A quick round-up of some interesting studies that have been published over the last several weeks. Researchers from the AIDS Clinical Trials Group report that IL-2 is not effective at sustaining CD4 T cell counts during treatment interruptions. On a similar topic, Sonia Molina-Pinelo and colleagues report a novel association between thymus volume and CD4 T cell decline during treatment interruptions. Another ACTG group finds potentially important links between immune activation levels and CD4 T cell recovery during antiretroviral therapy. Finally, researchers from Emory University report that IL-15 may positively impact the CD4 T cell pool in SIV-infected macaques on antiretroviral therapy, providing a strong rationale for studying this cytokine as an immunotherapy in HIV infection.
JAIDS Journal of Acquired Immune Deficiency Syndromes. 42(2):140-148, June 2006.
A Pilot Study Evaluating Time to CD4 T-cell Count <350 cells/mm3 After Treatment Interruption Following Antiretroviral Therapy +/- Interleukin 2: Results of ACTG A5102.
Henry, Keith MD; Katzenstein, David MD; Cherng, Deborah Weng MS; Valdez, Hernan MD; Powderly, William MD; Vargas, Michelle Blanchard MA; Jahed, Nasreen C. MPH; Jacobson, Jeffrey M. MD; Myers, Laurie S. MS; Schmitz, John L. PhD; Winters, Mark MS; Tebas, Pablo MD; A5102 Study Team of the AIDS Clinical Trials Group
Abstract
Background: Although an intermittent antiviral treatment (ART) strategy may limit long-term toxicity and cost, there is concern about the risk for virologic failure, selection of drug resistance mutations, and disease progression. By boosting CD4 T-cell counts, interleukin 2 (IL-2) could safely prolong the duration of treatment interruption (TI) in a CD4-driven strategy.
Methods: The AIDS Clinical Trials Group (ACTG) study A5102 evaluated 3 cycles of IL-2 before TI, on clinical and immunologic outcomes, using a CD4 T-cell count of <350 cells/mm3 as the threshold for restarting ART. Forty-seven HIV-infected subjects on potent ART with CD4 T-cell counts of >=500 cells/mm3 or more and HIV RNA levels of less than 200 copies/mL were randomized to arm A (ART + three 5-day cycles of IL-2 at 4.5 million U, Sc, BID every 8 weeks, n = 23) or arm B (ART alone, n = 24) for 18 weeks (step 1). At the end of step 1, subjects with a CD4 T-cell count of >=500 cells/mm3 or more stopped ART until a CD4 count of <350 cells/mm3 (step 2). CD4 T-cell count, time to return of viremia, and the emergence of drug resistance mutations after TI were compared between study arms.
Results: IL-2 recipients maintained higher CD4 counts during TI for 48 weeks with a waning of the CD4 effect by 72 weeks. A sustained CD4 T-cell count of more than 350 cells/mm3 and more durable TI were associated with a higher nadir CD4 T-cell count before ART and higher naive CD4 T-cell count at entry. After TI, a higher viral set point and drug resistance mutations at virologic rebound were associated with a shorter time to CD4 T-cell count of less than 350 cell/mm3. There were no differences in the magnitude of virologic rebound (at week 8 of step 2, median log10 HIV RNA level was 4.23 for arm A and 4.21 for arm B) or the steady-state HIV-1 RNA level after week 8.
Conclusions: IL-2 before TI did not prolong time to CD4 of less than 350 cells/mm3. A TI strategy utilizing a CD4 T-cell threshold of less than 350 cells/mm3 for restarting ART appears generally safe with most subjects in both arms remaining off ART for more than 1 year. Implications of our results for TI strategies include the potential advantage of starting ART at higher CD4 T-cell levels while avoiding any drug resistance and evaluating immunomodulators or drugs to reduce T-cell activation and HIV-1 RNA rebound during the TI.
JAIDS Journal of Acquired Immune Deficiency Syndromes. 42(2):203-206, June 2006.
Thymic Volume Predicts CD4 T-Cell Decline in HIV-Infected Adults Under Prolonged Treatment Interruption.
Molina-Pinelo, Sonia BSc; Vivancos, Jorge MD; De Felipe, Beatriz BSc; Soriano-Sarabia, Natalia BSc; Valladares, Angela MD; De la Rosa, Rafael MD, PhD; Vallejo, Alejandro PhD; Leal, Manuel MD, PhD
Abstract
Objective: To analyze the predictive capacity of thymic volume in CD4 T-cell loss after treatment interruption in HIV-infected patients with high nadir CD4 count.
Methods: Thirty-nine HIV-infected patients with CD4 counts greater than or equal to 500 cells/[mu]L, nadir CD4 counts greater than or equal to 250 cells/[mu]L, and plasma viral loads less than 50 copies/mL for at least the past 12 months began a treatment interruption program. The event of interest for this study was the decrease of CD4 count below 350 cells/[mu]L. Kaplan-Meier curves were used for all time-to-event analyses, and log-rank tests were used for comparison between groups in the univariate analysis. All variables with statistical association with CD4 T-cell loss were analyzed using multivariate Cox proportional hazards regression models.
