Antiretroviral resistance


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ARVs are included in the drugs with narrow therapeutic index. It's important for every doctors and health care workers to understand mechanism of ARV resistance. Video file is available in the following link:

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Antiretroviral resistance

  1. 1. Antiretroviral Resistance Dr Aung Zayar Paing
  2. 2. History (Human War with Microbes)1800s - Germ Theory1928 - discovery of Penicillin by Alexander Fleming1940 - Mass Production of Penicillin1942 - First patient was treated and cured with Penicillinlate 1940s - Penicillin resistant Staphylococcus aureus found1951 - first antiviral drug - IDU (iododeoxyuridine) wasdescribed
  3. 3. History (Human War with Microbes)1981 - first AIDS cases found in US1984 - Scientist identified HIV as a cause of AIDS1987 - First ARV (Zidovudine) was approved for use.late 1980s to 1990s - Zidovudine resistant HIVdetected
  4. 4. Survival of the fittestA struggle for existence inevitably followsfrom the high rate at which all organic beingstend to increase. from ‘On the Origin of Species’ (1859)
  5. 5. Mutations in HIVMutations 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
  6. 6. Mutants
  7. 7. Properties of mutationSome mutations confer resistance to antiretroviral drugs whichmeans that the viruses can replicate with the presence of theARV.Mutant viruses are less fit to replicate than wild type viruses.In order to reduce both wild type and mutant viruses, antiretroviralregimen must contain (at least) 3 drugs which target differentlocations of viral proteins and/or different viral proteins.When the patient is initiated with HAART viral load decreasesand mutation rate also decreases.
  8. 8. If the levels of ARV in the blood drops below therapeutic levels, the virus grabs thischance 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 interactionIf the HIV viral load is increased under treatment, then HIV can replicate underselective conditions and can develop resistance to treatment.
  9. 9. Video Show
  10. 10. 2 Types of Resistance TestingGenotypic 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.
  11. 11. Nucleoside Reverse Transcriptase Inhibitors: Mechanism of Action
  12. 12. Mutations which confer Resistance to NRTIThymidine 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 TDFK65R This mutation emerges from tenofovir, abacavir, or didanosine containing regimen. Virus with this mutation is resistant to all NRTI except AZT.
  13. 13. Non-Nucleotide Reverse Transcriptase Inhibitors: Mechanism of Action
  14. 14. Mutations which confer Resistance to NNRTIK103N 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.
  15. 15. Genetic BarrierGenetic Barrier of ARV = number of mutations needed for HIV to becomeresistant to specific ARV ARV No of mutation needed NVP 1 3TC 1 AZT or d4T 2 Triomune 4 Kaletra 4Regimens with a high genetic barrier to resistance require a greater numberof critical mutations to become treatment ineffective.Regimens with a low genetic barrier to resistance require fewer criticalmutations to render treatment ineffective.
  16. 16. Preventing Antiretroviral ResistanceAlthough resistance is inevitable in antiretroviral war, we can delayor 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)