by Chael Needle

As reported at the Forty-fourth Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), new data based on twenty-four week interim results from a Phase III study showed that a statistically significant greater percentage of HIV-positive patients taking a tipranavir-based regimen achieved a treatment response versus those taking a regimen containing one of several marketed protease inhibitors (PIs). Tipranavir is being developed by Boehringer Ingelheim. In the RESIST-1 study, treatment response was achieved as measured by greater decreases in viral loads and greater increases in CD4 cell counts in those taking tipranavir plus ritonavir compared to those taking a protease inhibitor (lopinavir, saquinavir, amprenavir, or indinavir) plus ritonavir.  

As the name of the study suggests, RESIST-1 (Randomized Evaluation of Strategic Intervention in Multi-Drug ReSistant Patients with Tipranavir) and a related study, RESIST-2, enrolled patients with advanced HIV disease who, on average, previously received twelve antiretroviral drugs, were experiencing virologic failure, and had documented PI resistance.  Patients enrolled in RESIST-1 were randomized to receive a 500mg/200mg twice-daily dose of tipranavir plus ritonavir or another PI plus ritonavir at its standard boosting dose. Tipranavir was boosted with low-dose ritonavir in order to achieve better drug concentrations, says Charles Hicks, M.D., Associate Professor of Medicine in the Division of Infectious Diseases at Duke University Medical Center and one of the study’s lead investigators. Ritonavir slows down the actions of the enzymes—primarily in the liver—that metabolize and detoxify substances such as tipranavir and clear them from the body. “The net result is that for any given amount of the drug the presence of ritonavir slows the elimination of the drug and thereby allows it to accumulate in greater quantity. This, in turn, translates into greater [antiretroviral] activity.”

One of tipranavir’s primary differences from other currently available protease inhibitors is that it is non-peptidic. This means tipranavir isn’t composed of peptides, short chains of amino acids that combine to form proteins, and therefore is made up of theoretically more flexible molecules than other PIs. This flexibility suggests that tipranavir potentially has the ability to adapt its structure as HIV mutates and changes its protease structure and therefore can continue to be active against the virus.

It is too early to forecast the resistance profile of tipranavir itself, however, because of “insufficient information.” Says Dr. Hicks: “To understand the resistance generated by a particular drug, you ideally have to be able to administer that drug as the first drug within any class” in order to more accurately determine if exposure to that particular drug conferred resistance. “It’s been suggested that some mutations, when they are present, may have a more substantial effect on the function of tipranavir.” Dr. Hicks adds that these might not necessarily be bad mutations as “there are patients who have all [of them] who are being treated with tipranavir and respond very well to therapy.” Researchers will learn more in the next year after studies including treatment-naive patients progress.

At least two important features of how tipranavir interacts with other anti-HIV medications should be noted. An earlier study of tipranavir being co-administered with other protease inhibitors—saquinavir, amprenavir, and lopinavir—led to a significant reduction in the amount of the other PI in the body. Co-administration didn’t affect tipranavir very much. “The results suggested that, at least given our current dosing methodologies, tipranavir and a second protease inhibitor is not a good idea,” says Dr. Hicks. “The exception is ritonavir which is used as a boosting approach.”

But combining isn’t necessarily always discouraging. The most efficacious results in studies so far “were seen not just when tipranavir was able to be used by itself, but when tipranavir was selected to be used when the patient still had at least one other drug that was able to be effective. The principle of treating HIV with more than a single new drug leads to much better outcomes was convincingly re-demonstrated in this [present] study,” says Dr. Hicks. “Tipranavir shouldn’t necessarily be ‘saved’ until the patient has absolutely nothing left.”

Dr. Hicks also made special note of the fact that the RESIST-1 results are only the first report and that it will be “important to follow the population for a longer period of time to make sure the initial very promising results are durable—that people who achieve benefit are able to sustain that for a longer period.” The interim analyses of RESIST-1 and RESIST-2 did make it possible for the October submission of a New Drug Application to the FDA, however.

Chael Needle wrote about DB289, a potential treatment for PCP, in the November issue.

December 2004