Results: Twenty-three percent of the patients had a decrease in CD4 count to less than 350 cells/[mu]L. In the univariate analysis, only thymic volume was statistically significant with this event (P = 0.02). Nadir CD4 count nearly reached statistical significance. However, age, sex, HCV coinfection, CD4 count, T-cell receptor excision circle-bearing cells, and early viral load rebound did not show statistical differences. Thymic volume and CD4 T-cell loss were independently associated using Cox proportional hazards regression model (P = 0.04; relative risk, 0.76; 95% confidence interval, 0.59-0.99).
Conclusions: In this study, we demonstrate for the first time that thymic volume predicts CD4 T-cell loss in patients with nadir CD4 count greater than or equal to 250 cells/[mu]L under treatment interruption.
http://www.journals.uchicago.edu/JID/journal/issues/v194n1/36091/brief/36091.abstract.html
The Journal of Infectious Diseases 2006;194:000
Determinants of CD4+ T Cell Recovery during Suppressive Antiretroviral Therapy: Association of Immune Activation, T Cell Maturation Markers, and Cellular HIV-1 DNA
Miguel Goicoechea, Davey M. Smith, Lin Liu, Susanne May, Allan R. Tenorio, Caroline C. Ignacio, Alan Landay, and Richard Haubrich
Abstract
Background: Suboptimal CD4+ T cell recovery during antiretroviral therapy (ART) is a common clinical dilemma.
Methods: We analyzed viral and immunologic predictors of CD4+ T cell recovery in 116 human immunodeficiency virus type 1 (HIV-1)–infected subjects who had suppressed viremia (50 copies/mL) while receiving ART. Successive measurements of T cell immunophenotypes and cellular HIV-1 DNA levels were obtained before and during receipt of ART. On the basis of increases in the CD4+ T cell count, subjects were classified as immunologically concordant (demonstrating an increase of 100 CD4+ T cells/mm3) or discordant (demonstrating an increase of <100 CD4+ T cells/mm3) after 48 weeks of ART.
Results: In adjusted analyses, CD4+ and CD8+ T cell activation at baseline was negatively associated with immunologic concordance at week 48 of ART (odds ratio [OR], 0.80 [P = .04] and 0.67 [P = .02], respectively). High memory (CDRA-CD62L-) CD8+ T cell counts at baseline (OR, 0.33 [P = .05]) predicted less CD4+ T cell recovery, whereas increased naive CD4+ T cell counts were associated with higher increases in CD4+ T cells (OR, 1.19 [P = .052]). Neither the cell-associated HIV-1 DNA level at baseline (P = .32) nor the cell-associated HIV-1 DNA level at week 48 of ART (P = .42) was associated with immunologic concordance during ART.
Conclusions: These results support the potential clinical usefulness of the baseline determination of immune activation and maturation subsets in the prediction of CD4+ T cell recovery during viral suppression. Furthermore, identification of individuals with reduced potential for CD4+ T cell recovery during ART may provide a rationale for the initiation of early therapy for some patients.
http://www.jci.org/cgi/content/abstract/JCI27564v1
J. Clin. Invest., doi: 10.1172/JCI27564
IL-15 induces CD4+ effector memory T cell production and tissue emigration in nonhuman primates
Louis J. Picker, Edward F. Reed-Inderbitzin, Shoko I. Hagen, John B. Edgar, Scott G. Hansen, Alfred Legasse, Shannon Planer, Michael Piatak Jr., Jeffrey D. Lifson, Vernon C. Maino, Michael K. Axthelm, Francois Villinger
Abstract
HIV infection selectively targets CD4+ effector memory T (TEM) cells, resulting in dramatic depletion of CD4+ T cells in mucosal effector sites in early infection. Regeneration of the TEM cell compartment is slow and incomplete, even when viral replication is controlled by antiretroviral therapy (ART). Here, we demonstrate that IL-15 dramatically increases in vivo proliferation of rhesus macaque (RM) CD4+ and CD8+ TEM cells with little effect on the naive or central memory T (TCM) cell subsets, a response pattern that is quite distinct from that of either IL-2 or IL-7. TEM cells produced in response to IL-15 did not accumulate in blood. Rather, 5-bromo-2'-deoxyuridine (BrdU) labeling studies suggest that many of these cells rapidly disperse to extralymphoid effector sites, where they manifest (slow) decay kinetics indistinguishable from that of untreated controls. In RMs with uncontrolled SIV infection and highly activated immune systems, IL-15 did not significantly increase CD4+ TEM cell proliferation, but with virologic control and concomitant reduction in immune activation by ART, IL-15 responsiveness was again observed. These data suggest that therapeutic use of IL-15 in the setting of ART might facilitate specific restoration of the CD4+ T cell compartment that is the primary target of HIV with less risk of exhausting precursor T cell compartments or generating potentially deleterious regulatory subsets.
Comments