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Effect of intensification of long-term highly active antiretroviral therapy (HAART) with raltegravir on proviral HIV-1 DNA in blood and gut associated lymphoid tissue (GALT): a randomized, placebo controlled trial . - PowerPoint PPT Presentation
Effect of intensification of long-term highly active antiretroviral therapy (HAART) with raltegravir on proviral HIV-1 DNA in blood and gut associated lymphoid tissue (GALT):
a randomized, placebo controlled trial
Jason Brunetta1, Colin Kovacs1,2,Tae Wook-Chun3, Janet Raboud2,4, Desheng Su4, Mario Ostrowski2,5,Gabor Kandel 2,5, Graham Smith 1, Rupert Kaul 2,4, Roberta
Halpenny 1, Duncan Chege2, Mona Loutfy 1,2,5
1Maple Leaf Medical Clinic, Toronto, Ontario, Canada; 2University of Toronto, Toronto, Ontario, Canada; 3Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA; 4Division of Infectious Diseases, University Health Network, Toronto, Ontario,
Canada; 5 St. Michael’s Hospital, Toronto, Ontario, Canada
Conflict of Interest Disclosure
Funding for this project was provided by a Research Grant from Merck Frosst Canada
Ltd.
Background Eradication of HIV remains elusive due to the persistence of viral
reservoirs.
- The gut-mucosal compartment is an important viral reservoir
- Viral reservoirs mainly consist of long-lived and latently infected CD4+ T cells
New HAART drug classes may help target these latently infected
reservoirs. E.g;
- Integrase inhibitors (e.g. raltegravir)
- Entry/fusion inhibitors
Background Recent studies examining raltegravir intensification therapy failed to
show a reduction in plasma HIV RNA [Reviewed in Schulze, et al JID 2011]
- However, changes in plasma viremia may not reflect changes in the mucosal reservoir.
1 recent study suggested no reduction in proviral DNA in the gut
[Yukl et al, AIDS 2010]. However, this pilot study:- was an open-label study without controls
- had a relatively small sample size (n=7)
- intensified participants with raltegravir for a brief period (12 weeks).
HYPOTHESIS
Raltegravir intensification in long-term suppressed individuals will decrease blood and sigmoid CD4+ T cell HIV proviral levels.
Methods Study design
– A prospective, double-blind, placebo-controlled randomized controlled trial (ClinicalTrials.gov # NCT00520897)
Enrolled participants
– HIV-infected individuals recruited from the Maple Leaf Medical Clinic
Inclusion criteria
– Sustained virologic suppression (<50 viral copies/ml) for over 4years– Participant must be on first standard HAART with 2-3 NRTIs and 1-2 PIs or
an NNRTI for at least four years Exclusion criteria
– Active AIDS-defining illness in past six months– Abnormal clinical laboratory test results at screening
Methods – Study schematic
Raltegravir-intensification
(400mg twice/day)
Placebo
Randomize
n=12
24 HIV+ patients fully suppressed on
HAART
4w 8w 12w 16w 28w 40w 48w
Primary analysis at week 48
n=12
Measured Outcomes:- Blood & sigmoid HIV-1 proviral DNA in CD4+ T cells- Blood CD4+ T cell counts
48w 0w Sigmoid biopsy
Blood phlebotomy
4w 8w 12w 16w 28w 40w 48w
48w 0w Sigmoid biopsy
Blood phlebotomy
Study Endpoints Primary endpoint
Determine if 48 weeks of raltegravir intensification in long-term virologically suppressed participants on HAART is associated with a change in HIV-1 proviral DNA in blood and sigmoid CD4+ T cells
Secondary endpointDetermine effect of raltegravir intensification on blood CD4+ T cell populations
Laboratory methods
BloodPhlebotomy
Ficolldensity
separationPBMC/Sigmoid
CD8Depletion
Real time PCR:HIV-1
Proviral DNA amplification &
quantitation
Sigmoidoscopy
0.5 & 1.0 ug/ml Collagenase-IItissue digestion
(30 min each)
CD4+ T cell counts done on whole blood (counts/mm3) using FACS
HIV-1 DNA copy number per 1x106 CD4+
T cells reported(LOD: 2.6 copies)
PBMC
GALT
Results – Table 1
Baseline clinical and demographic characteristics were similar between the groups.
Results
TreatmentMedian
Baseline proviral load (log10)
Medianw48 proviral load
(log10)
Raltegravir group 3.05 3.11
Placebo group 2.86 2.91
No difference in blood HIV DNA proviral load between groups at week 48 (p=0.62)p from ANCOVA
Results
TreatmentMedian
Baseline CD4 count (cells/mm3)
Medianw48 CD4 count
(cells/mm3)
Raltegravir group 665 690
Placebo group 610 700
No difference in blood CD4+ T cell counts between groups at week 48 (p=0.25)p from ANCOVA
Results
TreatmentMedian
Baseline proviral load (log10)
Medianw48 proviral load
(log10)
Raltegravir group 3.10 2.84
Placebo group 3.20 3.08
No difference in sigmoid HIV DNA proviral load between groups at week 48 (p=0.74)
p from ANCOVA
Summary In virologically suppressed patients on HAART, 48 weeks of
raltegravir-intensified therapy, as compared to placebo,- did NOT result in decay of blood or sigmoid HIV DNA in CD4+ T-lymphocytes
- had NO impact on blood CD4+ T cell populations
Extending raltegravir intensification out to 96 weeks also did NOT
result in any significant decrease in HIV DNA in blood or sigmoid
CD4+ T lymphocytes (data not shown)
Additional novel approaches are required to help reduce the latent
viral reservoir.
Acknowledgments All the patients
Research staff at Maple Leaf Medical Clinic- For working on this project
Dr. Kandel for sigmoid biopsies
HIV Statistical Analytical Group at UHN- Dr. Janet Raboud’s team
Duncan Chege for analytical work, work on presentation & slides
Funders
