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ARV Drug Resistance

ARV Drug Resistance. HAIVN Harvard Medical School AIDS Initiative in Vietnam. Learning Objectives. At the end of this lecture, each trainee should: Know how HIV develops resistance Know factors increasing the risk for developing HIV resistance Understand genotypic resistance testing.

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ARV Drug Resistance

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  1. ARV Drug Resistance HAIVN Harvard Medical School AIDS Initiative in Vietnam

  2. Learning Objectives At the end of this lecture, each trainee should: • Know how HIV develops resistance • Know factors increasing the risk for developing HIV resistance • Understand genotypic resistance testing

  3. Outline of Presentation • What is resistance? • How does resistance develop? • Drug resistance in infants and children • Resistance testing

  4. What is HIV Drug Resistance? • Process by which changes (mutations) in the HIV virus allow the virus to become tolerant to antiretroviral drugs. • Resistance is the consequence of mutations that emerge in the viral proteins targeted by antiretroviral agents. Clavel and Hance. N Engl J Med 2004;350:1023-35

  5. How does resistance develop? • Two important concepts: • HIV has an extremely high rate of virus replication and production. • The reverse transcription of viral RNA into DNA is prone to error (i.e mutations). On average one mutation is introduced for each viral genome produced.

  6. How does resistance develop? • Each patient, therefore, develops a mixture of viral ‘quasi-species’, each differing by one or more mutations. • These mutations may confer some selective advantage to the virus, such as a decrease in its susceptibility to an antiretroviral agent. • Potent combination ART prevents the development of resistant strains by maximally suppressing viral replication.

  7. How does resistance develop? • However, administration of antiretrovirals in an insufficiently potent manner selects for resistant strains. Drug resistance emerges when HIV continues to replicate in the presence of levels of drugs that are insufficient to block viral replication but sufficient to exert a positive selective pressure on variants with decreased drug susceptibility.

  8. How does resistance develop?

  9. Reversion to Wild-Type Virus After Discontinuing ARV 0

  10. Pediatric HIV Drug Resistance • HIV drug resistance occurs when: • When an infant acquires a resistant virus from the mother or • When resistance mutations develop because of ARV exposure for prophylaxis or treatment.

  11. HIV resistance: Perinatal Acquisition ARV-naive mother infected with HIV already resistant to ARV Mother exposed to ARVs before becoming pregnant Mother exposed to ARVs during pregnancy (either for her own health or PMTCT) Drug Resistant Virus in-utero intrapartum postpartum during breastfeeding Infant

  12. HIV resistance: ARV Exposure Infant or child with HIV Exposure to subtherapeutic levels of ARVs during breastfeeding (i.e. from mothers receiving ART) Infant ARV prophylaxis of MTCT intervention (i.e. single-dose NVP) Treatment with ARVs (see next slides) Drug Resistant Virus

  13. Drug concentration in blood Changes of drug concentration in blood during treatment Time Time Failed to take medication Failed to take medication HIV resistance: ARV Exposure Resistant HIV Wild-type HIV Regular medication Lower limit of effective drug concentration in blood

  14. HIV resistance: ARV Exposure 0 Social/Caregiver issues Regimen issues Poor potency Toxicities Wrong dose Poor adherence Host genetics Poor absorption Insufficient drug level Rapid clearance Viral replication in the presence of drug Poor activation Resistant virus Drug interactions

  15. Examples: Case 1 • You wish to start an 8 month old infant male on antiretroviral therapy. • He was born to a mother who was diagnosed with HIV infection during labor. • The mother received no antiretroviral therapy for PMTCT. • The infant received single dose NVP only.

  16. What regimen should you start? • A) d4T / 3TC / NVP • B) AZT / 3TC / NVP • C) AZT / 3TC / ABC • D) AZT / 3TC / LPV-r (Aluvia)

  17. Resistance acquired from infant PMTCT: single dose NVP N Engl J Med 2007; 356: 135-147.

  18. Children less than 12 months who have been exposed to NVP during PMTCT Vietnam MOH Guidelines recommend: • Preferred regimen: AZT + 3TC + LPV/r • Alternative regimens: • a. d4T + 3TC + LPV/r • b. ABC + 3TC + LPV/r • c. AZT + 3TC + NVP or d4T + 3TC + NVP

  19. Resistance testing Types of resistance tests: • Genotypic testing: look for specific mutations in the genetic structure of the reverse transcriptase and protease enzymes that could cause drug resistance. • Phenotypic testing: measure the ability of a patient’s virus to grow in the presence of known concentrations of ARV. The test is very expensive and not available in Vietnam.

