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Antivirals for HIV
Yasir Waheed, PhD
Some HIV Facts
• HIV – the Human Immunodeficiency Virus is
the retrovirus that causes AIDS
• HIV belongs to the retrovirus subfamily
lentivirus.
• HIV attaches to cells with CD4 receptors (T4
cells and macrophages).
HIV Life
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Cycle
Step 1: Attachment of virus at the CD4
receptor and chemokine co-receptors CXCR4
or CCR5
Step 2: viral fusion and uncoating
Steps 3-5: Reverse transcriptase makes a
single DNA copy of the viral RNA and then
makes another to form a double stranded
viral DNA
Step 6: migration to nucleus
Steps 7-8: Integration of the viral DNA into
cellular DNA by the enzyme integrase
Steps 9-11: Transcription and RNA processing
Steps 12-13: Protein synthesis
Step 14: protease cleaves polypeptides into
functional HIV proteins and the virion
assembles
Step 15: virion budding
Step 16: Virion maturation
Anti- HIV Drug Targets2
Three types of drugs are
currently in clinical use:
1. nucleoside and
nucleotide reverse
transcriptase (RT)
inhibitors
2. non-nucleoside reverse
transcriptase inhibitors
3. protease inhibitors (PIs)
Nucleoside and Nucleotide Analogs
• Nucleoside analogs (NRTI) act as chain terminators
or inhibitors at the substrate binding site of RT
• NRTI’s must be phosphorylated (three steps) to their
5’-triphosphate form to become active inhibitors.
• Nucleotide analogs (NtRTI) already contain a
phosphate group and only go through 2 steps to
become active.
• The 5’-triphosphate of the NRTI’s compete with the
2’-deoxynucleoside’s 5’-triphosphate for binding to
reverse transcriptase leading to viral DNA chain
termination3.
Nucleoside Analogs
• There are currently 7 FDAapproved NRTI’s and one
nucleotide analog.
• The first anti-HIV drug approved
was the NRTI known as AZT or
Zidovudine (1987).
• AZT was discovered as a
treatment of AIDS during a
screening process for the
identification of effective AIDS
treatments.
• Antiviral selectivity due to
higher affinity for HIV RT than
human DNA polymerases.
Non-Nucleoside Analogs
• Non-nucleoside analog reverse transcriptase
inhibitors (NNRTI’s) inhibit viral DNA replication by
binding at the allosteric non-bonding site of RT,
causing a conformational change of the active site.
• NNRTI’s do not require bioactivation by kinases.
• Three NNRTI’s are currently approved for clinical use
in combination therapy: nevirapine, delavirdine, and
efavirenz.
Non-Nucleoside Analogs
Delavirdine
Benzoxazinone
Nevirapine
Protease Inhibitors
• During the reproduction cycle of HIV a specific
protease is needed to process the polyproteins
into mature HIV components.
• If protease is missing non-infectious HIV is
produced.
• HIV protease inhibitors are specific to HIV
protease because it differs significantly from
human protease.
• The 6 PI’s currently approved for clinical use were
all designed by using structure-based drug design
methods.
HIV Protease
• The crystal structure of
HIV protease was first
obtained
at
Merck
Laboratories.
• HIV protease is a 99
amino
acid
aspartyl
protease that functions as
a homodimer with one
active site.
• The active sites of
protease are hydrophobic.
Protease Inhibitors
• ABT-378 or lopinavir
was approved in 2000
for use in combination
with ritonavir (a PI)
(Kaletra)
• Ritonavir
strongly
inhibits
the
metabolism of ABT378.
Some Alternative Therapies
• Virus adsorption inhibitors – interfere with
virus binding to cell surface by shielding the
positively charged sites on the gp-120
glycoprotein
– Polyanionic compounds
• Viral coreceptor antagonists – compete for
binding at the CXCR4 (X4) and CCR5 (R5)
coreceptors
– bicyclams and ligands
Virus Adsorption Inhibitors
• Cosalane was originally
developed as an anticancer
agent
by
researchers at Purdue
University and the U.S.
National Cancer Institute.
