antiretroviral resistance
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Antiretroviral Resistance
Dr Aung Zayar Paing
History (Human War with Microbes)
1800s - Germ Theory
1928 - discovery of Penicillin by Alexander Fleming
1940 - Mass Production of Penicillin
1942 - First patient was treated and cured with Penicillin
late 1940s - Penicillin resistant Staphylococcus aureus found
1951 - first antiviral drug - IDU (iododeoxyuridine) was
described
History (Human War with Microbes)
1981 - first AIDS cases found in US
1984 - Scientist identified HIV as a cause of AIDS
1987 - First ARV (Zidovudine) was approved for use.
late 1980s to 1990s - Zidovudine resistant HIV
detected
Survival of the fittest
from ‘On the Origin of Species’ (1859)
A struggle for existence inevitably follows from the high rate at which all organic beings tend to increase.
Mutations in HIV
Mutations occur naturally whether or not the patients are taking ART.
Mechanisms for mutations in HIV
Rapid replication of HIV - 10 billion particles per day
Reverse transcription of HIV lack of proof reading mechanism.
This leads to the occurrence of mutated HIV virons.
So there are two types of virus particles in body.
Wild type (non-mutated virus particles)
Mutated virus particles
Mutants
Properties of mutation
Some mutations confer resistance to antiretroviral drugs which
means that the viruses can replicate with the presence of the
ARV.
Mutant viruses are less fit to replicate than wild type viruses.
In order to reduce both wild type and mutant viruses, antiretroviral
regimen must contain (at least) 3 drugs which target different
locations of viral proteins and/or different viral proteins.
When the patient is initiated with HAART viral load decreases
and mutation rate also decreases.
If the levels of ARV in the blood drops below therapeutic levels, the virus grabs this
chance to replicate to produce more and more virons.
Decrease of ARV blood levels can be triggered by:
Non-adherence
Poor absorption
Poor potency
Poor activation
Host genetics
Rapid clearance
Drug-to-drug interaction
If the HIV viral load is increased under treatment, then HIV can replicate under
selective conditions and can develop resistance to treatment.
Video Show
2 Types of Resistance Testing
Genotypic Test
The test results will pinpoint the exact HIV genes where
the mutation or mutations occur.
e.g., K103N means that amino acid K (lysine) in codon
103 of reverse transcriptase was replaced with amino
acid N (asparagine)
Phenotypic Test
It resembles sensitivity tests of antibiotics
The result shows which ARV is sensitive and which is
resistant.
Nucleoside Reverse Transcriptase Inhibitors: Mechanism of Action
Mutations which confer Resistance to NRTI
Thymidine analogue mutations (TAMs)
Selected by thymidine analogues (d4T and AZT)
The greater the number of TAM, the greater the degree of NRTI resistance and cross-
resistance.
M184V
This mutation develops rapidly in 3TC or FTC containing HAART.
Virus carrying this mutation is highly resistant to 3TC and FTC.
But it can delay the development of TAMs and can increase susceptibility to AZT, d4T,
and TDF
K65R
This mutation emerges from tenofovir, abacavir, or didanosine containing regimen.
Virus with this mutation is resistant to all NRTI except AZT.
Non-Nucleotide Reverse Transcriptase Inhibitors:
Mechanism of Action
Mutations which confer Resistance to NNRTI
K103N
Most common NNRTI resistance mutation
Usually seen before M184V in HAART with
AZT/D4T-3TC-NVP/EFV
Most NNRTI resistance is associated with high-level
cross-resistance to other drugs in the class.
Genetic Barrier
Genetic Barrier of ARV = number of mutations needed for HIV to become
resistant to specific ARV
Regimens with a high genetic barrier to resistance require a greater number
of critical mutations to become treatment ineffective.
Regimens with a low genetic barrier to resistance require fewer critical
mutations to render treatment ineffective.
ARV No of mutation needed
NVP 1
3TC 1
AZT or d4T 2
Triomune 4
Kaletra 4
Preventing Antiretroviral Resistance
Although resistance is inevitable in antiretroviral war, we can delay
or control it to be minimum.
Precautions
Always ask whether the patient had ART exposure or not (PMCT,
Dual drug regimen, etc.)
Always think of drug-to-drug interaction when new drug(s) added
Always to be cautious to stop HAART containing ARV with
different half-lives (NVP, EFV) (to stop with tail-off as much as
possible)
Always ask patients not to use traditional drugs (possibility of drug
interaction)
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