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• Gender specific and drug-specific – rather than class-specific
• Viral dynamics generally concordant with exceptions
• PARTNERS suggests plasma VL is a good surrogate
• Insight from PreP pharmacokinetic studies - Rectal TFV / TFV-DP levels higher than vaginal - TFV-DP in VT: TFV gel >>> TDF (po), some rectal exposure also
Thompson et al. AIDS Res Hum Retrovirol 2014;29:1
Else et al. AVT 2011;16:1149
Hendrix et al PLoS One 2014; 8(1): e55013
Else et al. Antiviral Therapy 2011; 16:1149 ; Cohen, et al. Annals Int. Med, 2007
Breast Milk
• residual transmissions (3.3-5.6% in Kesho Bora trial)
• > three quarters vertically infected infants in Kisumu Breastfeeding Study (ZDV/3TC + NVP or NFV) had resistance to both NVP and 3TC
• in the BAN study (cART initiated post-partum) almost a third of HIV+ infants had multiclass resistance
Zeh et al. PLoS Med 2011;8:e1000430
Fogel et al. CID 2011;52:1069
Kesho Bora Study Group, Lancet ID 2011 Mar;11(3):171
van der Perre Science Trans Med 2012;4:
Tuaillon et al; J Immunol 2009
Valea et al Revrovirology 2011
Chasela NEJM 2010 ;362 :2271
Importance of cell-to-cell transmission in Breast Milk
• cell-to cell infection may be important route of early postpartum transmissions through breastfeeding
• Macrophages
• T & B cells more likely to be activated, memory
Tuaillon et al; J Immunol 2009
van der Perre Science Trans Med 2012;4:
Valea et al Revrovirology 2011;8:34
• CD4+ T cells freshly purified from BM and plasma
• T cells in BM more likely to be activated, memory cells
• Spontaneous HIV antigen-secreting T cells present in BM and plasma
• HIV detected in 4/7 aviremic, and 5/8 viraemic mothers
• ART does not completely suppress cell-associated viral replication
Importance of cell-to-cell transmission in Breast Milk
Breast Milk Transmissions – Phylogenetic analyses
• Nested within RCT of vitamin supplementation • Mothers were free to choose breastfeeding after counselling • ARVs not available during study • MTCT (N=61) – infant PCR- (6w) subsequently became PCR+
CD4+ T cells – including latent infected resting memory T cells GALT Follicular Dendritic Cells Haemopoietic Stem Cells Monocyte-macrophages
Other cells ?
Buzon et al. Nat Med 2014;20:139
• Hierarchy of PI accumulation methodological differences
• Activated vs resting (ex-vivo) ZDV-TP, CBV-TP
ARV concentrations by compartment
relative to PBMC concentrations
Fletcher C V et al. PNAS 2014;111:2307-2312
Different patterns of HIV RNA decay
from FDCs in lymph nodes
Association between decay rate of
virions from FDC pool and
intracellular drug levels
ARV Concentrations in Lymphatic Tissue
• HIV+ patients starting ART (N=12; including EFV [6], ATVr [4], DRVr [2]) • Serial ileum/rectal/LN biopsies through M1-M6 • Flash-frozen tissue, minced and disaggregated • PBMCs and tissue extracts washed twice, lysed • LC-MS/MS analysis • Patterns of RNA decay in tissue: no change
• ? Different TK activity (TK2 vs TK1 in lymphocytes)
• host restriction factors- SAMHD1, APOBEC3G, etc
Kumar et al. Mol Cell Ther 2014;2:10
Carter. Ann Rev Microbiol 2008;62:425
Gavegnano et al. Antivir Chem Chemother 2009;20:63
Perno et al. Antivir Res 2006;71:293
Aquaro et al. Antiviral Res 2002;55:209
Galvegano et al. Mol Biol Int 2012;625983
Gavegano et al. AAC 2013;57:1262
Aquaro et al. J Leukoc Biol 2006;80:1103
Could PK of ARVs differ in Macrophages ?
Ex-vivo / in-vitro studies of PK in macrophages
intracellular PK • Intracellular [ZDV- TP], [CBV- TP], [3TC- TP], [FTC-TP] : M<<< T cells • Intracellular [TFV/TFV-DP]: M T cells • Intracellular [RAL]: M << T cells (independent of activation)
Arner et al. JBC 1992;267:10968
Perno et al. AVT 2006;71:293
Aquaro et al. J Leukoc Biol 2006;80:1103
Gavegano et al. AAC 2013;57:1262
Aquaro et al. Antiviral Res 2002;55:209
Galvegano et al. Mol Biol Int 2012;625983
PD • In-vitro models suggest NRTIs more active in MM than CD4+ lymphocytes • ddNTP:dNTP ratios are higher • EC50 of NRTI/NNRTI : chronic >>> acutely infected M • RAL: poor potency in M • EC50 of PI : chronically infected M >> T cells, but still retained some
activity
Drug Metabolism within Compartments
CNS
CYP P450 (2B6, 3A4, 2D6)
UGTs
Transporters (ABCG2, ABCC5/10,
ABCB1, SLCO1A2
Breast milk
CYP P450 (1B1, 4Z)
may inhibit gut UGT1A1
Transporters (ABCG2, ABCC1/3/6,
SLC15A2, SLC29A1, SLCO2B1/3A1
Lungs
CYP P450 (1A1, 2C19)
Transporters (ABCC1/10,
ABCG2; SLCO3A,
SLC22A7, SLC15A2)
GALT, lymph nodes
Transporters (ABCB1,
ABCC1/2/10, ABCG2;
SLCO3A1, hENTs)
CYPs (3A4, 2B6)
Genital tract
Transporters (ABCG2,
ABCC1/10/12,; SLCO3A1)
Placenta
CYPs (1A1, 2E1, 3A4/5)
UGTs
transporters (ABCB1, ABCC1,
ABCG2; SLC22A3 [OCT3],
SLC29A1,2 [hENT1&2)
Brain CYP 2B6
Can we improve existing drugs?
• ‘Boost’ concentrations within compartments through transporter inhibition