AIDS Clinical Trials Group Grant: The Division of Infectious Diseases continues to provide scientific leadership and to obtain funding in a wide range of clinical research in both HIV and non-HIV disciplines. Dr. Robert Larsen serves as co-chair of A5225, Dr. Fred Sattler is a member of the protocol team for A5241, Dr. Brenda Jones served as member of the TB Working Group and Dr. Jens Kort served on the Phase IIIB concept proposal team of CCR5 Inhibitor (PR507).

Our NIH-supported ACTG Clinical Trials Unit and Clinical Research Site is one of the major components of the research efforts of the Division. The current grant is in its 22nd year of funding. Over the past decade USC was one of the top performing sites in the United States and led accrual of number of different high-priority studies and ranked at the top of more than 50 different ACTG Clinical Trials Units, in the categories of total accrual of research subjects. The Unit has consistently been at the top of the list for enrollment of underprivileged minorities and has also been successful in enrolling women. We believe the inclusion of ethnic minorities and women is of great importance based on genetic differences that predispose them to different risks for drug-related toxicities and disease complications.

NIH National TB Curriculum Consortium and TB Trials Consortium: Dr. Brenda Jones has established liaisons with public health clinics in Southern California caring for large numbers of patients with tuberculosis (TB). She serves as the Principal Investigator at USC for the NIH National TB Curriculum Consortium (2003-2008) and the TB Trials Consortium (TBTC) [200-93-0693], an investigator-driven consortium funded by the CDC and modeled after the ACTG. She is working with other investigators planning future collaborative efforts between the TBTC and the ACTG to address the treatment and prevention of HIV-related TB.

Dr. Jones and her TB research staff have been highly efficient in enrolling > 360 patients into TBTC studies in the last five years. Dr. Jones is committed to making major contributions to ACTG Network studies such as ACTG 5221. She is also working with Dr. Neil Kaplowitz, Chief of the Gastrointestinal and Liver Diseases Division, to define genetic markers that predispose patients to serious adverse effects of medications like the ansamycin rifalazil to be studied by the ACTG Network. Finally, she is exploring feasibility studies to evaluate use of an INFg assay and nucleic acid amplification methods for diagnosis and management of TB in HIV co-infected patients. Thus, Dr. Jones’ contributions will be invaluable in the design and conduct of future nationwide studies of tuberculosis.

California Collaborative Treatment Group and California NeuroAIDS Tissue Network Grants: The Infectious Diseases Division is also a member of the California Collaborative Treatment Group (CCTG, Robert Larsen, M.D., USC Principal Investigator) of the University-wide AIDS Program of the University of California, also in its 20th year, and the NIMH study evaluating neurocognitive effects of HIV (California NeuroAIDS Tissue Network, Robert Larsen, M.D., USC Principal Investigator), which was successfully re-competed for an additional five years of funding.

Scientific Contributions: Our participation in these collaborative research groups has emphasized development of treatment and prevention modalities for HIV and its complications. For example:

Dr. Brenda Jones has 15 years of experience in clinical research of tuberculosis (TB) and, as indicated above, she now serves as the PI at USC for the NIH National TB Curriculum Consortium (2003-2008) and CDC TB Trials Consortium (TBTC) [200-93-0693]. She has served as an active member of the ACTG Mycobacterial-Bacterial Study Group and was a major force in enrolling patients for ACTG 177, 222 and 309. Dr. Jones is working with collaborators at the CDC who are planning important studies with the ACTG to develop more effective and safer strategies for prevention and treatment of TB-HIV co-infected patients such as ACTG studies A5221 (a strategy of immediate versus deferred initiation of antiretroviral therapy for HIV infected persons treated for tuberculosis) and A5233, which Dr. Jones will be implementing at USC.

Dr. Jones has been mentoring our ID fellow, Dr. Martin Sattah, to utilize the infrastructure that she has developed over the last two decades to continually be a leading performance site for the CDC TB studies for which she has enrolled >360 subjects in the last five years. She and Dr. Sattah have initiated a pilot study on the use of the interferon gamma release assay (T-SPOT.TB) in HIV infected patients with active tuberculosis. Dr. Jones is expected to be equally productive in enrolling subjects in ACTG 5221 and 5233 and other upcoming ACTG and CCTG TB studies.

Dr. Michael P. Dubé serves on the ACTG Optimization of Antiretroviral Therapy (OpART) Committee and is a member of the A5257s metabolic and cardiovascular complications study team, currently in active protocol development. Previously, he was protocol chair for the ACTG metabolic study A5005s, which has yielded a total of nine publications (four in the past year), including seven as first or senior author. Several of these have set the standard for current and future metabolic studies in this field. Dr. Dubé was also the protocol chair for a multicenter ACTG study of extended-release niacin and has served as a protocol member on a variety of other ACTG studies.

