Antiviral Agents

Jason J. Schafer, PharmD, MPH, BCPS, AAHIVP

Associate Professor, Jefferson College of Pharmacy
Educational Goals
• Explain the lifecycle of viruses and the principles of
antiviral therapy

• Describe the mechanisms of action of antiviral agents

used for HSV, CMV, HIV, viral hepatitis, and influenza
infections

• Discuss the rationale for the selection of antivirals

considering the problem of drug resistance
Viral Replication
Drugs for Herpes Simplex Virus (HSV)
• Acyclovir
• Valacyclovir
Drugs for HSV
• Valacyclovir is a prodrug

• Valacyclovir is converted to acyclovir after oral administration

• Serum levels are 3-5x greater than oral acyclovir and are close to
those achieved by intravenous acyclovir

• Overall, valacyclovir has better bioavailability (70% vs 20%)

leading to less frequent dosing
Drugs for HSV
• Acyclovir/Valacyclovir
• Guanosine analogs

• Require three phosphorylation steps

• Compete with guanosine triphosphate for DNA polymerase

• Incorporated into viral

DNA and cause
chain termination
Drugs for HSV
• Require viral thymidine
kinase for initial
phosphorylation

• Selective activation, so
active drug accumulates
in infected cells only
Drugs for HSV
• Mechanisms of resistance
• Change in thymidine kinase
• Change in DNA polymerase

• Because agents share mechanisms of action,

they will also share mechanisms of resistance
 Cross resistance
Drugs for HSV
• Adverse effects:
• Acyclovir:
• Mild – headache, nausea, diarrhea
• Severe – nephrotoxicity, neurotoxicity

• Valacyclovir
• Mild – headache, nausea, diarrhea
Drugs for HSV
Drug Acyclovir Valacyclovir

Dosage form Oral, IV, topical Oral

Kinetics Renal elimination Renal elimination

Poor bioavailability Better bioavailability

Advantages IV form available for Less frequent dosing

encephalitis required

Better bioavailability

Disadvantages Oral form requires No IV form

frequent dosing
Cost
Drugs for Cytomegalovirus (CMV)
• Ganciclovir
• Valganciclovir
• Cidofovir
• Foscarnet
Drugs for CMV
• Valganciclovir is a prodrug

• Valganciclovir is converted to ganciclovir after oral administration

• Serum levels are similar to those achieved by intravenous

ganciclovir

• Overall, valganciclovir has better bioavailability (60% vs 10%)

leading to less frequent dosing
Drugs for CMV
• Guanosine analogs

• Use virus specific

phosphotransferase for
initial phosphorylation

• Also active against HSV

• Use thymidine kinase
• Cross resistance with acyclovir
Drugs for CMV
Ganciclovir Valganciclovir

Bioavailability 8% 60%

Dosage forms IV, oral Oral

Used for Yes Yes (preferred)

Prophylaxis
Used for IV only Yes
Treatment
Drugs for CMV
• Ganciclovir/Valganciclovir
• Adverse Effects
• Myelosuppression (ex. Neutropenia)
• Up to 40% incidence

• Fever, rash, increased liver function tests

• Carcinogenic, embryo toxic

Drugs for CMV/HSV
• Cidofovir
• Cytosine nucleotide analog

• Inhibits viral DNA polymerase

• Does not require phosphorylation by viral enzymes

• Activity is maintained against HSV or CMV with altered or
deficient phosphorylation enzymes

• Resistance:
• Due to mutation in DNA polymerase
• Can be cross resistant with ganciclovir
Drugs for CMV/HSV
• Disadvantages of cidofovir:
• IV only
• Nephrotoxicity – 25% of patients must stop therapy
• Rare: neutropenia, metabolic acidosis

• Role of cidofovir:
 Not preferred agent for treatment or prophylaxis
 Used if CMV resistant to/don’t tolerate ganciclovir
 Can be considered for acyclovir-resistant HSV
Drugs for CMV/HSV
• Foscarnet
• Unique mechanism of action

• Inorganic pyrophosphate

• Forms complexes with viral DNA polymerase

• Active against ganciclovir resistant strains of CMV

• Can also be used for HSV, even if acyclovir resistant

Drugs for CMV/HSV
• Disadvantages of foscarnet:
• IV only
• Nephrotoxicity
• Anemia

