1st International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment
July 7-11, 2001
Buenos Aires, Argentina
Highlights from the 1st IAS Conference on HIV Pathogenesis and Treatment
written for NATAP by Michael Norton, PA
A day or two prior to the start of the conference, I attended a few of the pharmaceutical satilitte symposiums. Two of these conference I attended had information I thought of interest to the NATAP readership that was not dealt with during the official conference.
At the Agouron meeting: Richard Ogden gave an update on Capavirine. Capavirine has been touted as a second generation NNRTI. Approximately 1 year ago the FDA placed on hold trials looking at Capavirine due to a vasculitis, that was seen in dogs taking the drug as part of the investigational process.
Here are some of the things Dr. Ogden had to say about Capavirine:
Commentary: Questions remain about the potency of this compound as a second generation NNRTI. The initial results from the interrupted trials showed less then stellar results when compared to the placebo. Still too little is understood about Capavirine at this point to say whether or not it could make a contribution to the treatment of patients, especially NNRTI experienced patients.
On a separate note, this is a time where perhaps the community, both medical and patient advocacy, could show support for the work being done at Agourons facility in La Jolla, CA. That research includes drug development against multiple HIV targets. On July 6, Agouron/Pfizer announced they were ceasing their involvement and thus assistance in the development and thus understanding of Remmune. While this single step may not seem overly important given the lack of clear therapeutic or prophylactic benefits with regards to Remmune. It is important for the global human community to have the resources of Pfizer and the research experience and facilities of Agouron continue in the field of HIV medicine.
At this Summers Resistance Wksp, resistance data on CPV was presented suggesting its utility against NNRTI resistance, but ultimately (as stated above) CPV must be studied in patients with NNRTI resistance to evaluate its effectiveness.
See NATAP Resistance Wksp reports: Preliminary
Capravirine (NNRTI) Resistance Data
Abbott Laboratories Satellite Symposium
Dale Kempf of Abbott continued to introduce new concepts in an attempt to understand the development of resistance for Abbotts drug Kaletra. Specifically concentrating on the large registrational trial that compared Kaletra to Nelfinavir tid in a double blind placebo controlled manner, Kempf proposed the reason there has not been documented Kaletra resistance in these antiretroviral naive patients who were receiving the Kaletra based regimen, is because of Lopinavirs short half-life once RTV is eliminated. The schematic below illustrates the concept.
- - - - - - - -LPV/r levels while RTV is
inhibiting degradation of LPV - - - - -
*note level is high in relation to WT and mutant IC 50
- - - - - - - - - - - Level of drug required
to inhibit mutant virus - - - - - - - - -
* * * * * * * * * * * * * Selective Pressure Zone * * * * * * * * * * * * * * *
- - - - - - - - - - - Level of drug required to inhibit wild type (WT) virus - - - -
Dales proposal is based on the fact that once RTV has been eliminated the LPV kinetics are not linear but rather fall off precipitously. Therefore a patients drug concentration of LPV would only briefly be in the selective pressure zone where mutant strains are most readily selected.
Another correlate of this proposal is that perhaps the difference seen between patients who virologically rebounded on LPV/r (all had WT and were most were able to subsequently and without a change in therapy re-suppress) versus those who rebound on NFV (some with protease mutations) did so because of the both the different troughs (NFV perhaps being close to the IC50 of the mutant virus and maybe even WT in a number of patients) plus the time spent in this selective pressure zone when doses are missed or delayed.
Dale has put forward a plausible scientific hypothesis that requires further
testing, another possible explanation for the lack of resistance seen among
the LPV/r genotypic results is, patients on Kaletra whose virus rebounded were
simply not taking their antivirals at that particular time, which led to viremia
but no resistance. If that were the case, this would explain why they didnt
find resistance, why at least the
M184V was not present, and why these patients so readily re-suppressed.
At the same Abbott sponsored symposium David Ho gave a brief overview of the future of HIV therapy. He spoke about the work his and other groups have done to date showing that completely suppressive HAART therapy is far short of complete suppression. He and his collaborators continue to search for therapies that will improve on potency of the currently available regimens. During this symposium he took the opportunity to highlight the work that is being done with entry inhibitors and emphasized a hope that these new approaches will contribute to the extinguishing of HIV replication in conjunction with HAART. He took particular interest in the Schering Plough compound SCH-C. SCH-C is a CCR-5 entry inhibitor that blocks HIV infection both in vitro and in vivo. It shows activity against different clades of HIV. Unlike the entry inhibitors further along in clinical development, T20 and T1249 from Trimeris, this agent is available in an oral formulation. It is currently undergoing phase 1 clinical trials. To date what has been noted is at higher doses there seems to be an elongation of the QT interval. Further study of this compound in HIV+ individuals is scheduled to get underway next month in New York City at the Aaron Diamond Institute and also in France. More about David Hos comments at this conference will be forthcoming in a report of the opening night session.