No Evidence for Decay in the Latent Reservoir in HIV-infected Patients Receiving Intensive...
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No Evidence for Decay in the Latent Reservoir in HIV-infected Patients Receiving Intensive Enfuvirtide (ENF)-containing Antiretroviral Therapy •In a single-arm, exploratory study (ACTG A5173), treatment-naive HIV-infected patients with CD4 cell count ≥100/mm 3 and VL ≥1000 copies/mL initiated therapy with ENF/TDF/FTC/SQV/rtv. •Subjects who achieved a VL<50 and continued on ENF-containing ART were tested every 24 weeks for the frequency of latently-infected resting, memory CD4 T cells (measured as infectious units per million cells, IUPM) for a planned duration of 96 weeks. •We analyzed the latent reservoir decay rate in subjects who attained a VL <50 and remained on ENF-containing ART for at least 48 weeks. •T cell activation was assessed by measuring CD38 % and density •Original target enrollment was 40. Because of slow enrollment and latent reservoir data showing no evidence of decline, an independent review committee recommended an early stop to accrual. Rajesh Gandhi 1 , Ron Bosch 2 , Evgenia Aga 2 , Mary Albrecht 3 , Elizabeth Adams 4 , Lisa Demeter 5 , Barbara Bastow 6 , Robert Siliciano 7, 8 , Janet Siliciano 8 , Joseph Eron 9 for the ACTG A5173 Team 1 Massachusetts General Hospital; 2 Harvard School of Public Health; 3 Beth Israel Deaconess Hospital; 4 National Institutes of Health; 5 University of Rochester; 6 Social & Scientific Systems, Inc; 7 Howard Hughes Medical Institute, Baltimore, MD; 8 Johns Hopkins School of Medicine; 9 University of North Carolina •In previously treatment-naive HIV-infected patients who received ENF-containing ART, we did not detect a decline in latent reservoir size over 96 weeks. •We can exclude, with 95% certainty, that the half-life of latent reservoir decay with intensified, suppressive therapy is <11 months. •In this small study, baseline CD4 cell count is inversely related to size of latent reservoir; this should be confirmed in larger studies •The stability of the latent reservoir, which is similar to that seen in previous studies of less intensive ART, suggests that new strategies are needed to eradicate HIV from the latent reservoir. CONCLUSIONS Poster # 424 • HIV persists in resting memory CD4 T cells in patients receiving antiretroviral therapy (ART), with estimated half-life of 44 months. • The stability of this latent reservoir may be due to ongoing HIV replication. • We assessed whether initiation of intensive ART with a multi-target regimen that includes fusion, protease and reverse transcriptase inhibitors leads to decay in the HIV latent reservoir. METHODS ACKNOWLEDGMENTS Rajesh T. Gandhi M.D., Infectious Diseases Unit, Mass. General Hospital, GRJ 504, 55 Fruit St, Boston, MA 02114 Telephone: 617-724-9690 Fax: 617-726-7653 e-mail: [email protected] RESULTS (Continued) • 9 subjects had both virologic suppression and continued ENF- containing ART for at least 48 wks; these subjects had a median of 4 latent reservoir measurements each (analysis cohort) • The 9 subjects did not differ from subjects who discontinued ENF prior to wk 48 (n=7) or did not have virologic suppression (n=3) in terms of age, gender, baseline CD4 count or VL. • Of the suppressed, ENF-treated subjects, 4 had a slight decay in the number of latently-infected cells and 5 subjects had a slight increase (Figure 1). • Overall, there was no evidence for decay in the latent reservoir (95% confidence interval for half-life: 11 months to infinity). BACKGROUND RESULTS •19 subjects initiated intensive ART with ENF/TDF/FTC/SQV/rtv. •Median age 36 yo; 17 (89%) male; 11 (58%) Caucasian; 5 (26%) Hispanic; 2 (11%) African- American. • Median baseline CD4 cell count: 262/mm 3 (range 146-597); median baseline VL: 4.8 log 10 (63,000) copies/mL. •7 subjects stopped ENF prior to week 48: 5 RESULTS (Continued) Latent