PI Perspective #17

December 1995     View PDF     En español

Advances in Protease Inhibitor Development

The widespread availability of protease inhibitors is now a few months away and, for some people, it is already here. On November 7, the FDA Antiviral Advisory Committee recommended accelerated approval for saquinavir in combination with currently available antiviral drugs for people with advanced disease. This should put the drug in pharmacies in as little as three months. At the same time, new or enlarged expanded access programs have been announced for some of the other protease inhibitors.

Results from several studies continue to show impressive anti-HIV activity of this family of compounds. These results show that it may be possible to slow the development of resistance to these drugs by using them in combinations. Additionally, data makes it clear that people who achieve consistently higher drug levels in the blood have better antiviral activity and greater CD4+ cell count increases. It is therefore important to take these drugs so that their absorption will be maximized—for ritonavir (formerly ABT-538) and saquinavir this means taking them with food, but on an empty stomach with indinavir (formerly MK-639). It is also important to take these drugs at designated times to ensure adequate drug levels. If drug levels get too low, there is an increased risk of developing resistance to that drug.

Indinavir Sulfate (also known as MK-639 and Crixivan from Merck)
Merck is currently supplying indinavir to about 1400 people in an expanded access program which might be enlarged after the first of the year. The company expects to file for FDA accelerated approval in early 1996.

One recently reported study compared indinavir alone to either AZT alone or the two drugs combined. Results of this first combination study show the clear superiority of indinavir to AZT, but also that combining them may lead to a more sustained suppression of virus than indinavir alone, suggesting that the combination may be slowing the development of resistance. The study enrolled 73 people who had less than two weeks prior AZT use and with CD4+ counts below 500 and HIV RNA counts above 20,000. Volunteers received AZT alone (200mg three times daily), indinavir alone (600mg four times daily), or the combination. As might be predicted, people on AZT alone had only a slight decrease in HIV RNA which returned to original levels after 24 weeks. People receiving either indinavir alone or the combination had an average 2.5 log drop in HIV RNA after 12 weeks of therapy. Interestingly, people on indinavir alone sustained a 1.5 log drop in HIV RNA at 24 weeks whereas people on the combination had a sustained 2.5 log drop, suggesting that the combination may be able to delay drug resistance. Additionally, people on the combination had slightly greater increases in CD4+ cell counts (averaging about 75 after 24 weeks) compared to people on indinavir alone (about 50 after 24 weeks). However, the overall level of CD4+ cell increase seems surprisingly modest compared to reports from earlier indinavir studies.

A second study, testing revised doses of indinavir, enrolled people with CD4+ counts between 150 and 500 and HIV RNA counts over 20,000. Volunteers received either 800mg every 8 hours, mg every 8 hours or 800mg every 6 hours of MK-639. People on all three doses had similar antiviral 1,000 and CD4+ cell responses. The median maximum HIV RNA drop was about 2 logs and after 24 weeks there was still a 1.5 to 2 log decrease. There was also an average increase of about 100 CD4+ cells at 24 weeks on all three doses. No previously unreported toxicities were seen in the study. As a result of this study, Merck decided to use the 800mg every 8 hours dosing schedule for their phase III studies.

The only one known drug interaction with indinavir and is with rifabutin. Indinavir significantly increases rifabutin levels in the blood and the dose of rifabutin should be cut in half if the drugs are used simultaneously. It is also very likely that there will be an interaction with rifampin, astemizole (Hismanal), terfenadine (Seldane) and loratadine (Claritin).

Ritonavir (previously known as ABT-538, from Abbott Laboratories)
Abbott Labs expects to file for FDA accelerated approval of ritonavir in early 1996. Abbott will initiate a compassionate use program for about 1500 people in December, 1995 or January, 1996 (call the Project Inform Hotline for more information). Additionally, a new soft-gel capsule is likely to be introduced in November 1995 with high hopes of making the drug more palatable. In the meantime there are several recommendations to better cope with the foul taste of the current liquid formulation. Salty foods seem to mask the taste and fatty foods (like chocolates) may help to better dissolve the drug. To get rid of the aftertaste, users might try rinsing with a mouthwash or wine.

