ANTI-VIRAL

PHARMACOLOGY

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  What do you already know about HIV/AIDS?

 What are the key differences between HIV and

AIDS?
 Why can a person be HIV-positive for years without

showing symptoms?

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 HIV/AIDS
• Chronic viral infection with no cure

• HIV infects vital cells in the human immune system such as

helper T cells (specifically CD4+ T cells), macrophages, and

dendritic cells→ their destruction lead to immune impairment

• Decreased immunity  increase risk of OIs

• HIV progresses overtime to death, if no prevention measures or

treatment are given

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 HIV virus

 Retrovirus family

 Two serotypes:

• HIV-1- major causes of HIV pandemic

• HIV-2 – less transmissible and associated with a lower viral
burden and a slower rate of clinical progression - less
virulent

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 HIV virus

 Single stranded RNA

virus

 Contains two copies of

the genome inside its

capsid

 It has RT enzyme etc...

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 HIV Receptors

 HIV first binds to receptor

primarily CD4
 Then to co-receptors
(CXCR4/CCR5)
 Gp120, on the HIV envelope
binds to CD4 and to co-
receptor CXCR4
 Gp41, then causes fusion of
the viral envelope with the
plasma membrane of the cell

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HIV life cycle

Important steps include

 Attachment(need

receptor and co-receptor)

 Reverse transcription

 Integration

 Release and maturation

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Classes of Anti-Retroviral drugs
Anti-Retroviral drugs act at different sites of the HIV life cycle

1. Reverse transcriptase enzyme inhibitor

Include NRTIs and NNRTIs

2. Protease enzyme inhibitors

Protease Inhibitors

3. Fusion/entry
Fusion Inhibitors

4. Integrase Inhibitors and GP-41, Co-receptors

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 Replication cycle of HIV-1 and site of action of ARV drugs

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Objective of ART
• To maximally suppress HIV replication ⇒ preserved/improved

immune function ⇒ reduced HIV related morbidity and mortality

⇒ improved quality and length of life

N.B. The success of achieving the objective is determined more by

adherence

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 Nucleoside reverse transcriptase inhibitors (NRTIs)

 Lamuvidine 3TC
 Stavudine d4T
 Zidovudine (Azidothiamidine) ZDV (AZT)
 Abacavir ABC
 Didanosine DDI
 Emtricitabine FTC

 Zalicitabine DDC

Nucleotide RTIs
 Tenofovir (TDF)

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 Nucleoside analog mimic host substrate
 Lamuvidine cytosine

 Zalicitabine cytosine

 Emtricitabine cytosine

 Stavudine thymine

 Zidovudine thymine

 Abacavir guanine

 Didanosine adenine

 Tenofovir adenine
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NRTI Combination Tablets
• Tenofovir + Emtricitabine (Truvada®)

• Abacavir + Lamivudine (Epzicom®)

• Zidovudine (ZDV) + Lamivudine (3TC)

 (Combivir ® or Lamuzid ® or Duovir®)

• Zidovudine (ZDV) + Lamivudine (3TC) + Nevirapine (NVP)

• Zidovudine + Lamivudine + Abacavir (Trizivir®)

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 Non nucleoside reverse transcriptase inhibitors
(NNRTIs)

 Efavirenz EFV, EFZ

 Nevirapine NVP

 Delavirdine DLV

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 Protease inhibitors
 Amprenavir APV

 Fosamprenavir f-APV

 Indinavir IDV

 Lopinavir/ritonavir LPV/r

 Nelfinavir NLV

 Ritonavir RTV

 Saquinavir SQV

 Atazanavir ATZ
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 Fusion inhibitors
 Enfuvirtide

Co-receptor or chemokine (CCR5) receptor antagonist

 Maraviroc

Integrase inhibitors
 Dolutegravir

 Raltegravir

 Elvitegravir

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 Highly Active Anti- Retroviral Therapy (HAART)
 Combination of at least 3 drugs, usually:
• 2 NRTIs + 1 NNRTI
• 2 NRTIs + 1-2 PIs
• 3 NRTIs
 HAART
• Durably inhibit virus replication

• Avoid development of resistance

• Reduce plasma HIV RNA levels & gradually increase CD4 cells

 Therapy with only one or two agents allows HIV to overcome

therapy through resistance mutations

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 HAART…

• Don’t combine because of antagonism

- AZT + d4T

- DDC + 3TC

• Don’t combine b/c of overlapping toxicity

- DDC + d4T

- DDC + DDI

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 NRTIs
 The first available agents for the Rx of HIV infection

