XV International AIDS Conference

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XV International AIDS Conference

• July 11-16, 2004
• Bangkok

HIV/07-04/0720/06-06
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Introduction

• MTCT
• Antiretroviral therapy
• New?
• Personal Interest

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Late Breakers

• Breastfeeding Grannies
• LPV levels in pregnancy
• RCT of antibiotics to prevent chorioamnionitis
• NO reduction in PTB or MTCT

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Breastmilk

• Ten women on ART
• NVP levels 68 90 of plasma
• Nelfinavir levels 6 24 of plasma
• 8 women no detectanle virus in plasma or milk
• One plasma VL lt 50, colostrum 172
• One plasma VL 96 , colostrum 261

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Increased risk of pre-eclampsia foetal death
associated with HAART
Suy A et al. XV IAS, Bangkok, July 2004. Abs
ThOrB1359
6
Single dose NVP for prevention of MTCT

• 61 patients1
• Duration of NVP in plasma following single dose
  was variable
• Drug levels where resistance can be selected for
  occurred up to 3-4 weeks
• Median T1/2 was 58.3 hrs (22.9 160.0)

1 Cressey TR et al. XV IAS, Bangkok, July 2004.
Abs ThOrB1352 2 Morris L et al. XV IAS, Bangkok,
July 2004. Abs ThOrB1353
7
Single dose NVP for prevention of MTCT

• 155 women 20 infants with high-level NVP
  resistance following single dose NVP2
• K103N in 55/55 women with resistance mutations at
  6 months post-NVP
• 10/13 children had Y181C 3/13 had K103N at 6
  months post-NVP
• These mutations associated with higher viral
  loads and lower CD4 counts

1 Cressey TR et al. XV IAS, Bangkok, July 2004.
Abs ThOrB1352 2 Morris L et al. XV IAS, Bangkok,
July 2004. Abs ThOrB1353
8
Addition of CBV to single dose NVP for prevention
of MTCT

• 61 mothers with 6 week follow-up
• Most common NNRTI mutations
• K103N (8), Y181C (7), A190G (5), Y188C (4), V106A
  (3), V106M (3)
• No NRTI mutations detected
• 68 evaluable infants
• 5 HIV infected

McIntyre J et al. XV IAS, Bangkok, July 2004. Abs
LbOrB09
9

• Personal Interest

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Superinfection

• Mbeya Cohort
• 600 female CSWs
• Unique recombinant forms detected in 28 cohort

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Breakthrough HIV infection in long-term exposed
seronegative individuals

• 12 infected from cohort of 94 partners of known
  HIV-positive individuals
• 2 seronegative with low level DNA (gt6/12)
• None infected with same strain as regular partner
• Hypothesis they are immune to their partners
  strain but not others

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Prevalence and Predictive Factors of Coreceptor
Tropism

• Coreceptor tropism is associated with disease
  progression and will be an important
  consideration in use of coreceptor antagonists
• Phenosense assay for tropism in 861 patients
• 265 assay failures
• 80 CCR5 (R5) 20 CXCR4 (X4) or dual tropic

Moyle WePeB5725
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Prevalence and Predictive Factors of Coreceptor
Tropism

• Viral load significantly higher in X4/dual tropic
• CD4 cell count lower in X4/dual tropic
• R5 predicted by viral load lt 5000 copies/mL and
  CD4 cell count
• gt 300 cells/mcL (89)
• X4 poorly predicted by viral load gt 100,000
  copies/mL and CD4 cell count lt 50 cells/mcL (55)

Moyle WePeB5725
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Improved CD4 Cell Counts With Prednisolone

• Uncontrolled observational trial 56 ART-naive
  patients treated with prednisolone 5 mg/day for
  0.5-11.5 years
• CD4 minimum 300 cells/mcL (mean 565 cells/mcL)
• Compared with 135 untreated patients in same
  clinic (mean CD4 612)
• CD4 increased 44.4 per year in first 6 years, vs.
  49.7 decrease in untreated patients

STI structured treatment interruption Ulmer
TuPeB4582
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Improved CD4 Cell Counts With Prednisolone

• 86 patients treated with prednisolone during STI
  vs 41 without
• CD4 decrease of 0.47/day with prednisolone vs
  0.77 without
• Nonsignificant trend towards lower viral load
  with prednisolone
• Mechanism of benefit not investigated
• ? Related to decreased immune activation

STI structured treatment interruption Ulmer
TuPeB4582
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Anti-retroviral therapy studies
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Fusion Inhibitors

