Co-infection, Opportunistic Infections and Malignancies

Transcription

1 BHIVA Best of CROI Feedback Meetings London North East England North West England Edinburgh Birmingham BHIVA Best of CROI Feedback Meetings 2012 Co-infection, Opportunistic Infections and Malignancies Dr Ed Wilkins North Manchester General Hospital 1

2 Co-infection and malignancies HCV/HIV clinical data: Telapravir Bocepravir HCV/HIV DDI s Bocepravir TMC 435 Daclatasvir HCV monoinfection GS 7977 Worth a mention Malignancy NADM and link to CD4 / VL factors NHL after VL suppression TB STRIDE and IRS 1 vs. 4 vs. 8 week ART start Co-infection and malignancies HCV/HIV clinical data: Telapravir Bocepravir HCV/HIV DDI s Bocepravir TMC 435 Daclatasvir HCV monoinfection GS 7977 Worth a mention Malignancy NADM and link to CD4 / VL factors NHL after VL suppression TB STRIDE and IRS 1 vs. 4 vs. 8 week ART start 2

3 Background HIV accelerates the natural course of hepatitis C Successful HAART can slow down fibrosis progression but not back to the rate in HCV monoinfection Liver disease associated with HCV infection has become a leading cause of morbidity and mortality among HIV-infected patients Rockstroh J, et al., Am J Gastroenterol 1996; 91: Graham CS, et al., Clin Infect Dis. 2001;33: Weber R et al., Arch Intern Med 2006; 166: New HCV agents on the horizon: What are the possible challenges? Higher HCV viral loads in HIV/HCV co-infection Lower probability of EVR Higher risk for resistance development Drug-drug interactions between HIV drugs and the new oral HCV agents Overlapping drug toxicities 3

4 Study 110: Telaprevir in HIV/HCV co-infected patients Part A: no ART T/PR TVR + PR PR Follow-up SVR PR48 (control) Pbo + PR PR Follow-up SVR Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC) T/PR TVR + PR PR Follow-up SVR PR48 (control) Pbo + PR PR Follow-up SVR Weeks Dieterich D, et al. 19th CROI; Seattle, WA; March 5-8, PR Abst. Pegylated 46 interferon/ribavirin, TVR Telaprevir,SVR Sustained virologic response Telaprevir: previous data on DDIs with HIV antiretrovirals HIV antiretroviral Studies completed Atazanavir/r Darunavir/r Fosamprenavir/r Lopinavir/r Efavirenz Raltegravir Tenofovir Recommendation Clinical and laboratory monitoring for hyperbilirubinaemia is recommended Not recommended TVR dose increase necessary (1125 mg q8h) No dose adjustment required Increased clinical and laboratory monitoring is warranted DDI Drug-druginteractions van Heeswijk R, et al. 18th CROI Abstract 119 4

5 Patients with Undetectable HCV RNA (%) Study 110: SVR Rates 12 Weeks Post-Treatment (SVR12) n/n = 5/7 11/16 12/15 28/38 T/PR *Patient was defined as SVR12 if HCV RNA was < LLOQ in the visit window No ART EFV/TDF/FTC ATV/r/TDF/FTC Total 45 2/6 4/8 4/8 10/22 PR Dieterich D, et al. 19th CROI; Seattle, WA; March 5-8, Abst. 46 Study Design: BOC + PEG/RBV for HCV/HIV coinfection (SVR12 results) Weeks Arm 1 PEG2b +RBV 4 wk Placebo + PEG2b + RBV 44 wk Follow-up SVR-24 wk Arm 2 PEG2b +RBV 4 wk Boceprevir + PEG2b + RBV 44 wk Futility Rules Follow-up SVR-24 wk Two-arm study, double-blinded for BOC, open-label for PEG2b/RBV 2:1 randomization (experimental: control) Boceprevir dose 800 mg TID 4-week lead-in with PEG2b/RBV for all patients PEG-2b 1.5 µg/kg QW; RBV mg/day divided BID Control arm patients with HCV-RNA LLOQ at TW 24 were offered openlabel PEG2b/RBV+BOC via a crossover arm Sulkowski M, et al.; 19th CROI; Seattle, WA; March 5-8, Abst. 47 5

