Distribution and Effectiveness of Antiretrovirals in the Central Nervous System

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1 Distribution and Effectiveness of Antiretrovirals in the Central Nervous System Scott Letendre, MD Associate Professor of Medicine HIV Neurobehavioral Research Center and Antiviral Research Center University of California, San Diego 15 April 2007 Second HIV Infection and the Central Nervous System, Venice, Italy

2 Acknowledgements Study Volunteers University of California, San Diego Ronald Ellis Allen McCutchan Igor Grant Jennifer Marquie-Beck Mariana Cherner Steven Paul Woods Robert Heaton Rodney von Jaeger National Institutes of Health NIMH, NINDS, NIDA CHARTER Group David Clifford Ann Collier Benjamin Gelman Christina Marra Justin McArthur Susan Morgello David Simpson

3 Antiretroviral Distribution Development of New Antiretrovirals All ARVs Acceptable Good Number of Drugs

4 Background Possible Explanations for Persistent NeuroAIDS Shifts in the demographics of the epidemic Delayed initiation of ART in some Incomplete suppression of HIV in the CNS Immune reconstitution inflammatory syndrome Neurotoxins that are not eliminated by ART Failure to silence activated macrophages and astrocytes Co-pathogens, e.g., Hepatitis C

5 Background Possible Explanations for Persistent NeuroAIDS Shifts in the demographics of the epidemic Delayed initiation of ART in some Incomplete suppression of HIV in the CNS Immune reconstitution inflammatory syndrome Neurotoxins that are not eliminated by ART Failure to silence activated macrophages and astrocytes Co-pathogens, e.g., Hepatitis C

6 Antiretroviral Distribution Distribution to the Brain Can Be Limited W.M. Pardridge, UCLA

7 Antiretroviral Distribution Structure of the Blood-Brain Barrier Clinical Care Options

8 Antiretroviral Distribution Factors Influencing Distribution into CNS Protein Binding Molecular Weight Lipophilicity Ionization Molecular pumps NRTIs > PIs ~ NNRTIs NRTIs > NNRTIs > PIs PIs ~ NNRTIs > NRTIs Tenofovir P-glycoprotein Organic anion transporters

9 Antiretroviral Distribution Class Averages of Distribution into CNS Unbound MW LogP Cmin IC50 Estimate NRTIs 96% , NNRTIs 14% , PIs 4% , FIs 8% 4, UCSD Analysis of Public Domain Data

10 Antiretroviral Distribution Within Class Differences in Distribution Antiretroviral concentrations in CSF may estimate those in the brain Some antiretrovirals reach therapeutic concentrations in CSF Others do not Antinori et al, Clin Infect Dis, 2005

11 Antiretroviral Distribution LPV Levels in CSF Typically Exceed IC [Lopinavir] (ng/ml) Time After Dose (hours) Extent of CSF penetration was 0.27% of plasma concentrations

12 Antiretroviral Distribution Fewer ATV Levels Exceed the IC [Atazanavir] (ng/ml) Time After Dose (hours) Extent of CSF penetration was 1% of plasma concentrations

13 Antiretroviral Distribution Availability of Human CSF PK Data Varies Number of PK Studies > 2 Emtricitabine Didanosine Abacavir Tenofovir Delavirdine Lamivudine Zalcitabine Nevirapine Stavudine Tipranavir Amprenavir Zidovudine Darunavir Atazanavir Efavirenz Saquinavir Enfuvirtide Lopinavir Indinavir Ritonavir Nelfinavir

14 Antiretroviral Distribution Availability of Human CSF PK Data Varies Number of PK Studies > 2 Emtricitabine Didanosine Abacavir Tenofovir Delavirdine Lamivudine Zalcitabine Nevirapine Stavudine Tipranavir Amprenavir Zidovudine Darunavir Atazanavir Efavirenz Saquinavir Lopinavir Enfuvirtide Indinavir Ritonavir Nelfinavir

15 Antiretroviral Distribution Estimated Distribution of Newer ARVs Unbound MW Cmin IC50 Est. LogP P-gp NNRTIs Etravirine 0.1% > 5 Yes Rilpivirine 1% High No Protease Inhibitors Darunavir 5% 548 3, Yes CCR5 Antagonists Maraviroc 24% Yes Vicriviroc 16% No Integrase Inhibitors Raletgravir 17% Yes Elvitegravir Yes

16 Antiretroviral Effectiveness Factors Influencing Effectiveness in the CNS Both transiting and resident cells can produce HIV virions Resident cells tend to be longer-lived Some NRTIs may be more effective in macrophages Protein binding may be less in the CNS CNS may have distinct resistance mutations Some drugs are eliminated more slowly from the CNS than from other compartments

17 Antiretroviral Effectiveness Slower Declines with More Advanced Disease Letendre et al., Clinical Infectious Diseases, Under Review

18 Antiretroviral Effectiveness Conceptual Model Reduce Neurotoxins Antiretrovirals Reduce HIV Replication in the CNS Cognition Improves Adequate Neuroprotection

19 Antiretroviral Effectiveness Nadir CD4 Counts > ~200 and Normal Cognition Reduce Neurotoxins Antiretrovirals Lymphoid- Derived CNS-Derived Cognition Maintained Neuroprotection Maintained

