HIV and the Central Nervous System Impact of Drug Distribution Scott L. Letendre, MD. Professor of Medicine University of California, San Diego

Transcription

1 HIV and the Central Nervous System Impact of Drug Distribution Scott L. Letendre, MD Professor of Medicine University of California, San Diego

2 Disclosures Grant/research support Abbvie Gilead Sciences Merck ViiV Healthcare Consultancy Merck ViiV Healthcare Conference support Abbvie ViiV Healthcare Funds for investigator-initiated research were paid to University of California, San Diego by: Abbott GlaxoSmithKline/ViiV Healthcare Merck

3 Summary Antiretroviral drugs differ in their distribution into the CNS. Antiretroviral drugs are used in combination, making the contribution of an individual drug difficult to determine Estimates of distribution correlate best with indicators of HIV replication or immune response. Estimates of drug distribution correlate less consistently with neurocognitive functioning. Several factors can alter the impact of HIV disease. Many conditions can influence neurocognitive functioning other than HIV.

4 Antiretroviral drugs differ in their distribution into the CNS

5 Multiple Issues to Consider Regarding ART Effectiveness in the CNS Suppression of HIV replication Lymphocytes Monocytes & macrophages Immune recovery Potency Slow metabolism Protein binding Protected compartments Intracellular distribution Molecular transporters Toxicity Metabolism & Distribution Neurotoxicity Central NS Peripheral NS Hepatotoxicity Renal toxicity Metabolic & vascular disorders

6 Pharmacokinetics in CSF and Blood Indinavir Darunavir Fosamprenavir Lopinavir Atazanavir Best et al, AIDS 2009; 23:83-87; Capparelli et al, AIDS 2005; 19:949-52; Letendre et al, 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, 2009; Letendre et al, 9th Intl Workshop on Clinical Pharmacology of HIV Therapy, 2009; Letendre et al, Antimicrobial Agents and Chemotherapy 2000, 44:2173

7 CNS Penetration Effectiveness Ranks 2010 NRTIs Much Above Average Above Average Average Below Average Zidovudine Abacavir Didanosine Tenofovir Emtricitabine Lamivudine Zalcitabine Stavudine NNRTIs Nevirapine Delavirdine Etravirine Efavirenz PIs Indinavir-r Darunavir-r Atazanavir Nelfinavir Fosamprenavir-r Atazanavir-r Ritonavir Indinavir Fosamprenavir Saquinavir Lopinavir-r Saquinavir-r Tipranavir-r Entry/fusion inhibitors Integrase inhibitors Maraviroc Enfuvirtide Raltegravir Letendre SL, Topics Antiviral Medicine 2011; 19(4):137-42

8 CNS Penetration Effectiveness Ranks 2010 Much Above Average NRTIs Above Average Average Abacavir Emtricitabine NNRTIs Below Average Tenofovir Lamivudine Etravirine Efavirenz PIs Darunavir-r Atazanavir-r Lopinavir-r Entry/fusion inhibitors Integrase inhibitors Maraviroc Raltegravir Letendre SL, Topics Antiviral Medicine 2011; 19(4):137-42

9 CNS Penetration Effectiveness Ranks Much Above Average NRTIs Above Average Average Below Average Abacavir Emtricitabine NNRTIs Etravirine 1,2 Tenofovir Lamivudine Rilpivirine 3 Efavirenz PIs Darunavir-r Atazanavir-r Lopinavir-r Entry/fusion inhibitors Integrase inhibitors Maraviroc Dolutegravir 1Tiraboschi 4 Raltegravir Elvitegravir/c et al, J Antimicrob Chemother 2012;67: ; 2Nguyen et al, J Antimicrob Chemother 2013;68:1161-8; 3 Mora-Peris et al, J Antimicrob Chemother 2014; 3Letendre et al, CROI 2013, Abstract 178LB

10 Dolutegravir Concentrations in CSF Decline Over Time but Exceed the IC50 IC50 for wild-type HIV = 0.2 ng/ml Median CSF/IC50 ratio: Week 2: 91 Week 16: 66 Letendre et al, CROI 2013, Abstract 178LB

11 Estimates of antiretroviral drug distribution into the CNS correlate best with indicators of HIV replication or immune response

12 Estimates of Lower Drug Distribution Into the CNS Are Associated With: Higher HIV RNA levels in CSF CSF viral escape Higher soluble biomarker levels in CSF Neurocognitive impairment but inconsistently 50 c/ml Assay 2 c/ml Assay Cross-sectional Yes1 Yes3 Longitudinal Yes2 No4 Included patients with plasma HIV RNA > 50 HIV RNA 2-50 c/ml associated with NCI Comment Letendre et al, 1CROI 2010, 2CROI 2012, 3CROI 2009, 4CROI 2013

