VIRUS

&
Treatment of viral
infection
DR. Dr. Nico L Lumbuun, SpFK
Pharmacology Department
Faculty of Medicine-UPH
 Viruses
Obligate intracellular parasites
Consist of a core genome in a protein shell & some
are surrounded by a lipoprotein
Lack a cell wall and cell membrane
Do not carry out metabolic processes
Replication depends on the host cell
Has a specific surface for a specific receptor target

Anti Viral
Antiviral agents must either block viral entry into or
exit from the cell or be active inside the host cell
 Viral Life Cycle
1. Adsorption (binding & attachment)
fusion & penetration to host cell
2. Un-coating of viral capsule
3. Early transcription Early
translation
4. Genome Replication
5. End state of transcription
6. New viral assembly
7. Budding & release
Sites of Drug Action
 Antiviral
compounds
Many well-known antiviral
compounds are nucleoside and
nucleotide analogs:

Acyclovir is a nucleoside
analog similar to guanosine, but
contains an acyclic sugar group

AZT is a nucleoside analog

similar to thymidine, but contains
an azide group
 Antiviral Classification

Antivirus

Anti-nonretrovirus Antiretrovirus

Antivirus Antivirus Antivirus NRTI NtRTI NNRTI PI Viral entry

for for for HBV & inhibitor
herpes influenza HCV

Zidovudin, Nevirapine Enfuvirtide

Didanosin Efavirenz
Asiklovir Amantadin, Lamivudin
Gansiklovir Rimantadine Interferon
Foscarnet Oseltamivir, Tenofovir, Saquinavir
Zanamivir Adefovir Ritonavir
Acyclovir:
Close to a perfect antiviral drug (specific, nontoxic).

Highly effective against herpes simplex virus (HSV), less so

against varicella-zoster virus (VZV).

Highly selective and extremely safe.

Acyclic guanine derivative that inhibits viral DNA synthesis.

It is a prodrug, a precursor of the antiviral compound.