 Have activities against both HIV-1 and HIV-2

 Pro-drugs ⇒ the Drugs enter the cell & get phosphorylated to

produce the active triphosphates

 Phosphorylated NRTIs:

 Compete for HIV RT binding and incorporate into viral DNA

 Lack 3’ – hydroxyl group necessary for DNA polymerization

• Terminates viral DNA strand elongation

• Prevent copying of viral RNA to DNA

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 Zidovudine (AZT)
• Thymine analogue

• Active against HIV-1 & 2

• After intracellular phosphorylation it terminates viral DNA

chain elongation by competing with thymidine triphosphate

• Has additive/synergistic effect with most NRTIs, NNRTIs, & PIs

• Antagonistic effect with d4T

• Dose adjustment in renal impairment and hepatic failure

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 AZT…
Adverse drug reactions
 Nausea(food reduce), headache, anorexia, fatigue, malaise,
myalgia, and insomnia
 Usually resolve with in the first few weeks of therapy

 Bone Marrow Suppression

• Anemia (fatigue)
 Monitor Hgb

• Neutropenia
 Nail hyperpigmentation (chronic use)

 Serious hepatic toxicity, with or without steatosis and lactic

acidosis, is rare but can be fatal
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 AZT…
Adverse drug reactions

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 AZT…
 C/I in patients with preexisting anemia

 Concurrent use of other myelosuppressive drugs should be

avoided

 Used to treat HIV infection combination with other ARV drugs

 As monotherapy

• Prevent mother-to-child transmission of HIV

• Post exposure prophylaxis

24  Efficacy may increase in combination with other agents

Lamivudine (3TC)
• Deoxycytidine analogue

• Phosphorylated intracellularly

• Also act against hepatitis B virus

 Approved for treatment of chronic active hepatitis B

• Antagonizes zalcitabine by interfering with its phosphorylation

• Dose adjustment in renal failure

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 3TC…
Adverse drug reactions :
• One of the least toxic antiretroviral drugs

• Rarely occurring adverse effects

 Headache

 Nausea

 Neutropenia

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Stavudine(d4T)
• Thymine analogue, intracellularly phosphorylated

• Antagonism with AZT

Adverse drug reactions

• Peripheral neuropathy (more severe with ddI/ddC)

• Lactic acidosis and hepatic steatosis (common with ddI)

• Pancreatitis (Rare, incidence increased with ddI)

• Lipodystrophy syndrome, especially lipoatrophy

• Headache, nausea, rash, and elevated hepatic transaminases

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Stavudine(d4T)

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 Abacavir(ABC)
• Guanosine analogue

• Intracellularly phosphorylated

• Can be taken with or without food

Adverse drug reactions

• Hypersensitivity reaction: in the first 6wks - is unique and
potentially fatal adverse effect that needs discontinuation
 Symptoms: high fever, skin rash, malaise, fatigue, abdominal
pain nausea…
• Respiratory complaints (cough, pharyngitis, dyspnea), Myalgia,
headache, and paresthesia (rare)
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 Common Adverse effects of NRTIs
 Nausea, headache

 Lactic acidosis, fatty liver

• ddI >d4T >ZDV

• Rare with ABC, TDF, 3TC, FTC

 Lipoatrophy

 Mitochondrial toxicity

• ddI/DDC/d4T > ZDV/3TC/FTC/ABC

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 NNRTIs

• Are generally effective against HIV-1

• Don’t require intracellular activation

• All are substrates for CYP3A4 (Nevirapine and delavirdine are
primarily substrates )
• Efavirenz and nevirapine are moderately potent inducers of
hepatic CYP3A4, whereas delavirdine is a CYP3A4 inhibitor
• Directly bind to sites on reverse transcriptase and cause
conformational change and inactivate the enzyme
 Non – competitive inhibition of HIV RT
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 NNRTIs…
Adverse Reactions
• Hypersensitivity reactions (esp. NVP)

 Rate of rash that requires discontinuation

 NVP > EFV>DLV

• Hepatotoxicity: NVP > EFV

• Cross resistance across entire class

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Nevirapine (NVP)
• Dosing: 200 mg QD x 2 weeks, then 200 mg BID

• PMTCT

Adverse reactions

• Rash(in first 4-8wks.)

• Hepatotoxicity

• Fever, nausea, headache and somnolence

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Nevirapine
• Drug interactions (induces liver enzymes)

 NVP reduces ethinyl estradiol and norethindrone conc. by

20%, and alternative methods of birth control are advised

 Rifampicin reduces NVP by 37%. Do not combine NVP and

Rifampicin

 NVP drug interactions with PIs

•  Saquinavir, indinavir and lopinavir conc.

