Virological suppression and PIs. Diego Ripamonti Malattie Infettive - Bergamo

Transcription

1 Virological suppression and PIs Diego Ripamonti Malattie Infettive - Bergamo

2 Ritonavir-boosted PIs Boosted PIs: 3 drugs in one The intrinsic antiretroviral activity Viral suppression and high baseline viral load The low level viremia The high genetic barrier Boosted PIs and MDR viruses Boosted PIs and deintensification strategy

3 Boosted Protease Inhibitors: 3 drugs in one

4 Multi-step HIV inhibition by PIs Rabi SA et al. J Clin Investig; 2013;123:3848

5 The intrinsic antiviral activity of boosted PIs

6 Boosted-PIs as single-drug regimens in naive patients MONARK study: pts with HIV RNA <10 5 copies/ml, CD4 >100 cells/ml (83 pts) (53 pts) 64% Resistance to LOP in 5/83 pts (6%) < 50 copies copies >400 copies intensification discontinuation missing 47% at week 96, Meynard JAC 2010 Delfraissy JF et al. AIDS 2008;22:385

7 HIV DNA median log cell/10 6 PBMC Boosted-PIs as single-drug regimens in naive patients Impact of LOP/r monotherapy on blood HIV DNA at week 48 2 MONARK study (OT analysis) Baseline HIV DNA in monotherapy arm HIV DNA 4 responders Non responders 1,5 1 0,5 0 LOP/r 46 pts LOP/r+ AZT/3TC 26 pts 3 2 2,86 p= ,16-0,5-1 -0,77-0,69 1-1,5 p= Avettand-Fenoel V et al. JAC 2010

8 Boosted PIs and Low Level Viremia

9 Low level viremia and boosted PIs The ARTEMIS trial Long-term HIV RNA Suppression Ripamonti D et al. AIDS Rev 2013

10 Low level viremia and boosted PIs Viral suppression in patients with baseline HIV RNA >10 5 copies/ml the ARTEMIS Trial DRV/r arm LOP/r arm Ripamonti D et al. AIDS Rev 2013

11 Percent of patients Boosted PIs and low level viremia MONOI study: HIV RNA <1 copies/ml at baseline and week 48 (observed data analysis) DRV/r + 2 NRTIs DRV/r mono 100% HIV RNA 80% 59,3% 44,0% 49,5% 37,0% <1 other 60% 40% 66,0% 63,0% 20% 40,7% 50,5% 0% Baseline n=113 Week 48 n=101 Baseline n=112 Week 48 n=96 Lambert-Niclot S et al. JID 2011;204:

12 Percent of patients Boosted PIs and low level viremia MONET study: HIV RNA <5 copies/ml at baseline and week 144 (observed data analysis) DRV/r + 2 NRTIs DRV/r mono HIV RNA 100% 80% 3,1% 5,6% 17,8% 11,1% 1,6% 2,0% 5,5% 4,9% 12,6% 12,7% > <5 60% 40% 79,1% 83,3% 80,3% 80,4% 20% 0% Baseline n=129 Week 144 n=108 Baseline n=127 Week 144 n=102 Data on file, Janssen

13 Cellular HIV-1 DNA and PI-mono Dynamics of total cellular HIV-1 DNA over time Substudy in MONET, 130 pts, 144 weeks Substudy in MONOI, 160 pts, 96 weeks similar HIV DNA evolution median delta HIV-1 DNA: 0.35 vs 0.51 log copies/10 6 PBMC Geretti AM et al. HIV Trial 2013;14:45-50 Lambert-Niclot S et al. Plos One 2012;

