PPT Rusconi "Le multiresistenze dell'HIV/AIDS"

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PPT Rusconi "Le multiresistenze dell'HIV/AIDS"

  1. 1. Le Multiresistenze dell’HIV/AIDS Stefano Rusconi Divisione Clinicizzata di Malattie Infettive DIBIC “Luigi Sacco” Università degli Studi di Milano Impossibile visualizzare l'immagine. La memoria del computer potrebbe essere insufficiente per aprire l'immagine oppure l'immagine potrebbe essere danneggiata. Riavviare il computer e aprire di nuovo il file. Se viene visualizzata di nuovo la x rossa, potrebbe essere necessario eliminare l'immagine e inserirla di nuovo. Impossibile visualizzare l'immagine. La memoria del computer potrebbe essere insufficiente per aprire l'immagine oppure l'immagine potrebbe essere danneggiata. Riavviare il computer e aprire di nuovo il file. Se viene visualizzata di nuovo la x rossa, potrebbe essere necessario eliminare l'immagine e inserirla di nuovo. Milano,  Palazzo  delle  Stelline,  22  marzo  2014  
  2. 2. Resistance  to  an8viral  drugs   •  The  (in)ability  of  the  virus  to  replicate  in  the  presence  of  an6retroviral  drugs   •  Caused  by  changes  in  relevant  part  of  the  virus  genome  (muta6ons)   2   The  emergence  of  resistance  is  the  inevitable  consequence  of  incomplete  suppression   of  HIV  (HBV/HCV)  replica8on  by  the  current  an8retroviral  drugs,   and  is  a  major  limita8on  of  an8viral  therapy  
  3. 3. Viral  escape   •  The  ability  of  a  virus  to  escape  an6viral  pressure  depends  also  upon  the   characteris6cs  of  drugs   •  Gene6c  barrier:  the  number  of  muta6ons  required  by  the  virus  to  develop  a  fully   resistant  virus   –  Low  gene8c  barrier:  drugs  whose  efficacy  is  lost  with  a  single  muta6on   –  High  gene8c  barrier:  drugs  whose  efficacy  is  lost  only  aAer  the  sequen6al   appearance  and  selec6on  of  a  substan6al  number  of  muta6ons   3  
  4. 4. Dinamica virale e resistenza farmacologica Pressione farmacologica Tempo Virus “selvaggio” (sensibile al farmaco) Virus “mutante” (resistente al farmaco) viremia
  5. 5. Utilizzo (combinato) di antiretrovirali anti HIV-1 Pressione farmaco A Tempo Viremia Pressione farmaco B Pressione farmaco C ... “Functionally disabled HIV”
  6. 6. Selec8on  -­‐>  Resistance     A  single  muta8on  preexis8ng  therapy,  selected  under  an8viral   pressure:  an  easy  and  rapid  phenomenon       Inconsistent  an8viral  pressure  Viral  load   Time   Wt   Res.  variant   For  instance  NNRTI  (K103N)   (gene6c  barrier=1)   6  
  7. 7. Selec8on  +  Genera8on  -­‐>  Resistance      A  muta8on  preexis8ng  therapy,  conferring  only  marginal   resistance,  selected  under  an8viral  pressure...   Selec8on   Viral  load/  frequency   Time   Wt   Single  mut.   Double  mut.   …  a  long-­‐term  phenomenon   For  instance,  ritonavir-­‐boosted  PIs   7  
  8. 8. Selec8on   Viral  load/  frequency   Time   Wt   Single  mut.   Double  mut.   Resist.mut.   For  instance,  ritonavir-­‐boosted  PIs   Evolu8on  toward  high  resistance  and  high  fitness   Selec8on  +  Evolu8on    A  muta8on  preexis8ng  therapy,  conferring  marginal  resistance,   selected  under  an8viral  pressure,  followed  by  the  genera8on  of   further  muta8ons  while  con8nuing  an8viral  therapy     8  