6 Virologic Response Over Time -up to 12 Weeks Post-Treatment (SVR12) % HCV RNA Undetectable 3/34 3/64 5/34 27/64 8/34 38/64 11/34 47/64 10/34 42/64 9/34 37/61 Three patients undetectable at FW4 have not yet reached FW12 and were not included in SVR12 analysis. Sulkowski M et al., 19th CROI; Seattle, WA; March 5-8, Abst. 47 ; Use of antiretroviral therapy [PI/r allowed based on DDI with ritonavir] * To maintain blinding in this continuing study, data is only shown where at least 1 patient in each treatment group is represented. HIV PIs included ATVr, DRV/r, LPV/r, famp/r, SAQ/r NRTIs included TDF, ABC, 3TC, FTC PI Bocepravir/PR Any* 34 (100) 64 (100) HIV Protease Inhibitors 31 (91) 54 (84) ATV/r Lopinavir/r Darunavir/r 13 (38) 10 (29) 7 (21) 20 (31) 16 (25) 12 (19) NRTIs 33 (97) 60 (94) Integrase Inhibitors 4 (12) 11 (17) CCR5 antagonists 1 (3) 1 (2) Sulkowski M, et al. 49TH IDSA, 2011; Abstract. LB-37 Sulkowski M, et al. 49TH IDSA, PR Pegylated 2011; Abstract. interferon/ribavirin, LB-37 B- Boceprevir 6

7 Effect of ATV/r, LPV/r and DRV/r Co-administration on PK of Boceprevir Co-administered drug Ratio Estimate of co-administered drug (in combination vs. boceprevir alone) GMR (90% CI) AUC τ C max C min Atazanavir 0.95 (0.87, 1.05) 0.93 (0.80, 1.08) 0.82 (0.68, 0.98) Lopinavir 0.55 (0.49, 0.61) 0.50 (0.45, 0.55) 0.43 (0.36, 0.53) Darunavir 0.68 (0.65, 0.72) 0.75 (0.67, 0.85) 0.65 (0.56, 0.76) Co-administration with ATV/r does not alter boceprevir AUCτ, but coadministration withlpv/r and DRV/r decreases boceprevir AUCτ45% and 32%, respectively. HulskotteE et al., 19thCROI; Seattle, WA; March 5-8, Abst. 771LB Effect of Boceprevir Co-administration on PK of Ritonavir-boosted ATV, LPV and DRV Co-administered Drug Ratio Estimate of Co-administered Drug (in Combination vs. Alone) GMR (90% CI) AUC 0-last C max C min Atazanavir (ATV) 0.65 (0.55, 0.78) 0.75 (0.64, 0.88) 0.51 (0.44, 0.61) Lopinavir (LPV) 0.66 (0.60, 0.72) 0.70 (0.65, 0.77) 0.57 (0.49, 0.65) Darunavir (DRV) 0.56 (0.51, 0.61) 0.64 (0.58, 0.71) 0.41 (0.38, 0.45) Boceprevir co-administration reduces the exposure of ATV, LPV, and DRV 35%, 34%, and 44%, respectively, and reduces trough concentrations 49%, 43%, and 59%, respectively. Mean ATV C min decreased from 693 ng/ml to 357 ng/ml; mean LPV C min decreased from 6,730 ng/ml to 3,805 ng/ml; mean DRV C min decreased from 3,220 ng/ml to 1,321 ng/ml. Hulskotte E et al., 19th CROI; Seattle, WA; March 5-8, Abst. 771LB 7

