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Virological predictors of clinical outcome

Virological predictors of clinical outcome. Anna Maria Geretti Royal Free Hampstead NHS Trust & UCL Medical School London. Mortality risk with detectable viraemia during HAART. Cumulative mortality stratified by % VL ≥400 cps/ml recorded during 18 months after HAART initiation.

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Virological predictors of clinical outcome

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  1. Virological predictors of clinical outcome Anna Maria Geretti Royal Free Hampstead NHS Trust & UCL Medical School London

  2. Mortality risk with detectable viraemia during HAART Cumulative mortality stratified by % VL ≥400 cps/ml recorded during 18 months after HAART initiation n=2046 patients who started HAART before 2002 Follow-up: 8898 patient-years after 18 months on HAART 100% 51%-75% 76%-99% 26%-50% Cumulative mortality 1%-25% 0% 0 18 36 54 72 Months after starting HAART Lohse et al, Clin Infect Dis 2006

  3. Determinants of HAART outcomes • Drug exposure • Adherence • PK • Compartments • Host-related factors • Immune status • Genetics • Tolerability • Drug potency • IC50 value • Genetic barrier to resistance • Virological factors • Viral load • Sequence variability • Drug-resistance

  4. First-line HAART in the UK HAART regimen started • Drug-naïve cohort (n= 1175) • Started HAART in 1996-2006 • 82% achieved a VL<50 cps/ml • At median 3.5 months • IQR 2.4, 5.5 months Geretti et al, EHDRW 2008

  5. Independent predictors of achieving a VL <50 No effect of gender, risk group, ethnicity, or B vs non-B subtype Geretti et al, EHDRW 2008

  6. Exploring the determinants of HAART failure • Impact of low-level viraemia • Impact of HIV-1 subtype • Impact of transmitted drug resistance

  7. Exploring the determinants of HAART failure • Impact of low-level viraemia • Impact of HIV-1 subtype • Impact of transmitted drug resistance

  8. Study objectives • Investigate the long-term virological outcomes of a large cohort initially showing good responses to first-line HAART • Explore the occurrence and impact of low-level viraemia between 50 and 400 cps/ml Geretti et al, Antiviral Therapy 2008

  9. Drug-naïve cohort (n= 1386) Started HAART in 1996-2005 Achieved a VL <50 cps/ml In the following year: In follow-up On HAART No VL >400 cps/mL Study population HAART regimen at first VL <50 cps/ml Note: 320 (23.1%) changed the initial regimen before achieving <50 cps/ml due to toxicity (allowed) Geretti et al, Antiviral Therapy 2008

  10. Virological status in the first year after achieving a VL <50 cps/m Low-level rebound = 50-400 cps/ml Geretti et al, Antiviral Therapy 2008

  11. Virological status in the first year after achieving a VL <50 cps/m 269 patients Blips per person 1 84.8% 2 13.4% 3 1.5% 4 0.4% 85 patients Consecutive VL >50 2 in 54.1% 3 in 28.2% ≥4 in 17.6% Low-level rebound = 50-400 copies/ml Low-level rebound = 50-400 cps/ml Geretti et al, Antiviral Therapy 2008

  12. Predictors of low-level rebound • Multivariate model • Factors analysed: age, gender, risk group, ethnicity/country of birth, baseline CD4 and VL, CD4 at first VL <50 cps/ml, time from start of HAART to first VL <50 cps/ml, HAART regimen, year when first achieved a VL <50 cps/ml, HAART changes for toxicity prior to first VL <50 cps/ml Geretti et al, Antiviral Therapy 2008

  13. Virological outcomes Follow-up started 1 year after 1st VL <50 cps/m Lasted for median 2.2 years (range 0.0–7.4) Failure = VL >400 cps/ml Failure rate = 86 patients (6.2%) Consistent undetectability 5.0% Transient low-level rebound 8.2% Persistent low-level rebound 14.1% Low-level rebound = 50-400 cps/ml Geretti et al, Antiviral Therapy 2008

  14. Predictors of virological failure Multivariate model Factors analysed: As in previous analysis + VL status in the first year after achieving a VL <50 cps/m Geretti et al, Antiviral Therapy 2008

  15. Effect of VL on the detection of resistance(multivariate analysis) RAMs: resistance-associated mutations RR: Relative risk Geretti et al, IHDRW 2009

  16. Number of mutations detected by VL strata* *in patients with ≥1 mutation N= 270 399 850 1014 888 858 809 Geretti et al, IHDRW 2009

  17. Exploring the determinants of HAART failure • Impact of low-level viraemia • Impact of HIV-1 subtype • Impact of transmitted drug resistance

  18. Subtype Study population • Drug-naïve cohort (n=2116) • Started HAART in 1996-2006 • Most commonly 2 NRTIs + 1 NNRTI • ≥12 months of follow-up • Excluded patients with TDR Outcomes measured: • Time to VL suppression <50 cps/ml • For those who achieved <50, time to rebound >1000 cps/ml • Median follow-up of 39 months (IQR 23, 67) • Ethnicity and risk group strongly associated with subtype (P<0.001) Geretti et al, Clin Infect Dis 2009

  19. N = 64 1381 255 37 51 118 N = 13 238 51 7 7 19 Responses to first-line HAART by subtype 1906/2116 (90%) achieved VL suppression <50 cps/ml 335/1906 (18%) rebounded >1000 cps/ml Geretti et al, Clin Infect Dis 2009

