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HIV Resistance Testing Clinical Implications

HIV Resistance Testing Clinical Implications. Cyril K. Goshima, M.D. Director, AIDS Education Project November 8, 2006. Why HIV Resistance Testing. Virologic failure is common and has significant consequences.

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HIV Resistance Testing Clinical Implications

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  1. HIV Resistance TestingClinical Implications Cyril K. Goshima, M.D. Director, AIDS Education Project November 8, 2006

  2. Why HIV Resistance Testing • Virologic failure is common and has significant consequences. • EuroSIDA large, multinational, observational cohort, n=3496, monitored pts. from the time of starting HAART. 3-class virologic failure within 6 yrs. of follow-up was seen in 21.4% of those who received ARV. These 3-class failures experienced higher rates of disease progression.

  3. Why HIV Resistance Testing • Multiclass-experienced pts. must often use existing drugs to attempt viral suppression • Cross-resistance occurs. • Recent prospective studies have suggested that resistance testing is helpful in improving response to a new regimen.

  4. When to Use Resistance Testing • DHHS Guidelines • Recommend testing: acute infection, suboptimal virologic suppression after treatment is initiated, treatment failure. • Consider: chronic infection < 2 yrs. • Which test is not recommended

  5. Resistance Testing • Genotypic Resistance Testing • Phenotypic Resistance Testing • Combined Geno/Pheno • “Virtual Phenotype” Testing • Fusion Inhibitor Resistance Testing • Replication Capacity • New tests for chemokine receptor inhibitors, integrase

  6. Genotypic Resistance Testing • Detects mutations in the HIV genome associated with resistance to specific drugs. • Advantages • Adequate turn-around time (1-2 wks) • Less expensive • Detect mutations that may precede phenotypic resistance • Widely available • More sensitive in detecting mixtures of resistant and wild type viruses

  7. Genotypic Resistance Testing • Disadvantages • Indirect measure of resistance • Relevance of some mutations unclear • Unable to detect minority variants (<20 – 25% of viral sample) • Complex patterns may be difficult to interpret • Genotypic correlates of resistance not well defined for non-B subtypes.

  8. Phenotypic Resistance Testing • Measures the patient’s HIV isolates ability to replicate in the presence of varying concentration of specific drugs. • Advantages • Direct and quantitative measure of resistance • Method can be applied to any agent incl. new where genotypic correlates are unclear • Can assess interactions among mutations • Accurate with non-B HIV subtypes.

  9. Phenotypic Resistance Testing • Disadvantages • Susceptibility cut-offs not standard between assays • Clinical cut-offs not defined for some drugs • Unable to detect minority species • Complex technology • More expensive • Longer turn-around time.

  10. How We Identify a Mutation • How do we identify a resistance mutation? M 184 M M 184 “M” is the “wild type” amino acid “184” is the codon position

  11. How We Identify a Mutation • How do we identify a resistance mutation? M 184 V M 184 V “M” is the “wild type” amino acid “184” is the codon position “V” is the mutant amino acid

  12. How We Identify a Mixture M 184 M/V M 184 M/V “M” is the “wild type” amino acid “184” is the codon position “M/V” is the mixture of wild type & mutant amino acid

  13. Definitions for Phenotypic Resistance Testing • IC50 = Concentration of drug required to inhibit replication by 50% • Fold Change = IC50 pt./IC50 reference • Cut Off = Fold change or concentration below which the virus is considered susceptible, above which non-susceptible • Biological Cut Off = Fold change based on variations in clinical samples from treatment naïve individuals.

  14. Definitions for Phenotypic Resistance Testing • Clinical Cut Off = Fold change based on virologic response to ARV in Clinical Trials • Replication Capacity: The ability of a pt’s virus to replicate in the absence of drug

  15. NRTIs

  16. NRTI Mutations • Single point mutation can result in high level resistance e.g. M184V (3TC, FTC), K65R (TDF) • TAMS pattern of mutations e.g. codons 41, 67, 70, 210, 215, 219 (AZT, D4T) • 2 other patterns that are selected for by AZT/DDI & DDI/D4T • Q151M:resist. all NRTI except TDF • T69insertion + 1 or more TAMS @ 41, 210, 215: resist. all NRTI

  17. Common Mutations: NRTIs • TAMS = thymidine analog mutations (aka ZDV mutations): M41L, D67N, K70R, L210W, T215F/Y, K219E/Q • NAMS = nucleoside analog mutations: TAMS plus E44A/D, A62V*, K65R, T69D, T69ins, L74I/V, V75A/I*/M/S/T, V77L*, Y115F, F116Y*, V118I, Q151M, M184I/V *Secondary mutations seen with Q151M