  9. 9. Selec8on   Viral  load/  frequency   Time   Wt   Single  mut.   Double  mut.   Resist.  mut.   For  instance  boosted  PI   Evolu8on  toward  high  resistance  and  high  fitness   Events  that  require  a  long-­‐term  failing  treatment   to  occur   Triple/quadruple  mutant   Selec8on  +  Genera8on  -­‐>  Resistance      A  muta8on  preexis8ng  therapy,  conferring  marginal  resistance,   selected  under  an8viral  pressure,  followed  by  the  genera8on  of   further  muta8ons  while  con8nuing  an8viral  therapy     9  
  10. 10. Drug  Resistance  in  Europe  during  1997-­‐2012  (EuroSIDA)   A.  Schultze  et  al.,  EACS  2013  
  11. 11. Drug  Resistance  in  Europe  during  1997-­‐2012  (EuroSIDA)   A.  Schultze  et  al.,  EACS  2013  
  12. 12. Drug  Resistance  in  Europe  during  1997-­‐2012  (EuroSIDA)   A.  Schultze  et  al.,  EACS  2013  
  13. 13. The RAM prevalence significantly varied according to the viremia levels P <0.001 (Chi-squared test for trend) 54   72   76   87   78   66   0   20   40   60   80   100   Prevalenceofsampleswith atleast1MRM(%) Viremia ranges (copies/mL) N  samples                    3,726                      374                        270                        227                      1,060                  1,173                    622   Fabeni et al., V ICAR 2013
  14. 14. Viremia ranks (copies/mL) Overview of 11,986 genotypic requests from clinical samples with different viremia ranks over the years. 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Overall (N=11,986) Naive (N=4,711) Experienced (N=7,275) >100,000 10,000-100,000 1,000-10,000 500-1,000 200-500 50-200 In experienced patients 1,115 (15.3%) samples had viremia values ≤500 copies/mL Fabeni et al., 8° EHDRW 2013, V ICAR 2013
  15. 15. 15 Methods WHO – list 20091 Group 0 Patients with no detected mutation (used as a reference group) Patients having at least one mutation Group 1 show no drug resistance to their prescribed drug (classified as ‘susceptible’ or as ‘potential low level resistance’) Group 2 resistant to at least one of their prescribed drugs (classified as ‘Low-level resistance‘, ‘Intermediate' or as ‘High level resistance‘) Stanford2 version 6.0.5 •  Virologic endpoint: –  time to first of two consecutive viral load>500 copies/mL after six months of therapy •  Definition TDR (two steps): 1Bennett PlosOne 2009, 2Liu CID 2006 EuroCoord-CHAIN: L. Wittkop et al., Lancet Infect Dis. Feb 28, 2011
  16. 16. 16 Virological failure according to TDR In adjusted analysis*: Ø  Patients with resistance to ≥1 drug: - significant higher risk of VF compared to patients without mutations - HR: 3.3 (2.5; 4.4) P<10-4 Ø  patients receiving a fully active cART and patients with no mutation: - risk of VF was not significantly different - HR: 1.4 (0.9; 2.3) P=0.17 Time after start of therapy (month) % VF 6 7 8 10 11 129 0 5 10 15 20 25 *All models stratified by cohort ; multivariable models ajusted for: Gender, age, pre-treatment viral load and CD4 count, year of treatment start, previous AIDS diagnosis, subtype, HIV transmission risk group, origin EuroCoord-CHAIN: L. Wittkop et al., Lancet Infect Dis. Feb 28, 2011