20 Antiretroviral Effectiveness Nadir CD4 Counts < ~200 or Impaired Cognition Reduce Neurotoxins Penetrating Antiretrovirals Antiretrovirals Lymphoid- Derived CNS-Derived Cognition Improves Reduced Improve Neuroprotection

21 Antiretroviral Effectiveness CNS Penetration-Effectiveness Score NRTIs Abacavir Emtricitabine Didanosine Zidovudine Lamivudine Tenofovir Stavudine Zalcitabine NNRTIs Delavirdine Efavirenz Nevirapine PIs Indinavir Amprenavir-r Amprenavir Indinavir-r Atazanavir Nelfinavir Lopinavir-r Atazanavir-r Ritonavir Darunavir-r Saquinavir Saquinavir-r Fusion Inhibitors Tipranavir-r Enfuvirtide

22 Antiretroviral Effectiveness Higher CPE Scores and Lower Viral Loads in CSF Letendre et al, Archives of Neurology, Under Review

23 Antiretroviral Effectiveness Higher CPE Scores and Lower Viral Loads in CSF CNS HIV AntiRetroviral Therapy Effects Research Project, Years 01-03

24 Antiretroviral Effectiveness Higher CPE Scores and Lower Viral Loads in CSF Letendre et al, 14th CROI, Abstract 369

25 Antiretroviral Effectiveness HIV RNA Suppression and NP Improvement Improvement in GDS Not Suppressed N=14 Χ 2 = 6.3; p =.01 Suppressed N=17 Letendre et al, Ann Neurol 2004

26 Antiretroviral Effectiveness Distribution and Cognitive Effectiveness Author Year Design N Effect Penetration Measure Giancola 2006 C-S 165 Similar Global Performance ² 1, 2, ³ 3 Penetrators Antinori 2004 C-S 165 Similar Global Performance No. of Penetrators Cysique 2004 P 97 Improved Learning, Recall & Motor ³ 3 Penetrators Evers (a) 2004 C-S 306 Improved Choice Reaction Times Multiple Evers (b) 2004 P 110 Similar Visual Evoked Potentials Multiple Letendre 2004 P 31 Similar Global Performance No. of Penetrators Robertson 2004 P 29 Similar Global Performance No. of Penetrators Chang 2003 P 33 Similar Performance & MRS ³ 2 Penetrators Marra 2003 P 25 Improved Global Performance ZDV, IDV Dougherty 2002 P 96 Similar MSK Improvement Single vs. Multiple von Giesen 2002 P 104 Improved Psychomotor Speed (Trend) NVP vs. EFV Sacktor 2001 P 73 Similar Psychomotor Performance Single vs. Multiple

27 Antiretroviral Effectiveness Effect Similar Global Performance Similar Global Performance Distribution and Cognitive Effectiveness Author Year Design N Effect Penetration Measure Giancola 2006 C-S Improved 165 Similar Learning, Global Performance Recall & Motor² 1, 2, ³ 3 Penetrators Antinori 2004 C-S 165 Similar Global Performance No. of Penetrators Cysique 2004 Improved P 97 Improved Choice Learning, Reaction Recall & Times Motor ³ 3 Penetrators Evers (a) 2004 C-S Similar 306Visual Improved Evoked Choice Reaction Potentials Times Multiple Evers (b) 2004 P 110 Similar Visual Evoked Potentials Multiple Similar Global Performance Letendre 2004 P 31 Similar Global Performance No. of Penetrators Robertson 2004 Similar P 29 Global Similar Global Performance No. of Penetrators Chang 2003 Similar P 33 Performance Similar & & MRS ³ 2 Penetrators Marra 2003 P 25 Improved Global Performance ZDV, IDV Dougherty 2002 Improved P 96 Similar Global MSK Improvement Performance Single vs. Multiple von Giesen 2002 Similar P 104MSK Improved Improvement Psychomotor Speed (Trend) NVP vs. EFV Sacktor 2001 P 73 Similar Psychomotor Performance Single vs. Multiple Improved Psychomotor Speed (Trend) Similar Psychomotor Performance

28 Summary and Conclusions Neuroeffectiveness Estimates are an Unmet Need Accurate estimates of neuroeffectiveness are an important unmet clinical need Research into estimation methods should Utilize more sensitive HIV RNA assays Account for antiretroviral potency in plasma Account for inter-individual differences in drug concentrations Therapeutic drug monitoring of plasma and perhaps CSF may improve neuroeffectiveness

29 Summary and Conclusions Current Methods are Imperfect Molecular characteristics provide estimates of pharmacokinetics but are not perfect Pharmacokinetics provide estimates of effectiveness but are also not perfect Data are available for only a subgroup of the most commonly used antiretrovirals

30 Summary and Conclusions Cohort Studies Can Provide Valuable Data Cohort studies should control for diseaseand treatment-related data Immunologic and neurologic disease stage Spectrum of regimens prescribed Antiretroviral experience and resistance Reductions in HIV RNA levels in plasma Cohort studies have important limitations Expert guidelines to guide future analyses Controlled studies, such as randomized clinical trials