Salvage Therapy Studies for Individuals Whove Failed a Protease Inhibitor: ACTG 398, ACTG 400, and ICC study #006
A Discussion of ACTG 384 and the New Direction of Research in the ACTG
Written by Jules Levin, NATAP
This is a report of salvage therapy studies that will begin soon and offer individuals who have failed a protease inhibitor potent multi-drug combination salvage therapy. Two studies are offered by the ACTG and a third study is offered by the ICC. The AIDS Clinical Trials Group (ACTG) is the arm of the Federal governments NIH (National Institutes of Health) that conducts AIDS studies. In July, the ACTG will begin two new 48 week studies for individuals who have failed protease inhibitors. These two studies will explore new experimental treatments that it is hoped will suppress protease resistant virus. As well, this article describes the new direction of research by the ACTG, and ACTG 384 which exemplifies this new direction.
ACTG 398 is for individuals who have failed single or multiple protease inhibitor(s), and will offer them a 5 drug regimen consisting of 1592U89+efavirenz+adefovir (PMEA) in addition to a protease inhibitor. The protease part of the regimen will consist of either 141W94 (amprenavir) alone or 141W94 in a double protease combination with either nelfinavir, indinavir, or Fortovase (SGC saquinavir). Investigators plan to enroll 460 study participants.
ACTG 400 is for individuals who have failed only nelfinavir, and will offer them a 4 or 5 drug regimen consisting of efavirenz+2 NRTIs plus a protease inhibitor therapy. The protease therapy will consist of 1 or 2 drugs: ritonavir+saquinavir, indinavir, 141W94, or indinavir+141W94. This study plans to enroll 300 participants.
Both of these studies are expected to begin in July. There are 32 ACTG sites throughout the US and Puerto Rico and are listed with contact information below. It is optional to a site whether or not they want to pick up an ACTG study. So, you have to check with your local site to determine if they offer these studies. If you are interested it may be important to contact the site quickly for information because enrollment could fill up quickly.
Adefovir, efavirenz, 1592U89, and 141W94 are new drugs that have not yet been approved by the FDA and therefore are not yet commercially available. Except for 141W94, they are available through an expanded access program sponsored by the pharmaceutical company developing the drug. The contact information for these expanded access programs are available at the end of this article. An expanded access program for 141W94 is targeting July for a startup. Under consideration is a unique plan to offer various regimens using 141W94. 1592 and efavirenz should receive FDA accelerated approval in the Fall 98.
Studies 398 and 400 will examinethe influence of baseline genotypic and phenotypic protease inhibitor and RT inhibitor resistance profiles and the biologic phenotype (syncytium inducing vs. non-syncytium inducing capacity) on subsequent plasma HIV-1 RNA and CD4 cell count responses. As well, the studies will evaluate the genotypic and phenotypic resistance profiles to the study drugs that emerge on treatment and their relationship to the plasma HIV-1 RNA and CD4 cell count responses. There will be several important substudies including a pharmacokinetics study to determine the PK relationships between the study drugs: 141W94 with indinavir, nelfinavir and saquinavir; efavirenz with protease inhibitors. There will be substudies evaluating immunological responses. Investigators will try to determine to the extent possible the relationship between drug exposure (as measured by a combination of PK and compliance) to drugs and the degree of duration of response and the emergence of resistance. As well, a PK relationship profile will be conducted for ritonavir+saquinavir when co-administered with efavirenz.
The ICC (Inter Company Collaborative) is a coalition of the major AIDS pharmaceutical companies. ICC study #006 will offer 5 different open-label treatment regimens. Three regimens will be for individuals whove failed protease inhibitors but are naive to NNRTIs, and two regimens with simplified dosing regimens to treatment naive persons. The study will be open label and will be available at 6 sites. Originally, the study was supposed to begin in February but its been delayed. The first few regimens are expected to begin enrollment in early June. The study will enroll 25 persons in each regimen at 7 different sites. The 3 regimens for protease failures are:
MKC-442 is a NNRTI in early development which has shown a -1.30 log reduction in viral load in a 15 day study. This trial is the first to study the combination of two NNRTIs.
The two simplified dosing regimens are for protease inhibitor naive individuals:
The 7 sites which will offer the study are:
It is advisable to call as soon as possible.
New Direction of Research in the ACTG and ACTG 384. 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 individuals 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 Im limited by space Im 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:
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. 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 diminished. 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, then a person can start therapy with DMP-266 and save the protease option. Or, it may be preferable to start with a protease regimen and then switch to a NNRTI regimen. By starting some study participants on a nelfinavir regimen first, and switching them to a DMP-266 regimen next, the study addresses that question.
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. Three years from now, we expect to have better drugs available for treating individuals who have failed the currently available drugs. 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.
ACTG Sites. Not all sites offer all ACTG studies. It is the sites option. So, you have to check with a site to see if they plan to offer it. It is advisable to call as soon as possible.