Contents Network Scientific Research Plan Introduction ............................................................................. 3 Scientific Research Committee Summaries ................................................................................. 4

Translational Research and Drug Development Scientific Committee.............................. 4

Optimization of Antiretroviral Therapy Scientific Committee 10

Optimization of Co-Infection and Co-Morbidity Management Scientific Committee........ 20

Hepatitis Scientific Committee ........................................................................................ 23

Womens Health Inter-Network Scientific Committee...................................................... 25

International Program...................................................................................................... 28

Challenges and Barriers to Implementing Research Plans ........................................................ 30 Performance Evaluation Committee ........................................................................................... 33

Cross-Network and External Collaborations ............................................................................... 36 Network Laboratory Summary ................................................................................................... 42 Appendices

Appendix A. ACTG Studies............................................................................................. 66

Appendix B. ACTG Protocol Status and Scientific Priority .............................................. 75

Appendix C. ACTG Protocol Timelines ........................................................................... 81

Appendix E. Publications and Meeting Abstracts............................................................88

Network Scientific Research Plan The ACTG network has had a very productive year, as summarized in this document. For ease of presentation, we have included the protocol list and the requested details related to all current studies in tables appended to the end of the narrative section of the report. These tables include the current status, projected or actual open dates, projected and actual end of accrual dates, projected and actual end of follow-up dates, estimated cost of protocol from concept to publication, and assessment of the protocols relative scientific priority (see Appendices A-D). A separate bibliography in alphabetical order incorporating publications and scientific presentations of ACTG network studies for this grant year is also included as an appendix to the narrative portion of this report (see Appendix E. The Statistical and Data Management Center is based at the Harvard School of Public Health Center for Biostatistics in AIDS Research, Statistical and Data Analysis Center. The SDMC grant is separate from but integrally linked with the ACTG Network Leadership Group Core and Network Laboratory grant. As such, the SDMC annual progress report has been independently prepared by Michael Hughes, Ph.D., as the Principal Investigator of the SDMC grant, and is a separate document submitted concurrently with this annual progress report.

2007-2008 ACTG Annual Progress Report 3

TRADD Committee Progress Report

1. Summary of Progress by Scientific Committee in Each Research Priority Area A. Translational Research and Drug Development Phase I/II Studies with Novel Entry Inhibitors A5191 involved the first in-human subject study of a new orally available CXCR4 antagonist, AMD070. The initial characterization of the pharmacokinetics (PK) of this compound in healthy volunteers, as well as a description of the ability of this drug to produce a predictable leukocytosis, presumably as a result of CXCR4 blockade, has been previously presented; and a manuscript describing these results was published. Additionally, the concentrations of AMD070 have been shown to increase with 14-day concomitant low-dose ritonavir dosing in healthy volunteers. An amendment to this protocol will initiate post-study ophthalmology visits to gather ocular safety information in response to animal toxicity data of both the PHB and free-based formulations of AMD070. A5210 is a phase Ib/IIa dose-finding safety and activity study of AMD11070 in HIV-infected subjects, with the starting dose based on the results of A5191. The study is on hold for safety concerns, and a manuscript is in preparation. Phase I/II Studies with Inhibitors of HIV-1 Uncoating, RT, and Transport of HIV DNA to

