BHIVA AUTUMN CONFERENCE 2010 Including CHIVA Parallel Sessions Dr Alan Winston Imperial College Healthcare NHS Trust London 7-8 October 2010, Queen Elizabeth II Conference Centre, London BHIVA AUTUMN CONFERENCE 2010 Including CHIVA Parallel Sessions Dr Alan Winston Imperial College Healthcare NHS Trust London COMPETING INTEREST OF FINANCIAL VALUE > 1,000: Speaker Name Alan Winston: Statement Dr. Winston has been awarded investigator initiated study grants, received speaker honorarium or attended advisory boards for Abbott, Boehringer-Ingelheim, BMS, Gilead Sciences, GSK, Merk & Co., Pfizer, Tibotec and ViiV Healthcare. Date 27 September 2010 7-8 October 2010, Queen Elizabeth II Conference Centre, London 1
The CNS penetration effectiveness score: What does it mean? Alan Winston St. Mary s Hospital, London October 2010 UK CHIC 1996-2007 200 150 100 any CNS event PML TOXO CRYP HIVe 50 0 1996/7 1998/9 2000/1 2002/3 2004/5 2006/7 Garvey et al PS6/5 Cologne EACS November 2009 2
HIV associated dementia in cart era Dore: AIDS, Volume 17(10).July 4, 2003.1539-1545 St. Mary s Cohort % anci 75 65 55 45 35 25 15 5-5 24-39 40-49 50-56 57-67 Interquartile age groups (years) 45 subjects on ART with plasma HIV RNA<50 copies/ml anciobserved in14/45 (31%) subjects associated with younger age (p=0.03) AIDS Res Hum Retroviruses. 2009 Aug;25(8):765-9 3
Why do we need a CNS penetration score? CNS penetration of ART Scoring instruments The evidence 4
CNS penetration of ART Scoring instruments The evidence CNS drug penetration Solon E, et al. Drug Metab Dispos. 2002;30: 1164-9 5
CSF : plasma ratios Antiretroviral Agent CSF : plasma ratio Commentson study Reference NRTIs abacavir 36 % AntimicrobAgents Chemother49, 2504-6 (2005) didanosine N.D. PharmWorld Sci17, 218-21 (1995) emtricitabine 43 % 16th CRIO. 2009. Montreal, Canada: poster 702 lamivudine 30 % Lancet 351, 1547-51 (1998) tenofovir 4 % unlikelytoexceedwildtypeic 50fortenofovir 15th CROI. 2008: Boston, MA zidovune 40 % Lancet 351, 1547-51 (1998) NNRTIs efavirenz 0.5 % below1%-maybesufficienttosuppresswildtypevirus 16th CROI. 2009. Montreal, Canada: poster 702. nevirapine 63 % thehighestcsf:plasmaratiodescribedtodate Clin Infect Dis 41, 1787-93 (2005) Boosted PIs atazanavir < 1 % unlikelytobeabovetheic 50forwildtypevirus AIDS 23, 83-7 (2009) lopinavir 0.23 % AIDS 19, 949-52 (2005) darunavir 0.8 % intherangerequiredtosuppressionwildtypevirus AIDS Res Hum Retroviruses 25, 457-61 (2009) Other classes maraviroc 2% J AcquirImmune DeficSyndr. 2010 Aug 11 raltegravir 3% PLoSOne. 2009 Sep 1;4(9) N.D. not detected in CSF in studies to date CNS penetration reference score Abacavir CSF concentrations Abacavir Concentration (ng/ml) Plasma CSF 2000 1000 100 10 Time After Dose (hours) Limitations Definition of IC 50 Inter-subject variability CSF exposure, not cerebral Population studied 0 2 4 6 8 10 12 14 16 IC 50 =70 ng/ml CapparelliEV et al. AntimicrobAgents Chemother. 2005;49:2504-2506 6
Raltegravir and CSF IC 95 PLoS One. 2009 Sep 1;4(9) Raltegravir and CSF PLoS One. 2009 Sep 1;4(9) 7
A new approach to classification Highest Level of evidence Lowest Pharmacodynamics Pharmacokinetics Drug characteristics Clinical results Incidence of NCI NC function Concentration above IC 50 Definition of IC 50 Consistent with CNS penetration CNS Penetration effectiveness score (CPE): 2007 additive score 0 / 0.5 / 1 2010 additive score 1 / 2 / 3 / 4 LetendreS et al. ArchNeurol2008;65:65-70 / LetendreS et al. CROI 2010, Poster 430 CNS penetration of ART Scoring instruments The evidence 8