  20. VL suppression 1.00 Median time to VL suppression Subtype A 2.6 months Subtype C 2.8 months Subtype B 3.1 months Multivariate analysis* Time to VL suppression shorter for A (HR 1.35 [1.04,1.74] P=0.02) and C (HR 1.16 [1.01,1.33] P=0.04) vs B 0.80 0.60 Probability of achieving <50 cps/ml A B C 0.40 0.20 Log-rank p<0.0005 0.00 *adjusted for age, centre, HAART regimen, calendar year, baseline CD4 and VL 0 3 6 9 12 Analysis time (months) Number at risk A 66 23 9 5 2 B 1550 785 332 218 169 C 272 10 41 23 17 Geretti et al, Clin Infect Dis 2009

  21. VL rebound 1.00 Multivariate analysis* Time to VL rebound shorter for C vs B (HR 1.40 [1.00, 1.95] P=0.05) 143 rebounds: virological failure 192 rebounds: non-adherence or treatment discontinuation Time to virological failure similar for C vs B 0.80 0.60 Probability of remaining <50 cps/ml 0.40 A B C Log-rank p=0.09 0.20 0.00 0 12 24 36 48 60 *adjusted for age, centre, HAART regimen, calendar yr, baseline CD4 and VL, and time to VL suppression Analysis time (months) Number at risk A 64 49 34 22 17 15 B 1381 1167 830 630 454 317 C 255 197 116 74 48 30 Geretti et al, Clin Infect Dis 2009

  22. CD4 recovery over time 500 400 CD4 count (cells/mm3) 300 A B C 200 100 0 6 12 18 24 30 36 Time since ART initiation (months) Number in analysis A 66 50 57 42 38 28 20 B 1550 1253 1174 970 796 668 552 C 272 225 201 167 121 93 63 Geretti et al, Clin Infect Dis 2009

  23. Exploring the determinants of HAART failure • Impact of low-level viraemia • Impact of HIV-1 subtype • Impact of transmitted drug resistance

  24. 100 Detected by routine methods 10 Detected by ultrasensitive methods 1 Mutation Frequency 0.1 0.01 Natural background 0.001 Detection of TDR 6-13% of naïve patients in Europe & N America1-9 Rates doubled10-16 1. Masquelier JAIDS 2005; 2. Wensing JID 2005; 3. Booth JAC 2007; 4. Geretti COID 2007; 5. SPREAD AIDS 2008; 6. Vercauteren AIDS RHR 2008; 7. Peuchant AIDS 2008; 8. Bannister JAIDS 2008; 9. Weinstock JID 2004; 10. Peuchant AIDS 2008; 11. Metzner AIDS 2005; 12. Johnson PLoS ONE 2007; 13. Johnson PLOS Med 2008; 14. Siemen JID 2009; 15. Geretti JAIDS 2009; 16. Goodman IHDRW 2009

  25. The clinical significance of low-frequency TDR Metzner, Antivir Ther 2007 Peuchant, AIDS 2008 Johnson, PLOS Med 2008 No Siemens, JID 2009 Impact on virological responses Geretti, JAIDS 2009 Goodman IHDRW 2009 Yes Different methods, interpretative cut-offs, populations, HAART regimens

  26. The FIRST study N=258 • HR for failure in patients with NNRTI resistance • Bulk : 12.4 [3.41-45.1] • UDS: 2.50 [1.17-5.36] USD = Ultra deep sequencing Siemen et al, JID 2009

  27. Impact of NNRTI TDR on responses to first-line NNRTI-based HAART • Case control study • Patients with virological failure (n=18) vs those who achieved and maintained VL suppression <50 for ≥24 weeks (n=75) • Pre-HAART sample tested by sensitive PCR • Targets: K65R, K103N, G190A, Y181C, M184V • Interpretative cut-off of 0.5-0.9% Geretti et al, JAIDS 2009

  28. NNRTI TDR reduces responses to first-line NNRTI-based HAART Resistance at baseline • 7/18 cases vs 0/75 controls • 2 K103NHIGH 1 G190AHIGH 4 K103NLOW Odds of virological failure • Bulk resistance p=0.006 • 4 K103NLOW p=0.001 • Combined p <0.0001 HIGH= detected also by bulk genotyping; LOW= detected only by PCR (>0.9%) Geretti et al, JAIDS 2009

  29. K103N >2% or >2000 cps/ml predicts failure of first-line NNRTI-based HAART Fit 99% confidence band VF 0.5 0 Clinical virology VF (>400 c/mL) Non-VF -0.5 -1 103.3 = 1995 c/mL 0 1 2 3 4 Log copies of RNA with K103N mutation Fit 99% confidence band 1 VF 0.5 Clinical virology VF (>400 c/mL) 0 Non-VF -0.5 -1 0 2.5 5 7.5 10 12.5 15 Percent of RNA with K103N mutation Fit plot for VF (>400 c/mL) GS-01-934 (n=487) • TDF/FTC/EFV • ZDV/3TC/EFV • K103NLOW in 16/476 (3.4%) patients • 6/16 (38%) of patients with K103NLOW had VF VF = virological failure Goodman et al, IHDRW 2009

  30. Conclusions-1 • Low risk of virological failure once suppression is achieved and maintained for 1 year • Consistent suppression <50 the optimal target • NNRTI-based HAART least likely to result in low-level viraemia and virological failure • Women at increased risk of virological failure • Problems with long-term adherence • Cultural and social-economic factors • Resistance testing at low VL yields clinically useful information

  31. Conclusions-2 • Predominantly NNRTI-based HAART achieves excellent outcomes regardless of the infecting subtype • Subtype C patients show an increased risk of rebound possibly related to non-adherence

  32. Etravirine Efavirenz Nevirapine Conclusions-3 • Low-frequency K103N mutants as prevalent as bulk-detectable resistant variants • Significantly associated with virological failure • Patients infected with single NNRTI mutants • ? Impact on second generation NNRTIs

  33. Thank you a.geretti@medsch.ucl.ac.uk

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