Disclosures Introduction to ARV Drug I have no disclosures - PDF document

12/6/2017 Disclosures Introduction to ARV Drug I have no disclosures Resistance New Clinicians’ Workshop Susa Coffey, MD Division of HIV, ID and Global Medicine Introduction ARS Question Which resistance test do you order for What this is: ART-naïve patients?  For new clinicians (not experts)  Focus on 1. Standard genotype (RT and PR)  Currently-used ARVs 2. Standard phenotype (RT and PR)  Common resistance scenarios 3. Genotype + phenotype (RT and PR)  Genotype tests 4. Integrase phenotype  Approaches to interpreting R test 5. RT/PR/IN genotype results  DNA genotype: a few words 1

12/6/2017 Mechanisms of HIV Drug Mechanisms of HIV Drug Resistance Resistance  Mutations may decrease susceptibility to ARVs,  High rate of HIV replication- 10 9 virions per day and cause or contribute to virologic failure  Many mutations and quasi species  (a few mutations may increase susceptibility) RT: error-prone, no copyediting   Some may also decrease viral fitness  In setting of drug pressure with viral replication, selection of resistant viruses  Some single mutations severely impact certain ARVs; but often an accumulation of mutations  <- Inadequate adherence to ART may be required to significantly reduce virologic <- Wrong ARVs (potency), wrong doses (drug levels),  drug-drug interactions, absorption issues, etc. response, esp. with NRTIs and PIs  Some ARVs may retain residual activity (eg,  (Corollary: in absence of drug pressure, possible 3TC/FTC) “disappearance” of mutations [minority populations])  Cross-resistance within an ARV class is common Bottom Line: Assume that once there, always there (archived) When to do Resistance Test: Case: Transmitted Drug DHHS Recommendations Resistance  Before ART, at first visit (as close to the time of infection as possible)  31 yo man with new diagnosis of HIV,  Resistance mutations more likely to be detected earlier in chronicity unknown (no previous HIV the course of HIV infection test)  GT: RT, PR; IN if concern for transmitted INI resistance  CD4: 525, HIV RNA: 93,000 c/mL  GT: RT - M41L, K103N; PR – L63P  Virologic failure – do on failing ARVs or shortly after d/c (w/in 4 weeks)  GT for 1 st or 2 nd ART, add PT if “known or suspected complex drug resistance pattern”  IN GT if virologic failure on INI  Suboptimal virologic response on ART  Pregnancy DHHS Adult/ Adolescent ART Guidelines. July 2016. 2

12/6/2017 Transmitted HIV Drug Resistance Prevalence of Transmitted HIV Drug Resistance in US, 2006-2009 in MSM, 2010-2012 Genotypic analysis of samples from newly diagnosed patients Newly diagnosed MSM patients age ≥ 13 in in CDC National HIV Surveillance System (N = 12,668) CDC National HIV Surveillance System, 8 20 15.6% jurisdictions (N = 9,629) 16 All cases with sequences 12 Cases classified as recent infections Cases classified as long-standing infections 7.8 8 6.8 4.1 4 0 1 or more 1-class 3-class NNRTI NRTI PI 2-class Transmitted Drug Resistance Mutations (TDRMs) INSTI: case reports, but no significant transmitted resistance—0.2% in one study in N. Carolina Ocfemia MCB, et al. CROI 2012. Abstract 730. Banez Ocfemia, XXIV HIV Drug Resistance Workshop, 2015. Menza TW et al, AIDS 2017. Genotype Test Genotype Test  Standard GT examines RT and PR M184V  For IN, must order special test  First letter: WT amino acid  With GT, often possible to  Number: codon predict/anticipate resistance depending on position the specific mutations, but is not a direct  Second letter: mutant amino measure of resistance acid  A, alanine  G, glycine  M, methionine  S, serine  C, cysteine  H, histidine  N, asparagine  T, threonine  D, aspartate  I, isoleucine  P, proline  V, valine  E, glutamate  K, lysine  Q, glutamine  W, tryptophan  F, phenyalanine  L, leucine  R, arginine  Y, tyrosine 3

12/6/2017 Phenotype Test Phenotype (with GT)  Measures inhibition of viral replication by individual ARVs in vitro  IC 50 = concentration of drug required to inhibit viral replication by 50%  Compares patient virus IC 50 to that of a reference strain, -> fold-change in IC 50 relative to the reference strain FC = IC 50 patient __ IC 50 reference NRTI Resistance Limitations of GT and PT  A number of key mutations for 3TC/FTC, Conventional tests reliably detect  TDF/TAF, ABC, + numerous others mutant virus that comprises about 20% of the circulating viral  Some single mutations severely impact quasispecies viral replication, but with others an accumulation of mutations usually required May miss minority populations  for high-level resistance HIV RNA must be >500-1,000 c/mL   (More = worse) Do not assess interaction of ARVs   Strategy:  Know key mutations (below)  Look up others 4