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• Has no effect on ritonavir and nelfinavir
Efavirenz (EFV)
• Dosing: 600 mg at bed time

• Food Interactions

 High-fat meals increase absorption 22%  increases side effects

 Taken initially on an empty stomach

• Efavirenz is cleared via oxidative metabolism, mainly by CYP2B6

and to a lesser extent by CYP3A4

• Moderately inducer of CYP3A4, induces its own met.

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Efavirenz
Adverse drug reaction

• CNS Changes: resolve after the first months of therapy

• Dizziness, impaired concentration, dysphoria, vivid or

disturbing dreams, and insomnia (commonly reported)

• Depression, hallucinations, and/or mania

• Rash: usually mild to moderate

• Headache, increased hepatic transaminases, and elevated

serum cholesterol
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Efavirenz…
• Drug interactions (induce liver enzymes)

 Rifampicin decreases EFV levels by 25%  increase EFV to 800mg

 EFV decreases levels of phenytoin, phenobarbital, and

carbamazepine  Need to monitor anticonvulsant levels

 Efavirenz has a variable effect on HIV protease inhibitors

•  Indinavir, saquinavir, and lopinavir conc.

• Ritonavir and nelfinavir conc.

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 Protease inhibitors (PIs)
• HIV PIs are peptide like chemicals that competitively inhibit the

action of the virus aspartyl protease

• These drugs prevent proteolytic cleavage of HIV polyproteins

(gag and pol), and inhibit production of:

 Essential structural comp. (p17, p24, p9, and p7) and

 Enzymes (reverse transcriptase, protease, and integrase)

• Prevents the metamorphosis of HIV virus particles into their

mature infectious form

• Inhibit HIV1 and HIV2 replication

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 PIs…
• All but nelfinavir (CYP2C19 ) are metab. predominately by CYP3A4

• Most of these drugs inhibit CYP3A4 at clinically achieved conc.

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 PIs…
Adverse drug reactions
 Lipodystrophy, hyperlipidemia

 Nausea, vomiting, diarrhea

 Insulin resistance/hyperglycemia

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 Ritonavir
• Absorption is rapid and is only slightly affected by food

• Metabolized primarily by CYP3A4 and to a lesser extent by

CYP2D6

• Multiple drug - drug interactions

• Used at low dose as a pharmacokinetic enhancer of other PIs

• ADRs: major adverse effects are, dose dependent

 NVD, anorexia, abdominal pain (reduced by taking with meal)

 Elevation in serum total cholesterol & triglycerides

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 Amprenavir and fosamprenavir

• Amprenavir is non-peptide HIV protease inhibitor

• Fosamprenavir is a prodrug of amprenavir

 Greater water solubility and improved oral bioavailability

• ADRs:

• NVD (common)

 Fosamprenavir has much less frequent adverse effects

• Hyperglycemia, fatigue, paresthesia, and headache

• Skin eruption (more likely to occur than in the other PIs)

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 Lopinavir
• Poor bioavailability

• Moderate- to high-fat meal increases oral bioavailability by up to

50% (taken with food)

• Co-formulated with ritonavir

• LPV/r (Kaletra) common combination

 LPV’s AUC is increased by >100 fold

• ADRs: NVD, elevated total cholesterol and triglycerides (the

most common)

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 Atazanavir
• Absorbed rapidly after oral administration

• Absorption  by food (should be taken with food) and low

gastric PH (aqueous solubility)

• Does not cause fat redistribution, dyslipidemia, & glucose

intolerance

• ADRs: hyperbilirubenemia that is not associated with

hepatotoxicity; diarrhea, nausea - first few weeks of therapy

• Proton pump inhibitors and H2 blockers should be avoided

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 Entry Inhibitors
A. Enfuvirtide
 As a peptide, it must be given subcutaneously.

 It is an expensive medication.

B. Maraviroc
 It is well absorbed orally hence it is formulated as an oral tablet.

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Integrase Inhibitors
o Raltegravir (RAL)

o Dolutegravir (DTG)

o Cabotegravir (CAB)

A. Raltegravir (RAL)
 RAL is the first of antiretroviral drugs known as integrase inhibitors.

 RAL specifically inhibits the final step in integration of strand

transfer of the viral DNA into host cell DNA.

 RAL has a half-life of approximately 9 hours and is therefore dosed

twice daily.
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 Raltegravir
 Common side effects: nausea, headache and diarrhea as the

most.
 RAL, in combination with other ARVs, is approved for therapy

of treatment-experienced patients with evidence of viral

replication despite ongoing ART

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 Summary

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 The end
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