  17. 17. 17 Impact of TDR according to treatment strata 0.1 1 10 No TDR TDR and fully- active cART TDR and resistant No TDR TDR and fully- active cART TDR and resistant No TDR TDR and fully- active cART TDR and resistant ALL 2NRTI+1NNRTI 2NRTI+1PI/rtv HR* TDR and fully active TDR and fully active TDR and fully active TDR and resistant TDR and resistant TDR and resistant No TDR No TDR No TDR ALL 2NRTIs + 1NNRTI 2NRTIs + PI/rtv *All models stratified by cohort ; multivariable models ajusted for: Gender, age, pre-treatment viral load and CD4 count, year of treatment start, previous AIDS diagnosis, subtype, HIV transmission risk group, origin EuroCoord-CHAIN: L. Wittkop et al., Lancet Infect Dis. Feb 28, 2011
  18. 18. Impact  of  Minority  Drug  Resistant  and  X4  variants  in   Naive  Pa6ents  Star6ng  ART  with  <100  CD4/mm3   M.  Casadellà  et  al.,   CROI  2014,  abs  602  
  19. 19. Primary  resistance  to  integrase   inhibitors  in  Europe  (Spread)   M.  Casadellà  et  al.,   CROI  2014,  abs  580  
  20. 20. Primary  resistance  to  integrase   inhibitors  in  Europe  (Spread)   M.  Casadellà  et  al.,   CROI  2014,  abs  580  
  21. 21. Impact  of  RAL/EVG  selected   muta6ons  on  DTG  cross-­‐resistance   Pa6ent   viruses   containing   Q148H/K/R   muta8ons   displayed   reduced   DTG   suscep8bility   with   a   median   fold   change   in   IC50   (FC)=4.6   (range   1.7   to   96.0).   Q148K  viruses  that  emerge  less  frequently  than  Q148H/R  variants  exhibited  larger   reduc6ons  in  DTG  suscep6bility  compared  to  Q148H/R  viruses.   All   pa6ent   viruses   contained   one   or   more   addi6onal   IN   muta6ons   with   G140   subs6tu6ons  occurring  most  frequently  followed  by  E138  subs6tu6ons.  Based  on   the  analysis  of  a  panel  of  SDMs,  a  single  muta6on  at  posi6on  148  did  not  reduce   DTG   suscep6bility   (DTG   FC=0.5   to   0.7).   However,   the   addi8on   of   a   second   muta8on  at  posi8on  140  conferred  measurable  reduc8ons  in  DTG  suscep8bility   (FC=2.2  to  58).  The  further  introduc6on  of  addi6onal  muta6ons  at  posi6ons  74,   92,   97   and   138   conferred   incremental   reduc6ons   in   DTG   suscep6bility.   Q148K   SDMs   containing   addi8onal   muta8ons   displayed   larger   reduc8ons   in   DTG   suscep8bility  than  corresponding  Q148H/R  SDMs.   W.  Huang  et  al.,  CROI  2014,  abs  595  
  22. 22. Clin  Microbiol  Infect.  2013  Jan  4.  doi:  10.1111/1469-­‐0691.12100.  
  23. 23. Weeks 24201612840 Oneminussurvival 1,0 0,8 0,6 0,4 0,2 0,0 1.50+ 1-1.49 <1 GSS Figure  1a.  Time  to  first  undetectable  HIV-­‐RNA  by  GSS   Clin  Microbiol  Infect.  2013  Jan  4.  doi:  10.1111/1469-­‐0691.12100.  
  24. 24. Weeks 24201612840 Oneminussurvival 1,0 0,8 0,6 0,4 0,2 0,0 1.50+ 1-1.49 <1 Weighted GSS Figure  1b.  Time  to  first  undetectable  HIV-­‐RNA  by  weighted  GSS   Clin  Microbiol  Infect.  2013  Jan  4.  doi:  10.1111/1469-­‐0691.12100.  
  25. 25. 0,1 1 10 100 GSS GSS 1-1.5 GSS >1.5 Weighted GSS Weighted GSS 1-1.5 Weighted GSS >1.5 LogScale Factors  associated  with  virological  response  at  six  months   according  to  mul8variate  analysis  (AOR)   Clin  Microbiol  Infect.  2013  Jan  4.  doi:  10.1111/1469-­‐0691.12100.  
