The ACTG is planning to begin an ambitious program with a new research direction called ALLRT (Adult AIDS Clinical Trials Group Longitudinal Linked Randomized Trials Protocol). ALLRT will seek to enroll both treatment naive and experienced individuals in a number of studies offering them a continuing series of treatment options that will last for years. The overarching goal is to follow the same individuals for years and try to identify treatment strategies that can maximize the sustaining of an individual’s health and survival for as many years as possible.

Major questions to be addressed are how to best achieve long-term suppression of viral replication with the least possible toxicity, cost, with the widest degree of treatment options, how to maintain and restore immunological function, and how to prevent disease progression and opportunistic infections. An important goal will be to identify when individuals should switch therapy and what to switch to. Individuals in the program will be followed for changes in immune status, virus activity in compartments besides the blood such as in the CSF, lymph tissue, genital tract, etc., and factors that may effect individual drug absorption and other pharmacological concerns. A strong emphasis will be placed on monitoring genotypic and phenotypic resistance to evaluate their use in therapy decision making.

The program is attempting to identify factors associated with occurrence of opportunistic infections; and, the relationship between HAART, viral load suppression and CD4 increase and the development of infections and the relationship with improved immunity. What are the factors associated with improvements in infections or decreases in the incidence of infections for some individuals receiving HAART? I could continue explaining the program, but as I’m limited by space I’m trying to briefly summarize. ACTG 384 is a study being used to start the program and reflect its goals.

ACTG 384 is a complicated study which addresses four important treatment questions. Over 500 treatment naive individuals will be randomized to one of six 3 or 4 drug regimens:

• ddI+d4T+DMP-266 (efavirenz)

• ddI+d4T+nelfinavir

• AZT+3TC+DMP-266

• AZT+3TC+nelfinavir

• ddI+d4T+nelfinavir+DMP-266

• AZT+3TC+nelfinavir+DMP-266

If a person fails a NNRTI (DMP-266) 3 drug regimen they will then receive a protease 3-drug regimen (nelfinavir) as a second treatment. If the regimen they failed first is a nelfinavir 3-drug regimen they will receive a DMP-266 3-drug regimen as a second treatment. And they will also switch the NRTI combination. So, if a person failed their first regimen containing AZT/3TC, they will receive d4T/ddI in their second regimen; and, if the first regimen they fail contains d4T/ddI the second regimen will contain AZT/3TC.

There are two important treatment questions being addressed here. If a person takes d4T/ddI first, how will they respond to subsequent treatment with AZT/3TC. We do not know the answer to this question. If a person fails AZT/3TC, how will they respond to d4T/ddI as a next NRTI treatment. We are not sure about that either. We do know if a person fails AZT/3TC first the response to subsequent treatment with d4T is diminshed. So, the first question addressed by this study is trying to learn more about the sequencing of NRTIs.

A second question addressed by the study is can initial treatment with a NNRTI (DMP-266) be equal in potency and durability to initial therapy with a protease (nelfinavir). If so, a person may want save the protease option. Or, it may be preferable to start with a protease regimen and then switch to a NNRTI regimen.

A third question addressed by the study is whether a 3 or 4 drug regimen (containing a NNRTI and protease) used as initial therapy will be better in the context of treating a person over the long term. If a person fails the 4 drug regimen, the next regimen they will receive will contain two different NRTIs than they received in the first regimen. For example, if their first regimen contained AZT/3TC, the next regimen will contain d4T/ddI.

If a person fails the first 3-drug regimen and the second 3 drug regimen, they will receive a salvage therapy. If a person fails a 4-drug regimen they will receive a salvage therapy. The drugs to be used in the salvage therapy regimens are being discussed now. It will vary as to when a person may reach the point where they need the salvage regimen. It may take years before some individuals reach the point. So, the goal of the study investigators is to design a salvage therapy that offers the best treatment available at the time a person needs it. The fourth and overarching goal of this study is to try and identify strategies for sequencing drug combinations in such a way that individuals will benefit for the most number of years.