reservoir in subjects on non-ENF HAART (historical controls) Latent reservoir in A5173 subjects Siliciano J et al. Nat Med (2003) 9:727-8 Immune activation and the latent reservoir • Although in the analysis cohort, CD38 density on CD4 & CD8 cells was inversely correlated with log IUPM, after adjustment for baseline CD4 count, there was no evidence for an association between T cell activation & IUPM (repeated measures analysis). • Among subjects with HIV RNA <50, at week 48 there was no evidence for a difference in immune activation between those who remained on ENF (n=10) and those who previously discontinued ENF (n=5); similar results were seen at weeks 24, 72 and 96. VL decay in patients initiating ENF-containing ART • Mean change in VL from day 0 to 7: -1.27 log 10 c/mL (n=18) • No association between baseline CCR5 density & change in VL from day 0 to 7 (range day 4- 9) with the ENF-containing regimen Baseline factors and the latent reservoir • Size of latent reservoir (average log IUPM) was inversely correlated with baseline CD4 count (r=-0.77, p=0.016) (Figure 2); association persists after adjustment for baseline VL. • Trend towards association between baseline VL and average log IUPM (r=0.62, p=0.077); however, when adjusted for baseline CD4 count, baseline VL no longer related to average log IUPM (r=0.36, p=0.38). Figure 1 Figure 2: Baseline CD4 count vs. latent reservoir size We would like to acknowledge Carrie Dykes, John Schmitz, Michael Para, Christopher Pilcher, Lynne Peeples, Camlin Tierney, Anne Kmack, Lynette Purdue, Tianxi Cai, David Wininger, Cheryl Marcus, Melissa Kerkau, James Rooney, James Thommes & all the members of the A5173 team. We would also like to thank the
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RESULTS . RESULTS (Continued). RESULTS (Continued). CONCLUSIONS. No Evidence for Decay in the Latent Reservoir in HIV-infected Patients Receiving Intensive Enfuvirtide (ENF)-containing Antiretroviral Therapy. Rajesh T. Gandhi M.D., Infectious Diseases Unit, - PowerPoint PPT Presentation
Transcript of No Evidence for Decay in the Latent Reservoir in HIV-infected Patients Receiving Intensive...
No Evidence for Decay in the Latent Reservoir in HIV-infected Patients Receiving Intensive Enfuvirtide (ENF)-containing Antiretroviral Therapy
• In a single-arm, exploratory study (ACTG A5173), treatment-naive HIV-infected patients with CD4 cell count ≥100/mm3 and VL ≥1000 copies/mL initiated therapy with ENF/TDF/FTC/SQV/rtv.
• Subjects who achieved a VL<50 and continued on ENF-containing ART were tested every 24 weeks for the frequency of latently-infected resting, memory CD4 T cells (measured as infectious units per million cells, IUPM) for a planned duration of 96 weeks.
• We analyzed the latent reservoir decay rate in subjects who attained a VL <50 and remained on ENF-containing ART for at least 48 weeks.
• T cell activation was assessed by measuring CD38 % and density• Original target enrollment was 40. Because of slow enrollment and
latent reservoir data showing no evidence of decline, an independent review committee recommended an early stop to accrual.
Rajesh Gandhi1, Ron Bosch2, Evgenia Aga2, Mary Albrecht3, Elizabeth Adams4, Lisa Demeter5, Barbara Bastow6, Robert Siliciano7, 8, Janet Siliciano8, Joseph Eron9 for the ACTG A5173 Team
1Massachusetts General Hospital; 2Harvard School of Public Health; 3Beth Israel Deaconess Hospital; 4National Institutes of Health; 5University of Rochester; 6Social & Scientific Systems, Inc; 7Howard Hughes Medical Institute, Baltimore, MD; 8Johns Hopkins School of Medicine; 9University of North Carolina
• In previously treatment-naive HIV-infected patients who received ENF-containing ART, we did not detect a decline in latent reservoir size over 96 weeks.
• We can exclude, with 95% certainty, that the half-life of latent reservoir decay with intensified, suppressive therapy is <11 months.