Activation of the drug requires three kinase activities to be

present in the cell to convert acyclovir to a triphosphate derivative,
the actual antiviral drug.
Activation of
acyclovir:
Acyclovir has no effect on
host DNA replication because
the first kinase activity is not
found in an noninfected cell.
Cellular enzymes complete
the synthesis.
Incorporated into viral DNA,
lacks the 3 OH of the sugar
ring.
Growing DNA chain
terminates, replication is
blocked.
Acyclovir (Clinovir)
- MOA : blocks DNA replication by termination of DNA chain
- Indication : HSV-1, HSV-2 (herpes genital), Varicella-zoster
Virus (VZV), EBV, CMV
- ADR : GIT irritation, skin irritation (topical), headache
- Doses :
* Oral preparation : tablet 200, 400mg, 800mg; capsule 200mg,
suspension 200mg/5mL):
Herpes genital 1000 mg/day (5x200 mg/day)
Herpes zoster 4000 mg/day (5x800 mg/day)
* Topical: ophthalmic cream 3% for keratitis herpetic;
cream/oint 5% for herpes labial, genital
* Intravenous: 30 mg/kgBW/day for herpes encephalitis,
severe HSV & VZV
 Antivirus for herpes & CMV
Valacyclovir (Valtrex)
- converted to acyclovir via hepatic metabolism
- Indication : HSV, VZV, EBV & prophylaxis of CMV
- Doses :
- Oral preparation : FC caplet 500 & 1000mg
* herpes genitalia 1000mg/day (2x500mg) for 7-10 days
recurrent episode (2x500mg) for 5 days
* herpes zoster: s/d 3000 mg/day (3x1000mg) for 7days
- ADR : = acyclovir
 Antivirus for herpes & CMV
Ganciclovir (Cymevene)
- Indication: Life threatening or sight threatening such as
retinitis CMV (for AIDS pts :th/ & prevention)
- Doses :
Induction dose 5 mg/kg IV at a constant rate over 1 hour,
every 12 hours; for 14 to 21 days
Maintenance & prevention: IV: 5 mg/kg IV once a day, 7
days/week or 6 mg/kg IV once a day, 5 days/week. Or oral
3x1000mg a day or 6x500mg a day with food.
Local CMV retinitis:
Implant intraocular (intra vitreal) 4,5 mg
- Preparation : capsule 250, 500mg/vial, 4,5mg/implant
- ES : mielo-supression, carcinogenic, embriotoxic
 Antiviral for hepatitis
Ribavirin (Rebetol) a nucleoside analog
- MOA : inhibit mRNA viral sinthesis
- Indication :
* Severe RSV (Respiratory Syncytial Virus) in pediatrics,
influenza virus
* hepatitis C (combine w/ peginterferon alfa-2a
[Pegasys] or peginterferon alpha-2b [PEG-Intron])
Dosis : taken with food 2x/day, for 24-48 weeks or longer.
Preparation : Capsule 200mg
- Contraindication : pregnancy, may cause harm or
death to the fetus
- ADRs : Anemia, drowsy, dizzy, or confused
 Antiviral for hepatitis
Lamivudine (nucleoside reverse transcriptase inhibitor)
- Indication : chronic HBV; combination th/HIV
- Doses :
adult : orally 100 mg/day (HBV)
orally 300mg/day (HIV combine with AZT & Abacavir)
children <12 yo : 1 mg/kgBW increased to 100 mg/day.
Duration of Th/: HBeAg (-) pts : 1 year
HBeAg (+) pts: >1 year
- ADR : Generally well tolerated.
Rarely : Fatigue, Headache & nausea.
 Antiviral for hepatitis
Interferon
- Not specifically antiviral, causing elaboration of effector
proteins in infected cells, resulting in inhibition of viral
pentration & uncoating, mRNA synthesis and translating,
or virion assembly and release.
Indication : chronic infection of HBV & HCV (combine w/
ribavirin), sarcoma Kaposi in AIDS pts, hairy cell leukemia,
and chronic myelogenous leukemia, malignant melanoma,
condylomata acuminata, relapsing multiple sclerosis.
ADR : influenza-like syndrome, mielo-supression, fatigue,
leucopenia; depression, anorexia, alopecia, mood
impairment, irritable.
 Interferons
Interferon Alfa
1. Endogenous proteins
2. Induce host cell enzymes that inhibit viral RNA translation
and cause degradation of viral mRNA and tRNA
3. Bind to membrane receptors on cell surface, may inhibit
viral penetration, also uncoating, mRNA synthesis,
translation, virion assembly and release
 Interferons
Pegylated interferon Alfa
A linear or branced polyethylene gylcol (PEG) moiety is
attached to covalently to interferon
Increased half-life and steady drug concentrations
Less frequent dosing
Th/ chronic hepatitis C in combination with ribavirin
The treatment of choice, used w/ ribavirin, and listed on
the WHO's List of Essential Medicines for HCV.

Approval of Sofosbuvir and Simeprevir in 2013 by the FDA.

Newer medications, may displace the peginterferons as the
preferred treatment.
Interferon

