‘Start and Stop’ Antiretroviral Protocols To Be Evaluated by Growing Number of Therapeutic Converts
Dozen or more studies underway
Interest in the virologic and immunologic effects of antiretroviral treatment interruption has been growing ever since Franco Lori first presented data on the by-now notorious “Berlin patient.” And a fascinating presentation, by Dr. Veronica Miller of Frankfurt, Germany, at the Salvage Therapy meeting in Toronto earlier this year stirred things up further still: viral genotype reverting to wild-type during a median two month unplanned treatment interruption in 26/39 (66%) HIV-infected individuals treated at a Frankfurt HIV clinic.
Martin Delaney, Linda Grinberg and Mark Harrington held several recent discussions about the concept of a possible collaboration among FAIR (Foundation for AIDS and Immunologic Research), Project Inform and TAG focusing on a protocol, protocols, or workshop on the topic of research on structured drug holidays in HIV infection. Pursuant to these discussions, at the Forum for Collaborative HIV Research/NIAID/Project Inform/TAG co-sponsored workshop on The Challenges of Clinical Trial Design in Evaluating HIV Antiretroviral Use in Heavily Pre-Treated Individuals, Linda, Mark and Ben Cheng met with Veronica Miller and Schlomo Staszewski of the Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main in order to further explore the idea of a workshop or protocol on “drug holiday” research. Mark Harrington reports.
Veronica reviewed her research to date and defined some outstanding questions. The “drug holiday” research was not planned; the clinicians simply decided empirically to offer some patients a total treatment interruption because they had run out of options and were sick of taking scores of toxic pills every day to no effect. There are several other approaches, such as looking at a “drug holiday” when the patient’s virus is well controlled as opposed to a rescue therapy situation. In addition, there has been interest in so-called “pulsed-dose therapy” since last year’s TAG/amFAR symposium on HIV reservoirs and Franco Lori’s presentation at Chicago in 1999. In Toronto, we decided to clarify terminology. “Drug holiday” is an easily abused concept, as shown by recent Glaxo Wellcome advertisements for Combivir, conflating “drug holidays” with non-adherence. Therefore, at lunch, we decided to take a stab at inventing some clearer definitions.
- A structured treatment interruption (STI) would be a planned, agreed-upon total treatment interruption, of yet-to-be defined length, between the simultaneous cessation of all antiretroviral treatments and the re-initiation of a new, modified, intensified or recycled regimen. It would be “structured” in being planned and agreed upon between doctor and patient. Before, during and after the STI, the patient would be carefully monitored for viral load, CD4 count and (potentially) other important parameters such as viral resistance.
- Pulsed-dose therapy (PDT) would be any approach which involved a sequence of more than one STI followed by the re-initiation of a new, modified or recycled regimen.
In Toronto, it became clear that there is a good deal of as-yet-uncoordinated structured drug holiday research already underway or in the late planning stages. So far, however, there has been no effort to coordinate the work, to ensure that the protocols generate useful comparative information, or to assure that they do not duplicate approaches, waste resources, or leave critical gaps which could be addressed up front. For example:
- Franco Lori’s RIGHT group is conducting parallel studies of pulsed-dose therapy (PDT) in SIV-infected monkeys and in humans.
- Avidan Neumann’s group recently published the COMET study showing that a one month drug holiday is safe in a group of ten previously therapy naive individuals treated with HAART who interrupted therapy, then resumed after a one month STI: viral load plunged as before, and no drug resistance emerged.
- After Doug Nixon and G.M. Ortiz from the Diamond Center showed that four of twelve (33.3%) patients who had discontinued drug at some time during a study of HAART in primary HIV infection (PHI) blunted the rebound of their viremia during the drug holiday due to broad and vigorous CTL responses, David Ho and Marty Markowitz started a prospective study of structured treatment interruptions (STIs) in acute and chronic HIV infection.
- Tony Fauci’s group at NIH has enrolled eighteen patients in a study of the safety, virologic and immunologic effects of a three month STI in people who had experienced maximal suppression on HAART for extensive periods of time. NIAID’s Richard Davey recently disclosed results on the first group of these patients. Some experienced a rapid viral rebound and were successfully rechallenged with HAART, while others had a slower rebound to a lower viral set-point. (In the NIAID study, patients rebounding over 5,000 copies are immediately restarted on HAART.)
Many more studies are in the planning stages:
- Following the intriguing results of the S.F. cohort experiencing virologic failure and continuing immune benefit. Steven Deeks, Mike McCune and Mario Roederer in San Francisco are planning to study structured treatment interruptions (STIs) followed by mega-HAART and to measure the kinetics of viral and lymphocyte responses during the STI and during the rechallenge periods.
- Mike Saag and colleagues at the University of Alabama are going to biopsy lymph nodes during STIs and afterwards to investigate the hypothesis that the STI and rechallenge may perturb lymphocyte redistribution (and thymic output?) patterns. This is known as the “HOL ‘N’ BOP” (holiday & biopsy) study.
- The CPCRA’s Doug Mayers has proposed a patient choice/randomization scheme in which multiply drug resistant patients can choose between two mega-HAART randomizations:
- Mega-HAART vs. drug holiday. Those randomized to initial mega-HAART would be sub-randomized to receive either genotypic resistance alone (GART) or geno- and phenotypic resistance tests to help select the mega-HAART. Those randomized to the drug holiday would receive GART or GART/PART at four months to choose a mega-HAART regimen based on viral load.
- Mega-HAART vs. maintenance on current (presumptively partially suppressive) regimen. Again, the sub-randomization to GART or GART/PART would take place, and those on maintenance would receive GART or GART/PART at four months and have the choice of a mega-HAART regimen. Regardless of its feasibility, this study would obviously depend on the refunding of the CPCRA.
- Spencer Cox reports that both the ACTG HIV research agenda committee and the Immunology research agenda committee have drug holiday concept sheets in the early planning stages.
- At the Salvage Conference, Bill Cameron proposed a clinical endpoint trial in multiply drug resistant patients comparing a six-month drug holiday with mega-HAART.
We discussed whether it might be possible to incorporate these issues into Project Inform’s Eighth Immune Restoration Think Tank (IRTT-8), planned — according to Ben — for Chicago in October 1999. Generally it was felt that this was too far away, given the accelerating pace of the research and the patient interest. A separate, short and focused workshop, preferably held sometime in the summer, might be more to the point. We felt that, given the urgency of the issue and the difficulty of scheduling a long meeting soon, a meeting of two-and-one-half days might be ideal in length
After a conference call and some preliminary e-mails, we decided to schedule the workshop for late summer somewhere in the Boston/Cambridge area. Both Martin Markowitz and Veronica Miller agreed to serve on the steering committee, and Project Inform secured a West Coast researcher to do so as well. A summary of the meeting is scheduled to appear in next month’s TAGline.