• Role of foscarnet:
Not preferred for treatment or prophylaxis
Used if CMV resistant to/don’t tolerate ganciclovir
Can be considered for acyclovir-resistant HSV
 Drugs for CMV
Drug Ganciclovir Valganciclovir Cidofovir Foscarnet

Dosage form Oral, IV Oral IV IV

Kinetics Renal Renal elimination Long half-life Renal elimination

elimination
Better Renal elimination
Poor bioavailability
bioavailability
Advantages Less toxic than Oral form can be No No
cidofovir and used for myelosuppression myelosuppression
foscarnet treatment

Disadvantages Oral form No IV form Nephrotoxicity Nephrotoxicity

cannot be used and difficult to
for treatment Myelosuppression administer
 Summary: Agents Used for CMV and HSV
Drug HSV Treatment HSV CMV Treatment CMV
suppression/ suppression/
prophylaxis prophylaxis
Acyclovir and ++ (IV acyclovir +
Valacyclovir for encephalitis)
Ganciclovir and +/- +/- ++ ++
valganciclovir
(100x more Valganciclovir
active than preferred
acyclovir)

Cidofovir + if acyclovir + if ganciclovir

resistant resistant

Foscarnet + if acyclovir + + if ganciclovir +

resistant resistant
Questions ???
HIV Life Cycle

Blocked by CCR5
inhibitors
Role of Antiretroviral Drugs
• cART: combination antiretroviral therapy

• Goals of therapy
• To achieve maximal suppression of HIV replication and prevent
disease progression
• Reduce plasma HIV RNA levels to undetectable levels
• Improve CD4 cell counts and restore immune system function
Current Targets Of Therapy
• CCR5 co-receptor
• Entry inhibitor (CCR5 antagonist)

• GP41
• Fusion inhibitor

• Reverse transcriptase enzyme

• Nucleoside (nucleotide) reverse transcriptase inhibitors
• Non-nucleoside reverse transcriptase inhibitors

• Integrase enzyme
• Integrase inhibitors

• Protease enzyme
• Protease inhibitors
HIV Life Cycle

Blocked by CCR5
inhibitors
 CCR5 Antagonist - Maraviroc
CD4+ Co-receptor Virus-Cell
Binding Binding Fusion

glycoprotein 41 (gp41)
gp120

CD4+

CD4 cell Co-receptor GP41 fusion to

membrane CCR5/CXCR4 CD4 cell
CCR5 antagonist Fusion Inhibitor
Adapted from: Moore JP, et al. Proc Natl Acad Sci U S A. 2003;100:10598-10602.
HIV Life Cycle

Blocked by CCR5
inhibitors
Nucleoside Reverse Transcriptase
Inhibitors (NRTIs)
• Mechanism of action
• Structural analogues of nucleoside bases

• Competitively bind to reverse

transcriptase enzyme
• Incorporated into DNA chain
Thymidine
• Terminate DNA synthesis
Zidovudine
Reverse
Transcriptase
Viral DNA Chain
Terminated Nucleoside
Analogue
 Reverse
Transcriptase
Viral DNA Chain
Terminated Nucleoside
Analogue

Thymidine

Zidovudine
NRTIs
Brand Generic Name Manufacturer Approval
Name Date

Epivir Lamivudine GSK 1995

Ziagen Abacavir GSK 1998

Epzicom Abacavir/lamivudine GSK 2004

Viread Tenofovir disoproxil fumerate (TDF) Gilead 2001

Vemlidy Tenofovir alafenamide (TAF) Gilead 2016

Emtriva Emtricitabine Gilead 2003

Truvada TDF/emtricitabine Gilead 2004

Descovy TAF/emtricitabine Gilead 2016

NRTIs - Adverse Effects
• Class Effects • Individual Drug Effects
• Very well tolerated • Abacavir
• Lactic acidosis • Hypersensitivity reaction
• Rare • Characterized by ≥ 2 of the
following sign/symptoms:
• Fever, rash, N/V/D or abdominal
pain, malaise, dyspnea/cough.
• Onset = 4-6 weeks
• Can be fatal