13 Higher CPE Values Are Associated With Undetectable CSF HIV RNA 2,207 CSF Viral Loads in 413 Adults p < Letendre et al, CROI 2012, Abstract Low-Level CSF Viral Loads Model R2 = 0.22, p < Letendre et al, CROI, 2009, Abstract 484b

14 Estimates of Lower Drug Distribution Into the CNS Are Associated With: Higher HIV RNA levels in CSF CSF viral escape Higher soluble biomarker levels in CSF Neurocognitive impairment but inconsistently 50 c/ml Assay 2 c/ml Assay Cross-sectional Yes1 Yes3 Longitudinal Yes2 No4 Included patients with plasma HIV RNA > 50 HIV RNA 2-50 c/ml associated with NCI Comment Letendre et al, 1CROI 2010, 2CROI 2012, 3CROI 2009, 4CROI 2013

15 Different Drugs May Influence Risk for CSF Viral Escape First Author Sample Size Percent With CNS VE Rawson % Cusini % Protein CPE Edén % Neopterin Not ZDV 1, % WBCs PI/r Use ATV Use Pinnetti % - ATV/r Use ABC+3TC Use Eden % Neopterin Not noted Perez-Valero4 Weighted median 1Rawson CSF Correlates ART Correlates CPE 10.3% et al, Journal of Infection 2012;65:239-45; 2Cusini et al, J Acquir Immune Defic Syndr 2013;62:28-35; 3Eden et al, J Infect Dis 2010;202(12): ; 4Perez-Valero et al, J Intl AIDS Soc 2012;15(Suppl 4):18189; 5Pinnetti et al, CROI 2014, Abstract 443; 6Eden et al, CROI 2014, Abstract 445 Published case series/reports of CSF Viral Escape: Canestri et al, CID 2010; Peluso et al, AIDS 2012; Khoury et al, J Neurovirol 2013

16 The CSF Risk Score Cross-sectional analysis of 1,053 adults receiving combination ART who underwent CSF evaluation at study entry ( ) Multivariable logistic regression model to identify correlates of CSF HIV RNA > 50 copies/ml Internal validation by 5-fold cross-validation and bootstrapping CSF HIV Risk Score developed by weighting regression units for retained variables as integer points Condition Value Odds Ratio Race White 1.00 Black Other No 1.00 Yes % % < 85% < Current MDD 4-Day Adherence CPE Value P < < < < , > 10, ART Duration (months) Risk Score 10 Plasma HIV RNA (copies/ml) p value > <6 4 Hammond et al, CROI 2014, Abstract 509

17 Estimates of antiretroviral drug distribution correlate less consistently with neurocognitive functioning

18 Advanced immune suppression Genetic Hostrelated Comorbid conditions HIVrelated Immune activation Persistent HIV replication Behavior Viral proteins Protein glycation Microbiome Viral hepatitis Other pathogenrelated CMV Neuronal injury & HAND Coagulation imbalance Cellular toxins Oxidative stress Drugrelated ART toxicity Stimulant & opiate use Polypharmacy Copyright S. Letendre, 2014

19 Simplified Model of Pathogenesis ART ART Neurotoxic HIV proteins HIV Immune & glial activation Neuronal injury Cognitive impairment Comorbid conditions Copyright S. Letendre, 2014

20 Most Well-Designed Studies Found That CPE Comparisons Had Medium Effect Sizes Cysique et al, 2004, N = 97 Chang et al, 2003, N =33 Cysique et al, 2009, N = 31 Tozzi et al, 2009, N = 185 Letendre et al, 2008, N = 467 Smurzynski et al, 2011, N = 2, Effect Size Cysique et al, BMC Neurology, 2011;11:148

21 Recent Reports Continue to Be Inconsistent N NP Duration Finding Notes Ciccarelli1 C-S 101 C - Beneficial 2010 version stronger than 2008 version Ciccarelli2 C-S 215 C - Beneficial Adjusted CPE using GSS Casado3 C-S 69 B - Trend toward benefit Beneficial in CD4 < 200 Vassallo4 L 96 C 22 months Beneficial ~25% were not virologically suppressed Ellis5 RCT 49 C 16 weeks No association Beneficial in subgroup Cross6 L 69 C ~1 year No association Binary transformation only Wilson7 C-S 118 B - Detrimental on 2 tests Binary transformation only Substance users only Kahouadji8 C-S 93 B - Detrimental on 1 test Methodological flaws C-S = Cross-sectional, L = Longitudinal, RCT = Randomized clinical trial, C = Comprehensive, B = Brief, GSS = Genotype Susceptibility Score 1Ciccarelli et al, Antivir Ther 2013;18:153-60; 2Ciccarelli et al, CROI 2013, Abstract 405; 3Casado et al, J Neurovirol 2014;20: 54-61; 4Vassallo et al, AIDS 2014;28: ; 5Ellis et al, Clin Infect Dis 2014;58: ; 6Cross et al, S Afr Med J 2013;103:758-62; 7Wilson et al, J Clin Exp Neuropsych 2013;35:915-25, 8Kahouadji et al, HIV Med 2013;14:311-5.