  26. 26. Detec8on  of  NNRTI  resistance  muta8ons   ager  interrup8ng  NNRTI-­‐based  regimens   V.  Cambiano  et  al.,   CROI  2014,  abs  593  
  27. 27.   •Among   the   208   individuals   with   a   resistance   test   performed  aAer  stopping  suppressive  NNRTI-­‐based   ART  (see  characteris6cs  in  table  1),  12%  (n=25,  95%   CI:   8%-­‐17%)   had   ≥1   NNRTI   resistance   muta8on   detected  at  the  first  resistance  test  following  ART   treatment  interrup8on.       •In  those  with  at  least  1  NNRTI  resistance  muta8on   detected   the   median   8me   between   TI   and   the   resistance  test  was  12  months  (IQR:  3-­‐20  months).       Detec8on  of  NNRTI  resistance  muta8ons   ager  interrup8ng  NNRTI-­‐based  regimens   V.  Cambiano  et  al.,   CROI  2014,  abs  593  
  28. 28. Detec8on  of  NNRTI  resistance  muta8ons   ager  interrup8ng  NNRTI-­‐based  regimens   V.  Cambiano  et  al.,   CROI  2014,  abs  593  
  29. 29. Decay Rate of Archived HIV-1 Drug Resistance Mutations   J.  De  La  Cruz  et  al.,  CROI  2014,  abs  604  
  30. 30. Prevalence  of  Minority  Resistant  Variants  to  ETR,   DRV  and  RAL  at  Baseline  in  the  ANRS  139  TRIO   Trial   C.  Charpen6er  et  al.,  CROI  2014,  abs  605    
  31. 31. Prevalence  of  Minority  Resistant  Variants  to  ETR,   DRV  and  RAL  at  Baseline  in  the  ANRS  139  TRIO   Trial   C.  Charpen6er  et  al.,  CROI  2014,  abs  605  
  32. 32. P.  Di  Vincenzo,  S.  Rusconi  et  al.,  HIV  Medicine  (2010)  11,  530–534   Prevalence   of   muta8ons   and   determinants   of   genotypic   resistance  to  etravirine  (TMC125)  in  a  large  Italian  resistance   database  (ARCA)  
  33. 33. Determinants  of  genotypic  resistance  [Tibotec  (TBT)  score  0–2  or  >2]  to  TMC125       <  0.001     0.015     0.005   <  0.001   0.964     0.004   <  0.001   <  0.001   0.002   0.665   <  0.001   0.369   0.207    Category  TBT  score  0-­‐2  TBT  score  >2  AOR  95%CI  p   This  mul8variate  analysis  was  conducted  with  the  endpoint  of  having  a  TBT  score  4  2.   Values  in  the  TBT  score  columns  are  n  (%),  with  the  excep8on  of  mean  (median)  for  age.  AOR  for  age  is  for  each  addi8onal  10  years.   *Reference  category.   AOR,  adjusted  odds  ra8o;  CI,  confidence  interval;  ND,  not  determined;  EFV,  efavirenz;  NVP,  nevirapine;  PI,  protease  inhibitor;  T20,  enfuvir8de.   P.  Di  Vincenzo,  S.  Rusconi  et  al.,  HIV  Medicine  (2010)  11,  530–534  
  34. 34. TMC125 Control 0 –1 –2 –3 Changeinlogviralload(mean) Weeks 0 4 8 12 16 59 56 46 36 2959n (TMC125) = 57 55 49 33 2957n (control) = Initial 1.3 log decline in viral load was not sustained past 8 weeks, possibly affected by limited activity of the background regimen. TMC125-C227: Change in viral load (observed) B. Woodfall et al., HIV8, Glasgow Nov 12-16, 2008. Abstract PL5.6