12/6/2017 NRTI Resistance: NRTI Resistance: M184I/V K65R  Selected by 3TC, FTC (sometimes ABC), Selected by TDF/TAF, ABC, ddI  cause resistance to 3TC, FTC Causes resistance to TDF/TAF, all   Very common -- 3TC/FTC have low genetic other NRTIs except AZT barrier to resistance Increases susceptibility to AZT   Cross resistance: decreases susceptibility to Decreases viral fitness  ABC, ddI (especially if TAMs) Increases susceptibility to TDF/TAF, AZT , d4T   Partially restores activity if TAMs present  Decreases viral fitness NRTI Resistance: NRTI Resistance: TAMs L74V/I Thymidine-associated mutations (TAMs) Selected by ABC and ddI  Selected by AZT, d4T  (L74V sometimes selected by TDF) Decrease susceptibility to AZT, d4T, TDF/TAF,   ABC; to all NRTIs if numerous Resistance to ABC and ddI  Cross resistance: increases with increasing  Increases susceptibility to TDF/TAF,  number of TAMs AZT (More = worse)  2 pathways:   M41L, L210W, T215Y (more resistance; incl. more impact on TDF)  D67N, K70R, T215F, K219Q/E 5

12/6/2017 Case 1: PrEP Failure Case 2: Audience Response Which ART regimen would be most likely 31 yo MSM on PrEP (TDF/FTC,  to be effective? Truvada), presents to clinic after 1. Rilpivirine (RPV)/TAF/FTC (Odefsey) absence of 6 months, reports spotty 2. EVG/cobi/TAF/FTC (Genvoya) adherence to Truvada. HIV Ab+, HIV RNA 65,000 c/mL. 3. DTG/ABC/3TC (Tivicay) HIV genotype: RT – K65R, M184V; PR –  4. DRV/r + rilpivirine + TDF/FTC WT. RT – K65R, M184V PR – WT Bottom Line: need 3 active ARVs, if possible (especially if ARVs have low genetic barrier to resistance). NNRTI Resistance: NNRTI Resistance Important Mutations Several single mutations confer high- K103N   level resistance to certain NNRTIs;  Commonly selected by EFV numerous others contribute to resistance Emerges early in VF (low genetic barrier to resistance)  Resistance to EFV, NVP  Low genetic barrier to resistance (except  By itself, does not decrease susceptibility to ETR, RPV  etravirine) Y181I/V/C/F/G/S  Cross resistance is common  Selected by NNRTIs  Cross resistance to all NNRTIs   Strategy : E138K   Know K103N, Y181///, E138K Selected by RPV  Usually occurs with M184I or M184V; this enhances  Look up others  resistance to RPV  Be aware of mutation scoring system for Resistance to RPV, cross resistance to EFV, ETR  etravirine (ETR) 6

12/6/2017 Case 2: NNRTI Resistance Case 2: NNRTI Resistance  53 yo man with VF years ago on Could we use rilpivirine (or etravirine) +  EFV/TDF/FTC (Atripla), now on 2 NRTIs as his next ART regimen? atazanavir/ritonavir + TDF/FTC; VL <40 K103N alone should not affect RPV or ETR  c/mL x years. His friends take “one pill a Issues:  day,” and he requests this.  Accuracy of GT?  Previous GT (while on EFV/TDF/FTC): Mutations may fade from view with time  and removal of selective drug pressure GT captures strains that comprise >5-20% of  the circulating viruses Once there, always there: “archived”  mutations Bottom Line: caution in interpreting – consider what may be hidden from view White, KL. Toronto 2013. Abs 87. Case 3: 1 st ART Failure Case 3: Audience Response Could you use etravirine (ETR) in her  35 yo woman on RPV/TAF/FTC (Odefsey). next regimen? HIV RNA suppressed x 2 years, then increases to >5,000 c/mL in setting of several months of OTC PPI use. 1. Yes – should have full activity  Genotype: 2. No – not effective after rilpivirine  RT - K101E, E138K, Y181C, M184I failure  PR - no mutations 3. I need more information RT: K101E, E138K, Y181C, M184I PR: none 7