• HLA-B*5701 testing
identifies risk (2-9%)
• Use abacavir only if HLA test is
negative
NRTIs - Pharmacokinetics
• All oral agents with good bioavailability

• Not metabolized by CYP enzymes

• Few drug-drug interactions

• Elimination
• Most agents cleared through renal pathways
• Require dose adjustment if renal dysfunction (except abacavir)
Nucleotide Reverse Transcriptase
Inhibitor
• Tenofovir disopoxil fumerate (TDF)

• Analogue of adenosine

• Same mechanism of action as NRTIs

• Similar kinetics and adverse effects

• Can cause nephrotoxicity
• Due to accumulation of drug in the proximal tubule
• Can cause bone mineral density losses

• Advantage: Co-formulated with other antiretroviral agents

Nucleotide Reverse Transcriptase
Inhibitor
• Tenofovir alafenamide (TAF)

• Analogue of adenosine

• Same mechanism of action as NRTIs

• Less systemic exposure compared to TDF

• Safer, less nephrotoxicity and less bone mineral density losses

• Advantage: Co-formulated with other antiretroviral agents

TDF versus TAF

• 91% lower tenofovir plasma levels with TAF compared to TDF reduces the risk of
tenofovir-associated kidney and bone toxicity

Gilead Sciences. www.gilead.com

HIV Life Cycle

Blocked by CCR5
inhibitors
Non-Nucleoside Reverse Transcriptase
Inhibitors (NNRTIs)
• Mechanism of action
• Non-competitive binding to reverse transcriptase

• Stop DNA synthesis

• Not analogues of nucleoside bases

• Bind adjacent to (not at) catalytic site of enzyme

 NNRTIs
Brand Name Generic Name Manufacturer Approval Date

Sustiva Efavirenz BMS 1998

Atripla Efavirenz, emtricitabine, TDF Gilead, BMS 2006

NNRTIs - Adverse Effects
• Class Effects • Individual Effects
• Hepatotoxicity • Efavirenz
• Rash • CNS symptoms
• Usually mild-moderate • Drowsiness, dizziness,
depression, impaired
concentration
• Dose in evening, on an
empty stomach to avoid
daytime symptoms
• Vivid dreams
NNRTIs - Pharmacokinetics
• Absorption
• Increased when taking with food
• Not recommended with efavirenz due to ↑CNS side effects

• Elimination
• Metabolized in liver by CYP3A4

• Efavirenz also induces the metabolism of CYP3A4 substrates

• Significant drug interactions

• No dose adjustment in renal impairment
HIV Life Cycle

Blocked by CCR5
inhibitors
Integrase Inhibitors
• Raltegravir (Isentress)
• Mechanism of action:
• Inhibits insertion of HIV DNA into human DNA

• Indication:
• Treatment naïve patients and experienced patients

• Advantages:
• Not metabolized by CYP450
• Well tolerated

• Disadvantage:
• Twice daily dosing
Integrase Inhibitors
• Elvitegravir
• Mechanism of action:
• Inhibits insertion of HIV DNA into human DNA

• Advantages:
• Once daily dosing with boosting (cobicistat)
• Co-formulated
• Elvitegravir, TAF, emtricitabine and cobicistat (Genvoya)

• Disadvantages
• Metabolized by CYP3A4, serum creatinine elevations with cobi
• GI side effects similar to protease inhibitors
Integrase Inhibitors
• Dolutegravir (Tivicay)
• Mechanism of action:
• Inhibits insertion of HIV DNA into human DNA

• Indication:
• Approved for use in treatment naïve and experienced patients

• Advantages:
• Well tolerated with once daily dosing, minimal CYP metabolism
• Co-formulated – dolutegravir/abacavir/lamivudine (Triumeq)
• Active against HIV resistant to raltegravir and elvitegravir

• Disadvantages
• Some drug-drug interactions
HIV Life Cycle

Blocked by CCR5
inhibitors
Protease Inhibitors (PIs)
• Mechanism of Action
• Bind to protease enzyme
• Prevent cleavage of HIV polyproteins
• Prevent production of mature virus