• Cosalane was developed
from a chemical known as
ATA
(aurintricarboxylic
acid), which has long been
known
to
have
anti-HIV activity.
• The result was cosalane.
• Cosalane binds to the HIV
gp-120 protein.
Viral Coreceptor Antagonists
• Bicyclams are a type of viral
coreceptor antagonist.
• They are very specific and
potent
X4
coreceptor
antagonists.
• Bicyclams
belong to a
class
of
macrocyclic
polyamines consisting of
two cyclam units linked by
an aliphatic bridge
• Bicyclams with an aromatic
linker apparently had higher
antiviral activity.
• One such compound is
AMD3100.
Combination Therapy
• Combination therapy often called HAART is
standard care for people with HIV.
• Monotherapy created virus resistance to the
individual drug. Some combination therapies
increase the time it takes for the virus to become
resistant.
• Combinations of a PI or NNRTI with one or two
NRTI’s is often recommended.
• Combination therapy may reduce individual drug
toxicity by lowering the dosage of each drug
Drug Toxicity and Side Effects
• All available antiretroviral drugs are toxic.
• Side effects of nucleoside analogs are lactic
acidosis and severe hepatomegaly with
steatosis (enlarged fatty liver).
• Other side effects of anti-HIV drugs include
pancreatitis, myopathy, anemia, peripheral
neuropathy, nausea, and diarrhea.
Reducing Drug Toxicity
• The use of combination therapy:
– Combining agents with favorable synergistic
properties allows a decrease in dose or dosing
frequency
– Ritonavir alone cause gastrointestinal side effects
but when used in combination with other PI’s it
can be administered at a lower dose.
10 Million Patients on Antiretroviral Therapy
2013 Global AIDS Response Progress Reporting (WHO/UNICEF/UNAIDS)
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Principles of HIV Drug Resistance
• Not all drug failure is due to resistance
• Partial HIV suppression promotes resistance
• Resistance may fade but not disappear when
a drug is stopped
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Principles of Resistance (2)
• Some mutations allow certain viruses to resist
the effects of one or more antiretroviral drugs.
• Each infected person has a mixture of viruses,
some of which are resistant to some
medications.
• The drug resistant virus usually grows faster
and better than the drug susceptible virus.
• The drug resistant virus replaces the drug
susceptible virus in the patient.
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Resistance Testing
• Two types:
– Genotyping
• Less expensive
• Can usually be completed in 1-2 weeks
– Phenotyping
• More expensive
• Generally takes 2-3 weeks to complete
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Suspect Resistance in the Setting of
Treatment Failure
• Due to HIV’s high transcription error rate and
high level of replication, mutant HIV variants
constantly generated.
• These variants often contain mutations that
confer variable levels of resistance to
antiretroviral agents.
• Poor adherence or suboptimal regimens can
lead to resistance and ‘viral breakthrough’.
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How Does Resistance Develop?
• Results from changes (mutations) in the
genetic information in the virus.
• These changes occur whenever HIV is
replicating.
• Every possible mutation occurs tens of
thousands of times each day.
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Resistance Mutations
• For some drugs (NNRTIs and 3TC), a single
mutation causes high-level resistance.
– Resistance to these drugs occurs very quickly
• For other drugs (most NRTIs and PIs), many
mutations must occur before high-level
resistance is observed.
– Resistance to these drugs occurs more slowly
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Cross-Resistance
• Resistance to one drug can cause resistance to
others of the same class
– NNRTI: complete cross-class resistance
– NRTI: partial cross-class resistance
– PI: partial cross-class resistance
• Partly overcome by ritonavir boosting
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Minimize Emergence of
Viral Resistance
• Never prescribe ARVs in the absence of
adherence counseling and support
• Never prescribe monotherapy or dual therapy
• Ensure optimal serum drug concentrations
– Avoid drug interactions
– Diagnose and manage malabsorption
• If ARV medications are to be discontinued,
stop all drugs at the same time
– Possible exception: NNRTI-based regimen
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2003 vs. 2005 WHO Guidelines
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THANKS