• In this small study, baseline CD4 cell count is inversely related to size of latent reservoir; this should be confirmed in larger studies
• The stability of the latent reservoir, which is similar to that seen in previous studies of less intensive ART, suggests that new strategies are needed to eradicate HIV from the latent reservoir.
CONCLUSIONS
Poster # 424
• HIV persists in resting memory CD4 T cells in patients receiving antiretroviral therapy (ART), with estimated half-life of 44 months.
• The stability of this latent reservoir may be due to ongoing HIV replication.
• We assessed whether initiation of intensive ART with a multi-target regimen that includes fusion, protease and reverse transcriptase inhibitors leads to decay in the HIV latent reservoir.
METHODS
ACKNOWLEDGMENTS
Rajesh T. Gandhi M.D., Infectious Diseases Unit,
Mass. General Hospital, GRJ 504, 55 Fruit St, Boston, MA 02114
Telephone: 617-724-9690Fax: 617-726-7653
e-mail: [email protected]
RESULTS (Continued)• 9 subjects had both virologic suppression and continued ENF-containing ART for at least 48
wks; these subjects had a median of 4 latent reservoir measurements each (analysis cohort)• The 9 subjects did not differ from subjects who discontinued ENF prior to wk 48 (n=7) or
did not have virologic suppression (n=3) in terms of age, gender, baseline CD4 count or VL. • Of the suppressed, ENF-treated subjects, 4 had a slight decay in the number of latently-
infected cells and 5 subjects had a slight increase (Figure 1).• Overall, there was no evidence for decay in the latent reservoir (95% confidence interval for
half-life: 11 months to infinity).
BACKGROUND
RESULTS • 19 subjects initiated intensive ART with ENF/TDF/FTC/SQV/rtv. • Median age 36 yo; 17 (89%) male; 11 (58%) Caucasian; 5 (26%)
Hispanic; 2 (11%) African-American.• Median baseline CD4 cell count: 262/mm3 (range 146-597); median
baseline VL: 4.8 log10 (63,000) copies/mL. • 7 subjects stopped ENF prior to week 48: 5 because of toxicities
related to injection site reactions (at weeks 1-13); 2 for reasons not related to toxicity.
RESULTS (Continued)
Latent reservoir in subjects on non-ENF HAART (historical controls)Latent reservoir in A5173 subjects
Siliciano J et al. Nat Med (2003) 9:727-8
Immune activation and the latent reservoir• Although in the analysis cohort, CD38 density on CD4 & CD8 cells
was inversely correlated with log IUPM, after adjustment for baseline CD4 count, there was no evidence for an association between T cell activation & IUPM (repeated measures analysis).
• Among subjects with HIV RNA <50, at week 48 there was no evidence for a difference in immune activation between those who remained on ENF (n=10) and those who previously discontinued ENF (n=5); similar results were seen at weeks 24, 72 and 96.
VL decay in patients initiating ENF-containing ART• Mean change in VL from day 0 to 7: -1.27 log10 c/mL (n=18)• No association between baseline CCR5 density & change in VL
from day 0 to 7 (range day 4-9) with the ENF-containing regimen
Baseline factors and the latent reservoir• Size of latent reservoir (average log IUPM) was
inversely correlated with baseline CD4 count (r=-0.77, p=0.016) (Figure 2); association persists after adjustment for baseline VL.
• Trend towards association between baseline VL and average log IUPM (r=0.62, p=0.077); however, when adjusted for baseline CD4 count, baseline VL no longer related to average log IUPM (r=0.36, p=0.38).
• No evidence for association between average log IUPM and age, baseline CCR5 density, baseline CD4 and CD8 activation (measured by % CD38+ cells and CD38 density).
Figure 1
Figure 2: Baseline CD4 count vs. latent reservoir size
We would like to acknowledge Carrie Dykes, John Schmitz, Michael Para, Christopher Pilcher, Lynne Peeples, Camlin Tierney, Anne Kmack, Lynette Purdue, Tianxi Cai, David Wininger, Cheryl Marcus, Melissa Kerkau, James Rooney, James Thommes & all the members of the A5173 team. We would also like to thank the subjects and the staffs of the sites who participated in this study.