14 Boosted PIs and Genetic Barrier

15 PIs and Genetic Barrier Primary PI mutations at virological failure by regimen Drug class NRTI PI ACTG (1809 pts, 96 wks) TDF/FTC+ DRV/r TDF/FTC+ ATV/r TDF/FTC+ RAL 3 (DRV arm) 8 (ATV arm) 17 (RAL arm) 0 (DRV) 0 (ATV/) ACTG (1857 pts, 96 wks) TDF/FTC+ ATV/r TDF/FTC+ EFV ABC/3TC+ ATV/r ABC/3TC+ EFV 16 (PI arms) 36 (EFV arm) NEAT-01 3 (805 pts, 96 wks) DRV/r + TDF/FTC DRV/r + RAL 0 (TDF arm) 1 (RAL arm) 1 (ATV) 0 (TDF arm) 0 (RAL arm) NNRTI Study (708 pts, 96 wks) TDF/FTC+ EVG/c TDF/FTC+ ATV/r 0 (PI arm) 4 (EVG arm) 0 (ATV arm) II 1 (DRV arm) 1 (ATV arm) 11 (RAL arm) (EVG arm) 1. Landovitz RJ et al. CROI Daar E et al. Ann Intern Med Raffi F, et al. CROI Abstract 84LB. 4. Rockstroh J, et al. JADS. 2013;62:

16 PIs and Genetic Barrier Efficient suppression of minority drug-resistant HIV-1 variants present at primary HIV-1 infection by boosted PI-regimens 109 pts from Zurich PHI Genotype: no primary mutations HAART: AZT/3TC+LOP/r Genotypic test for minority variants* (K103N, M184V): 15/109 (13.8%) pts with resistance variants No further selection of 184V up to months Metzner KJ et a. J Infect Dis. 2010;201:

17 PIs and Genetic Barrier Low frequency HIV-1 drug resistance mutations and risk of failure on NNRTI-based regimens 985 naive pts from 10 studies Genotype: no primary mutations NNRTI-based HAART Genotypic test for minority variants* (K103N, Y181C and M184V, K65R): 187/985 (18.9%) pts with resistance variants Sistematic review and pooled analysis Higher risk of failure: HR: 2.3 (95%CI 1.7 to 3.3) ** Li JZ et al. JAMA 2011;305: ** Corrected for: initial HIV RNA, baseline CD4, adherence, ethnicity

18 Boosted PIs and MDR

19 Patients with viral load <50 copies/ml at Week 48 (%) DUET: Virological response at Week 48 (TLOVR) with fully active ETR and fully active DRV p=0.0011* 74% 53% ETR + BR (n=227) p=0.0177* 83% 71% Placebo + BR (n=236) p=0.0283* 80% 64% p=n/a 100% 86% /108 57/107 62/75 55/78 33/41 28/44 3/3 6/7 Number of active NRTIs in the BR (PSS) Total number of active agents used (including ETR + DRV) N.Clumeck, ET AL. Fully active ETR = patients with ETR FC 3; DRV = patients with DRV FC 10; ETR and DRV were not included in the PSS calculation; Analysis excludes patients who discontinued for reasons other than VF; *Logistic regression; According to Antivirogram

20 Boosted PIs and LDR

21 Deintensification strategies Alternative strategies to standard HAART Initial therapy Dual Regimens Study Arms Time (weeks) NEAT-01 PROGRESS TDF/FTC+ DRV/r RAL+ DRV/r TDF/FTC+ LOP/r RAL+ LOP/r Boosted PIs GARDEL 2NRTIs + LOP/r 3TC+ LOP/r 48 - Antiviral potency - High genetic barrier - Low risk of resistance Switching therapy Dual regimens ATLAS MIDAS 3TC+ ATV/r TDF/FTC+ DRV/r MRV+ DRV/r PIVOT Monotherapy. OK04 MONOI MONET PIVOT LOP/r DRV/r DRV/r DRV/r (80%) > 4 yrs

22 Grazie

23 Cellular HIV-1 DNA and PI-mono Dynamics of total cellular HIV-1 DNA by patients categories Torres-Cornejo A et al. AIDS 2014;28:201

24 PIs in experienced patients POWER 3: 144 weeks follow up Pozniack A et al. 9 HIV Drug Therapy, Glasgow 2008

25 PIs and compartments