Pharmacology of antiretrovirals and chemoprophylaxis

Stephen Kerr, PhDHIV-NAT, Thai Red Cross AIDS Research CentreKirby 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

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

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

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

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

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

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

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

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

C24

hrs (

ng/m

L, n

g/g

or fm

ol/g

)

Patterson, KB et al. Sci Trans Med. 2011; 3(112)112re4

100X10X

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

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

PrEP Studies with positive results

Partners TDF2 BKK-TDF iPrEX0

102030405060708090

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

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

Anderson, PL et al. Science Translational Medicine (2012) 4(151):151ra125

16 fmol/106 PBMC reduced HIV incidence by 90%

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 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

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