Dr. Dubé mentored Dr. Samir Gupta during his K23 work at Indiana University on renal and cardiovascular complications of HIV disease, yielding four peer-reviewed publications as senior author. Dr. Gupta was recently awarded his first R01 as Principal Investigator and Dr. Dubé will serve as Co-Investigator on this project at USC.

Dr. Robert Larsen is currently the protocol vice chair for ACTG study A5225, an investigation drawn from the concept sheet he proposed in April 2004. Previously, Dr. Larsen was a key member of clinical trials in the ACTG responsible for the licensure of fluconazole and itraconazole for HIV-associated cryptococcosis and histoplasmosis. His pioneering work with combination therapies for cryptococcal meningitis set the stage for the ACTG 159 trial, which evaluated high doses of amphotericin B alone and combined with flucytosine as induction therapy for cryptococcal meningitis. He contributed to the protocol strategy for the management of intracranial hypertension for ACTG 202. Further, he is vice chair for the Bacterial and Mycoses Study Group (BAMSG) evaluation of the safety and activity of amphotericin B alone or combined with fluconazole for treatment of AIDS-associated cryptococcal meningitis. Finally, he has been the lead investigator of the California NeuroAIDS Tissue Network neurosyphilis study at USC.
Dr. Larsen manages our weekly Fungal/ID Clinic in the Rand Schrader Clinic. His enthusiasm for conducting quality clinical research is immediately contagious to students, residents, fellows and staff who work with him in the Clinic. This is an ideal setting for accrual of sizable numbers of subjects for ACTG, CCTG, MSG and NeuroAIDS Network studies.

Dr. Fred Sattler continued his research programs to study metabolic complications of HIV infection and its treatment, including HIV-associated wasting and lipodystrophy, dyslipidemias and alterations in glucose tolerance. He was PI for an NIDDK R01 grant to study metabolic-hormonal-dysregulation in HIV (R01 DK 49308) to investigate mechanisms that adversely affect muscle physiology and fat metabolism in HIV-positive patients with or at risk for wasting and lipoatrophy. As an outgrowth of those studies, Dr. Sattler was awarded a large multicenter R01 (Hormonal Regulators of Muscle and Metabolism in Aging, AG18169) to determine the molecular and regulatory effects of endogenous anabolic hormones on net muscle protein (actin and myosin) anabolic balance and the effects of these hormones on regional fat (hepatic, visceral and intramyocellular lipid), insulin sensitivity and lipid metabolism in older persons with muscle wasting and central obesity, a model similar to that occurring in HIV. Dr. Sattler is also conducting an investigator-initiated study to determine the effects of testosterone replacement in hypogonadal men with abdominal obesity and insulin resistance to assess whether his recently observed indirect evidence of benefits in insulin sensitivity during replacement doses with this androgen is due to decreases in visceral adipose tissue, hepatic fat or intramyocellular lipid using 2-stage hyperinsulinemic euglycemic clamps and magnetic resonance spectroscopy.

Faculty Research Areas

Joseph J. Cadden, M.D.
Social Support Services for Patients with HIV
Sociological Effects on Family Members or Children When Mother or Female Caregiver is HIV Positive
Blocking Chemokine Receptors in Patients with HIV
New HIV Therapies

Michael P. Dubé, M.D.
Metabolic, Cardiovascular, and Anthropometric Complications of HIV and Antiretroviral Therapy

P. Jan Geiseler, M.D.
Clinical Evaluation of New HIV Drugs
Antiretroviral Therapy for HIV-1

Paul D. Holtom, M.D.
Bone and Joint Infections
Hospital Epidemiology

Brenda E. Jones, M.D.
Development of a Tuberculosis Curriculum
New Methods for the Treatment and Prevention of Tuberculosis
Tuberculosis and HIV Infection
Diagnostics for Tuberculosis
Biomarkers for Tuberculosis Treatment Response
Vitamin D Receptor Gene Expression Profile Analysis in Tuberculosis Patients

Robert A. Larsen, M.D.
HIV and West Nile Viral Infections of Central Nervous System
Diagnosis and Management of CNS Syphilis
Treatments Strategies for Systemic Fungal Infections
Fungal in vitro Susceptibility to New Antifungal Agents

Alejandro Sanchez, M.D.
AIDS-Associated Cryptococcal in vitro Susceptibility Testing
HIV-Associated Central Nervous Infections
TB-HIV Coinfections
Histoplasmosis in Non-Endemic Areas

