Download No Evidence for Decay in the Latent Reservoir in HIV

Poster # 424
No Evidence for Decay in the Latent Reservoir in HIV-infected Patients Receiving Intensive
Enfuvirtide (ENF)-containing Antiretroviral Therapy
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
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]
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
BACKGROUND
RESULTS (Continued)
RESULTS (Continued)
• 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.
• 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 latentlyinfected 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).
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.
METHODS
• 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 latentlyinfected 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.
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.
Figure 1
Latent reservoir in A5173 subjects
Latent reservoir in subjects on nonENF HAART (historical controls)
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
CONCLUSIONS
Siliciano J et al. Nat Med (2003) 9:727-8
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 2: Baseline CD4 count vs.
latent reservoir size
• 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.
ACKNOWLEDGMENTS
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.