The evidence in HIV infection Management of OIs Management of HIV infection Survival PML and CNS penetrating cart Gasnault et al. CROI 2008 abstract 385 9
The evidence in HIV infection Management of OIs Management of HIV infection o Neuroasymptomatic subjects o Neurosymptomatic subjects The evidence in HIV infection Management of OIs Management of HIV infection o Neuroasymptomatic subjects Primary HIV infection 10
Primary HIV infection Animal model: 8 rhesus monkeys infected SIV 4 (50%) Rx ART (tenofovir plus nelfinavir) 4 (50%) Rx placebo All CNS parameters normalised in active Rx group Locomotor activity AIDS 2009, 23:1187 1195 The evidence in HIV infection Management of OIs Management of HIV infection o Neuroasymptomatic subjects Primary HIV infection Electively commencing ART 11
Electively commencing ART Odds Ratios for Cognitive Impairment According to CD4 Nadir Strata (All Subjects) Neurology sub-study START Ellis et al. CROI 2010, poster 429 Electively commencing ART ALTAIR study ART-naïve study, examining 3 randomised treatment arms: 1.TDF/FTC + EFV 2.TDF/FTC + ATV/r 3.TDF/FTC + AZT + ABC CNS sub-study Neurocognitive function computerised testing at baseline and week 48 Cerebral 1 H-MRS at baseline and week 48 Subject characteristics Overall N=30, EFV (N=9), ATV/r (N=9) and AZT/ABC (N=12) All neuro-asymptomatic Winston A, Duncombe C, et al. Clin Infect Dis. 2010 Mar 15;50(6):920-9 12
ALTAIR NC testing results: Composite speed score Executive function Composite speed change (baseline to week 48) Change number of errors ( baseline to week 48) p=0.15 p=0.04 p=0.71 p=0.02 + + TDF/FTC/EFV TDF/FTC/ATV/r TDF/FTC/AZT/ABC TDF/FTC/EFV TDF/FTC/ATV/r TDF/FTC/AZT/ABC Changes in cerebral metabolites NAA Cho Cr p=0.041 p=0.054 + mi TDF/FTC/EFV TDF/FTC/ATV/r TDF/FTC/AZT/ABC Summary: Greater improvements in NC function testing observed in the quadruple NRTI arm Greater recovery in neuronal CNS metabolites were observed in the EFV-containing arm Data suggest that different ART may have different cerebral effects Winston A, Duncombe C, et al. Clin Infect Dis. 2010 Mar 15;50(6):920-9 Neuronal damage and ART Frontal White Matter NAA Total months exposure NRTIs Journal of NeuroVirology, 11: 356 364, 2005 13
Neuronal damage and ART Neurons stained for microtubule-associated protein-2 (MAP-2): (A) normal untreated cultures (B) dendritic beading (C) pruning of dendrites (D) loss of neuron density Following 6 days exposure to ARVs at reported plasma concentrations: (B) and (C) cultures treated with atazanavir (D) maximal damage seen with efavirenz CROI 2010, poster 435 The evidence in HIV infection Management of OIs Management of HIV infection o Neuroasymptomatic subjects Primary HIV infection Electively commencing ART Stable on ART 14
Subjects on ART To determine whether antiretroviral regimens with good central nervous system (CNS) penetration control HIV in cerebrospinal fluid (CSF) and improve cognition, n=101 Higher CPE scores correlate with: lower CSF viraemia lower NC performance CSF HIV RNA NC performance Variable Odds-ratio LCL UCL P Value Variable Odds-ratio LCL UCL P Value Nadir CD4 count 1.2 0.96 1.49 0.1 NNRTI Regimen 1.71 0.51 5.73 0.39 Number of ARV Agents 0.7 0.44 1.12 0.14 CPE rank 2 3.22 0.95 10.87 0.06 Entry NPZ4 0.86 0.61 1.12 <0.001 CSF HIV RNA < 50 0.27-0.25 0.79 0.31 Number of ARV Agents -0.38-0.59-0.17 0.001 CPE rank 2-1.08-1.66-0.5 <0.001 ARV includes efavirenz -0.29-1.09 0.51 0.48 Marra et al. AIDS. 2009 Jul 17;23(11):1359-66 CPE score in the UK (CHIC) Factors independently associated with a CPE score >3 included greater pre-treatment HIV RNA level (p=0.005) calendar year (2000 and 2003, p<0.0001) female heterosexual subjects were less likely to be prescribed cart with a CPE score >3 than individuals from other HIV risk groups (p<0.0001). Garvey, Winston, Sabin. CROI 2010 poster 427 15
