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The development of cross-resistance
from the use of a protease inhibitor (1/96)
This subject has been much discussed; we are all concerned that the development of cross-resistance can be a limiting factor in the potential benefit from the use of protease inhibitors. A brief explanation of cross-resistance is that treatment with one protease inhibitor can cause resistance to a second protease inhibitor without someone ever having been treated with that second inhibitor.
Both Abbott and Merck agree that prior treatment with one of their inhibitors will cause a large enough degree of cross-resistance to the other, so as to render use of the second one as ineffective. In other words, prolonged treatment with ritonavir, wherein resistance to ritonavir starts to develop, will cause cross-resistance to Crixivan. Likewise, prior treatment with Crixivan will cause cross-resistance to ritonavir. The practical effect of this is that, if you choose to use ritonavir first, you may not benefit from the future use of Crixivan. Similarly, if you choose to use Crixivan first, you may not benefit from the subsequent use of ritonavir.
Reversing resistance?
There is a potential development, that could ease our concerns about the development of cross-resistance. Similar to the relationship that we believe exists between AZT and 3TC (where, it is believed that 3TC may reverse the resistance that develops from prolonged treatment with AZT), it is possible that scientists may discover a like relationship between 2 drugs that may reverse the resistance that develops from use of one protease inhibitor.
For example, we may discover that treatment with one particular protease inhibitor may reverse the resistance that develops from the prior use of a different protease inhibitor. Published reports from researchers at Glaxo Wellcome indicate that saquinavir and the Vertex protease inhibitor, being developed by Glaxo, may have such a special relationship; that the development of resistance for one is reversible by treatment with the other. Of course, these findings were from in vitro experiments and must be tested in humans, but there is some promise for hope and exciting developments (Tisdale et al, Antimicrobial Agents and Chemotherapy, Aug. 1995, p. 1704-1710).
At a January '96 meeting with Glaxo, doubts were raised about whether Glaxo is fully committed to quickly studying these possibilities. They may be content to delay this direction of research. This would be a tremendous setback for people with HIV and AIDS. In this meeting, I pressured them to quickly initiate studies of VX-478 in combination with other protease inhibitors. In fairness to Glaxo, after an initial resistance, they said they will pursue this direction in a timely way, but I will be following up with continuing dialogue. This research needs to be initiated as quickly as possible, for both safety and efficacy reasons: (1) many individuals will shortly be taking indinavir, saquinavir or ritonavir; with the entry of Glaxo into trials of VX-478, some individuals may experiment with combining 478 with one of the other three, and safety concerns need examination; (2) we need to explore the potential for efficacy, that may exist by combining VX-478 with other inhibitors. This research direction is particularly significant for individuals with extensive drug experience and few treatments options remaining; the prospect of combining 2 drugs (especially, in this case, a potentially potent combination of 2 protease inhibitors), neither of which they've ever taken, is a very promising option that must quickly be explored.
Saquinavir and Crixivan or ritonavir cross-resistance
Roche and Merck have disagreed about the effect that pre-treatment with saquinavir will have on subsequent use of Crixivan. Merck says, they believe that prolonged pre-treatment with saquinavir may start the process of the development of resistance to Crixivan; so that, if one takes Crixivan after having used saquinavir, that person may develop resistance to Crixivan sooner than if they had not used saquinavir at all. Roche says, they don't believe this will occur. Although, we have tried to resolve this difference of opinion, it remains in dispute. Finally, after pressure from our community and the FDA, both companies have agreed to conduct a "special resistance" study. They will take individuals with a minimum of 6 months pre-treatment with saquinavir and switch them to Crixivan. After enrolled in the study, their viruses will be examined for resistance patterns at baseline and then followed over time. We hope that this study will expand our understanding of cross-resistance concerns. The same potential problem exists for sequential use of saquinavir and ritonavir. Pre-treatment with saquinavir may cause the same cross-resistance development for subsequent use of ritonavir.
In this special resistance study, two overall developments will be examined. First, the short-term response of individuals to the switch in treatment. That is, after an individual changes treatment from saquinavir to Crixivan, will he or she experience the full extent of the initial drop in viral load, that individuals usually experience with Crixivan treatment. The second question is will the anti-viral benefits last as long as, after the switch, as they would have from an initial treatment with Crixivan without pre-treatment with saquinavir.
However, until we have more information, individuals who have to make treatment choices now, are put in a difficult and unenviable position. They must choose saquinavir, ritonavir or Crixivan with a limited understanding of what cross-resistance developments may occur.
Saquinavir/ritonavir combination
At this moment, the first combination of 2 protease inhibitors is being studied for safety. Once it is established that combining saquinavir and ritonavir is safe, further studies will be conducted, examining efficacy and optimal dosing for each drug in the combination. There are two reasons why the combination of these 2 drugs is promising. Abbott says, saquinavir and ritonavir have complementary resistance profiles, and in cell culture, ritonavir resistant viruses retain full sensitivity to saquinavir. Second, ritonavir's metabolism inhibits the metabolism of other drugs when administered concomitantly. Indeed, due to the inhibition of saquinavir metabolism by the presence of ritonavir, in animal studies, the plasma concentration of saquinavir increased by 200-fold.
Individuals must be cautioned not to combine these 2 drugs, on their own, until we learn from the ongoing studies about the overall safety of this combination. We are unsure which dose to use for each drug; using the wrong doses could be dangerous. Still, it is expected that soon we may have sufficient information from these studies, to make some treatment decisions.
Potential developments
Other protease inhibitors, which are in earlier stages of development, may have less problems with cross-resistance. The Glaxo/Vertex protease inhibitor, VX-478, promises to have less concerns about cross-resistance. In addition to the potential relationship between saquinavir and VX-478, referred to above, other protease inhibitors may also have a relationship with VX-478 that would improve cross-resistance concerns. Glaxo says, from in vitro studies, without any pre-treatment with Crixivan, that combining Crixivan with VX-478 indicates additive benefits. Other drug manufacturers are trying to develop protease inhibitors that would have minimal cross-resistance problems. Upjohn is hoping to enter a phase I trial, with a 3rd generation protease inhibitor, which they say would not have such prohibitive cross-resistance concerns.
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About the author: Jules Levin is the Executive Director of NATAP, based in New York City.
The National AIDS Treatment Advocacy Project (NATAP) is a New York State non-profit corporation dedicated to facilitating the effort for development of effective treatment for HIV.
Last modified 2/14/96
by Jules Levin
copyright © 1996 natap
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