- Doses :
HBV infection :
Adult : SC/IM, 5 millionU/day (once/d) or 10millU (3xweekly)
Children : 6 millionU/m2BSA 3xweekly for 4 6 month.
HCV infection :
* Interferon -2b mono th/ (3MillionU SC/IM,3xweekly)
* Peg-interferon -2a 180g SC, once a week, for 48 weeks
* Peg-interferon -2b 0.5-1.5g/kg, 1x/week for 6 months
* Combination Peg-interferon + ribavirin more effective for
chronic HCV
HIV pts: Interferon- 3million U3x weekly th/
thrombocytopenia HIV pts who are resistant with
zidovudine.
Antiretroviral (Anti-HIV) Agents
The first available agents: Nucleoside analog class
competitive inhibition of the viral reverse
transcriptase
Nonnucleoside reverse transcriptase inhibitors
The protease inhibitors
The combination of at least two antiretroviral
agents (cocktail therapy) enhancing potency
and delaying resistance
 Antiviral for HIV infection
Classification :
Reverse Transcriptase Inhibitors
- Nucleoside reverse transcriptase inhibitors (NRTI) ;
zidovudine (AZT), lamivudine, zalcitabine, stavudine
- Non-nucleoside reverse transcriptase inhibitors (NNRTI) ;
nevirapine, efavirenz
Protease inhibitors (PI)
Saquinavir, ritonavir, indinavir, nelvinavir, amprenavir
Steps in replication of HIV targeted by antiviral drugs:
Nucleoside Reverse Transcriptase Inhibitors (NRTI)
Reverse transcriptase (RT) an enzyme used to
generate complementary DNA (cDNA) from tRNA.
NRTI: a competitive inhibitor of HIV-1 reverse transcriptase
Active in early state of HIV replication inhibit acute
infection for the susceptible cells, but lack of effect in cells
already infected by HIV.
Indication : HIV (HIV-1 & HIV-2) infection
Needs enzyme cell host activation (phosphorylation) in
cytoplasm.
Strongly recommended to use as a component of 3 4
other HIV drugs in a regiment of th/ HIV.
 Non-Nucleoside RTI for HIV
- MoA: act by binding non-competitively to the RT.
- Bind directly to a site on the viral RT that is near to
but distinct from the binding site of the NRTIs.
- Neither compete with nucleoside triphosphates nor
require phosphorylation to be active.
- Specific activity against HIV-1
- The rapid emergence of resistance , therefor prohibits
monotherapy
- No cross-resistance between the NNRTIs & the NRTIs
or the protease inhibitors
- Metabolized by the CYP3A P450 isoform, excreted
in the urine
 Protease inhibitors
Including ritonavir, nelfinavir, saquinavir, indinavir and
amprenavir.

Viral RNA from translation Polyproteins,

transcription Immature budding particles
protease

Final structural proteins,

Mature virioncore

Combination th/ with other agents is recommended to avoid

emergence of resistance, because of specific genotypic
alterations
 INTEGRASE STRAND TRANSFER
INHIBITORS (INSTIs)
A new class of drugs used in the treatment of HIV.
The first integrase inhibitor is raltegravir (approved 2007),
elvitegravir and other drugs were in clinical trials in 2011.
Raltegravir as an initial regimens for treatment-nave pts,
also be used as part of a salvage regimen in treatment-
experienced patients when resistance or side effects have
limited the use of other available agents.
Dosing: 400 mg PO 2x/d. Dose adjustment is not required
for mild to moderate hepatic insufficiency or severe renal
insufficiency. Should be caution in patients with severe
hepatic impairment.
ADRs: Stevens-Johnson syndrome, toxic epidermal
necrolysis, and hypersensitivity reactions.
 Fusion and Entry Inhibitors
Enfuvirtide, an analogue of the HIV protein that mediates fusion
w/ the cell membrane.
Enfuvirtide + HIV protein impaired conformation w/ membrane
cell host prevent it fusion to the host cell
Miraviroc, blocks one of the proteins (CCR5) of HIV, that acts as a
receptor for the HIV. Only active against HIV strains that are R5
tropic.
 Preferred Antiretroviral Regimens for Initial Treatment of HIV-1 Infection in Non-Pregnant
Adults and Adolescents
Dual N(t)RTI NNRTI or PI or INSTI
a,b c
tenofovir plus efavirenz atazanavir plus ritonavir raltegravir
emtricitabine
darunavir plus ritonavir (once-
(co-formulated +
as Truvada) daily dosing)

tenofovir plus Fosamprenavir plus ritonavir

lamivudine (once-daily
dosing)

Options are listed alphabetically. For recommendations for ART use during pregnancy, see Management
of HIV-Infected Pregnant Women Including Prevention of Perinatal HIV Transmission.
Fixed-dose combinations should not be used in patients who need dose adjustment due to renal
failure. When combination pills are used, patients should be educated about which drugs are combined
in that pill.
a
When efavirenz is used with tenofovir + emtricitabine; Atripla is a fixed-dose, three-drug combination
pill, can be prescribed.
b
For women considering pregnancy or likely to become pregnant, efavirenz, or combination pills
containing efavirenz, should be avoided. If there are no alternatives for efavirenz in women of
childbearing age, clinicians should strongly advise the use of effective contraception and should obtain a
pregnancy test before initiation.
c
Disadvantage to this regimen is twice-daily dosing; however, the benefit of increased tolerability may
outweigh the limitation of twice-daily dosing.
http://www.hivguidelines.org/clinical-guidelines/adults/antiretroviral-therapy/
Regimens Not Recommended or Contraindicated for Initial Treatment of HIV Infection
Drug or Regiment not Recommended Rationale
Abacavir + lamivudine + zidovudine (co-formulated Higher rates of virologic failure with triple NRTI
as Trizivir) therapies
All triple and quadruple NRTI therapies

