by Chael Needle

In June, the FDA granted accelerated approval to Aptivus (tipranavir), a non-peptidic protease inhibitor made by Boehringer Ingelheim, for use in combination therapy with patients who are highly treatment-experienced patients, show evidence of viral replication, or have HIV-1 strains resistant to multiple protease inhibitors. Twenty-four-week data coming out of two controlled studies comparing Aptivus/ritonavir with other ritonavir-boosted PIs (these RESIST studies were covered in this column in the December 2004 issue) showed that Aptivus/r produced better treatment responses than the others as well as reduced viral loads and increased T cells more effectively. Dosed in 250 mg capsules twice daily, Aptivus must be coadministered with ritonavir to boost the drug’s therapeutic levels. The FDA will continue to monitor Aptivus’s toxicity profile and will keep an eye on treatment-naive study results as well as those of the ongoing RESIST studies in order to consider traditional approval. Ongoing studies are also investigating Aptivus for the treatment of women, children, and those coinfected with hepatitis.

A first-step in considering if Aptivus/ritonavir might be an appropriate addition to your regimen is to have your physician conduct resistance testing. Aptivus can be helpful, says Dr. Brady L. Allen, “when a patient has failed multiple protease inhibitors and has anywhere from one to twenty protease mutations—in other words, highly resistant patients.” Dallas-based Dr. Allen, a clinical attending physician at Baylor University Medical Center and an active staff physician at AHL Medical Group, where he helps treat 1,500 HIV/AIDS patients, adds that a good candidate for Aptivus is one who “hopefully has another active drug—one that they are not resistant to—to combine with Aptivus, such as T-20 [Fuzeon, a fusion inhibitor], or a non-nucleoside, or perhaps a new nucleoside that they are not resistant to. It would be good to have two or more active drugs in your regimen.” His clinical experience has shown him that Aptivus is generally well-tolerated and patients who have had no other options have done quite well on the drug.

Patients who should be more cautious are those whose only active drug in their regimen would be Aptivus, says Dr. Allen. “They may be wasting it, but, if they have no options in the foreseeable future, they may have to use it anyway. If those patients can afford to wait for another active drug to come down the line, they probably should—or enroll in a study where they could use Aptivus with one of the new CCR5 inhibitors.” Other patients who should be cautious are those who are allergic to sulfa drugs, he says. And “for patients coinfected with hepatitis B or C, Aptivus [has been associated with] slightly more liver function abnormalities than we see with the other protease inhibitors.” This doesn’t mean that those who are coinfected cannot use Aptivus, only that they need to carefully monitor their liver function regularly to avoid damage or possible fatality. Patients should be wary of Aptivus’s potentially harmful interaction with other protease inhibitors and a list of other drugs contraindicated to the whole class of PIs.

Other drug interactions have been found to be beneficial. Studies have shown, for instance, the addition of T-20, or Fuzeon, to an Aptivus-containing regimen will effect a greater response rate, “especially in patients who have never taken Fuzeon,” notes Dr. Allen. “Even though Fuzeon is a difficult drug because it’s injectable, [the combination] often gives patients a lot of hope if they can use two active drugs in order to get their virus under control again.”

Dr. Allen cited one decision for patients and physicians that might be more controversial than others. Often patients will have a multiple-protease-resistant virus “but the replication capacity of their virus is very low so they’re not clinically or immunologically progressing. The question is: Should those particular patients, now that you have, say, Fuzeon and Aptivus, go ahead and take their shot now in order to totally suppress [their virus] or should they wait to see if their T cells start deteriorating? Clearly, in patients who have failed everything, that drug is going to be useful. But, patients who might be immunologically stable yet virologically failing—i.e., their T cells are okay but their viral loads are elevated—have a dilemma: to move to this new therapy, assuming they have other active drugs in their regimen, or not. I think [the switch] could be very helpful.

“On the other hand, those patients might be clinically stable for another few years without doing anything differently. There is the chance, however, that if viral replication is allowed to continue on a non-suppressive antiretroviral regimen, there may be progressive development of more protease-resistant mutations which could markedly impair the response to Aptivus in the future.” At any rate, says Dr. Allen, these are “tough calls,” but ones which a patient and his or her physician can make together.

Chael Needle wrote about initiating treatment issues in infants with HIV in the June issue.

August 2005