8 HIV Breakthroughs in B/PR Group Overall, 7 patients had HIV breakthrough (>50 copies HIV RNA at 2 consecutive visits): 3/64 randomized to B/PR, and 4/34 to PR HIV RNA (copies/ml) Regimen BL TW4 TW12 TW24 TW36 EOT FW4 ATV/r <50 < LPV/r <50 <50 < ATV/r <50 <50 <50 < ATV/r, atazanavir/ritonavir; LPV/r, lopinavir/ritonavir The only subject to change ART. LPV/r changed to ATV/r at TW42; ATV/r to DRV/r at FW24. Boceprevir: DDIs with HIV antiretrovirals HIV antiretroviral Studies completed Atazanavir/r Darunavir/r Fosamprenavir/r Lopinavir/r Efavirenz Raltegravir Recommendation In general not recommended; EMEA says can be considered on a case-by-case basis if patient has no prior HIV drug resistance and is suppressed Not recommended Not recommended No dose adjustment required DDI Drug-drug interactions Hulskotte E et al., 19th CROI; Seattle, WA; March 5-8, Abst. 771LB De Kanter C et al., 19th CROI; Seattle, WA; March 5-8, Abst. 772LB FDA Safety Announcement, dated 08 Feb 2012 EMA press release, dated 17 Feb 2012 Merck "Dear Health Care Provider" letter, dated 06 Feb

9 Tolerability and safety: first signals from pilot trials 34% and 23% of T/PR and PR patients, respectively had rash; no severe rashes were reported in either group Preliminary safety data of B/PR in co-infected patients showed a profile consistent with that observed in monoinfected patients (Anemia 41% vs. 26%) HIV Breakthroughs were observed in 3/64 patients in the BOC group and 4/34 patients in the control group Dieterich D, et al. 19th CROI; Seattle, WA; March 5-8, Abst. 46 Sulkowski M et al., 19th CROI; Seattle, WA; March 5-8, Abst. 47 TMC 435 Once daily, NS3/4 A PI Potent anti-hcv for GT1 Antiviral activity also against GT 2, 4, 5, and 6 Currently in Phase III for GT 1 and 4 Good safety profile Substrate for CYP3A4 Standard PCK study healthy volunteers No alteration in ARV drug levels Ouwerkerk-Mahadevain S et al., 19th CROI; Seattle, WA; March 5-8, Abst. 49 9

10 TMC 435 drug-drug interactions with ARV s EFV RPV TDF RAL Design: C212 TMC-435 open-label, single-arm study in HIV/HCV co-infection (n=100) Weeks HCV treatment-naive subjects and prior relapsers TMC + PegIFN/RBV PegIFN/RBV Post treatment follow-up TMC + PegIFN/RBV PegIFN/RBV Post treatment follow-up Prior HCV non-responders and cirrhotics TMC + PegIFN/RBV PegIFN/RBV Post treatment follow-up Allowed ART: 3TC, FTC, TDF, ABC, rilpivirine, maraviroc, raltegravir and T20 PegIFN Pegylated interferon, RBV Ribavirin, 3TC Lamivudine, FTC - Emtricitabine Ouwerkerk-Mahadevain S et al., 19th CROI; Seattle, WA; March 5-8, Abst

11 Daclatasvir (BMS ) No clinically relevant PK interactions occurred between DCV and TDF No clinically significant effects of DCV on EFV or ATV/r exposure. DCV dose adjustments to 30 mg QDwith ATV/r (300/100 mg QD) and 90 mg QDwith EFV (600 mg QD) are expected to provide DCV exposure similar to that for 60 mg DCV administered alone DCV was generally well tolerated with all three ARVs Management issues with co-medications 11

12 ELECTRON Study Design for HCV Genotype 1 (Monoinfection) To evaluate the antiviral activity of 12 WEEKS Gs RBV in genotype 1 patients who were either: Prior null responders (<2 log10 reduction in HCV RNA at week 12 of a Peg/RBV regimen Treatment naïve wk N=10 Genotype 1 null responders (GS RBV ) SVR12 N=25 Genotype 1 treatment naïve (GS RBV) SVR12 RBV dosing in all arms, independent of HCV genotype, was 1000mg for patients <75kg and 1000mg for those >75kg Gane M et al., 19th CROI; Seattle, WA; March 5-8, Abst. 54LB ; Pt. # Characterization of Prior Null Response Prior Treatment HCV RNA decrease from baselineto W12, log 10 IU/mL Number of prior courses Liver Fibrosis (kpa) Fibrosis Stage 5085 PEG/RBV F PEG/RBV F PEG/RBV n/a 2* 6 F PEG/RBV n/a 2 ź 9.9 F PEG/RBV F PEG/RBV F PEG/RBV F PEG/RBV F PEG/RBV F PEG/RBV F3 * Patient 5088 received a prior course of IFN/RBV ź Patient 5089 received a prior course of IFN monotherapy 12