  18. NRTI Signature Mutations *TAMS=Thymidine analog mutations.

  19. NNRTIs

  20. Common Mutations: NNRTIs • Delavirdine (DLV) • L100I, K103N, V106M, Y181C, I; Y188L, G190E/Q • P236L(rare), Y318F • Efavirenz (EFV) • L100I, K103N, V106M, Y181C, I; Y188L, G190A, S, E, Q…; P225H • Nevirapine (NVP) • L100I, K103N, V106A, M; Y181C, I; Y188C, L, H; G190A, E, S, Q…,F227L

  21. NNRTI Multi-Drug Resistance Class Resistance • L100I, K101E or P, K103N or S, V106A or M, Y188C, H, or L, M230L • Resistance to one NNRTI usually confers cross resistance to all other agents (exceptions: 181 and EFV, 190A/S and DLV) • Continued viral replication in the presence of NNRTI results in accumulation of additional resistance mutations • May impact clinical utility of future NNRTIs

  22. NNRTI Novel Mutations • Those exhibiting a > 10 fold change: • K103R and V179D (in combination) • K101P

  23. PIs

  24. PI Resistance • Cross resistance is common • PI mutations are uncommon in boosted PI regimens • Multiclass experienced pts. may have been exposed to unboosted regimens • The number of primary PI mutations may predict the response to therapy e.g. TPV score 0-3 good, 4-7 intermediate, >8 poor or Kaletra

  25. PI Common Mutations

  26. Hypersusceptibility

  27. NRTI Increased Susceptibility

  28. NNRTI Increased Susceptibility

  29. PI Increased Susceptibility

  30. PI Hypersusceptibility • Mutation I50V, selected by LPVr and APV, increased susceptibility to ATV, TPV.

  31. Case Discussion • Patient CB, 42 y/o, homosexual male • Current Regimen (05/31/06): CBV/TDF/EFV • Past Drugs: CBV/ IDV, CBV/NFV • CD4/VL • Date: 09/08/05 349/8,810 • Date: 03/07/06 192/10,300 • Date: 06/02/06 186/9,400 • Date: 09/18/06 92/6,610 • Date: 10/17/06 /12,000

  32. Case Discussion • NRTI • M184V present (3TC/FTC resist, TDF hs) • Multiple TAMs • No K65R (TDF sens despite 41 & 215 mut) • NNRTI • No significant mutations • PI • 4 TPV assoc mut (intermediate response) • DRV sens

  33. Case Discussion • Was the CBV/TDF/EFV regimen a reasonable one? • There has been no response to this therapy after 3 mos. • What should you do? • Any suggestions on a possible new regimen?

  34. Discordance • Inaccurate genotype interpretation algorithm that does not account for novel or previously unknown mutation effect • Mixtures of wild type and resistant strains. Phenotype underestimates resistance • Variability in phenotypic susceptibility with specific mutations • Believe the genotype. Genotypic change may precede phenotypic resistance.

  35. Clinical Implications • Is there evidence for sequencing of NRTIs? • Should the initial regimen be a boosted PI or a NNRTI? • Is 3TC = FTC as far as resistance is concerned?

  36. Clinical Implications • Try to use at least 2 new potent agents to switch from a failing regimen. • The longer a failing regimen is continued, the more mutations accumulate. If there is no new agent, better to cont. the same regimen unless compelled to do otherwise. • Resistance is relative. 3TC cont. to have virological effect despite M184V mutation. Boosted PIs may have more of a response than an unboosted PI evidenced by a lower fold change.

  37. Clinical Implications • NRTI • TAMs can prevent K65R mutation. K65R is associated with multiple NRTI resistance and TDF resistance. ? Add ZDV to failing regimen • Continue 3TC or FTC despite a M184V mutation (hypersusc. ZDV, TDF, D4T; RC) • NNRTI • DC NNRTI as soon as mutations develop. There is no virological or RC advantage.

  38. Clinical Implications • PI • Never use an unboosted PI. • Antiretroviral susceptibility is on a continuum. Using drugs with the most activity (lower fold change) is a reasonable choice.

  39. Clinical Implications • In initial therapy, a boosted PI regimen may have an advantage over a NNRTI regimen because of fewer HIV mutations. (J. Bartlett, et al, JAIDS, 4(3): 323-331; Swiss HIV Cohort Study, oral abstract 72, XV International HIV Drug Resistance Workshop) Possible explanations maybe lower genetic barrier and pharmacokinetics with missed doses.

  40. Clinical Implications • Replication Capacity • Lower RC with certain NRTI (3TC) and PI (NFV). • No change in RC with NNRTI

  41. Acknowledgements • Monogram Bioscience, Sharon Martens, MN, ARNP/FNP • Dr. Joel Gallant, MD, MPH from Clinical Care Options HIV LLC, “Use and Interpretation of Resistance Tests in Multi-Class Experienced Patients,” September 2, 2005.

  42. Thank You Questions?

  43. Clinical Implications • Viruses with M184V + K65R mutations can be susceptible to TDF on phenotype, but must maintain the 184 with keeping on 3TC or FTC.

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