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Pharmacology of antiretrovirals and chemoprophylaxis

Pharmacology of antiretrovirals and chemoprophylaxis. Stephen Kerr, PhD HIV-NAT, Thai Red Cross AIDS Research Centre Kirby Institute, UNSW. Introduction. Urgent need for Primary HIV Prevention strategies 34 million people living with HIV in 2011

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Pharmacology of antiretrovirals and chemoprophylaxis

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  1. Pharmacology of antiretrovirals and chemoprophylaxis Stephen Kerr, PhD HIV-NAT, Thai Red Cross AIDS Research Centre Kirby Institute, UNSW

  2. Introduction • Urgent need for Primary HIV Prevention strategies • 34 million people living with HIV in 2011 • 2.5 million new HIV infections (UNAIDS 2012 Global Report) • High risk groups: young women, sero-discordant couples, MSM, IDU • Evidence for ART as a tool in HIV prevention • Prevention of mother to child transmission • HPTN 052 - Reduced infectiousness of persons on ART • Prophylaxis after high risk exposure (PEP) • Continuous/intermittent use for persons with ongoing exposure – pre-exposure prophaylaxis (PrEP)

  3. What are the desirable characteristics for PrEP? • Safe • Low toxicity potential • Effective • Should have significant efficacy in ‘real life’ situations • Pharmacokinetic properties • Rapidly target the appropriate sites of infection, in the correct concentrations, and for the right amount of time • Cost-effective • Must be affordable in ‘at risk’ populations • Acceptable • Topical agents must be acceptable when used in conjunction with sex; oral agents should have low pill burden • Good resistance profiles • Use for prevention should not limit therapeutic options for people who become infected

  4. Balance of vulnerabilities between virus and host Virus vulnerability Hours Days Weeks Window of opportunity for PrEP Adapted from Garcia-Lerma, JG et al, Trends Pharm Sci, 2010; 31(2):74

  5. Viral life cycle Shattock R J , and Rosenberg Z Cold Spring HarbPerspect Med 2012;2:a007385

  6. Pharmacokinetic-pharmacodynamic relationships Pharmacokinetics (PK) - Absorption - Distribution - Metabolism - Elimination • Pharmacodynamics (PD) • - How do in vivo drug • concentrations relate to • protective/toxic effects • - Limited understanding for PrEP Inter-patient variability

  7. Physical characteristics affect distribution Only free drug can freely diffuse across membranes: • Other physical characteristics important (eg ionization state at physiological pH) • Different relationships exist for systemic/genital/rectal compartments

  8. Pharmacology of TFV and FTC • TDF versus TVF • TVF & FTC require intracellular phosphorylation • NTRI-phosphates are ionized and persist in the cellular site of action after the drug is cleared from plasma 150

  9. Drug distribution into compartments Oral TDF±FTC Topical TVF Genital/rectal secretions Blood Plasma Genital/rectal tissue Total Total FUB FUB Mononuclear cells Compartmental drug concentrationvs time - Sufficient concentrations/time periods TVF FTC TVF-DP FTC-TP Tissue compartments: multiple sub-compartments – homogeneous drug? Only specific tissue sub-compartments are susceptible to HIV Some susceptible target cells circulate in and out of compartments Modified from Nichol, MR. & Kashuba, ADM. Clin Pharm Ther. 2010; 88(5)598

  10. Viral distribution and elimination after intercourse • Advanced imaging techniques, with cell free and cell associated HIV radiolabelled surrogates and simulated intercourse • Females (Louissant, NA. et al JID 2012; 205:725): • Retention in the vaginal lumen, concentrated in peri-cervical area • 1/3 of administered dose retained at 4 hours • Males (Louissant, NA. et al JAIDS 2012; 59:10): • Retention in the lumen, distribution to the rectosigmoid colon • Detectable at low levels at 24 hours • ART compartmental concentrations need to be maintained at sufficient levels for 24 hours after viral exposure Modified from Nichol, MR. & Kashuba, ADM. Clin Pharm Ther. 2010; 88(5)598

  11. Concvs time in plasma & female genital tract after oral TDF & FTC Drummond, JB et al. AIDS. 2007; 21(14)1899

  12. C24hrs of TDF/FTC after a single oral Truvada dose 100X 10X C24hrs (ng/mL, ng/g or fmol/g) Patterson, KB et al. Sci Trans Med. 2011; 3(112)112re4

  13. TVF concentrations – different administration routes MTN-001: crossover study of oral TDF:1% vaginal gel • TFV Cplasma 60x higher after oral vs vaginal administration • TFV-DP Cvaginal tissue 130x higher with vaginal vs oral administration • TFV Crectal fluid 5x higher with vaginal vs oral administration Hendrix et al. (2013) PLoS ONE 8(1): e55013

  14. Human clinical studies reported 39% Stopped early for futility 44% Lower or undetectable drug concentrations in subjects who seroconverted versus those who did not 62-75% 49% Percent effectiveness - ITT

  15. PrEP Studies with positive results 82% TDF detected 80% TDF detected 66% TDF detected 51% TDF detected Effectiveness N= 4747 M, F N= 1219 M, F N= 2413 IDU, M,F N= 2499 MSM, TG Slide adapted from KiatRuxrungtham

  16. The STRAND Study • Open label, randomized, crossover study of TDF. • 12 men and 12 women, HIV-negative • Each subject received 2, 4 or 7 TDF per week, for 6 weeks • Doses were directly observed M-F, and confirmed by text messaging or telephone on weekends • TDF-DP was measured in PBMC at the end of each 6 week dosing period • A pre-specified analysis was conducted with subjects from iPrEx

  17. Estimated HIV incidence in iPrEx 16 fmol/106 PBMC reduced HIV incidence by 90% Anderson, PL et al. Science Translational Medicine (2012) 4(151):151ra125

  18. Infection rates in CAPRISA 004, by TDF concentrations in CVF AbdoolKarim, SS et al. The Lancet (2011) 378:279

  19. Studies with negative results? • Discordant results may relate to: • Incidence of HIV in the population • Trial design/dosing regimen • Adherence to the study medications • Sexual behaviours • FEM-PrEP • Less than 30% of subjects who acquired HIV had TFV concentrations in plasma ≥ 10ng/mL (discordant pill count data) • VOICE • <30% had detectable TDF in plasma, and adherence was worse amongst younger, unmarried women most at risk for HIV (based on pill and un-used applicator counts, adherence was ~90%)

  20. Improving our understanding of PK/PD relationships • Non-human primates and humanized mice models • Histologic/biologic similarities & differences to humans • Optimization and standardization of sampling & processing • Standaridzation of dosing and virus challenge • Ex vivo studies – suggest dose response relationships, but further development needed • Dose fractionation studies to establish concentration-time relationships: Cmax, AUC, MIC and time > MIC • Assays need to discriminate between free and protein-bound concentrations in sub-compartments Aromano, J et al. AIDS Research Human Retroviruses (2013) doi: 10.1089/aid.2013/0122

  21. Summary • Drug concentrations for protection relate to route of viral exposure (vaginal, penile, rectal) • Drug concentrations at active sites differ by drug and administration route • Consistent PrEP use is associated with a protective effect in individuals with ongoing/repeated exposure to HIV • Limited data is available from human clinical studies and greater understanding of PK-PD relationships in animal and ex vivo models is needed to inform evidence based practice

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