13 SVR4 response to RIB for 12w GT1 null responders (N=10) GT1 naïve (n=25) GT2/3 naïve (n=10) n/n % LOD n/n % LOD n/n % LOD Week 1 1/ / /10 20 Week 2 7/ / /10 80 Week 4 10/ / / Week 10 19/ / / Week 11 9/ / / Week 12 9/ / / SVR 4 1/ / % genotype 1 prior null responders and treatment naïve patients achieved RVR 100% genotype 1 prior null responders had HCV RNA <LOD at end of treatment One genotype 1 prior null responder achieved SVR4 Gane M et al., 19th CROI; Seattle, WA; March 5-8, Abst. 54LB ; ELECTRON Rapid suppression provided by GS-7977/RIB in naïve and null GT1 No virological breakthrough on treatment Prior null responders relapsed after ETR Combination well tolerated Future studies will require addition of another DAA or longer treatment course for null responders Gane M et al., 19th CROI; Seattle, WA; March 5-8, Abst. 54LB ; 13

14 Known predictors of SVR HOST Fibrosis Age/sex Duration of infection BMI/steatosis IL28b polymorphism HIV VIRUS Genotype Viral load Quasispecies SNP s Worth mentioning Prometheus predictor not valid in mono-infected IL28, GT, Viral load, TE (fibrosis) Because devised in co-infected cohort? SVR results in lower fibrosis rates (by TE) Also true for those with advanced fibrosis Predictors of treatment response: Older age at treatment (< strong than mono-infected) Adding LDL receptor genotype to IL28b GT Increased IL6 and IL9 Low calcium during treatment (?surrogate marker for RIB levels) 14

15 Co-infection and malignancies HCV/HIV clinical data: Telapravir Bocepravir HCV/HIV DDI s Bocepravir TMC 435 Daclatasvir HCV monoinfection GS 7977 Worth a mention Malignancy NADM and link to CD4 / VL factors NHL after VL suppression TB STRIDE and IRS 1 vs. 4 vs. 8 week ART start DAD and NADM Background HIV positive individuals are at higher risk of non-aids defining malignancies (NADMs)* An increased risk of some specific NADMs has been seen in those with a lower CD4 count** However, the independent associations between the magnitude/duration of immunosuppression, the latest HIV RNA level, and the development of NADM remain unclear Information was collected on all new NADM from 1/1/2004-1/2/2010 *Grulich, Lancet 2007, Powles,JCO 2009, Shiels JAIDS 2009 **Silverberg, Cancer Epidemiol Biomarkers Prev 2011, Reekie Cancer 2010 Kesselring CID 2011, Bruyand CID 2009, Guiget Lancet Oncol

16 DAD NADM study - Objective To describe associations between the incidence rates (IR) of NADM and measures of immunosuppression and viraemia: -Latest CD4 count -Lagged CD4 count (by 6 months) -Nadir CD4 count - Time-averaged area-under-the curve (AUC) for CD4 -Duration of immunosuppression (<100/<200 CD4 cells/mm 3 ) -Latest HIV RNA -AUC for HIV RNA Incidence of first NADM (with 95% CI) stratified by different indicators of immunosuppression Latest CD4 (cells/mm 3 ) Lagged CD4 (cells/mm 3 ), 6 months < >500 < >500 Nadir CD4 (cells/mm 3 ) Time-averaged CD4 (cells/mm 3 )` < >500 < >500 16

