Relating virological outcome to baseline resistance

1.  Relating Virological Outcome to Baseline Resistance

a. Predicting Response to individual ARVs and to HAART regimens

Whether data is from clinical trials or from cohorts, understanding these relationships is key to developing the models which are predictive of the likely virologic outcome for each drug.  The resistance analysis generated by these predictive models is shown in the example below :

Virco was the pioneer in developing the concept of a Resistance Continuum: the idea that resistance is not an “on-off” phenomenon but rather increases proportionately as mutations accumulate. With the establishment of the Resistance Continuum, it was then critical to define Cut-Offs on the continuum as milestones of the degree of HIV resistance or the extent of virological activity remaining for a particular drug.

The development of Virco’s Clinical Cut-Offs  was enabled by the collaborations with pharmaceutical companies providing access to clinical trial data, but equally importantly by clinical cohorts providing access to baseline resistance and virological outcome data.  These values are updated on an ongoing basis.

The ultimate goal of research in this area is to develop models of Response Prediction. which would take both drug activity (the resistance factor) and drug potency into account in predicting virological response to a particular drug and a particular regimen. One of Virco’s research focuses is in bioinformatic and statistical analyses to develop such predictive models.

Virco is privileged to have as key collaborators in these areas:

• Chelsea & Westminster NHS Trust Hospital, London
• British Columbia, Center for Excellence in HIV Research, Canada
• Vanderbilt University, USA
• HIV/AIDS KompetenzNetz, Germany

b. Pyrosequencing and Research on Minority Species

Pyrosequencing or “ultra-deep sequencing” is a new and exciting  sequencing technology that offers dramatically improved sensitivity in detecting low-frequency viral variants, also known as viral quasi-species, compared to traditional population-based (Sanger) sequencing.
In collaboration with the University of Rome “Tor Vergata”, Virco has presented the results at CROI 2009 of two studies exploring resistance to integrase inhibitors, as well as an in-depth evaluation of viral tropism;

• paper 682: “Baseline variability of HIV-Integrase may correlate with viral evolution and virologic success in multi-experienced patients treated with raltegravir” by Francesca Ceccherini-Silberstein and Carlo Perno et al;
• paper 642 “The evolution of classical resistance to FTC occurs at rates lower than 3TC, and may be regulated by mutations different than M184V” by Valentina Svicher; and Carlo Perno et al. 

see:http://www.retroconference.org/AbstractSearch/Default.aspx?Conf=18

Based on the results of the Integrase study, the researchers suggest that the correlation between quasi-species identified at baseline and treatment failure may be occurring via pathways which are much more complex than simple drug-driven selection of the primary mutations currently identified. “The ability of the technology of the 454 Sequencing System to identify mutants at very low levels provides new insights on how HIV may develop resistance to new drugs such as Integrase inhibitors,” said Professor Perno from Tor Vergata University. His colleague Dr. Ceccherini-Silberstein added, “This technology will complement existing techniques and can provide a significant added value to HIV research.”

In addition to the collaboration with University of Rome, Virco is also working with scientists from Ghent (Chris Verhofstede and Linos Vandekerckhove), Royal Free Hospital (Anna Maria Geretti), and British Columbia, Center for Excellence in HIV Research, Canada (Richard Harrigan) to both evaluate existing tropism testing tools and to develop new and enhanced interpretation systems.
 
With the introduction of this new class of antiretroviral drug therapy, it is imperative to differentiate between HIV tropism via R5, X4 or dual R5/X4 infection at baseline, to decide on the utility of using a CCR5 antagonist  and to maximize optimal clinical response. The two main areas of focus on tropism testing to date are phenotypic assay-based and genotypic V3 loop sequencing plus predictive modeling-based interpretation. Virco is working in both areas to collaborate in developing the optimal clinically-relevant interpretation systems.