icaac 2009: hiv updates antonio urbina, md medical director hiv education st. vincent’s...
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ICAAC 2009: HIV Updates
Antonio Urbina, MDMedical Director HIV Education
St. Vincent’s Comprehensive HIV Center
A Local Performance Site of the New York/New Jersey AETC
October 2009
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Disclosures
• Speaker’s Bureau: Monogram, BMS, Gilead, Tibotec, Boehringer-Ingelheim
• Research Grant: BMS
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HIV in the US
• By 2015, 50% of HIV+ individuals will be over 50 (currently it’s 15-20-%) 1
• From 2000 to 2004, persons aged 40-49 years had the highest prevalence of HIV/AIDS and the steepest rise in prevalence
• As part of stimulus package, NIH providing funding opportunities to address gaps in knowledge– Immune Function and Host Defenses– Response to Treatment – PK and Pharmacogenomics– Metabolic Complications– Neurologic and Neuropsychiatric Complications– HIV Related Malignancies– Frailty and Functional Status– Complexity of Care
1. CDC MMWR 57:1073-1076
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HIV and Pregnancy
• Birth Defect Rate with Tenofovir Similar to US Population – Antiretroviral Pregnancy Registry began collecting
tenofovir data in 2001 and analyzed 10,471 cases involving any ARV and 1056 involving tenofovir
– Congenital anomaly rates with any tenofovir containing regimen (1,2 or 3rd trimester) were similar to general population
– Registry has no reports involving entry inhibitors or integrase inhibitors
Squires, et al. 49th ICAAC. Abstract H-917
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Novel ARV Strategies
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Nuc-Sparing Combinations
• Raltegravir/Atazanavir – Desirable combination as ATZ inhibits UGT-1– 30 pt, prospective 48 week single arm switch
study– Pts had to be on stable ARVs for at least 2
months with viral load <50 at screening– No history of PI resistance or ARV failure
while receiving a PI– And intolerance to current regimen
PJ Ruane, et al. 49th ICAAC
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Nuc-Sparing Combinations
PJ Ruane, et al. 49th ICAAC
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Nuc-Sparing Combinations
• Procedure:– Pts discontinued current regimen and started
RAL 400 mg BID + ATV 400 mg QD
• Results:– 27 people continued regimen for 36 weeks
• 2 pts stopped after 8 weeks (1 had viral rebound on phenytoin, the other pt had elevated Cr)
• 1 developed lung cancer after 36 weeks (vl <48)
PJ Ruane, et al. 45th ICAAC
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Nuc-Sparing Combinations
• ATZ [ ] were subtherapeutic in 4 pts (all had viral loads <48)
• ITT analysis at week 24: – 27/29 (93%) had viral loads <400– 24/29 (83%) had viral loads <48
• 7 pts had viremic blips from 48 to 83 copies• CD4 counts unchanged during follow up• TC and LDL fell significantly
PJ Ruane, et al. 49th ICAAC
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ARV Management
• BMS is conducting a dosing study using: – RAL 400 mg BID + ATZ 300 mg BID
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ARV Management
• QD Raltegravir– RAL has long intracellular half-life (t ½ ~29
hours)– 311 patients with HIV RNA <50 replaced PIs
with RAL– Based on drugs in background regimen, pts were
placed on:• RAL 800mg QD vs RAL 400 mg BID
Mena, et al. 49th ICAAC. Abstract H-920
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Mena, et al. 49th ICAAC. Abstract H-920
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ARV Management
• Results: – Median Follow up was 15 months (range 9-30 months)
– 5 pts discontinued RAL due to virologic failure• 1 in QD arm and 4 in the BID arm
• All 5 had failed NRTIs in the past
– 4 pts discontinued RAL for other reasons: • 1 voluntary withdrawal in the QD arm and 3 in the BID arm
(poor adherence 2, H/A 1)
– No difference in CD4 T cell gains
Mena, et al. 49th ICAAC. Abstract H-920
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STARTMRK Trial 96 WEEKS
Lennox J. et al. 49th ICAAC.
