California Collaborative Treatment Group
Richard Haubrich, University of California San Diego; Eric Daar, Harbor-UCLA Medical Center, Los Angeles; Michael Dubé, University of Southern California,
California AIDS Multi-Institutional Clinical Studies Award (CAMICS)
The California Collaborative Treatment Group (CCTG): Since 1986, the CCTG has been conducting high impact multi-centered, investigator-initiated clinical trials. The two major projects in our proposal will address two issues critical to the HIV epidemic in California: 1) CCTG 590- the impact of aging on response to antiretroviral therapy (ART) and 2) CCTG 592- prevention of HIV transmission by targeting HIV-infected subjects engaging in high risk sexual activities.
This proposal will request funding for two major clinical studies and site personnel to support these projects. All three sites will be integrally involved in the conception, design, conduct, and analysis of the studies. Both studies will be led by junior investigators: the first at UCSD (Goicoechea and Woelk) while the second at UCSD and USC (Morris and Milam). The site PIs will mentor these investigators. The CCTG has consistently completed and published proposed studies while also being able to rapidly change course to address new critical questions that emerge. This nimbleness results from our close collaboration and regular meetings to discuss ongoing and future research priorities. In addition, our group actively collaborates with colleagues in diverse disciplines, can leverage funds to augment the scope and depth of our studies, and can rapidly implement new protocols because of our efficient central administration and centralized electronic data capture.
The specific aims of CCTG 590 are: to compare changes (baseline to weeks 4 and 24) in gene expression profiles in subjects whose fully suppressive ART is intensified with maraviroc (MVC) and the impact of age on those changes; to evaluate the association between MVC-induced gene expression profiles and the rate of CD4 recovery, and compare differences by age group; and to evaluate the impact of MVC intensification on persistent immune activation and maturation phenotype (as measured by flow cytometry). CCTG 590 is a single-arm study which will enroll thirty subjects (equally divided between age 18-40 and > 50) with viral suppression on a stable ART regimen but with sub-optimal CD4 recovery. MVC will be added to their current HIV regimen for 24 weeks and then discontinued. Follow-up for an additional 12 weeks will evaluate safety and the immunological effects. Functional genomic analysis will be assessed by whole genome microarray expression (48,000 genes) done at baseline, week 4 and 24. Immune activation will be measured in the cellular and plasma compartments. Gene expression differences between age groups and responses to MVC therapy will be identified by and categorized into functional groups. CD4 cell changes before and after MVC therapy will be analyzed. This study could reveal pathogenic mechanisms accounting for reduced CD4 cell recovery in older HIV-infected subjects. Further, results could provide pilot data about whether individuals experiencing immune discordance, during suppressive ART, may benefit from MVC intensification.
The specific aims of CCTG 592 are to develop an interactive Internet application for use among HIV-infected MSM designed to reduce risky behavior responsible for HIV transmission; outcomes will include transmission-associated events: sexually transmitted infections (STI), initiation of ART to reduce transmission risk and genital track virology. CCTG 592 is a multi-site controlled clinical trial that seeks to determine the clinical efficacy, assessed by a reduction in new and recurrent STI, of the intervention. A total of 200 HIV-infected MSM will be randomized 1:1 (stratified by current ART use and availability of Internet at home) to receive the intervention or an attention control (risk survey alone). The Internet tool attempts to influence behavior by calculating the individual-subject risk of HIV transmission in the past month (based on their self-reported risk assessment) and deliver a prevention message based on a transtheoretical mode of behavior change. In California, the dramatic increase in syphilis cases could portend greater HIV infections in MSM. Thus, an intervention that reduces STI could reduce new HIV infections in California. The use of the Internet is of critical importance as a way to provide efficient and accessible means to reach target populations, but first must demonstrate efficacy before widespread implementation.