission of resistant virus to household contacts has been reported.

Yes. These drugs share cross resistance.

No. Cross-resistance to zanamivir and oseltamivir does not occur.

Yes. Both drugs share cross-susceptibility?

• cross-susceptibility is when the virus can be either susceptible or resistant to drugs that work the same way. In the case of Amantadine and Ramantidine, then, influenza A would be either susceptible to both or resistant to both because they both work on the same M2 protein.
• cross-resistance is when the virus figures out how to change its mechanism of action to get around one drug, other drugs that work the same way won't work either. For example, in the case of Amantadine and Rimantadine, when the virus changes the M2 protein to avoid Amantadine, then Rimantadine won't work either.

• Cross-susceptibility means that if rimantadine is effective against a particular viral strain, then amantadine is also effective against the same strain.
• Cross-resistance means that if a viral strain is resistant to rimantadine, it is also going to be resistant to amantadine.

CNS toxicity (e.g., nervousness, lightheadedness, difficulty in concentrating). The CNS side effects are more frequent with amantadine.

• Serious neurotoxic reactions, occasionally fatal,
• may be associated with high amantadine plasma levels (1-5 mg/mL).

Serious neurotoxic reactions, occasionally fatal, may be associated with high amantadine plasma levels (1-5 mg/mL).

Amantadine is more toxic than Rimantadine because the CNS side effects more frequent with amantadine. Also because serious neurotoxic reactions, occasionally fatal, may be associated with high amantadine plasma levels (1-5 mg/mL).

Amantadine is teratogenic in rodents; birth defects have been reported after exposure during pregnancy.

Zanamivir & Oseltamivir

Neuraminidase is an essential viral glycoprotein for viral release.

Zanamivir (Relenza®) and oseltamivir (Tamiflu®) are active against both influenza A and influenza B.

Both agents have been approved for prophylaxis (prevention) or treatment of acute uncomplicated influenza infection.

When administered for a 5-day course within 36-48 hours after the onset of symptoms, use of either agent shortens the severity and duration of illness and may decrease the incidence of respiratory complications in children and adults.

The earlier they are started, the more effective they are in treating influenza.

Administration may decrease the incidence of respiratory complications in children and adults

Unlike amantadine and rimantadine (which just treat influenza A), zanamivir (Relenza®) and oseltamivir (Tamiflu®) are active against both influenza A and influenza B.

Also, unlike amantadine and rimantadine (which are not recommended for treatment because of resistance), zanamivir (Relenza®) and oseltamivir (Tamiflu®) are the current recommended drugs for treatment or prophylaxis of influenza.

Zanamivir is administered via oral inhalation; oseltamivir is an orally administered prodrug that is activated in the gut and liver. Both drugs are also available in IV formulations.

Oseltamivir is an orally administered prodrug that is activated in the gut and liver.

In hospitalized patients with the flu, both drugs have been shown to reduce the duration of hospitalization and the risk of death. They may also decrease viral shedding and the risk of spread to contacts even when started more than 48 hours after the onset of illness.

Both drugs are about 70%-90% effective for prophylaxis after exposure to influenza A or B.

They should be given within 48 hours after a household exposure or other close contact with an influenza virus-infected person.

Yes. Viral resistance to this class of drugs has been reported in both A and B strains of the influenza virus.

Viral resistance, mainly to oseltamivir, is associated with a mutation in the viral neuraminidase (target modification).

No. There is no cross resistance between these and any other previous drug class.

Inactivated flu vaccines are not affected by antiviral drug therapy.

However, antivirals may interfere with the efficacy of the live-attenuated intranasal flu vaccine (FluMist®); they should be stopped at least 48 hours before and should not be started for at least 2 weeks after FluMist administration.

Zanamivir and oseltamivir are inhibitors of the viral neuraminidase enzyme.

Neuraminidase is an essential viral glycoprotein for viral release, therefore, these drugs inhibit viral release.

Zanamivir can cause cough, nasal and throat irritation; bronchospasm in patients with reactive airway disease has also been reported. It is generally not recommended for use in patients with asthma or COPD.

Zanamivir is generally not recommended for use in patients with asthma or COPD.

Potential side effects of oseltamivir include headache, nausea and vomiting. Taking the drug with food may reduce the incidence of GI effects.

Potential side effects of oseltamivir include headache, nausea and vomiting. Taking the drug with food may reduce the incidence of GI effects.

Neuropsychiatric events, including self-injury, delirium, and hallucinations, have occurred in some children and adolescents treated with oseltamivir, but causation has not been established (i.e., the data increasingly points to the influenza infection, not oseltamivir, as the cause of these events).

In 2009, the FDA issued an ‘emergency use authorization’ for the neuraminidase inhibitor peramivir.

This was around the same time as H1N1 epidemic.

Peramivir (given IV) is an investigational drug that inhibits viral neuraminidase.

Peramivir is administered via IV route.

The FDA authorized the use of peramivir in hospitalized adults or children with confirmed or suspected pandemic 2009 H1N1 influenza infection who cannot take or are not responding to treatment with oseltamivir or zanamivir.

Yes. The FDA authorized the use of peramivir in hospitalized adults or children with confirmed or suspected pandemic 2009 H1N1 influenza infection who cannot take or are not respondingto treatment with oseltamivir or zanamivir.

Many clinical isolates resistant to oseltamivir have, however, also been resistant to peramivir.

Yes. Many clinical isolates resistant to oseltamivir have, however, also been resistant to peramivir.

Susceptibility of the circulating influenza strains to antiviral drug therapy varies from one strain to another and from one flu season to another.

In recent years, however, susceptibility of circulating influenza strains has evolved rapidly and treatment recommendations have changed during the same flu season.

The CDC influenza website (www.cdc.gov/flu) provides frequently updated information on viral resistance/susceptibility to available anti-influenza drugs.

The CDC influenza website (www.cdc.gov/flu) provides frequently updated information on viral resistance/susceptibility to available anti-influenza drugs.