17 Incidence of first NADM (with 95% CI) stratified by duration of immunosuppression (years) <200 cells/mm 3 <100 cells/mm 3 Years, duration of immunosuppression RR /year: 1.05 (1.04, 1.06), p= RR /year: 1.05 (1.03, 1.07), p= Incidence of first NADM (with 95% CI) stratified by indicators of viraemia Latest HIV RNA AUC for HIV RNA Latest HIV RNA (copies/ml) RR /log higher (log 10 copies/ml): 1.05 (0.99, 1.13), p=0.13 RR /unit: 1.04 (1.00, 1.09), p=

18 Impact of immune recovery (subgroup of patients with a prior CD4 <200 cells/mm 3 ) 1.4 Years since last CD4 <200 Rate /100 PYRS None < >8 Years since last CD4 count <200 cells/mm RR per year 3 Before adjustment: 0.94 [0.92, 0.97], p= After adjusting for latest CD4 count: 0.99 [0.96, 1.03], p=0.65 Conclusions The risk of NADM (overall and the three most frequently observed cancers) is increased at low CD4 counts The risk is reduced in those whose CD4 count increases A low nadir CD4 remains associated with a persistent increase in risk In a subgroup of patients exploring duration of immunosuppression, data suggested that if patients recover from a prior low CD4 counts, that nadir CD4 is not relevant for your current risk 18

19 Incidence/predictors of NHL when achieved VL suppression (CNICS cohort) Inclusions: Initiated ART and suppressed VL <500 c/ml within 1y Follow/up after 1998 Exclusion NHL diagnosed after achieving VL <500 c/ml Results After suppression While suppressed All DLBCL 49 (64%) 21 (60%) Burkitt s 9 (12%) 6 (17%) Primary CNS 6 (8%) 2 (6%) Other / NOS 12 (16%) 6 (17%) 19

20 Conclusions Persistent high incidence of NHL despite ART (7-8 x HIV ve [KP and SEER cohorts] CD4 count (nadir and current) independent factor VL also contributes to risk Further reduction in NHL incidence Earlier diagnosis Initiating ART at higher CD4 Maintaining VL suppression Co-infection and malignancies HCV/HIV clinical data: Telapravir Bocepravir HCV/HIV DDI s Bocepravir TMC 435 Daclatasvir HCV monoinfection GS 7977 Worth a mention Malignancy NADM and link to CD4 / VL factors NHL after VL suppression TB STRIDE and IRS 1 vs. 4 vs. 8 week ART start 20

21 A5221: STRIDE study design Presumed or confirmed TB; EFV TDF FTC: RIF based country approved regimen: <2w or 8-12w. 806 patients from 4 continents, Half had confirmed TB, Median CD4 77, Median 10d and 70d Severity of IRS by CD4 Rate of IRS by CD4 and Randomised arm Severity of IRS by CD4 21

22 IRS timing and presentation Most frequent Lymphadenopathy (59%) New constitutional symptoms (54%) Radiographic changes (41%) CNS IRS uncommon (7%) Risk greatest in first 16w Median duration 87d (44, 139) Earlier Later P value Mediandays to IRS from TB treatment start Median days to IRS from ART start 29 (IQR 20, 69) 18 (10, 59) 82 (65, 99) 15 (7, 23) <0.001 NS Summary 7.6% overall developed IRS More frequent with: earlier ART & CD4 <50 Risk factors: High baseline VL & Lower CD4 Presentation Lymphadenopathy & constitutional symptoms Median onset 2w after ART: duration median 87d Severity More severe with earlier ART: no deaths 31% required hospitalisation, 54% steroids, 34% >1 invasive procedure 22

23 Competing risks in timing of ART during TB/HIV Early (<2 weeks) Benefits OIs Mortality Risks AEs IRIS Drug interaction Pill burden Late (>8 weeks) Benefits IRIS Risks OIs Mortality Wondwossen Amogne Degu et al., Abstract 144, CROI 2012 Study hypothesis After 24 wks of follow-up, ART one week after anti-tb as compared to 4 & 8 wks Primary: will reduce all-cause mortality Secondary: no significant differences in IR* of: Drug induced liver injury (DILI) discontinue anti-tb TB IRIS New ADI CD4 and HIV RNA response AFB smear conversion Wondwossen Amogne Degu et al., Abstract 144, CROI