1. The production of viral polypeptides from mRNA

2. Cleavage of polypeptides by protease to form functional HIV proteins

1 2

New
mRNA Viral Protease Functional
Polypeptides Enzyme Proteins
PIs
Brand Name Generic Name Manufacturer Approval Date

Norvir Ritonavir Abbott 1996

Prezista Darunavir Tibotec 2006

PIs - Adverse Effects
• Class Effects • Individual Effects
• Dyslipidemia • Darunavir
• Hepatoxicity • Caution with sulfa allergy

• GI upset
PIs - Pharmacokinetics
• Metabolized by CYP3A4
• Inhibit CYP3A4
• Many significant drug interactions!
• Boosting
• Give PIs concomitantly with ritonavir or cobicistat
• Takes advantage of drug interaction
PIs and Boosting
• Protease inhibitors are substrates for CYP 3A4

• Ritonavir and cobicistat are potent inhibitors of CYP 3A4

• The combination allows for enhanced PI absorption and

decreased PI metabolism
• Results:
• Higher and sustained therapeutic concentrations limiting the
possibility of suboptimal levels
• Longer half-lives and extended dosing intervals (i.e. daily dosing)

• Decreased pill burden

PIsPharmacokinetic
and Boosting Enhancement or “boosting”

IDV-RTV 400/400mg q12h

100
Indinavir Concentration (µg/mL)

IDV 800mg q8h

IC90
10

0.1

0 4 8 12 16 20 24
Time (h)
Hsu A. 12th Int'l AIDS Conf.1998, Abstract #22361
 Initiating HIV Therapy
• What to start:

DHHS Guidelines Recommended Regimens

Protease inhibitor based Darunavir + ritonavir + emtricitabine + TDF or TAF

Raltegravir + emtricitabine + TDF or TAF

Integrase inhibitor based **Elvitegravir + cobicistat + emtricitabine + TDF or TAF

Dolutegravir + emtricitabine + TDF or TAF
**Dolutegravir + abacavir** + lamivudine**

**Available as single tablet regimens**

**HLA-B*5701 testing required prior to abacavir use**
Initiating HIV Therapy
• Which integrase inhibitor to choose?

Agent Advantages Disadvantages

Raltegravir • Longest experience • Not a single tablet regimen
• Fewest drug interactions

Elvitegravir • Single tablet regimen • Requires boosting with cobicistat

• Many drug interactions

Dolutegravir • Single tablet regimen • Co-formulated with abacavir

• High barrier to resistance • Hypersensitivity
• Few drug interactions
• Active against raltegravir
and elvitegravir resistant
virus
Questions ???
Hepatitis B and C
• Treatment goals
• Sustained viral suppression for HBV = virologic control
• Sustained virologic response (SVR) for HCV = virologic cure
• Prevent progression to cirrhosis or hepatocellular carcinoma
Hepatitis B Viral Replication
Agents for Hepatitis B
• Inhibit viral replication • Modulate the immune
• Lamivudine* system
• Entecavir* • Interferon alpha
• Tenofovir (TDF and TAF)*

*Also active against HIV

Nucleoside/Nucleotide Analogs
• Mechanism of action:
• Compete with natural purine and pyrimidines for binding to HBV
DNA polymerase

• Require intracellular phosphorylation

• Renal elimination – require dose adjustment in renal impairment

Nucleoside/Nucleotide Analogs
Advantages: Disadvantages:
• Agents are given orally • Drug resistance can
with once daily dosing develop on therapy
• Lamivudine 70% by year 5
• Well tolerated, few
adverse effects with long • Relapse can occur once
term therapy therapy is discontinued
Nucleoside/Nucleotide Analogs
Selecting Therapy
• Selection based on potency and durability

• Entecavir and tenofovir (TDF or TAF):

• Most potent agents
• Lowest rates of resistance (good durability)
• Monitor for nephrotoxicity with TDF
• Well tolerated

• Lamivudine:
• Less potent, higher rates of resistance (less durable)

• Duration of treatment
• At least 1 year and often life-long
 Hepatitis C Life Cycle
1. Viral attachment and entry 1