the Nucleus Mifepristone is a progestational synthetic hormone that binds to glucocorticoid-receptor II (GCR-II), blocking cortisol action. It achieves anti-HIV activity in vitro by also blocking the binding of HIV vpr to its cellular receptor, GCR-II, and thereby preventing the transport of the viral pre-integration complex into the non-dividing cell nucleus. In vitro data and primate models of SIV infection suggested that mifepristone had potent antiviral activity. However, as reported in a manuscript in preparation, A5200 showed that up to 225 mg/day of mifepristone was safe and well tolerated but had no detectable anti-HIV activity in HIV-1-infected patients receiving no other active antiretroviral (ARV) drugs. Studies with HIV-1 Integrase Inhibitors A5244 is a study to measure the effect of treatment intensification with the integrase inhibitor, raltegravir (MK-0518), on the level of persistent low-level plasma RNA (< 50 copies/mL as measured by the single-copy assay [SCA]) in subjects on stable protease inhibitor (PI) or NNRTI regimens. Baseline results to be presented at the XVII International AIDS Conference show that viremia persists in the majority of subjects with pretherapy plasma HIV-1 RNA > 100,000 copies/mL despite years of suppressive antiretroviral therapy and that longer duration of suppressive ART is associated with lower levels of viremia. Anti-HIV Drugs with Other Novel Mechanisms of Action A5165 evaluated the safety, tolerability, and antiretroviral activity of beta-D-2,6-diaminopurine dioxolane (DAPD; amdoxovir) with or without mycophenolate mofetil (MMF) in HIV-1-infected patients following extensive antiretroviral therapy (ART). Mycophenolic acid (MPA) is a potent and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) and thus inhibits the de novo synthesis of guanosine nucleotides. Mycophenolate mofetil (MMF) is converted to MPA after oral absorption, and preliminary studies suggested that it might augment ART in HIV-infected patients. Results of A5165 showed that the addition of DAPD to a failing regimen resulted in a modest (mean -0.35 log) decrease in plasma viral load in heavily pretreated patients, but this effect was not augmented by the addition of MMF. A manuscript describing the results of this study has been published.

2007-2008 ACTG Annual Progress Report 4

TRADD Committee Progress Report

A5192 is a proof-of-concept study to examine the safety, tolerability, and antiretroviral activity of pegylated interferon-alpha in 13 HIV-infected subjects. Early trials employing recombinant IFN-alpha for the treatment of KS and pegylated-IFN-alpha for treatment of hepatitis C virus (HCV) had demonstrated concurrent reductions in HIV-1 viral loads. Results of A5192, presented at the 4th International AIDS Society Conference, found a significant decline in plasma viral loads over the course of treatment, with maximum effects occurring within the first 2 weeks of treatment with a prompt return to baseline. These antiviral effects were not associated with significant declines in CD4+ counts and suggest that antiviral properties are a dominant mechanism of effect for pegylated interferon. Immune-Based Therapies for Treatment of HIV A5015 was a phase II study to explore the basis of accelerated HIV disease progression associated with aging by examining various immunologic and virologic indices. The study found that heightened markers of TNF-related pathways were associated with age, reduced antibody response to neoantigen vaccination, and reduced nave CD4+ cell restoration. These results suggest that activation of TNF superfamily pathways may be an important factor contributing to age-associated differences in nave CD4+ cell recovery as well as to functional immune responses to HAART. A5102 was an open-label pilot study designed to evaluate the effect of IL-2 pulse therapy on the characteristics of antiretroviral treatment interruptions. Secondary results presented at 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (manuscript submitted for publication), found that subjects may be at a higher risk for cardiovascular events during treatment interruption due to increased immune activation and systemic inflammatory responses associated with rebound of HIV-1 viremia. ACTG 328 studied the virologic, immunologic, and clinical effects of interleukin-2 in subjects on HAART with moderately advanced HIV-1 infection. Published results have demonstrated that the addition of interleukin-2 to HAART in this patient population can significantly expand CD4+ T-cell counts without loss of virologic control. A5138 evaluated whether administration of CsA for the first 2 weeks of HAART as a means of blocking immune activation might improve CD4+ cell restoration in the setting of chronic HIV-1 infection. Although immune system recovery was not augmented by CsA, A5138 provided an opportunity to assess the impact of cyclosporine A on P-glycoprotein activity during ART initiation. P-glycoprotein is of interest in the setting of HIV therapy because certain antiretroviral agents are P-glycoprotein substrates, and P-glycoprotein expression on CD4+ T lymphocytes could decrease antiviral effects. Secondary results of A5138 (manuscript submit