Over the last four years our studies have shown that cycles of brief interruptions of Highly Active Anti-Retroviral Therapy (HAART) are not associated with adverse events, lack of resuppression upon reinitiation of therapy, loss of recall responses or lack of restoration of CD4 levels to pre-interruption levels upon achieving viral suppression following reinitiation of therapy. The long-range goal of this proposal is to determine whether, in suppressed patients, intermittent interruptions of HAART result in maintenance of immune parameters (e.g. CD4 counts, recall responses etc.) comparable to continuous HAART, while reducing overall long-term toxicity and cost. Specifically, we propose to test the hypothesis that repeated cycles of 2-8 weeks off HAART followed by 16 weeks on therapy (leading to a maintenance strategy decreasing drug exposure by 33%) is not inferior to continuous therapy over the same period, with non-inferiority defined by the sustained cellular and humoral immune response to a de novo antigen. Functional end-point of retained immune reconstitution will be evaluated in conjunction with viral suppression to <400 copies/ml and retention of CD4 cell count above baseline at the final observation when both intermittent and continuous study arms are on therapy. Additionally, we hypothesize that the cyclic therapy intervention will result in a significantly lower therapy-related toxicity while maintaining CD4 Tcell counts at levels significantly higher than pre-therapy levels during period off and on treatment. We will test these hypotheses in treatment-naive subjects with 200-350 CD4 cells/mm3 who successfully achieve viral suppression to <50 copies/ml during a 24 week """"""""run-in"""""""" period on lopinavir/ritonavir, lamivudine, stavudine to include a complete vaccination series against rabies from week 16 to 22 (de novo antigen) before randomization into study arms in a single-center, randomized, two-arm non-blinded study (n=74). We will monitor immune reconstitution and adherence to therapy and determine changes in the immune status of patients following HAART interruption. Therapy-induced toxicities will be monitored by assessing fat distribution, glucose/insulin metabolism, mineral bone density and liver, kidney and pancreatic function tests. We will also monitor viral resistance outcomes by determining genotypic changes in the HIV-1 protease and reverse transcriptase regions over time. In addition to addressing the needs of South Africa in relation to development of sustainable and affordable treatment strategies, this study advances our understanding of immune reconstitution in clade C HIV-1 infected subjects and of treatment interruption as a strategy to decrease drug toxicity in therapy-naive chronically infected persons. This hypothesis-driven proposal represents an international multidisciplinary research effort by the Wistar Institute, the Clinical HIV Research Unit and Departments of Haematology, Chemical Pathology, Medicine (Endocrinology Division) at the University of the Witwatersrand, the AIDS Virus Research Unit at the National Institute for Communicable Diseases in Johannesburg, and the University of Pennsylvania's Center for Clinical Epidemiology and Biostatistics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI051986-04
Application #
7009979
Study Section
Special Emphasis Panel (ZRG1-AARR-2 (04))
Program Officer
Livnat, Daniella
Project Start
2003-07-01
Project End
2007-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
4
Fiscal Year
2006
Total Cost
$647,069
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Dawany, Noor; Showe, Louise C; Kossenkov, Andrew V et al. (2014) Identification of a 251 gene expression signature that can accurately detect M. tuberculosis in patients with and without HIV co-infection. PLoS One 9:e89925
Papasavvas, Emmanouil; Hsue, Priscilla; Reynolds, Griffin et al. (2012) Increased CD34+/KDR+ cells are not associated with carotid artery intima-media thickness progression in chronic HIV-positive subjects. Antivir Ther 17:557-63
Azzoni, Livio; Foulkes, Andrea S; Firnhaber, Cynthia et al. (2012) Antiretroviral therapy interruptions result in loss of protective humoral immunity to neoantigens in HIV-infected individuals. AIDS 26:1355-62
Azzoni, Livio; Foulkes, Andrea S; Liu, Yan et al. (2012) Prioritizing CD4 count monitoring in response to ART in resource-constrained settings: a retrospective application of prediction-based classification. PLoS Med 9:e1001207
Firnhaber, Cynthia; Azzoni, Livio; Foulkes, Andrea S et al. (2011) Randomized trial of time-limited interruptions of protease inhibitor-based antiretroviral therapy (ART) vs. continuous therapy for HIV-1 infection. PLoS One 6:e21450
Azzoni, Livio; Foulkes, Andrea S; Firnhaber, Cynthia et al. (2011) Metabolic and anthropometric parameters contribute to ART-mediated CD4+ T cell recovery in HIV-1-infected individuals: an observational study. J Int AIDS Soc 14:37
Azzoni, Livio; Crowther, Nigel J; Firnhaber, Cynthia et al. (2010) Association between HIV replication and serum leptin levels: an observational study of a cohort of HIV-1-infected South African women. J Int AIDS Soc 13:33
Papasavvas, Emmanouil; Moore, Elizabeth C; Sun, Junwei et al. (2008) HIV type 1 viremia on ART is positively associated with polyclonal T cell proliferation in subjects with T cell IFN-gamma secretion levels comparable to those of uninfected subjects. AIDS Res Hum Retroviruses 24:1203-8