  35. 35. l  A large number of NRTI resistance-associated mutations were noted in this first line failure population l  Many NRTIs were recycled in this study l  TMC125 group l  37% recycled one, 9% two l  Control group l  35% recycled one, 12% two IAS-USANRTIresistanceassociatedmutations (%) 90 80 70 60 50 40 30 20 10 0 TMC125 Control 100 0 1 2 3 4 5 6 7 Group 16.9 10.2 15.3 20.3 28.8 8.8 10.5 22.8 38.6 10.5 6.8 1.7 7.0 Baseline NRTI mutations B. Woodfall et al., HIV8, Glasgow Nov 12-16, 2008. Abstract PL5.6 1.8
  36. 36.     Low-­‐Frequency  HIV-­‐1  Drug  Resistance  Muta8ons     and  Risk  of  NNRTI-­‐Based  An8retroviral  Treatment  Failure   A  Systema8c  Review  and  Pooled  Analysis   Systema6c  Review  and  Baseline   Characteris6cs     10  studies  with  985  pa6ents   were  iden6fied  as  mee6ng  the   inclusion  and  exclusion  criteria.     The  median  CD4  cell  count  was   229  cells/mm3  and  mean   plasma  HIV-­‐1  RNA  level  was  5.0   log10  copies/mL.     All  studies  evaluated  the   presence  of  NNRTI  muta6ons   K103N,  Y181C  (N=435)  and  NRTI   muta6ons  M184V  (N=228)  and   K65R  (N=163).   Li  et  al  JAMA  2011   •   Minority  drug-­‐resistant  variants  were  found  in  14%  (117/808).  
  37. 37. Baseline Parameter Odds Ratio (95% CI) P-Value Χ2 - test K103N >= 2,000 copies/mL K103N detectable and < 2,000 copies/mL 47.4 (5.2, 429.2) 1.19 (0.15, 9.71) 0.0006 0.8703 BL HIV RNA >100,000 0.98 (0.51, 1.88) 0.9471 BL CD4 >=200 0.60 (0.31, 1,16) 0.1282 Treatment arm 0.75 (0.40, 1.41) 0.3695 • Multivariate logistic regression to predict risk of VF with predictors treated as categorical variables •  16 of 476 (3.4%) evaluable participants had low-level K103N at baseline by AS-PCR (0.8-15%). • K103N >2% was also predictive of VF with Odds Ratio = 25.5 and P = 0.0002 Svarovskaia  et  al  XVIII  Inter  HIV  Drug  Resist    2009   Goodman  et  al  AIDS  2011   The presence of K103N mutant virus in plasma above 2000 copies/ml prior to therapy in treatment-naive individuals correlated with increased risk of virologic failure of efavirenz-containing triple-drug regimens
  38. 38. Prevalence of etravirine (ETR)-RAMs at NNRTI failure and predictors of resistance to ETR in a large Italian resistance database (ARCA) S.  Rusconi  et  al.,  Clin  Microbiol  Infect  2013  
  39. 39. Prevalence of etravirine (ETR)-RAMs at NNRTI failure and predictors of resistance to ETR in a large Italian resistance database (ARCA) S.  Rusconi  et  al.,  Clin  Microbiol  Infect  2013  
  40. 40. Adjusted risk of triple class virologic failure after the start of cART Lodwick R, for COHERE, 16th CROI; Montreal (CA), 2009
  41. 41. Boosted-PIs are associated with lower risk of HIV resistance at any level of adherence Lima VD et al, JID 2008 *Plasma viral load log * *
  42. 42. Differential Presence of Selected Drug Resistance in Patient Populations 70.7 66.1 61.3 37.2 70 10.1 61.5 23.7 0 10 20 30 40 50 60 70 80 Long-term treated patients (n=380) PHI (Untreated n=59) Prevalence(%) TAMs NNMs M184V PRAMs D Turner et al, J AIDS 37, 1627ff, 2004

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