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)