Dr Marta Boffito 15/10/ th Annual Resistance and Antiviral Therapy Meeting. Chelsea and Westminster Hospital, London

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1 18 th Annual Resistance and Antiviral Therapy Meeting Dr Marta Boffito Chelsea and Westminster Hospital, London Thursday 18 September 2014, Royal College of Physicians, London 1

2 virological response (SVR) under DAA-based modern HCV therapy? Ndumbi P et al. Delay in cart initiation results in persistent immune dysregulation and poor recovery of T-cell phenotype despite a decade virological response (SVR) under HCV/HIV DAA-based modern HCV therapy? Ndumbi P et al. Delay in cart initiation results in persistent immune dysregulation and poor recovery of T-cell phenotype despite a decade 2

3 virological response (SVR) under HCV/HIV DAA-based modern HCV therapy? Ndumbi P et al. Delay Early in cart initiation results in persistent immune dysregulation and cart poor recovery of T-cell phenotype despite a decade initiation virological response (SVR) under HCV/HIV DAA-based modern HCV therapy? Ndumbi P et al. Delay Early in cart initiation results in persistent immune dysregulation and cart poor recovery of T-cell phenotype despite a decade initiation Archin NM et al. HIV-1 expression within resting CD4+ CureT cells after 3

4 virological response (SVR) under HCV/HIV DAA-based modern HCV therapy? Ndumbi P et al. Delay Early in cart initiation results in persistent immune dysregulation and cart poor recovery of T-cell phenotype despite a decade initiation Archin NM et al. HIV-1 expression within resting CD4+ CureT cells after Margolis D et al. 744 and rilpivirine as two-drug New oral maintenance therapy: LAI (LATTE) week 48 results. strategies 21st Conference on virological response (SVR) under HCV/HIV DAA-based modern HCV therapy? Ndumbi P et al. Delay Early in cart initiation results in persistent immune dysregulation and cart poor recovery of T-cell phenotype despite a decade initiation Archin NM et al. HIV-1 expression within resting CD4+ CureT cells after Margolis D et al. 744 and rilpivirine as two-drug New oral maintenance therapy: LAI (LATTE) week 48 results. strategies 21st Conference on Retroviruses and Opportunistic InSTI Infections 2014 [Abstract #85] 4

5 virological response (SVR) under DAA-based modern HCV therapy? Ndumbi P et al. Delay in cart initiation results in persistent immune dysregulation and poor recovery of T-cell phenotype despite a decade Rockstroh In the era of IFN/RBV HCV Tx, lower SVR rates in HIV/HCV co-infected than HCV mono-infected subjects 1 st generation DAAs plus IFN/RBV showed same SVR rates, independently from historic prognostic factors (i.e. fibrosis stage, IL28B genotype, HCV subtype, CD4 count, baseline HCV RNA, wk 4 HCV RNA, etc) [Cotte et al. ] This is confimred with the use of newer DAAs and recent guidelines (i.e. EASL) no longer differentiate between HIV/HCV co-infected and HCV mono-infected subjects Drug-drug interactions, especially between HCV PI and HIV NNRTIs and PI/r-c 5

6 virological response (SVR) under DAA-based modern HCV therapy? Ndumbi P et al. Delay in cart initiation results in persistent immune dysregulation and poor recovery of T-cell phenotype despite a decade Ndumbi et al PLOS One 2014 cart increase CD4 cell counts but the increase may not reflect long-term immune recovery: persistence of T-cell dysregulation/loss of T-cell homeostasis Low CD4:CD8 ratio (<1.2) marker of AIDS and correlated with comorbidities (i.e. CAD [Lo et al AIDS 2010]) Objective: To assess the extent of T-cell phenotype recovery among a group of treated HIV-positive males with a suppressed VL for 10 years N = 44; groups: I. pre-cart CD4<200, II , III. >350; outcomes: 1. CD4 > 500, 2. normalization of ratio, 3. maintainance of CD3 T-cell homeostasis, 4. normalization of T-cell phenotype (primary outcome and involves all the above) RESULTS: Despite a decade of sustained successful cart, complete T-cell phenotype normalization occurred in only 16% of patients, most started cart with CD4 > 350 Failure to normalize T-cell phenotype was most apparent when commencing cart at CD4 < 200. Impact of impaired T-cell phenotype on immune restoration and comorbidities remains to be elucidated 6

