Project Inform - September, 1998

Abbott Laboratories' second generation protease inhibitor, ABT-378, appears to be quite potent and well tolerated. A small study enrolled 32 people who had not previously received anti-HIV therapy and who had a median HIV RNA level of 100,000 copies and a CD4+ cell count of 424 cells. People received 200mg ABT-378 and 100mg ritonavir—both taken twice a day—or 400mg ABT-378 and 100 mg ritonavir again both taken twice a day. People received ABT-378 and ritonavir for three weeks and then d4T and 3TC were added. There were no differences between the two doses. After the 3 weeks of only ABT-378 and ritonavir, people had an average viral load reduction of 2 logs and the addition of d4T and 3TC resulted in a further reduction of 0.2 logs. Ninety percent of the participants had a viral load below 400 copies HIV RNA after 24 weeks and they had a median increase of 150 CD4+ cells. ABT-378 and ritonavir were well tolerated without anyone having to discontinue use because of side effects. Abbott is hoping that ritonavir increases ABT-378 levels so dramatically that this combination will be able to overpower protease-resistant virus. Clinical studies of ABT-378 to test whether ABT-378 will be effective are planned in people who have virologically failed protease inhibitors. (Note: the use of ritonavir in this regimen is solely intended to increase the blood levels of the ABT-378 drug. The dose used in the study is NOT a recommended dose of ritonavir and should not generally be used.)

Pharmacia & Upjohn recently started a small study with their new protease inhibitor, tipranavir (PNU-140690). Twenty-four people who were on a two nucleoside analogue regimen but who have not previously taken a protease inhibitor participated in this study. People had an average viral load of about 30,000 copies HIV RNA and a CD4+ count of 400 cells prior to starting the study. Participants added 900mg, 1,200mg or 1,500mg of tipranavir taken three times a day to their existing dual nucleoside analogue regimen. A maximum 1.3 log reduction in HIV RNA was seen among those receiving the highest dose of tipranavir, however most people had a rebound in their viral loads. This was believed to be due to lack of adherence to the regimen, for in this study, tipranavir came in 150mg pills and, therefore, people taking the highest dose regimen had to take 30 pills a day. A new formulation is being developed which will allow individuals to take fewer pills per day. In laboratory studies, tipranavir has a completely different resistance profile compared to the existing protease inhibitors and thus might be useful against protease-resistant virus. However, similar claims about previous protease inhibitors have usually not translated into clinical success in heavily pretreated patients, so it is premature to believe this drug answers the need for a true salvage therapy. Results from studies like this in general are difficult to interpret. Given that study participants added tipranavir to an existing regimen, which is not considered the standard of care, it's impossible to figure out what the actual contribution of tipranavir, used correctly, might have been. A wise anti-HIV strategy typically includes simultaneously starting at least two drugs, which have not previously been used.

Agouron Pharmaceuticals recently licensed the development of a NNRTI S-1153 from Shionogi Pharmaceuticals. In laboratory studies, this drug is not completely cross-resistant with the existing NNRTIs. Furthermore, the company asserts that it is more difficult to develop resistance to this drug, as it requires more than one mutation to cause high-level resistance and, as a result, drug failure. The current NNRTIs (delavirdine, nevirapine and efavirenz) only require one mutation to cause drug failure. In a small study of 27 people, most of whom had been on prior anti-HIV therapies, S-1153 showed good activity. People received S-1153 at a dose of 8.3 mg/kg every 8 hours, 10mg/kg every twelve hours or 12.5mg/kg every twelve hours. People had a maximum median reduction in HIV RNA levels of 1.4 logs. The drug was generally well tolerated with mild gastrointestinal problems being the most common side effect. No cases of rash were reported.

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The original of this article can be found at http://www.projinf.org/pub/25/newdrugs.html