  20. Genotypic Testing • The genetic code of the sample virus is compared to the wild type • The genetic code is a long chain of molecules called nucleotides • Each group of 3 nucleotides = “codon”, defines a particular amino acid used to build a new virus Codon AAA ATG AGC Nucleotide Met Ser Lys Amino acid

  21. Genotypic Testing • Mutations are described by a combination of letters and numbers, i.e.: M184V = 3TC resistance • M: Methionine is the name for the amino acid in the wild type virus • 184: identifies the position of the codon • V: Valine is the name for the “changed” amino acid in the mutant sample Codon 184 Mutation Codon 184 AAAGTGAGC AAA ATG AGC Nucleotide Lys Val Ser Met Ser Lys Amino acid

  22. Genotypic Testing:Mutations Selected by nRTIs Multi-nRTI Resistance: 69 Insertion Complex (affects all nRTIs currently approved by the US FDA) 3TC d4T AZT IAS-USA 2007 www.iasusa.org

  23. Genotypic Testing: Mutations Selected by NNRTIs and PI EFV NVP Lopi/r IAS-USA 2007 www.iasusa.org

  24. Genotypic Testing: Limitations • The patient must be taking ARV at the time the test is done. • The test only detects mutations present in > 20% of circulating virus.. • The viral load must be > 1,000 copies/ml.

  25. Genotypic Testing: Limitations • Test is not widely available in Vietnam • Expensive (1,200,000 VND per test) • Genotype reports can be difficult to interpret in the setting of numerous resistance mutations.

  26. Resistance Topics: Genetic Barrier • Genetic barrier is the number of mutations required to confer resistance to a drug. • Low genetic barrier: high level resistance with only one mutation • NVP, EFV: K103N • 3TC: M184V • High genetic barrier: 3 or more mutations needed to develop high level resistance to most PI

  27. Resistance Topics: Cross-resistance • Cross-resistance within classes is common • Resistance to one NNRTI means resistance to all available NNRTIs • NVP and EFV • Resistance to one NRTI can indicate resistance to other NRTIs: • 3TC and FTC • There is less cross-resistance among PI • Use the results of resistance testing to choose second-line drugs with the least risk for resistance

  28. Common mutations in patients with treatment failure on 1st line ARV

  29. When to do resistance testing Indications for ordering test in Viet Nam: (ALL criteria should be met) • Patient must be currently taking ARV with good adherence for at least 6 months on the same regimen • Evidence for treatment failure (by clinical, immunological, and/or virological criteria) • Viral load testing done first and result > 1,000 • More than one 2nd Line ARV regimen available

  30. Example: Case #2 • A 3 year old boy whose mother recently died after a prolonged illness presents to the OPC. • He has been on ART x 1.5 years with d4T, 3TC, NVP. • Treatment failure was suspected based on decreased CD4 counts (immunological) and a failure to gain weight (clinical). • A viral load was performed and was 57000 copies/mL.

  31. Example: Case #2 • What are some reasons why he might have developed treatment failure? • If you did a genotype what type of resistance might you expect to see? • What would you choose for 2nd line therapy?

  32. Case 2: Genotype

  33. Case 2: Genotype NNRTI: • PI:IDV, SQV/r, NFV, LPV/r, ATV/r, TPV/r, fosAPV/r: • No mutations detected • All PI sensitive

  34. Key Points • Resistance occurs (1) when an infant acquires a resistant virus from the mother or (2) develops in the setting of an inadequately suppressive ARV therapy • When prescribing an ARV regimen, it is important to know a child’s prior ARV exposure (i.e. PMTCT regimen) • Dose ARVs carefully; remember to switch formulations as children cross thresholds of weight or age • Monitor and optimize adherence; Educating patients and caregivers about resistance may promote better adherence

  35. Key Points Monitor closely for ARV effectiveness and signs of treatment failure. For the patient who is failing therapy: check adherence issues first Testing for HIV resistance to ARVs has become an important component of clinical care Resistance assays can assist the clinician in selecting a maximally effective second line ARV regimen

  36. Thank You Questions?

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