ICAAC 2009: HIV Updates

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

Disclosures

• Speaker’s Bureau: Monogram, BMS, Gilead, Tibotec, Boehringer-Ingelheim

• Research Grant: BMS

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

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

Novel ARV Strategies

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


• 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)



• 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


ARV Management

• BMS is conducting a dosing study using: – RAL 400 mg BID + ATZ 300 mg BID

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

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


STARTMRK Trial 96 WEEKS

Lennox J. et al. 49th ICAAC.

STARTMRK Trial 96 WEEKS


ARTEN STUDY 48 WEEKS

Soriano, V. et al. 5th IAS

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.

New ARVs and Booster

L Xu, et al. 49th ICAAC.

GS-9350

Ramanathan, et al. 49th ICAAC. Abstract A1-1301

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

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.

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


IL-7


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


New ARVs

Jacobson, J. 49th ICAAC. Oral Abstract.

Jacobson, J. 49th ICAAC. Oral Abstract.

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

New ARVs


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)


New ARVs


HIV Latency

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

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Jones J, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 423b.

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

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

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

ICAAC 2009: HIV Updates

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