Fred R. Sattler, M.D.
Clinical Therapeutics and Pharmacokinetics of Antimicrobial and Antiviral Agents
Pathogenesis and Treatment of Muscle Wasting in HIV
Hormonal Regulators of Muscle and Metabolism in Persons Infected with HIV and the Elderly
Understanding Disorders of Fat and Lipid Metabolism in HIV and Aging

Special Basic and Translational Research Activities

Brenda E. Jones, M.D.
Dr. Jones has developed collaboration relationships with faculty in the Department of Preventive Medicine and the Division of Gastrointestinal and Liver Diseases at USC. As a result, her future studies will include the use of a novel system to quantify levels of gamma interferon for the diagnosis of tuberculosis and studies to determine the genetic susceptibility and risks for isoniazid hepatotoxicity (i.e., pharmacogenomics).

Robert A. Larsen, M.D.
Dr. Larsen continues his laboratory work on correlative studies involving a murine model of cryptococcal disease and an in vitro system to test fungal susceptibility.

Fred R. Sattler, M.D.
Dr. Sattler continued with the seventh year of his multicenter R01 study as the overall project Principal Investigator to assess “Hormonal Regulators of Muscle and Metabolism in Aging.” This study is investigating the effects of restoring testosterone and growth hormone individually and in combination to youthful levels on synthesis of myofibrillar proteins actin and myosin, muscle protein breakdown via activation of the ubiquitin-proteasome system and ligase (MuRF1, Atrogin 1,2 mRNA expression and protein synthesis), quantification of satellite cell activation in muscle cells and the effects of the local regulators IGF-1, IGFBP-4, MGF, mTOR, Akt, MyoD, myostatin, and follistatin on net myofibrillar protein balance.

Special Clinical Research Activities

Michael P. Dubé, M.D.
Metabolic, cardiovascular, and anthropometric complications of HIV and antiretroviral therapy: Dr. Dubé will collaborate as Co-Investigator on an NHLBI-funded project R01 HL095149-01 (Gupta-PI) entitled HIV, Inflammation, and Endothelial Dysfunction. In the ACTG, he will serve as Co-Investigator on an ACTG study of Cardiovascular, Anthropometric, and Skeletal Effects of Antiretroviral Therapy. Locally, he is serving as PI for ACTG trials as well as trials in the California Collaborative Treatment Group.

P. Jan Geiseler, M.D.
Antiretroviral therapy: Dr. Geiseler continued his work with and participation in studies to evaluate antiretroviral therapy utilizing new treatment medications and strategies in clinical trials being conducted by the AIDS Clinical Trials Group (ACTG) and California Collaborative Treatment Group for patients infected with HIV. Dr. Geiseler is currently the local PI for two ACTG trials. Trials A5175 and A5202 evaluate the efficacy of once daily protease inhibitor and once-daily non-nucleoside reverse transcriptase inhibitor-containing therapy in combination with nucleoside analogues.

Joseph J. Cadden, M.D.
Dr. Cadden is involved in three research studies as either PI or co-PI. The first is an NIH-funded study in which he serves as co-PI and site PI at USC. This study is being conducted with Amy Wohl, Ph.D., Chief Epidemiologist in the HIV Epidemiology Program DHS, to evaluate and develop better social support services for HIV-positive persons. In addition, he is the site PI for a study with Eric Rich, Ph.D. from UCLA, which will evaluate the sociological effects on family members and children when the mother or female caregiver is HIV positive. Lastly is the GRACE study (Gender Race and Clinical Efficacy), which is designed to look at clinical outcomes primarily in women with advanced HIV disease and who are highly anti-retroviral experienced.

Paul D. Holtom, M.D.
Bone and soft tissue infections: Dr. Holtom is initiating new studies to investigate novel treatment strategies for bone and joint infections, in collaboration with Drs. Michael Patzakis, Charalampos Zalavras and others in the Department of Orthopaedic Surgery. These studies include new antimicrobials for skin and soft-tissue infections and the in vitro and in vivo studies on local antibiotic therapy and the elution of antibiotics from PMMA beads and spacers.

Epidemiologic Studies: Dr. Holtom is the Hospital Epidemiologist at LAC+USC Medical Center and is conducting several studies with two of the infectious diseases fellows on the epidemiology of Staphylococcus aureus and invasive candidal disease. Dr. Holtom remains the Director of the Jeanette Wilkins Memorial Microbiology Laboratory, which facilitates conduct of these studies.