• Pfizer UK-427,857
• 10 to 100-fold fall VL at 10 days
• Schering-Plough
• SCH-D
• GSK

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Other new drugs

• Reverset (D-D4FC)
• Cytidine nucleoside analogue
• Active vs. resistant virus 0.8 log drop
• TMC 125 and 114
• Capravirine

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Novel Strategies

• 50 patients M184V CD4 gt 500
• 8 24 week data, continue 3TC vs. STI
• CD4 drop
• 73 with 3TC vs. 153 no 3TC
• Viral load rise
• 0.6 log vs. 1.2 log
• Replication capacity lower for 3TC

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IMANI-1 LPV/r as a single drug to 48 weeks

• 30 patients
• Mean vl 262,000 c/ml
• Mean CD4 169 cells/mm3
• 3 or 4 capsules BID based on weight
• At 48 weeks, 11 were non-completers
• LTFU (2), AE (2), non-adherent (2), deported (1),
  HBV (1), virological failure (3)
• Resistance not seen
• Mean CD4 increase 228 cells/mm3

p value not stated
Gathe JC Jr et al. XV IAS, Bangkok, July 2004.
Abs MoOrB1057
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Simplification to LPV/r single drug therapy
p value not stated
Arribas JR et al. XV IAS, Bangkok, July 2004. Abs
TuPeB4486
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CLASS ABC3TC with either EFV, APV/r or d4T

• No statistically significant differences to lt400
  lt50 c/ml by ITT mf
• Statistically significant differences in observed
  analysis favoured EFV arm (p0.038)
• No statistically significant differences in time
  to treatment failure
• Significantly longer duration of viral
  suppression for EFV vs. d4T (p0.007)
• In patients with viral load 100,000 c/ml at BL,
  lt50 c/ml s ITT mf at 96 wks were
• EFV 65 APV/r 64 d4T 49

Adapted from Bartlett JA et al. XV IAS, Bangkok,
July 2004. Abs TuPeB4544
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Meta-analysis of efficacy of 3 vs. 4 drugs in
therapy-naïve patients
ve number indicates result favoured 3 drug arm
LOQ lt50 copies/ml, except ACTG 384, ACTG 388a,
ACTG 388b (all lt400 copies/ml) ACTG 388a EFV
quad therapy ACTG 388b 2 PI quad therapy Week
72 data
Moyle GJ et alXV IAS, Bangkok, July 2004. Abs
TuPeB4519
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Antiretroviral studies

• Context study Fosamp/r v Lopina/r in PI exp
  (MoOrB1055)
• Toro studies T20 96 week FU ( MoOrB1058)
• SOLO study Fosamp/r od v Nelf ART naïve,
  subanalysis (TuPeB4503))
• XV IAC Bangkok July 2004

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Lipodystrophy/Metabolic toxicity

• Lipodystrophy
• - thymidine sparing NRTI backbone in
  ART naïve
• - Switch to NRTI sparing regimen
• Glucose metabolism in vitro studies with PIs

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Evolution of body fat over time following
initiation of ARV therapy(HIV positive,
treatment naïve individuals)
Australian lipodystrophy cohort starting
HAART Measurements by DEXA Initial increase in
central and peripheral fat Limb fat declines from
baseline after 1½ years Central abdominal fat
remains increased from baseline
Adapted from Mallon PWG, et al. AIDS 2003
971-979
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ACTG 384 Median Percent Change in Limb Fat from
Baseline by NRTI Assignment
20


10


0

-10


Median change

-20

plt0.05 within groups
-30
AZT3TC n69
plt0.05 between groups
-40
ddId4T n87
-50
16
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48
64
80
0
Weeks
Dubé MP. 4th International Workshop on Adverse
Drug Reactions and Liposystrophy in HIV 2002
San Diego, Calif. Abstract 27.
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Body composition metabolic changes on d4TddI
vs. ABC/3TC

• d4TddI n46
• ABC3TC n50
• 33 months follow-up
• 70 in both arms initially received a PI
• Loss of total regional fat were significantly
  greater with d4TddI (plt0.01)
• Significant metabolic changes
• Lower HDL on d4TddI (plt0.01)
• Higher LDL on d4TddI (p0.02)
• No significant differences in body cell mass, TG,
  TC or insulin