2. RNA release and migration

to endoplasmic reticulum
2

3. Translation and production of

polyprotein precursor
3
4. Cleavage of HCV polyprotein
into functional and structural 4
proteins (host and viral proteases)
5
5. RNA replication (polymerase)
6
6. Viral assembly, budding and
release
Hepatitis C Life Cycle
Processing of HCV Polyprotein

Structural Non-Structural

C E1 E2 NS2 NS3 NS4A NS4B NS5A NS5B

Auto-protease NS3/4A acts as a protease and

cleaves NS2- cleaves NS4B, NS5A and NS5B
Protease NS3 junction
enzymes NS3/4A goes on to serve a helicase
function during RNA replication
NS4B supports RNA replication
NS5A is a vital component of the
RNA replication complex; also helps
with new virus assembly
Viral core and NS5B goes on to become HCV RNA
envelope proteins polymerase
Hepatitis C Life Cycle
Targets for HCV Therapy – Direct Acting Antivirals (DAAs)

Non-Structural

NS2 NS3 NS4A NS4B NS5A NS5B

Grazoprevir Ledipasvir Sofosbuvir

Elbasvir
Velpatasvir
 Hepatitis C Treatment
Undergoing rapid change with availability of new DAAs

2011-2012 2013 2014-2015 2015-2016 2016-2017

Telaprevir Daclatasvir
Sofosbuvir/ledipasvir
Boceprevir Simeprevir Sofosbuvir/velpatasvir

Sofosbuvir Paritaprevir/ombitasvir/
ritonavir + dasabuvir Grazoprevir/elbasvir

• Complex regimens • Simple regimens

• Long duration • Short duration
• Poor tolerability • Good tolerability
• Modest SVR rates • High SVR rates
• Combined with IFN and ribavirin • IFN and ribavirin free
 Hepatitis C Treatment
Undergoing rapid change with availability of new DAAs

DAAs
2016
100
2011 95+
PegIFN
80 RBV 2001
Standard 70+
IFN 1998
60 55
1991
42 39
40 34

20 16
6
0
IFN IFN IFN/RBV IFN/RBV PegIFN PegIFN/ PegIFN/ DAA
6 mos 12 mos 6 mos 12 mos 12 mos RBV RBV/ Combos
12 mos DAA
SVR = Sustained Virologic Response = Cure
Hepatitis C Treatment
Undergoing rapid change with availability of new DAAs
• General treatment principles
• Treatment requires a combination of agents

• Some combination regimens are available in single tablets:

• Sofosbuvir/ledipasvir (Harvoni®), sofosbuvir/velpatasvir (Epclusa®) and
grazoprevir/elbasvir (Zepatier®)

• The selection of agents and treatment duration varies (12-24 wks)

• Depends on many factors including the HCV genotype, the presence of
cirrhosis, cost, and potential for drug-drug interactions

• Sustained virologic response (cure) is the goal of treatment and is

measured 12 weeks after therapy to ensure treatment success
Hepatitis C Treatment
Current treatment recommendations
Anti-Influenza Agents
Anti-Influenza Agents
• Zanamivir (Ralenza®) and Oseltamivir (Tamiflu®)

• Target neuraminidase

• Reduce spread of virus to neighboring cells

• Active against both influenza A and B

• Sporadic cases of resistance

• Must start treatment within 48 hrs of symptoms

• May shorten duration of symptoms by 1-2 days

Anti-Influenza Agents
• High risk groups benefit most from drug therapy:
• All hospitalized patients with confirmed, probable, or
suspected 2009 H1N1 or seasonal influenza
• Children younger than 5 years old

• Adults 65 years or older

• Pregnant women

• People with chronic conditions such as asthma,

immunosuppression
Anti-Influenza Agents
Rapid Antigen or Recommended Treatment
PCR Result
Influenza test not done but clinical Oseltamivir or zanamavir
suspicion
Positive influenza A or Positive A+B Oseltamivir or zanamavir

Positive 2009 Influenza A (H1N1) Oseltamivir or zanamavir

Positive A (H3N2) or B Oseltamivir or zanamavir

Check CDC website [www.cdc.gov] for updated information

Questions ???