The evidence in HIV infection Management of OIs Management of HIV infection o Neuroasymptomatic subjects Primary HIV infection Electively commencing ART Stable on ART Novel treatment approaches PI monotherapy 1 MONET: Changes in FAHI Cognitive Functioning Score over 48 weeks between study treatment arms DRV/r 2 MOST: Study terminated DRV/r + NRTIs 3 PIVOT: Study week 1. HIV Clin Trials. 2010 May-Jun;11(3):163-9 / 2. AIDS. 2010 Sep 24;24(15):2347-2354 16
The evidence in HIV infection Management of OIs Management of HIV infection o Neuroasymptomatic subjects o Neurosymptomatic subjects Not on ART On ART Detectable plasma viraemia Undetectable plasma viraemia Abacavir dementia study Study design Neurocognitively impaired HIV-infected subjects on ART eligible Randomised to ABC or placebo Primary outcome change NPZ-score N=105 Lack efficacy inefficacy of ABC per se prolonged benefit from existing therapy differences baseline characteristics baseline drug resistance CSF and plasma HIV-1 RT genotypes were discordant in 14/21 (67%) After 12 weeks ABC + SBT SBT Number subjects 39 44 Change NPZ-score 0.76 0.63 Rangechange in score -2.53 to 2.69-3.89 to 3.32 Balanced CPE score PLoS Clin Trials. 2007 Mar 30;2(3): 17
Balanced CPE score Genetic distance between CSF and plasma virus: 39 subjects on ART with HIV encephalopathy high genetic distance associated with o undetectable plasma viral load o low-balanced CPE score The detectable viral loads in plasma might favour virus diffusion across the blood brain barrier and high-balanced CPE score could prevent the viral replication in the CNS compartment AIDS 2010, 24:2403 2414 The evidence in HIV infection Management of OIs Management of HIV infection o Neuroasymptomatic subjects o Neurosymptomatic subjects Not on ART On ART Detectable plasma viraemia Undetectable plasma viraemia 18
CNS penetration effectiveness score: What does it mean? Advancement in scoring system assessing CNS drug penetration o Not just using CSF:plasma ratios Limitations o o o o o o Scores most often based on PK not PD data (PK data have limitations) Cerebral toxicities of ART not considered and may be paramount Clinical scenarios where CNS penetration may be important remain unknown Cohort studies may report biased results as CPE score biased Encompassing measures of drug resistance challenging Drug-drug interactions The evidence in HIV infection Management of Ois Management of HIV infection o Neuroasymptomatic subjects Primary HIV infection Electively commencing ART Stable on ART Novel treatment approaches o Neurosymptomatic subjects Not on ART On ART Detectable plasma viraemia Undetectable plasma viraemia 19
CNS Penetration Effectiveness Score (CPE) NRTIs 1 0.5 0 Abacavir Zidovudine Emtricitabine Lamivudine Stavudine NNRTIs Nevirapine Efavirenz PIs Fusion inhibitors Amprenavir Indinavir Lopinavir Atazanavir Didanosine Tenofovir Nelfinavir Ritonavir Saquinavir Tipranavir Enfuvirtide Letendre S et al. Arch Neurol 2008;65:65-70 CNS Penetration Effectiveness Score (CPE) 4 3 2 1 NRTIs Zidovudine Abacavir Emtricitabine NNRTIs Nevirapine Delavirdine Efavirenz Didanosine Lamivudine Stavudine Etravirine Tenofovir Zalcitabine PIs Indinavir-r Darunavir-r Fosamprenavir-r Indinavir Lopinavir-r Entry/Fusion Inhibitors Maraviroc Atazanavir Atazanavir-r Fosamprenavir Nelfinavir Ritonavir Saquinavir Saquinavir-r Tipranavir-r Enfuvirtide Integrase Inhibitors Raltegravir Letendre S et al. CROI 2010, Poster 430 20