with other agents. For these studies “the industry has been really good to us, in terms of donating drugs for trials,” Dr. Dieffenbach noted. His NIH division just completed a series of prevention trials using antivirals, and all of those drugs were donated, with the total cost of the drugs being approximately $50 or $60 million. “It’s been a very productive partnership because we built an industry, in terms of training a series of clinicians, putting together the infrastructure to run these kinds of drug trials. That has then largely become industry supported,” Dr. Dieffenbach said.
One lesson learned from this experience is the need to target two steps in the life cycle of the virus, according to Dr. Dieffenbach. Combinations that target a single step tend to have overlapping toxicities and run the risk of pharmacological and potentially virological interference, he said. He added that potency matters in terms of the dosing and the impact. “Unlike cancer chemotherapy, these are drugs that are designed to be taken every day for the rest of the patients’ lives so what we want is a safe drug,” Dr. Dieffenbach stressed.
HIV drug development benefited immensely from the ability to use viral load as a validated surrogate for response to therapy, Dr. Dieffenbach stressed. Dr. Nabel added that “the fundamental difference scientifically between HIV and cancer is that we really have a crystal clear biomarker—viral load—that makes it so much easier for everybody, because you really can rally to one thing. That’s how we ended up getting six targets of different classes because you were all aligned to that one thing,” he said. Dr. Nabel suggested that it would help the combination cancer therapy field if advocacy groups and scientists joined together to formulate a plan for showing the utility of biomarkers. “There has to be some kind of coalescence, and what may be hurting your efforts in advocacy and the scientific efforts is the lack of focus and the ambiguity and the biomarkers,” he said. He added that the use of HIV neutralizing antibody as a biomarker for vaccine effectiveness has also helped the development of HIV vaccines.
It is also helpful to have a system for measuring the comparative effectiveness of various combinations, Dr. Dieffenbach pointed out. He showed a recent effort to do this in HIV by Shen and colleagues (2008, 2009). These researchers, through simple mathematical manipulations, were able to rate combination therapies on their ability to inhibit virus replication and graphically represent which ones were the best treatments (see Figure 8-1). He raised the question of whether a similar approach could be used to compare the effectiveness of combination cancer chemotherapies.