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STARTMRK Trial 96 WEEKS
Lennox J. et al. 49th ICAAC.
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STARTMRK Trial 96 WEEKS
Lennox J. et al. 49th ICAAC.
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STARTMRK Trial 96 WEEKS
Lennox J. et al. 49th ICAAC.
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STARTMRK Trial 96 WEEKS
Lennox J. et al. 49th ICAAC.
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Lennox J. et al. 49th ICAAC.
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STARTMRK Trial 96 WEEKS
Lennox J. et al. 49th ICAAC.
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ARTEN STUDY 48 WEEKS
Soriano, V. et al. 5th IAS
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ARTEN STUDY 48 WEEKS
Soriano, V. et al. 5th IAS
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ARTEN STUDY 48 WEEKS
Soriano, V. et al. 5th IAS
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ARTEN STUDY 48 WEEKS
Soriano, V. et al. 5th IAS
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ARTEN STUDY 48 WEEKS
Soriano, V. et al. 5th IAS
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New ARVs and Booster
• GS-9350 is a potent, selective, CYP 3A inhibitor that lacks anti-HIV activity and has limited effects on adipocyte function in vitro– Other Properties:
• Reduced potentials for off-target drug interactions due to enzyme inhibition or induction
• Improved physiochemical properties over ritonavir, allowing tablet co-formulations with other agents
• Boosts CYP 3A substrates comparable to ritonavir in humans
L Xu, et al. 49th ICAAC.
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New ARVs and Booster
L Xu, et al. 49th ICAAC.
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GS-9350
Ramanathan, et al. 49th ICAAC. Abstract A1-1301
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New ARVs
• S/GSK 1349572 (572) was presented at IAS and showed great 10-day potency and higher barrier to resistance then RAL
• Back up INI S/GSK 1265744 (744) displayed equal potency during and after 10 days of monotherapy– Long half life (~ 30 hours)– 10 days of 744 (30 mg QD) to ARV naïve pts lowered viral load
by a median 2.6 log (range 3-1 log)– 7/8 had viral loads <50 at day 14– No mutations to RAL or ELV emerged– Fatigue, H/A dizziness and indigestion affected 1 person – No serious or severe AEs including laboratory and EKG
abnormalities
Min S et al. 49th ICAAC. Abstract H-1228
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New Agents
• INSPIRE Trial: Using IL-7 as a novel strategy for improving immune reconstitution in HIV
• IL-7:– Critical factor for thymopoiesis, homeostasis and
maturation of peripheral T-cells– Inhibits apoptosis of CD4 and CD8 T cells from HIV
infected patients– Increases T cell counts in chronic HIV infected patients– Different from IL-2 in that it stimulates recent thymic
emigrant, naïve, central and effector memory CD4 cells
Y. Levy, et al. 49th ICAAC.
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IL-7
• Methods: – HIV infected pts with 101-400 CD4 cells and
HIV RNA <50 while on ART received 3 weekly SQ injections of IL-7.
• 3 doses vs placebo were tested
– T cell subsets and thymopoiesis (RTE and sj/ß TRECs ratio quantification) analyses were performed
Y. Levy, et al. 49th ICAAC.
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IL-7
Y. Levy, et al. 49th ICAAC.
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IL-7
Y. Levy, et al. 49th ICAAC.
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IL-7
Y. Levy, et al. 49th ICAAC.
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IL-7
• Conclusions: – 3 injection cycle of IL-7 induced a dose dependent and
sustained increase in CD4 cells
– Higher proportion of patients experienced CD4 counts >500
– Trend toward higher thymic output at 20mcg/kg dose
– No clincial or laboratory side effects > grade 2 reported
– 4 pts (in 20mcg/kg) had transient increases in HIV RNA
Y. Levy, et al. 49th ICAAC.
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New ARVs
Jacobson, J. 49th ICAAC. Oral Abstract.
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New ARVs
Jacobson, J. 49th ICAAC. Oral Abstract.