7 virological response (SVR) under DAA-based modern HCV therapy? Ndumbi P et al. Delay in cart initiation results in persistent immune dysregulation and poor recovery of T-cell phenotype despite a decade HIV infection remains incurable = presence of quiescent provirus in long-lived memory T cells* Archin et al JID 2014 HIV infection requires lifetime cart unless the latent infection is eliminated Infection in these cells is established within days of HIV infection/refractory to immune system and Tx Multiple mechanism maintain the quiescent state of the HIV promoter and one of this is the HDAC** -N = 5 participants in whom resting CD4(+) T-cell-associated HIV RNA (rc- RNA) increased after a single dose of VOR -Received daily VOR Monday towednesday for 8 week cycles -VOR serum levels, peripheral blood mononuclear cell histone acetylation, plasma HIV RNA single-copy assays, rc-rna, total cellular HIV DNA, and quantitative viral outgrowth assays from resting CD4(+) T cells were assayed **cellular histone deacetylases In vitro, HDAC inhibitors led to acetylation of lysine residues on histone tails = led to the induction of transcription of the HIV promoter There are four classes of HDAC: Class I, which includes HDAC1, -2, -3 and -8 are related to yeast RPD3 gene; Class II, which includes HDAC4, -5, -6, -7, -9 and -10 are related to yeast Hda1 gene; Class III, also known as the sirtuins are related to the Sir2 gene and include SIRT1-7; Class IV, which contains only HDAC11 has features of both Class I and II. HDAC I, II, and III mediate the repression of HIV transcription -rc-rna measured after dose 11 and dose 22 increased significantly only in 3/5 subjects -Magnitude of rc-rna increase was much reduced vs single dose -Changes in histone acetylation were blunted -HIV latency disrupted by an initial VOR dose, the effect of subsequent doses much reduced 7

8 Histone deacetylase (HDAC) inhibitors Approved Vorinostat licenced by FDA in 2006 for treatment of cutaneous T cell lymphoma Romidepsin (Istodax) licenced the FDA in 2009 for cutaneous T-cell lymphoma Started phase III clinical trials Panobinostat (LBH589) is in clinical trials for various cancers including a phase III trial for cutaneous T cell lymphoma Valproic acid (as Mg valproate) in phase III trials for cervical cancer and ovarian cancer, also trialled in spinal muscular atrophy Started pivotal phase II clinical trials Belinostat (PXD101) has had a phase II trial for relapsed ovarian cancer, and reported good results for T cell lymphoma Started phase II clinical trials Mocetinostat (MGCD0103) undergoing clinical trials for treatment of cancers (including follicular lymphoma, Hodgkin lymphoma and acute myeloid leukemia) Abexinostat (PCI-24781) started a phase II trial for sarcoma,and lymphoma Entinostat (MS-275) in phase II for Hodgkin lymphoma, lung cancer and breast cancer SB939 starting a phase II trial for Recurrent or Metastatic Prostate Cancer (HRPC) Resminostat (4SC-201) an oral pan-hdaci. For Hodgkin lymphoma, hepatocellular carcinoma and has FDA Orphan Drug status Givinostat (ITF2357)[30] for Started phase I clinical trials CUDC-101 intended for cancer, it also inhibits EGFR and HER2 AR-42 started clinical trials in 2010 for various cancers (relapsed or treatmentresistant multiple myeloma, chronic lymphocytic leukemia or lymphoma), Orphan Drug designations from the FDA for two benign tumour types CHR-2845, CHR SC-202 selective, for advanced hematological indications CG for solid tumors ACY-1215, selective for HDAC6, in two clinical trials for multiple myeloma in combination with bortezomib and with lenalidomide (Revlimid, Celgene) ME-344, for solid refractory tumors Sulforaphane refractory leukemias and myelomas Quisinostat (JNJ ) virological response (SVR) under DAA-based modern HCV therapy? Ndumbi P et al. Delay in cart initiation results in persistent immune dysregulation and poor recovery of T-cell phenotype despite a decade 8

9 Margolis et al CROI 2014 The LATTE Study enrolled approximately 180 treatment naive patients given the novel InSTI 744 (CABOTEGRAVIR) with ABC/3TC to demonstrate efficacy and safety of 744 given at 10, 30 and 60 mg OD Primary goal was to determine whether those suppressed on this NRTIs + InSTI could be switched to a novel 744 plus RPV combination This may lead to long-acting formulations of these drugs to be used as maintenance therapy Viral suppression at 24 weeks was high and similar in all three doses of 744 and even higher than the TDF/FTC/EFV controls Of those suppressed that switched to 744 plus RPV over 90% maintained viral suppression after 24 weeks of maintenance therapy with good tolerability LATTE-2: Study Design Induction 265 subjects enrolled HIV RNA 1000 CD4 200 ART naïve Week - 20 Induction Period GSK mg + ABC/3TC Orally Once Daily Week - 16 Week - 12 Week - 8 Add RPV 25 mg once daily Week - 4 Randomization is 2:2:1 and stratified by HIV-1 RNA prior to Week (-8) (<50 c/ml, yes or no) Day IM Q4W Regimen IM Q8W Regimen Cont Oral Regimen Week -4 Qualification Visit For Maintenance and Addition of RPV 25 mg for All Subjects Day 1 Start of Maintenance and Randomization Visit 9