Brenda E. Jones, M.D.
Dr. Jones is the USC Principal Investigator of a 10-year contract (September 1999-2009) sponsored by the Centers for Disease Control and Prevention (TBTC) on the natural history and treatment of tuberculosis. The USC study site, which includes Los Angeles County TB Control, is one of 27 international study sites. The purpose of the Consortium is to address the research needs for the treatment and prevention of tuberculosis. A high priority of research is for improved treatment of latent tuberculous infection. An important secondary goal of the Consortium is to contribute to the global control of tuberculosis in HIV-infected persons.

In October 2003, Drs. Jones (PI) and Patricio Escalante (Co-Investigator, Pulmonary Division) were awarded a five-year NIH subcontract with UCSD to establish a National TB Curriculum Center (NTCC). The NTCC will coordinate the activities of a multidisciplinary team to develop and implement curriculum, using state-of- the-art technology for education. The Consortium consists of 23 partner schools, of which USC is one of the five coordinating centers.

Robert A. Larsen, M.D.
Dr. Larsen’s research is focused primarily toward understanding the mechanisms of pathogenesis and outcomes of central nervous system infections. He is also actively involved in other investigations including viral, fungal and bacterial pathogens.

Fungal infections: Dr. Larsen is a member of the NIH-sponsored Bacterial and Mycoses Study Group (BAMSG). The BAMSG has initiated a trial of amphotericin B plus fluconazole in persons with AIDS and cryptococcal meningitis. Dr. Larsen is a co-chair of this study being conducted in the U.S. and Thailand. The NIH-sponsored Adult AIDS Cooperative Trials Group has developed and is implementing an international study of AIDS-associated cryptococcal meningitis with high doses of fluconazole (AACTG 5225). Dr. Larsen is vice-chair of this study, which will be conducted in the U.S., Peru, Brazil and South Africa. Both trial concepts were proposed by Dr. Larsen and based on prior clinical studies that he has conducted at USC.

Bacterial infections: Dr. Larsen continues to study neurosyphilis in persons co-infected with HIV, as a subproject of the California NeuroAIDS Tissue Network (CNTN). A novel diagnostic approach to identify central nervous system infection with syphilis is being tested with samples collected as part of the CNTN program.

Other activities: Dr. Larsen is the USC primary site investigator for the California Collaborative Treatment Group (CCTG). Dr. Larsen also served as a site investigator of a Center for Disease Control and Prevention (CDCP) study of clinic and drug adherence in persons with HIV infection receiving highly active anti-retroviral drug therapy.

Fred R. Sattler, M.D.
Metabolic abnormalities in HIV infection and aging: Dr. Sattler has for a number of years provided his scientific and administrative leadership in the NIAID AIDS Clinical Trials Group involving studies that have evaluated the pathophysiology and management of HIV-associated weight loss, changes in body fat, and metabolic complications. He has served as a chair, co-chair, vice-chair or protocol team member for a number of studies including ACTG 313, 329, 392, 892, 5079, 5112, 5116s, 5124s and 5125s, which are either in the phase of study maintenance or were recently completed (ACTG 313, 329, 392, 892) and the results are being analyzed and/or prepared for manuscripts.

As an outgrowth of studies of AIDS muscle wasting, Dr. Sattler conducted investigator-initiated pilot studies in the USC GCRC to evaluate the effects of anabolic androgens in elderly subjects with loss of skeletal muscle mass (sarcopenia) and muscle strength and thus at risk for frailty and who have gains in central fat and are at risk for the metabolic syndrome. These studies have demonstrated dose-dependent improvements in muscle mass, maximal voluntary strength and leg power, which are necessary constituents for physical function, independence, and quality of life during aging. In addition, study subjects have had a dose-related decrease in total and central fat.

Based on the results of these studies, which have been presented at The Endocrine Society meetings, Dr. Sattler received funding from the National Institute of Aging (5-RO1-AG18169) to study the interactions of the growth hormone/IGF-1 and androgen axes in the molecular regulation of myofibrillar protein synthesis and breakdown and adipose tissue biology in elderly persons through use of stable isotope dilution methods. The translational effects of these interventions as measured by body composition (DEXA, MRI and total body water analysis by stable isotope biology), anthropometry, skeletal muscle strength, power, and physical function, maximal ventilatory capacity, and aerobic endurance are being measured in the USC GCRC. Dr. Sattler has also continued work on an investigator-initiated study on the GCRC to evaluate the role of androgen replacement to improve insulin sensitivity and other risk factors for the metabolic syndrome by carefully quantifying intra-abdominal adipose tissue stores, intramyocellular lipid, hepatic glucose output, and peripheral glucose disposal in older, hypogonadal men with central obesity and insulin resistance.