HIV Therapy & Interruption RCT in Resource Poor Clinic
Principal Investigator: Luis J Montaner
Abstract: 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.
Funding Period: ----------------2003 - ---------------2011-
more information: NIH RePORT
- 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 subjectsEmmanouil Papasavvas
The Wistar Institute, Philadelphia, Pennsylvania 19104, USA
AIDS Res Hum Retroviruses 24:1203-8. 2008..This finding suggests that T cell hyperresponsiveness may play a role in the pathogenesis of immune comorbidities on ART...
- Identification of a 251 gene expression signature that can accurately detect M. tuberculosis in patients with and without HIV co-infectionNoor Dawany
Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania, United States of America
PLoS ONE 9:e89925. 2014..Here we report a gene signature that can identify a tuberculosis infection in patients co-infected with HIV as well as in the absence of HIV...
- Association between HIV replication and serum leptin levels: an observational study of a cohort of HIV-1-infected South African womenLivio Azzoni
The Wistar Institute, Philadelphia, PA, USA
J Int AIDS Soc 13:33. 2010..Advanced HIV infection can result in lipoatrophy and wasting, even in the absence of ongoing opportunistic infections, suggesting that HIV may directly affect adipose tissue amount and distribution...
- Randomized trial of time-limited interruptions of protease inhibitor-based antiretroviral therapy (ART) vs. continuous therapy for HIV-1 infectionCynthia Firnhaber
Clinical HIV Research Unit, Faculty of Health Sciences, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa
PLoS ONE 6:e21450. 2011..The clinical outcomes of short interruptions of PI-based ART regimens remains undefined...
- Metabolic and anthropometric parameters contribute to ART-mediated CD4+ T cell recovery in HIV-1-infected individuals: an observational studyLivio Azzoni
HIV 1 Immunopathogenesis Laboratory, The Wistar Institute, Philadelphia, PA, USA
J Int AIDS Soc 14:37. 2011..We sought to determine if adiposity and molecules associated with lipid metabolism may affect the response to ART and the degree of subsequent immune reconstitution, and to assess their ability to predict CD4 recovery...
- Antiretroviral therapy interruptions result in loss of protective humoral immunity to neoantigens in HIV-infected individualsLivio Azzoni
The Wistar Institute, Philadelphia, Pennsylvania, USA
AIDS 26:1355-62. 2012..As ART interruption occur frequently in resource-constrained settings, we studied their effects on the ability to mount humoral immune responses against a neoantigen...