Shlay JC et al. XV IAS, Bangkok, July 2004. Abs
ThOrB1360
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Study 903 144 week data


plt0.001
p0.001
Bone mineral density
p0.064
Gallant JE et al. XV IAS, Bangkok, July 2004.
Poster 4538
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Study 903Mean (SD) Change in Hip BMD
Gallant JE et al. XV IAS, Bangkok, July 2004.
Poster 4538
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HIV-NAT 009 Lipodystrophy outcomes after
switching from NRTIs to IDV/rEFV
Boyd MA et al. XV IAS, Bangkok, July 2004. Abs
WePeB5867
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HIV-NAT 009 mtDNA mtRNA after switching from
NRTIs to IDV/rEFV
p0.007
p0.025
p0.005
p0.007
Boyd MA et al. XV IAS, Bangkok, July 2004. Abs
WePpB2064
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Pharmacology and Drug Interactions
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PK of TPV/r in combination with SQV, APV or LPV
TPV/r is currently unlicensed in the UK
Walmsley S et al. XV IAS, Bangkok, July 2004. Abs
WeOrB1236
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TDFABC intracellular drug levels

• 15 patients on TDFABC1 other NRTI
• Either TDF or ABC substituted for a new third
  drug (14/15 NNRTI, 1/15 PI)
• No substantial changes in IC concentrations seen
  after withdrawal of TDF or ABC
• Suggested IC half-life
• TDF DP 60 hrs
• CBV TP 12-19 hrs

Hawkins T et al. XV IAS, Bangkok, July 2004. Abs
TuPeB4627
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In vitro combination studies of TDFABC3TC

• TDFABC3TC OD has resulted in poor treatment
  outcomes
• TDFABC3TC showed additive anti-HIV activity in
  primary PBMCs
• No evidence for antiviral antagonism among TDF,
  ABC or 3TC

Myrick F et al. XV IAS, Bangkok, July 2004. Abs
WeOrB1237
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TDF ddI in combination
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Mitochondrial effects of adding TDF to a
ddI-containing HAART regimen
ddI doses not stated
plt0.05
plt0.01
plt0.05
plt0.001
Miro O et al. XV IAS, Bangkok, July 2004. Abs
WePeB5896
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Efficacy of TDFddI in therapy-naïve patients

• Retrospective analysis
• TDFddI 400mg OD n45
• Median duration of treatment 215 days
• TDFddI 250mg OD n33
• Median duration of treatment 356 days
• All patients reached lt50 copies/ml
• Time to treatment failure showed patients on
  TDFddI 250mg OD were more likely to remain on
  treatment (p0.005)

Tung M et al. XV IAS, Bangkok, July 2004. Abs
TuPeB4528
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HOPS Cohort Tolerability of TDFddI
Any discontinuation for toxicity, incident
clinical event, or any grade 3 or 4 serum
creatinine, phosphorus or bicarbonate
concentration Among patients without prior
histories of each AE
Miro O et al. XV IAS, Bangkok, July 2004. Abs
WePeB5922
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TDF renal function
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TDF associated with renal dysfunction

• TDF associated with significantly increased
  creatinine at months 6 12 vs. BL (plt0.05,
  n199)1
• Patients on TDF (n74) showed lower mean cystatin
  clearance (more sensitive than creatinine) than
  patients never treated with TDF (n84) (plt0.01)2
• This mild renal dysfunction may render kidney
  more vulnerable to nephrotoxic drugs2

1 Horberg MA et al. XV IAS, Bangkok, July 2004.
Abs WePpB2066 2 Mauss S et al. XV IAS, Bangkok,
July 2004. Abs WePeB5941
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TDF not associated with renal dysfunction

• 3 year analysis showed comparable renal safety
  between TDF (n296) d4T (n296)1
• 1,175 patients with creatinine gt120µmol/l no
  significant difference between TDF HAART regimens
  other HAART regimens2
• Overall risk of TDF-related nephrotoxicity was
  low in cohort of 206 patients3

1 Staszewski S et al. XV IAS, Bangkok, July 2004.
Abs WePeB5917 2 Jones R et al. XV IAS, Bangkok,
July 2004. Abs WePeB5893 3 Jaegel-Guedes E et
al. XV IAS, Bangkok, July 2004. Abs WePeB5937
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Reducing Short-term adverse events
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Switch from NFV 250mg to 625mg formulation GI
tolerability
Intensive analysis weekly basis, patient diary
data, highest intensity for each week used
NFV 625mg is currently unlicensed in the UK
Johnson M et al. XV IAS, Bangkok, July 2004. Abs
TuPeB4501
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Thank You