Daniel M. Keller, PhD
May 8, 2012 (Barcelona, Spain) — The development of drugs to treat hepatitis C virus (HCV) is progressing rapidly, but the terminology to quantify virologic response is lagging. A consortium of interested organizations is creating nomenclature for virologic responses in trials of direct-acting antiviral drugs, which are small-molecule inhibitors of viral enzymes that hold the promise of interferon-free treatment regimens.
During a poster session here at the International Liver Congress 2012, Donald Jensen, MD, professor of medicine at the University of Chicago Medical Center in Illinois, presented the rationale for and principles of the nomenclature being developed by the Hepatitis C Virus Drug Development Advisory Group (HCV DrAG).
HCV DrAG is a project of the Forum for Collaborative HIV Research, which has a subgroup devoted to HCV research with experts from the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver (EASL), and the Infectious Diseases Society of America. The forum is a broad consensus panel that includes industry representatives, members of American and European drug regulatory agencies, academic investigators, and representatives of advocacy groups.
Direct-acting antiviral drugs have potent antiviral actions and appear to produce a more rapid virologic response, with or without interferon, than interferon-based regimens without the new drugs. More intuitive and flexible virologic measures are needed that can adapt to these advances in HCV treatment.
"We wanted to do this before all the new oral therapies hit the market," Dr. Jensen told Medscape Medical News.
He said current terminology can be confusing when describing virologic response to the new therapies. "We felt that there was a need to have this description of virologic responses more consistent across studies — something that could also be used in manuscripts and in clinical practice," he said. A panel of experts set out to develop a nomenclature "that was intuitive, that made sense, and that was descriptive of virologic responses during the course of therapy for hepatitis C."
Considerations for Nomenclature Development
Comparisons between drugs or regimens is difficult or impossible without a common nomenclature. The propsed nomenclature will assign a description of the time frame and the level of response to the measures, as opposed to a qualitative description such as "rapid virologic response."
The proposed terminology for key decision points in treatment trials takes into account the assay-specific lower limits of quantification of HCV RNA (as opposed to lower limits of detection), with responses defined as quantifiable or unquantifiable levels of HCV RNA.
Key components in expressing virologic response are the week of treatment, the quantifiable decline in viral load from initiation of treatment (expressed as log10 decline), any lead-in treatment duration (days or weeks), and whether the target HCV RNA was detected or not. The panel explains that the lower limit of quantitation (LLOQ) of a virologic assay should be clearly specified. (One common problem in current trials is the use of different commercial assay systems.) The target may or may not be detected at levels below the LLOQ.
HCV viremia at levels less than the LLOQ in trials without a lead-in treatment period — what has been called a rapid virologic response — would now be W4U, meaning an unquantifiable HCV RNA level at week 4, whether detectable or undetectable. The old complete early virologic response will now be W12U, denoting a week 12 unquantifiable HCV RNA level.
For trials with a lead-in (LI) period at, for example, weeks 0 to 4, and unquantifiable levels at week 8 (the old rapid virologic response), the new nomenclature would specifically refer to it as LI4w-W8U. Each term would be appended with TD or TND to denote whether target HCV RNA was detected or not detected.
One holdover from the current system is sustained virologic response (SVR).
"We decided to keep SVR...but it will be sustained virologic response with a bracket after it" to denote how long the response has been sustained, Dr. Jensen noted. "We're going to keep [it] because I think that's a concept that will be consistent with future therapies."
Having a uniform reporting system will allow the comparison of results across clinical trials. In addition, the system will be able to adapt as virologic response times become shorter. Beyond clinical trials, specific terminology will aid in the development of treatment guidelines for clinical practice.
The panel has submitted a manuscript for publication. Dr. Jensen hopes that industry will adopt the system for their clinical trials and that journals will require the system as the accepted nomenclature. The US Food and Drug Administration and the European Medicines Agency, as part of the HCV DrAG working group, have stated that they would like the nomenclature to be adopted.
Dr. Jensen predicts that in the future, if very effective drugs come along and therapy becomes standardized, many of the current or proposed measures of virologic response will go by the wayside, and patients will be treated with a fixed course of therapy with an expectation of cure, as is now common with antibiotics for many infections.
George Papatheodoridis, MD, associate professor of medicine and gastroenterology at the Medical School of Athens University, staff member at Hippokration General Hospital in Athens, Greece, and member of the EASL Governing Board Scientific Committee, told Medscape Medical News that he would like to see a consensus terminology adopted, but he does not expect that it will happen soon.
Nomenclature is not the only problem in defining a response, Dr. Papatheodoridis noted.
He referred to a presentation at the congress in which researchers found a discrepancy in the viral levels of 28% of the more than 1000 samples tested with a new polymerase chain reaction (PCR) assay and the original PCR assay. With the original assay, 75% of samples had undetectable HCV DNA; with the new assay, only about 50% did. Such a difference might be reflected in the "response-guided therapy we're using now with the telaprevir or boceprevir combination," he said.
With the drugs currently in development, the companies decide which assays to use to report their findings. "All the trials are controlled by the companies. They are not controlled by us," Dr. Papatheodoridis explained.
"Another problem, which is very relevant in clinical practice, is the timing of the HCV RNA determination," Dr. Papatheodoridis explained. We don't know if a difference of a few days is relevant. If you have some new excellent drug that achieves a 100% SVR 100%, you don't care, but these are not yet available.
Mark Thursz, MBBS, MD, professor of hepatology in the Department of Medicine at Imperial College London, United Kingdom and secretary general of EASL, agreed that measures of virologic response designed for interferon-based regimens are inadequate in an era of direct-acting antiviral drugs, "because the dynamics are much quicker now. A new set of specific targets are going to be really important when we assess how well the new drugs are working."
Dr. Jensen, Dr. Papatheodoridis, and Dr. Thursz have disclosed no relevant financial relationships.
The International Liver Congress 2012: Abstract 897. Presented April 20, 2012.