10 LATTE-2: Study Design Maintenance and Extension Continue From Induction Loading Dose Maintenance Period GSK744 LA 400 mg IM + TMC278 LA 600 mg IM Every 4 Weeks (Q4W) GSK744 LA 600 mg IM + TMC278 LA 900 mg IM Every 8 Weeks (Q8W) Extension Period Continue on or Switch to either Q4W or Q8W Loading Doses at Day 1 and Week 4 GSK mg + ABC/3TC Orally Once Daily Week 32 Key Study Events Primary Analysis Day 1 Dosing Regimen Randomization Selection Week 48 Analysis Dosing Regimen Confirmation W96 Add RPV 25 mg W102* W104 Subjects who WD aer at least 1 IM dose enter Long Term Follow Up Period *If eligible virological response (SVR) under DAA-based modern HCV therapy? Ndumbi P et al. Delay in cart initiation results in persistent immune dysregulation and poor recovery of T-cell phenotype despite a decade 10

11 Landovitz et al CROI 2014 ATV/r, RAL, and DRV/r are equivalent for virologic efficacy ATV/r is less well tolerated than DRV/r or RAL Largely due to cosmetic hyperbilirubinemia RAL is superior to both PI/r regimens with regard to combined tolerability and virologic efficacy DRV/r is superior to ATV/r VF with resistance was rare More frequently observed with RAL Analyses are ongoing to evaluate: Cardiovascular, metabolic, skeletal, fat, inflammatory biomarkers, behavior, adherence, and key subgroup differences A5257 Study Design* HIV-infected patients, 18 yr, with no previous ART, VL 1000 c/ml at US Sites (N=1809) Randomized 1:1:1 to Open Label Therapy Stratified by screening HIV-1 RNA level ( vs < 100,000 c/ml), A5260s metabolic substudy participation, cardiovascular risk ATV 300 mg QD + RTV 100mgQD + FTC/TDF 200/300 mg QD (N=605) RAL 400 mg BID + FTC/TDF200/300mg QD (N=603) DRV 800 mg QD + RTV 100 mg QD + FTC/TDF 200/300 mg QD (N=601) Study Conclusion 96 weeks after final participant enrolled Follow-up continued for 96 weeks after randomization of last subject (range 2-4 years) regardless of status on randomized ART *With the exception of RTV, all ART drugs were provided by the study 11

12 Cumulative Incidence of Virologic Failure Difference in 96 wk cumulative incidence (97.5% CI) ATV/r vs RAL 3.4% (-0.7%, 7.4%) DRV/r vs RAL 5.6% (1.3%, 9.9%) ATV/r vs DRV/r -2.2% (-6.7%, 2.3%) Cumulative Incidence of Tolerability Failure Difference in 96 wk cumulative incidence (97.5% CI) Favors RAL Favors DRV/r ATV/r vs RAL 13% (9.4%, 16%) DRV/r vs RAL 3.6% (1.4%, 5.8%) ATV/r vs DRV/r 9.2% (5.5%, 13%) 12

13 Cumulative Incidence of Virologic or Tolerability Failure Difference in 96 wk cumulative incidence (97.5% CI) Favors RAL Favors RAL Favors DRV/r ATV/r vs RAL 15% (10%, 20%) DRV/r vs RAL 7.5% (3.2%, 12%) ATV/r vs DRV/r 7.5% (2.3%, 13%) Tolerability Failure Toxicity Associated Discontinuation of randomized ART * ATV/r (N=605) RAL (N=603) DRV/r (N=601) Any toxicity discontinuation 95 (16%) 8 (1%) 32 (5%) Gastrointestinal toxicity Jaundice/Hyperbilirubinemia Other hepatic toxicity Skin toxicity Metabolic toxicity Renal toxicity (all nephrolithiasis) Abnormal chem/heme (excl. LFTs) Other toxicity *Participants allowed to switch therapy for intolerable toxicity 13

14 Resistance to Study Agents 1809 Participants ATV/r 75/94 VF Available 9 Any Resistance (1.5% of ATV/r) 5 isolated M184V 1 integrase mutation 2 T69D/T215AIT 1 K70N + M184V 295 Virologic Failures RAL 65/85 VF Available 18 Any Resistance (3% of RAL) 1 isolated integrase mutation 7 M184V 7 integrase + M184V 3 integrase + M184V + K65R 1 Baseline Missing 56 VF Failed to Amplify DRV/r 99/115 VF Available 4 Any Resistance (<1% of DRV/r) 3 M184V 1 integrase mutation 14