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

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Presentation on theme: "ARV failure and resistance for the paediatrician Douglas Watson, M.D. University of Maryland 11 December 2013."— Presentation transcript:

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


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) Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Efavirenz (EFV, Sustiva) Nevirapine (NVP, Viramune) Etravirine (ETV, Intelence) Delavirdine** (DLV, Rescriptor) Rilpivirine (Edurant) 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) 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 1 st -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 1 st line ART in children > 3 y of age

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

8 Expected fall in viral load TimeLog fold drop in viral load Fold-drop in viral load Viral load (example) 0-- 600,000100,000 1 month2100+< 6,000< 1,000 3 months31,000600100 6 months410,00060<50 If viral load at these follow up times is 3-fold or more than these examples, full suppression not likely


10 Viral load CD4 Count Start ZDV/3TC/NVP Nonadherence NVP resistance 3TC resistance Gradual ZDV resistance Clinical deterioration 1 year2 years Course of treatment failure

11 ABC NNRTI (NVP or EFV) Blocks reverse transcriptase by binding at active site NRTI (such as ABC(P 3 ) is added onto cDNA chain, blocking further reverse transcription cDNA Mechanism of reverse transcriptase inhibitors NRTI = Nucleoside reverse transcriptase inhibitor NNRTI = Non-nucleoside reverse transcriptase inhibitor HIV reverse transcriptase

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

13 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

14 Stavudine (D4T) Zidovudine (AZT) Abacavir (ABC) Tenofovir (TDF) 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 Nucleoside reverse transcriptase inhibitor resistance and cross-resistance

15 Summary: NRTI resistance patterns & options RegimenCommon patternOther patterns GenoResistanceOptions*GenoResistanceOptions* D4T/3TCM184V, TAMS 3TC > D4T, ZDV, ABC, DDI >TDF TDF/3TC (+/- ZDV)> (ZDV/3TC/ABC) (how good depends on # of TAMS) K65R, M184V or M184V, Q151M 3TC, TDF, ABC, DDI, d4T 3TC, ZDV, D4T, DDI, ABC, (TDF) ZDV/3TC (TDF/3TC) ZDV/3TC“““ TDF/3TCK65R, (M184V) 3TC, TDF, ABC, DDI, d4T ZDV/3TC ABC/3TCM184V, L74V 3TC, ABC, DDI ZDV/3TCM184V, K65R 3TC, TDF, ABC, DDI, d4T ZDV/3TC DDI/3TCM184V, L74V 3TC, ABC, DDI ZDV/3TC *Options: Underline = excellent, () = weak, others fair

16 NNRTI resistance 1 st generation (nevirapine, efavirenz, delavirdine) –High potency but low genetic barrier to resistance –Most commonly K103N- resistance to all 1 st 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 2 nd generation (Etravirine) –NO EFFECT of K103N –Resistance increases with other NNRTI mutations- 3 or more yield


18 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

19 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

20 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



23 IAS-USA, Topics in HIV Medicine, March 2013



26 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

27 WHO 2013

28 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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