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New ARVs
Jacobson, J. 49th ICAAC. Oral Abstract.
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New ARVs
Jacobson, J. 49th ICAAC. Oral Abstract.
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New ARVs
Jacobson, J. 49th ICAAC. Oral Abstract.
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New ARVs
Jacobson, J. 49th ICAAC. Oral Abstract.
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New ARVs
Jacobson, J. 49th ICAAC. Oral Abstract.
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Jacobson, J. 49th ICAAC. Oral Abstract.
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New ARVs
• MPC-42326 (Bevirimat dimeglumine)– New HIV class-maturation inhibitor
– Prevents protease-mediated Gag cleavage at CA-SP1
– Good oral bioavailability and long half life (60 hours)
– Active against drug resistant strains• Hypersensitive to protease resistant virus
– Metabolized via glucuronidation (UGT1A3)• Not CYP 450
Bloch M, et al. 49th ICAAC
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New ARVs
Bloch M, et al. 49th ICAAC
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New ARVs
• Bevirimat– Effectiveness of drug depends on whether or not pts
have polymorphisms on Gag• 501 Gag amino acids
• 5 of these emerged as important determinants of response
• Database sampling reveals that ~50% of pts have these polymorphisms
– Use of this drug will require a genotype or phenotype prior to use (just like tropism testing)
Bloch M, et al. 49th ICAAC
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New ARVs
Bloch M, et al. 49th ICAAC
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New ARVs
Bloch M, et al. 49th ICAAC
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New ARVs
Bloch M, et al. 49th ICAAC
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New ARVs
Bloch M, et al. 49th ICAAC
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New ARVs
Bloch M, et al. 49th ICAAC
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New ARVs
Bloch M, et al. 49th ICAAC
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New ARVs
Bloch M, et al. 49th ICAAC
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Bloch M, et al. 49th ICAAC
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HIV Latency
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No Decrease in Residual Viremia after ART Intensification with Raltegravir
No Decrease in Residual Viremia after ART Intensification with Raltegravir
Low level HIV replication may occur in pts with HIV RNA <50 c/mL
Study assessed intensification with RAL to decrease low level viremia
Intensification of current ART with RAL for 30 days in patients with HIV RNA <50 c/mL for >12 months
HIV RNA measured with single copy HIV RNA assay with sensitivity <1 c/mL
HIV RNA measured weekly before, during and after intensification
Results: No decrease in HIV RNA
Conclusion: Source of low level HIV RNA <50 c/mL likely to be from long lived cell population rather than actively replicating cells
HIV RNA Pre- and Post-Intensitification
Pre-Intensification Intensification Post-Intensification
Pre-Intensification Intensification Post-Intensification
0.04 l0.04 l0.140.14
0.040.04
2
1
0
-1
P=0.69P=0.69 P=0.38P=0.38
HIV
-1 R
NA
(lo
g10
co
pie
s/m
L)
HIV
-1 R
NA
(lo
g10
co
pie
s/m
L)
Jones J, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 423b.
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HIV Latency
• Latent infection of resting CD4 T cells is established early during HIV infection making eradication of HIV unachievable with current ART
• Following integration of viral DNA into cellular genome, the HIV long terminal repeat (LTR) promoter can revert to transcriptional silence
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HIV Latency
• One of the mechanisms through which HIV latency is maintained is by the action of histone deacetylases (HDACs) at the HIV LTR– 3 Classes: I, II, and III
• HDACs repress transcription through their ability to modify core histones of nucleosomes through deacteylation
• Deacetylation decreases the access of transcription factors to the DNA and recruits other histone modifying complexes that result in further transcriptional repression
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HIV Latency
• HDAC inhibitors lead to LTR activation and the escape of HIV from latency
• Investigators from UNC and Merck showed that inhibitors that target class I and II induced HIV expression from resting CD4 cells of aviremic patients 1
• As HDACs are responsible for other cellular processes, investigators will need to target compounds that are very specific in order to limit toxicity
1. Archin MT, et al. AIDS 23: 2009