pharmacology of antiretrovirals and chemoprophylaxis stephen kerr, phd hiv-nat, thai red cross aids...
TRANSCRIPT
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Pharmacology of antiretrovirals and chemoprophylaxis
Stephen Kerr, PhD
HIV-NAT, Thai Red Cross AIDS Research Centre
Kirby Institute, UNSW
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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)
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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
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Balance of vulnerabilities between virus and host
Infection established
• Small founder populations of immune cells in female genital tract, colo-rectum, male foreskin & urethra
Local expansion
• Early signal amplification
• Influx of CD4+ cells
• Seeding to distal sites
Systemic dissemination
• Establishment of lymphatic tissue reservoir
• High levels of viral replication
• Depletion of gut CD4+ cells
Virus vulnerability
Hours
Window of opportunity for PrEP
Days Weeks
Adapted from Garcia-Lerma, JG et al, Trends Pharm Sci, 2010; 31(2):74
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Viral life cycle
Shattock R J , and Rosenberg Z Cold Spring Harb Perspect Med 2012;2:a007385
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Pharmacokinetic-pharmacodynamic relationships
Dose administered Concentration at site of action
Drug effects (therapeutic/adverse)
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
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Physical characteristics affect distribution
Class/Drug Plasma protein binding
PI 95 – 99%
NRTI 7 – 49%
Maraviroc 85%
Raltegravir 83%
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
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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
TFV
FTC
3TC
ABC
ZDV
d4T
Raltegravir
Maraviroc
0 20 40
14
9
2
1
1
1
9
13
39
22
21
7
7
4.5
Half-life (h)
Plasma Intracellular
150
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Drug distribution into compartments
Modified from Nichol, MR. & Kashuba, ADM. Clin Pharm Ther. 2010; 88(5)598
Oral TDF±FTC
Genital/rectal secretions
Topical TVF
Blood Plasma Genital/rectaltissue
Mononuclear cells
Total FUB Total FUB
TVF-DPFTC-TP
TVFFTC
Compartmental drug concentration vs time- Sufficient concentrations/time periods
1. Tissue compartments: multiple sub-compartments – homogeneous drug?2. Only specific tissue sub-compartments are susceptible to HIV3. Some susceptible target cells circulate in and out of compartments
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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
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Conc vs time in plasma & female genital tract after oral TDF & FTC
Drummond, JB et al. AIDS. 2007; 21(14)1899
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C24hrs of TDF/FTC after a single oral Truvada dose
Blood plasma Seminal plasma
C-V fluid Vaginal tissue
Rectal tissue1
10
100
1,000
10,000
100,000
1,000,000TFV FTC TDF-DP FTC-TP
C2
4hrs (
ng/
mL
, ng
/g o
r fm
ol/g
)
Patterson, KB et al. Sci Trans Med. 2011; 3(112)112re4
100X10X
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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
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Human clinical studies reported
Stopped early for futility
Percent effectiveness - ITT
44%
39%
62-75%
49%
Lower or undetectable drug concentrations in subjects who seroconverted versus those who did not
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PrEP Studies with positive results
Partners TDF2 BKK-TDF iPrEX0
10
20
30
40
50
60
70
80
90
100
75
62
44
67
49TDF/FTCTDF
N= 4747M, F
N= 1219M, F
N= 2499MSM, TG
82% TDF detected
80% TDF detected
51% TDF detected
N= 2413IDU, M,F
66% TDF detected
Effe
ctiv
enes
s
Slide adapted from Kiat Ruxrungtham
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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
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Estimated HIV incidence in iPrEx
Anderson, PL et al. Science Translational Medicine (2012) 4(151):151ra125
16 fmol/106 PBMC reduced HIV incidence by 90%
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Infection rates in CAPRISA 004, by TDF concentrations in CVF
Abdool Karim, SS et al. The Lancet (2011) 378:279
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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%)
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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
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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