Transcript Powerpoint

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
– 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)
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
Balance of vulnerabilities between virus and host
Virus vulnerability
Infection
established
• Small founder
populations of
immune cells in
female genital
tract, colorectum, male
foreskin &
urethra
Hours
Local
expansion
• Early signal
amplification
• Influx of CD4+
cells
• Seeding to
distal sites
Days
Systemic
dissemination
• Establishment
of lymphatic
tissue reservoir
• High levels of
viral replication
• Depletion of
gut CD4+ cells
Weeks
Window of opportunity for PrEP
Adapted from Garcia-Lerma, JG et al, Trends Pharm Sci, 2010; 31(2):74
Viral life cycle
Shattock R J , and Rosenberg Z Cold Spring Harb Perspect Med 2012;2:a007385
Pharmacokinetic-pharmacodynamic relationships
Dose administered
Concentration at site
of action
Pharmacokinetics (PK)
- Absorption
- Distribution
- Metabolism
- Elimination
Inter-patient variability
Drug effects
(therapeutic/adverse)
Pharmacodynamics (PD)
- How do in vivo drug
concentrations relate to
protective/toxic effects
- Limited understanding for PrEP
Physical characteristics affect distribution
Only free drug can freely diffuse across membranes:
Class/Drug
Plasma protein
binding
PI
95 – 99%
NRTI
7 – 49%
Maraviroc
85%
Raltegravir
83%
• Other physical characteristics important (eg ionization state at
physiological pH)
• Different relationships exist for systemic/genital/rectal compartments
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
Plasma
Intracellular
13
Maraviroc
9
4.5
Raltegravir
d4T
1
ZDV
1
ABC
1
3TC
2
7
7
21
22
9
FTC
39
14
TFV
0
20
Half-life (h)
150
40
Drug distribution into compartments
Topical TVF
Oral TDF±FTC
Blood Plasma
Total
Genital/rectal
tissue
FUB
Total
Mononuclear cells
TVF
FTC
Genital/rectal
secretions
TVF-DP
FTC-TP
FUB
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 HIV
3. Some susceptible target cells circulate in and out of compartments
Modified from Nichol, MR. & Kashuba, ADM. Clin Pharm Ther. 2010; 88(5)598
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
Conc vs time in plasma & female genital tract after oral TDF & FTC
Drummond, JB et al. AIDS. 2007; 21(14)1899
C24hrs of TDF/FTC after a single oral Truvada dose
TFV
FTC
TDF-DP
FTC-TP
C24hrs (ng/mL, ng/g or fmol/g)
1,000,000
100X
10X
100,000
10,000
1,000
100
10
1
Blood plasma
Seminal
plasma
C-V fluid
Vaginal tissue Rectal tissue
Patterson, KB et al. Sci Trans Med. 2011; 3(112)112re4
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
Human clinical studies reported
39%
Stopped early for futility
44%
62-75%
49%
Percent effectiveness - ITT
Lower or
undetectable drug
concentrations in
subjects who
seroconverted
versus those who
did not
Effectiveness
PrEP Studies with positive results
100
90
80
70
60
50
40
30
20
10
0
82% TDF
80% TDF
66% TDF
51% TDF
detected
detected
detected
detected
75
67
62
49
Partners
N= 4747
M, F
TDF/FTC
TDF
44
TDF2
BKK-TDF
iPrEX
N= 1219
M, F
N= 2413
IDU, M,F
N= 2499
MSM, TG
Slide adapted from Kiat Ruxrungtham
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
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
Infection rates in CAPRISA 004, by TDF concentrations in CVF
Abdool Karim, SS et al. The Lancet (2011) 378:279
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%)
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 concentrationtime 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
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