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Recovery of Functional Immunity over 48 Weeks with
Darunavir-based Therapy in the GRACE Immunology Substudy
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Reported by Jules Levin
5th IAS July 19-22 2009, Capetown, South Africa
Christos Tsoukas1, Louise Gilbert1, Trevor Lewis1, George Hatzakis2, Ron Falcon3, Joseph Mrus3
1McGill University Health Centre, Montreal, QC, Canada; 2University of Southern California, Los Angeles, CA, USA; 3Tibotec Therapeutics, Bridgewater, NJ, USA
AUTHOR CONCLUSIONS
Few, if any, studies have prospectively assessed changes in in vitro immune function in response to ARV therapy
- This substudy from GRACE evaluated T-cell function in a racially diverse population comprised of more than 30% women
DRV/r (600/100mg twice daily)-based ART was associated with progressive immune recovery over 48 weeks in virologically suppressed patients
- Both immune phenotype and function of CD4+ and CD8+ cells were signifi cantly improved as evidenced by positive changes in the capacity to proliferate and the expression of intracellular cytokines by CD4+ cells
Functional recovery, as assessed by proliferative response and intracellular cytokine expression was also seen in unsuppressed patients, although to a lesser degree than in suppressed patients
Results from this substudy validate that virologic suppression with highly-active ART not only leads to increased CD4+ cell counts, but also improves in vitro immune function
INTRODUCTION
During the course of HIV-1 infection, multifactorial T-lymphocyte (T-cell)-mediated mechanisms contribute to the progressive loss of host immune function, including:
- Initial decreases in the number of CD4+ cells with concurrent increases in the CD8+ population1
- Immune dysregulation and activation characterized by an increased expression of T-cell cellular activation markers, CD38 and human leukocyte antigen-DR (HLA-DR)2-5
- Surface expression of CD38 on CD8+ cells is a powerful predictor of HIV progression6,7
- Decreased proportion of CD4+ cells expressing interleukin (IL)-2 and interferon (IFN)-γ and an increased proportion expressing IL-4 and IL-10 due to a shift from the T helper (TH)1 to TH2 phenotype8,9
· In addition to reduced viral load, successful antiretroviral therapy (ART) results in improvements in CD4+ counts and decreases in immune activation
· The majority of studies of immune recovery with ART have been cross-sectional in design, conducted primarily in Caucasian males and have not assessed direct in vitro immune function
· The aim of this prospective substudy was to quantitatively and qualitatively evaluate the recovery of functional immunity (T-cell function) with a darunavir/ritonavir (DRV/r)-based regimen in a diverse treatmentexperienced patient population from the GRACE (Gender, Race And Clinical Experience) study
- GRACE is the largest ART trial to focus on women with HIV-1 in North America, and was designed to assess sex and race differences in effi cacy, safety and tolerability of DRV/r plus an optimized background regimen over 48 weeks in treatment-experienced patients10 [see poster MOPE042]
METHODS
The GRACE study
GRACE was a multicenter, open-label, single-arm, Phase IIIb study conducted at 65 sites across the United States, Puerto Rico and Canada, which enrolled treatment-experienced patients (viral load ≥1000 HIV-RNA copies/mL) aged ≥18 years with documented HIV-1 infection (Figure 1)
aPatients were allowed to enter the study on treatment interruption of ≥4 weeks; bInvestigator-selected NRTIs and NNRTIs were allowed; ENF, TPV or agents from novel classes were not allowed; PI, protease inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; HAART, highly-active antiretroviral therapy; DRV/r, darunavir/ritonavir; ETR, etravirine; ENF, enfuvirtide; TPV, tipranavir; bid, twice daily; OBR, optimized background regimen
aWilcoxon rank-sum test; Red line represents median; BL, baseline
aWilcoxon rank-sum test; Red line represents median; HLA-DR, human leukocyte antigen-DR; BL, baseline
aWilcoxon rank-sum test; Red line represents median; PHA, phytohemagglutin; BL, baseline
TNF-α and IL-2 expression signify cantly increased in stimulated CD4+ cells (Figure 5)
- Less pronounced improvements in cytokine expression were
observed in unsuppressed patients (data not shown)
aWilcoxon rank-sum test; Red line represents median; SEB, Staphylococcal enterotoxin B; TNF, tumor necrosis factor;
BL, baseline; IL, interleukin; IFN, interferon
REFERENCES
1. Landay A, et al. AIDS 1990; 4: 479-497
2. Kestons L, et al. AIDS 1992; 6: 793-797
3. Kestons L, et al. Clin Exp Immunol 1994; 95: 436-441
4. Levacher M, et al. Clin Exp Immunol 1992; 90: 376-382
5. Giorgio JV, et al. J Infect Dis 1994; 170: 775-781
6. Giorgio JV, et al. J Acquir Immune Defi c Syndr 1993; 6: 904-912
7. Liu Z, et al. J Acquir Immune Defi c Syndr Hum Retroviral 1997; 16: 83-92
8. Klein SA, et al. AIDS 1997; 11: 1111-1118
9. Clerici M, et al. Immunol Today 1993; 14: 107-111
10. Squires K, et al. Presented at 5th IAS (International AIDS Society) Conference, Cape Town, South Africa, July 19-22, 2009. Poster MOPE042
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