Didanosine + stavudine There is high incidence of toxicities (peripheral

neuropathy, pancreatitis, hyperlactatemia) associated
with this combination

Etravirine (NNRTI) At this time, there are insufficient data to support

using this agent as initial therapy
Indinavir Inconvenient dosing and pill burden
Saquinavir (without ritonavir-boosting) Inferior efficacy unless boosted with ritonavir
Stavudine The toxicities associated with stavudine generally
outweigh the benefits when used as initial therapy,
particularly when used in combination with
didanosine

Tenofovir + didanosine + NNRTI High risk of early failure, possibly due to a lower
barrier to development of resistance; it is unknown
whether combining tenofovir + didanosine + a PI is
more efficacious
 Contraindicated Therapies and Components for Rationale
Initial Treatment (Do Not Use)

Emtricitabine + lamivudine These agents are interchangeable do not use in

combination
Fosamprenavir + lopinavir/ritonavir (co-formulated as The use of fosamprenavir with lopinavir/ritonavir
Kaletra) causes a bi-directional drug interaction that results in
lower drug levels
Ritonavir + nelfinavir Not easily tolerated and no additional boosting effect
on nelfinavir
Stavudine + zidovudine Pharmacologic antagonism between stavudine and
zidovudine
Two-drug therapy Insufficient data to recommend
Monotherapy Inferior efficacy
 HIV-Related Medications to Avoid or Use with Caution During Pregnancy
Medicationa,b Concern/Recommendation
Efavirenz (EFV) EFV is contraindicated during the first trimester due to teratogenicity. Significant
FDA Pregnancy Category D congenital CNS abnormalities have been seen in animal primates and in humans
Do not give to women of childbearing potential if other treatment options are available. If
pregnancy is discovered during the second or third trimester, an alternative regimen
should be offered but EFV can be continued if the benefits outweigh the risks

Stavudine/Didanosine (d4T/ddI) Should be avoided during pregnancy. If no alternative combinations are feasible, use with
FDA Pregnancy Categories
Stavudine Category C
Didanosine Category B
Ribavirin (non-ARV agent)
FDA Pregnancy Category X
Pegylated interferon (non-ARV
agent)
FDA Pregnancy Category C
caution.
Fatal lactic acidosis in pregnant or postpartum women has been reported
Several less severe cases of pancreatitis with or without lactic acidosis and hepatic failure
have also been reported in pregnant women
Monitor hepatic and renal function monthly if pregnancy occurs while taking
stavudine/didanosine
Ribavirin is an absolute contraindication during pregnancy
Effective contraception should be used during ribavirin therapy and for 6 months after
cessation of therapy
Fetal abnormalities demonstrated in animal and human studies
Its function as a nucleoside analogue may impact fetal DNA
Abortifacient effects in rhesus monkeys
Birth defects and fetal death with combination ribavirin therapy

Adapted from Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected
Women for Maternal Health and Interventions to Reduce
Antivirus untuk Avian Influenza
Etiology : AI H5N1 genotipe z
Transmission : Animal human
human human
Management :
- Prevention : vacination ? Prophylaxis?
- Antiviral th/ : oseltamivir (tamiflu), Zamivir
Dose for th/ (ASAP, best if <48h):
Adult/children 13yo, 2x75mg/day for 5 days
Children 1-13yo, 2x2mg/kgBW/day for 5 days
Prophylaxis : adult, 1x75mg/d for 10 days
pediatric dose, see next slide
 Avian Influenza (H5N1)
Pediatric dosage (not licensed for use <1 yo):
Weight Dosage (prophylaxis), for 10 days :
Under 15 kg 30 mg daily
15 to 23 kg 45 mg daily
24 to 39 kg 60 mg daily
40 kg and over 75mg daily
Oseltamivir & zanamivir, is a neuraminidase
inhibitors that acts as a blocker of viral release
from infected cells.