Session 83
Antiviral Therapy: New Drugs

• Poster 668: Anti-HIV Activity and Tolerability of DAPD, a Novel Dioxolane Guanosine RT Inhibitor: Initial Results of a Phase I/II 14-Day Monotherapy Clinical Trial (Authored by D.D. Richman, H. Kessler, J. Eron, M. Thompson, F. Raffi, J. Jacobson, J. Harris, B. McCreedy, J. Bigley, and F. Rousseau. Univ. of California, San Diego; Chicago Ctr. for Clin. Res., IL; Univ. of North Carolina at Chapel Hill; AIDS Res. Consortium of Atlanta, GA; Hotel Dieu-CHU, Nantes, France; Mt. Sinai Med. Ctr., New York, NY; and Triangle Pharm., Durham, NC)
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• Poster 672: Safety and Antiviral Efficacy of a Novel Once-Daily HIV-1 Protease Inhibitor BMS-232632: Preliminary Results from a Phase II Clinical Trial (Authored by I. Sanne, P. Piliero, R. Wood, T. Kelleher, A. Cross, A. Mongillo, and S. Schnittman. Johannesburg Hosp., S. Africa; Albany Med Ctr, NY; Somerset Hosp., South Africa; and Bristol-Myers Squibb)
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• Poster 673: The Safety, Efficacy and Viral Dynamics Analysis of Tipranavir, a New-Generation Protease Inhibitor, in a Phase II Study in Antiretroviral-Naive HIV-1-Infected Patients (Authored by Y. Wang, C. Daenzer, R. Wood, D. Nickens, M. Borin, W. Freimuth, J. Morales, S. Green, M. Mucci, W. Decian, and The Tipranavir Team. Pharmacia & Upjohn, Kalamazoo, MI; Somerset Hosp., Capetown, South Africa; Clin. Res. Puerto Rico, Inc., San Juan, PR; Hampton Rd. Med. Spec., Hampton, VA; and Pharmacia & Upjohn, Milan, Italy)
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This session was a mixed bag; with reports ranging from reporting on drugs for which there is not even animal safety data yet; to trials of a promising new NRTI, (DAPD), and two protease inhibitors (BMS-232632 and Tipranavir); to a trial showing that a new NNRTI (emivirine, formerly MKC-442) with two NRTIs is better than two NRTIs; to a trial which showed that no one knows what doses to use when emivirine is combined with efavirenz (sustiva) in a dual NNRTI combination.

Summarized below, in more detail, are three of the more interesting reports on DAPD, BMS-232632, and Tipranavir.

Poster 668: Anti-HIV Activity and Tolerability of DAPD, a Novel Dioxolane Guanosine RT Inhibitor: Initial Results of a Phase I/II 14-Day Monotherapy Clinical Trial

Doug Richman, from the University of California, San Diego, reported some early results from a trial of a new NRTI, DAPD, which has evidence in vitro (in test tube) of activity against strains of HIV resistant to drugs such as ZDV, 3TC, and abacavir. Preliminary results of a non-randomized, 14-day Phase I/II trial in 20 antiretroviral-naïve HIV-positive people were presented. The purpose of this study was to compare several doses of DAPD (25 mg, 100 mg, 200 mg, and 300 mg, all twice a day). All the doses were well tolerated, and the higher the dose, the greater the decrease in viral load, (up to 1.45 logs decrease).

According to Dr. Richman, these results suggest potent activity and a promising tolerability profile. This trial is ongoing and further work is warranted at higher doses, and in different patient populations. In addition, in response to a question from the audience, Dr. Richman stated that this drug does not appear to have a lot of mitochondrial toxicity -- the mechanism by which some of the other NRTIs may cause some serious side effects including fat deposition in the liver, and lactic acidosis, a potentially life-threatening condition.

Poster 672: Safety and Antiviral Efficacy of a Novel Once-Daily HIV-1 Protease Inhibitor BMS-232632: Preliminary Results from a Phase II Clinical Trial

BMS-232632 is protease inhibitor (PI) with potent activity in vitro (in the test tube), and a potentially unique resistance profile. Prior studies showed good safety and tolerability (up to 800 mg once a day), and the feasibility of once-daily dosing. This phase II study compared the safety and antiviral activity of three dose-levels of BMS-232632 (BMS), 200 mg, 400 mg, and 500 mg, all once a day, to nelfinavir (NFV), 750 mg three times a day. All people in the study also received ddI and d4T, and were antiretroviral-naïve, with HIV RNA >5,000 and <750,000 copies/ml. (BMS was administered as monotherapy the first two weeks.)

Ninety-one people were studied. The most common side effects events were diarrhea (22% BMS, 65% NFV), and nausea. Hyperbilirubinemia (an asymptomatic elevation of a chemical processed by the liver), not associated with liver enzyme elevations, was the most common lab abnormality (51%) seen with BMS. After 16 weeks of therapy, about 50% of people in each of the four groups had viral loads, HIV RNA, <50 copies/ml.

These preliminary results support the short-term safety, tolerability, and antiviral efficacy of BMS-232632, combined with ddI and d4t, as compared to a standard regimen of NFV, ddI, and d4T, in people with no prior HIV therapy. Longer trials of BMS will be of interest, as well as data on cholesterol and triglycerides, and more importantly, tests of the efficacy of BMS in people who have developed drug resistance to other protease inhibitors.

Poster 673: The Safety, Efficacy and Viral Dynamics Analysis of Tipranavir, a New-Generation Protease Inhibitor, in a Phase II Study in Antiretroviral-Naive HIV-1-Infected Patients

Tipranavir (TPV) is a new protease inhibitor, which in its original formulation had to be administered as ten pills three times a day. This two-week study was done to see if small doses of ritonavir (RVT) could be used to decrease the amount of TRV needed, while still achieving adequate blood levels. Thirty-one treatment-naïve people were randomized into three groups: TPV (1,200 mg, twice a day); and TPV + RTV (300 mg + 200 mg, twice a day; and TPV + RTV (1,200 mg + 200 mg, twice a day). (300 mg TPV and 100 mg RTV capsules were used in all three groups.)

After two weeks of treatment, the HIV RNA was reduced by 0.8, 1.4, and 1.6 logs, in Group 1, 2, and 3, respectively. The corresponding CD4 cell counts increased by 11, 77, and 73 cells, respectively. All regimens were well tolerated with no discontinuation for adverse events related to study medications. The most common adverse events were mild to moderate loose stools or diarrhea (52%), nausea (23%), and vomiting (13%). Thus, it appears that combing low doses of RTV, with TPV, may allow for twice-a-day dosing of TPV, and significantly reduce the number of TPV capsules needed.

Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.