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ARV failure and resistance for the paediatrician

ARV failure and resistance for the paediatrician. Douglas Watson, M.D. University of Maryland 11 December 2013. REVERSE TRANSCRIPTASE INHIBITORS (NRTIs & NNRTIs). Integrase inhibitors. Fusion Inhibitors. PROTEASE INHIBITORS. Attachment Inhibitors. HIV DRUG TARGETS.

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ARV failure and resistance for the paediatrician

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  1. ARV failure and resistance for the paediatrician Douglas Watson, M.D. University of Maryland 11 December 2013

  2. REVERSE TRANSCRIPTASE INHIBITORS (NRTIs & NNRTIs) Integrase inhibitors Fusion Inhibitors PROTEASE INHIBITORS Attachment Inhibitors HIV DRUG TARGETS

  3. Antiretrovirals in the U.S.- 2013 Nucleoside analogues (NRTIs) Zidovudine (ZDV, AZT, Retrovir) Lamivudine (3TC, Epivir) Tenofovir (TDF, Viread) Emtricitabine (FTC, Emtriva) Abacavir (ABC, Ziagen) Stavudine** (D4T, Zerit) Didanosine** (DDI, Videx) Protease inhibitors Lopinavir/ritonavir (LPV/r, Kaletra) Atazanavir (ATV, Reyataz) Fosamprenavir (fAMP, Lexiva) Darunavir (DRV, Prezista) Tipranavir* (TPV, Aptivus) Saquinavir* (SQV, Invirase) Nelfinavir* (NFV, Viracept) Indinavir** (IDV, Crixivan) Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Efavirenz (EFV, Sustiva) Nevirapine (NVP, Viramune) Etravirine (ETV, Intelence) Delavirdine** (DLV, Rescriptor) Rilpivirine (Edurant) Integrase inhibitors Raltegravir (RAL, Isentress) Elvitegravir Dolutegravir (Tivacay) Attachment inhibitor Maraviroc (Selzentry) Fusion inhibitor Enfuvirtide* (T-20, Fuzeon) P450 inhibitor (for “boosting” PIs) Ritonavir (RTV or r, Norvir) Cobicistat *Uncommonly used. **No useful role

  4. WHO 2013 recommendations for 1st-line ART in children < 3 y of age • “ABC should be considered the preferred NRTI whenever possible.” • LPV//r should not be given to infants < 14 d of age or in premature infants until after 14 d after their due date

  5. WHO 2013: Start with LPV/r and switching to NNRTI? • NOTE: • The quoted study enrolled only children with history of SD NVP exposure • The quoted study used < 50 copies/ml as primary endpoint and < 1,000 c/ml as secondary endpoint- NOT < 400 c/ml as stated above. • The switch-to-NVP group had fewer cases of VL > 50 but more cases of VL > 1,000 and more resistance than group that stayed on LPV/r

  6. WHO 2013 recommendations for 1st line ART in children > 3 y of age

  7. Treatment failure: progressive steps, different definitions Potency failure Adherence failure Virologic failure Genotypic failure (resistance) Immunologic failure Clinical failure

  8. Expected fall in viral load If viral load at these follow up times is 3-fold or more than these examples, full suppression not likely

  9. Course of treatment failure Start ZDV/3TC/NVP Clinical deterioration Gradual ZDV resistance Nonadherence NVP resistance 3TC resistance CD4 Count Viral load 1 year 2 years

  10. Mechanism of reverse transcriptase inhibitors NRTI = Nucleosidereverse transcriptase inhibitor NNRTI = Non-nucleoside reverse transcriptase inhibitor HIV reverse transcriptase ABC cDNA NRTI (such as ABC(P3) is added onto cDNA chain, blocking further reverse transcription NNRTI (NVP or EFV) Blocks reverse transcriptase by binding at active site

  11. The K103N mutation: how it can take over Sensitive K103 HIV wild type (wt) Resistant 103N HIV NVP blocks sensitive HIV, not resistant HIV Nevirapine wt always present In presence of NVP, only the resistant virus grows. Soon almost all virus is resistant!

  12. Drug resistance mutations in Thai patients failing D4T/3TC/NVP for an average of 4-5 months by viral load monitoring. Sungkanuparph S. CID 2007; 44:447–52

  13. Nucleoside reverse transcriptase inhibitor resistance and cross-resistance Zidovudine (AZT) Stavudine (D4T) Tenofovir (TDF) Abacavir (ABC) Didanosine (DDI) Lamivudine (3TC) or Emtricitabine (FTC) Thymidine analogue mutations (TAMS) Resistance AZT D4T TDF TAMS +184V Resistance 3TC, FTC > D4T, DDI, AZT, ABC > TDF K65R Resistance TDF, ABC, DDI D4T 3TC, FTC Hypersensitivity AZT L74V + M184V Resistance ABC DDI 3TC FTC Hypersensitivity AZT TDF M184V Resistance 3TC FTC Hypersensitivity TDF>AZT > D4T Q151M Resistance AZT, D4T, DDI, ABC > TDF, 3TC, FTC

  14. Summary: NRTI resistance patterns & options

  15. NNRTI resistance • 1st generation (nevirapine, efavirenz, delavirdine) • High potency but low genetic barrier to resistance • Most commonly K103N- resistance to all 1st generation • NVP also selects for Y181C (especially in newborns) which has mild effect on EFV but associated with increased failures • Other mutation patterns also seen • 2nd generation (Etravirine) • NO EFFECT of K103N • Resistance increases with other NNRTI mutations- 3 or more yield

  16. Protease inhibitor resistance • Some PIs select for drug-specific mutations (e.g. NFV, ATV) • Some PIs can be boosted or unboosted (ATV, fAPV)- low-level resistance may be clinically significant if not boosted • Boosted PIs more durable • Resistance to LPV requires 5-10 mutations • Virologic failure while receiving LPV/r usually due to nonadherence • Prolonged virologic failure while on LPV/r eventually will lead to LPV resistance

  17. Drug resistance testing • Commercial methods start with RT PCR of bulk virus in plasma • Not sensitive to minor strains- e.g. genotyping (sequencing) cannot detect strain representing < 10-25% of circulating virus • When to get resistance testing (resource-rich) • Baseline: resistant strains (especially NNRTI resistance) circulating in population • Whenever resistance suspected (e.g. failing and patient appears adherent) • Selective pressure- patient taking medication

  18. HIV drug resistance genotype • RT PCR bulk plasma virus to produce cDNA • Sequence pol gene • Derive predicted amino acid sequence • Identify mutations known to confer resistance (e.g. Stanford database, IAS-USA, etc.) • Virtual phenotype™ genotype interpretation • Identified set of significant mutations is matched with massive database of genotype-phenotype correlations • Reported as predicted fold resistance (used to also give number of matches) • Fold-resistance interpreted according to in vitro or clinical measure of activity

  19. IAS-USA, Topics in HIV Medicine, March 2013

  20. Interpretation of resistance testing • Complete treatment and viral load history are essential • What is current regimen and is patient taking it? • Many resistance mutations cause decreased viral fitness: if there is not selective pressure, wild-type virus rapidly outgrows mutant, but archive of mutant remains

  21. WHO 2013

  22. Johnny B. Goode • Newly infected adolescent • CD4 = 320, VL = 58,000 • Prescribed TDF/FTC/ATV/r • VL 1 month later = 5,200 • VL at 2 months = 4,000 • Genotype is wild-type • How do you interpret this situation? • How to proceed?

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