24 Study design Anti-TB ART start -Week 1 (arm 1) ART start -Week 4 (arm 2) ART start -Week 8 (arm 3) Day 0 Week 2 Week 4 Week 8 Week 12 Week 20 Week 24 ART = EFV, 3TC and D4T/TDF/ZDV TB treatment = 2RHZE/4RH Wondwossen Amogne Degu et al., Abstract 144, CROI 2012 Patient characteristics variable Arm 1 Arm 2 Arm 3 P value Age (mean +sd) Male sex n (%) 96 (56.1%) 85 (53.8%) 59 (40.7%) 0.02 BMI kg/m2 (mean +sd) Type TB diagnosis PTB +ve 30 (17.5%) 28 (17.7%) 41 (28.3%) PTB -ve 96 (56.1%) 80 (50.6%) 69 (40.7%) 0.08 (df=4) EPTB 45 (26.3%) 55 (34.8%) 35 (24.1%) CD4 (mean 95% CI) 75.5 ( ) 89.8 ( ) 90.2 ( ) 0.01 Log HIV RNA (mean +sd) Anti-TB before cart* 7 days (7-8) 28 days (28-30) 56 days (56-60) Wondwossen Amogne Degu et al., Abstract 144, CROI

25 Primary endpoints All cause mortality Arm 1 Arm 2 Arm 3 Total deaths IR/1000 person weeks X2 log rank= 1.7 df=2 P value 0.4 Mortality proportions before & after cart Arm 1 Arm 2 Arm 3 Before cart After cart Wondwossen Amogne Degu et al., Abstract 144, CROI 2012 Hepatotoxicity and IRS Drug-induced liver injury requiring discontinuing anti-tb Incidence of TB-IRS Wondwossen Amogne Degu et al., Abstract 144, CROI

26 Conclusions EFV-based ART1 week (arm 1) after anti-tb as compared to 4 (arm 2) & 8 weeks (arm 3) No difference in all-cause mortality 2/3 rd of deaths in week 8 occurred before ART Mortality trend for CD4 < 50 cells/µl ( arm 3) Comparable effect on CD4 at 24 weeks Comparable effect on HIV RNA levels at 24 weeks Wondwossen Amogne Degu et al., Abstract 144, CROI 2012 Co-infection and malignancies HCV/HIV clinical data: Telapravir Bocepravir HCV/HIV DDI s Bocepravir TMC 435 Daclatasvir HCV monoinfection GS 7977 Worth a mention Malignancy NADM and link to CD4 / VL factors NHL after VL suppression TB STRIDE and IRS 1 vs. 4 vs. 8 week ART start 26

27 BHIVA Best of CROI Working Party 2012 Dr D Asboe, Chelsea and Westminster Hospital, London Dr S Bhagani, Royal Free Hospital, London Dr D Churchill, Royal Sussex County Hospital, Brighton Mr S Collins, HIV-iBase Dr S Das, Coventry and Warwickshire Hospital Dr T de Silva, Royal Hallamshire Hospital, Sheffield Dr MJ Fisher, Royal Sussex County Hospital, Brighton Dr J Fox, Guy s and St Thomas NHS Foundation Trust, London Miss E Gathogo, Royal Free Hospital, London D N Kay, Northwick Park Hospital, London Prof S Khoo, University of Liverpool Dr R Kulasegaram, St Thomas Hospital, London Prof C Leen, Western General Hospital, Edinburgh Dr F Martin, University of York Dr G Moyle, Chelsea and Westminster Hospital, London Dr EC Ong, Royal Victoria Infirmary, Newcastle Dr A Palfreeman, Leicester Royal Infirmary Dr S Shaw, Brighton and Sussex University Hospitals NHS Trust Dr C Short, Imperial College London Dr GP Taylor, Imperial College London Dr A Ustianowski, North Manchester General Hospital Miss R Weston, Imperial College London Dr EGL Wilkins, North Manchester General Hospital BHIVA Best of CROI Feedback Meetings London North East England North West England Edinburgh Birmingham BHIVA Best of CROI Feedback Meetings