A small French study gave ritonavir to 25 people with CD4+ counts below 250 who had never been on antiviral therapy. Volunteers received ritonavir alone for two weeks and then added AZT + ddC. After 4 months, there was an average decrease in HIV RNA of 2.5 logs, with one third of the group now having undetectable amounts of virus. The group averaged an increase of about 125 CD4+ cells. Perhaps even more important, there was a substantial decrease in the number of infectious cells detected in blood after 16 weeks.

Another recent finding by Abbott Labs is that the combination of ritonavir and saquinavir (the Roche protease inhibitor), have a powerful drug interaction which might be either beneficial or harmful depending on how it is managed. In animals, when ritonavir and saquinavir were given together, the amount of saquinavir detected in blood accumulates rapidly over a few days, eventually reaching a level as much as 300 times that normally found. The interaction does not affect the blood levels of ritonavir. While it is still not known whether the same degree of interaction will occur in humans, there is a strong likelihood that it will be similar, although the degree may vary widely in different people. This might make the two drugs a very potent combination, especially if the effect is consistent, but it also brings a greatly increased risk of severe toxicity, especially at the currently used doses. Because of the many unknowns here, people are strongly discouraged from experimenting with the combination on their own until more is learned. The same process which causes this interaction results in several other known interactions between ritonavir and other drugs. When used with clarithromycin, clarithromycin levels are significantly increased; with fluconazole, ritonavir levels are increased by about 15%. Other interactions are likely with rifabutin, rifampin and itraconazole. Ritonavir should also not be taken with the anti-arthritis drug piroxicam (Feldene), the anti-ulcer drug cimetidine (Tagamet), the antihistamines terfenadine (Seldane), astemizole (Hismanal) and loratadine (Claritin), the antidepressant paroxetine hydrochloride (Paxil), the sedatives codeine, meperidine (Demerol and Mepergan), diazepam (valium), midazolam (Versed) alprazolam (Xanax) and triazolam (Halcion), the antifungals clotrimazole (Lotrimin and Mycelex), miconazole IV (Monistat IV) and ketoconazole (Nizoral) and the heart drugs bepridil hydrochloride (Vascor), encainide (Enkaid), flecainide (Tambocor) propafenone hydrochloride (Rythmol), and amiodarone (Cordarone).

This somewhat bewildering list of possible drug interactions suggest that although ritonavir may be highly desirable for its anti-HIV activity, it will create many problems in common use and require great care on the part of physicians.

AG1343 (also known as Viracept, from Agouron)
AG1343 is in an earlier stage of development than saquinavir, indinavir or ritonavir and consequently, less is known about its effects. A British study of AG1343 enrolled 20 people with CD4+ counts between 200 to 500, more than 20,000 copies of HIV RNA and who had either never been on antivirals or had discontinued other antivirals for at least one year. People received either 300mg or 600mg of AG1343 three times a day. After 28 days, people who had a greater than a one log drop in HIV RNA were allowed to continue on AG1343. Two people in the low dose group and 4 people in the high dose group had greater than a one log drop, but surprisingly people on the lower dose had better CD4+ cell responses. Because of the small numbers of people treated, it is difficult to know what, if anything, these results mean, except that a small number of those treated had substantial reductions in HIV RNA.

A second study enrolled 30 people with CD4+ counts above 200, more than 20,000 copies of HIV RNA and who had either never been on antivirals or had discontinued antivirals for at least one year. Volunteers received either 500mg, 600mg or 750mg of AG1343 twice a day and like the British study, people who had at least a one log drop in HIV RNA after 28 days of therapy were allowed to continue on an extension phase. The logic of a design which denies treatment to people whose response falls below an arbitrary threshold is uncertain. Some people think the approach might be in the patients’ best interests, while others think the opposite. Twenty-one of the thirty people enrolled qualified for the extension phase with people on the three different doses having similar HIV RNA responses (about a 1.5 log maximum decrease). As might be expected, people who achieved higher drug levels in their blood had better antiviral responses, but these were not necessarily the people who received the highest doses of the drug. Side effects noted from both studies were diarrhea (especially on the higher dose), fatigue, nausea and headache—very similar to the list reported for saquinavir.

Based on these studies, there is little clarity about the optimum dose of this drug. All doses show some level of antiviral activity, but the response does not seem clearly dose-related, as is usually the case. Since the level of antiviral activity is still somewhat below that reported for indinavir and ritonavir, it may be that higher doses will be required. It will be critical for the sponsor to identify an optimal dose before proceeding with efficacy studies.

Benefits of Combination Therapy Confirmed

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