22 Uncontrolled Longitudinal Studies Found Similar Effect Sizes but Came to Different Conclusions South Africa (Subtype C) France (Subtype B) OR = 0.64 Cross et al, S Afr Med J 2013;103(10): Odds ratio is calculated from data in the report Vassallo et al, AIDS 2014;28: Graph is adapted from Table 2 These findings are reassuring for South Africa... Odds ratios from multivariable regression: Initial (first) CPE: 0.54 End-of-follow-up (last) CPE: 0.65

23 Cognitive Intervention Trial 2 Multicenter, NIH-funded clinical trial randomizing people with HAND to initiating or changing to either CNS-targeted or untargeted ART Primary endpoint: 16 weeks of ART Adaptive randomization to balance: ART experience (naive vs. experienced) Entry CD4+ T-cell count (<200 vs 200) Severity of impairment (mild vs moderate-severe) HCV serostatus Ellis et al, Clin Infect Dis. 2014; 58(7):

24 Enrollment and Disposition Planned Enrollment: 120 CNS-T n = Lost to Follow-Up ITT Analysis n = Protocol Violation AT Analysis n = 23 ITT = Intent-to-treat AT = As treated CNS-T = CNS-targeted Non-CNS-T = Non-CNS-targeted 42 Non-CNS-T n = 30 7 ITT Analysis n = 23 4 AT Analysis n = 19 Ellis et al, Clin Infect Dis. 2014; 58(7):

25 Planned Secondary Analysis Identified a Possible Benefit in Those Who Enrolled With Suppressed HIV RNA Effect Size = 1.1 p = Better Global Deficit Score Change (Baseline to Week 16) Baseline Plasma HIV RNA CNS-T Non-CNS-T (n = 19) (n = 17) > 50 c/ml CNS-T (n = 7) Non-CNS-T (n = 6) 50 c/ml

26 HCV Coinfection May Alter the PK-PD Relationship in the CNS Letendre et al, CROI 2013, Abstract 407

27 HIV RNA in CSF May Increase Risk for New-Onset Depression Hazard Ratios for Depression CSF *p < 0.01 Plasma * * Error bars are 95% confidence intervals Unadjusted Model 1 Final Model Model 1: Adjusted for CSF/plasma HIV RNA and adherence Final model: Adjusted for Model 1 and lifetime MDD, lifetime alcohol and substance abuse, duration of ART, CPE, age, sex, race Hammond et al, CROI 2014, Abstract 33

28 Guidelines to Consult in the Clinic US DHHS Does not discuss CPE or CNS-active ART Earlier initiation of ART may prevent subsequent brain dysfunction EACS Mind Exchange BHIVA Use CNSactive ART for patients with HIV-associated cognitive impairment and CSF viral escape Without HAND: No evidence supports use of higher-cpe ART CPE score should not influence therapeutic decisions in subjects with neurocognitive impairment commencing ART With HAND: HigherCPE ART generally associated with better neurocognitive functioning, but evidence base is limited DHHS Guidelines: last updated 30 Oct 2013; EACS Guidelines: last updated Oct 2013; Mind Exchange: Clin Infect Dis. 2013;56(7): ; BHIVA Guidelines: last updated Nov 2013

29 DHHS Preferred Regimens (Naive) TDF-FTC EFV ATV/r CSF concentrations do not exceed inhibitory concentrations in some May increase risk of CSF viral escape DRV/r CSF concentrations exceed inhibitory concentrations in all RAL CSF concentrations exceed inhibitory concentrations in all EVG/c ABC-3TC Short- and long-term neurotoxicity in some No CSF pharmacokinetic data DTG CSF concentrations exceed inhibitory concentrations in all DTG No CSF ABC pharmacokinetic data on daily dosing Last updated 30 October 2013; Available at

30 Summary Antiretroviral drugs differ in their distribution into the CNS. Antiretroviral drugs are used in combination, making the contribution of an individual drug difficult to determine. Estimates of distribution correlate best with indicators of HIV replication or immune response. Estimates of drug distribution correlate less consistently with neurocognitive functioning. Several factors can alter the impact of HIV disease. Many conditions can influence neurocognitive functioning other than HIV.