New drugs that impact the virus in different ways are needed in order to make the next major advance in the treatment of HIV disease. However, progress is also needed on improving existing drugs and providing options for people who are failing current regimens. This article discusses the progress on new protease inhibitors (tipranavir and TMC-114) and reverse transcriptase inhibitors (capravirine and Reverset).
The body clears tipranavir from the blood quickly, so each 500 mg dose of tipranavir must be taken in combination with 200 mg of ritonavir. The ritonavir helps keep tipranavir in the blood longer. Both drugs are taken twice daily.
Studies show the primary side effects of tipranavir so far are vomiting, diarrhea and nausea, none occurring in more than 5% of people. Most were able to be managed in studies by taking tipranavir with a light snack. The addition of ritonavir brings the potential for elevation in lipid markers (triglycerides) and liver related enzymes.
Preliminary results from large studies are expected by the end of summer. If favorable, the company is expected to apply for drug approval with the Food and Drug Administration (FDA). The company indicates that an expanded access program will open once the application for approval has been filed.
Tipranavir is available to a small number of people nationwide through an open label safety study (OLSS). The study is open to people living within 100 miles of a phase III study site and who need tipranavir to construct an active treatment regimen. It is currently limited to people with fewer than 100 CD4+ cells. The study hotline number is 800-632-2464.
The dosing schemes and viral load responses at the end of two weeks (14 days) follow:
Viral load responses at the end of two weeks were similar among the three dose groups. Reductions in virus were comparable whether the person entered the study with resistance to only one other protease inhibitor or to all of the approved protease inhibitors. In test tube studies, TMC-114 was active even against virus with six or more protease resistant mutations. If these results hold up in larger studies, this could prove to be a very hopeful candidate for people who have problems with drug resistance in need of new treatment options.
In Europe, studies of capravirine are enrolling people who have never taken anti-HIV drugs. Studies in the U.S. and Canada are enrolling people who have been on failing regimens that included protease inhibitors and an NNRTI. The U.S. study will compare three different doses of capravirine + Kaletra + two NRTIs to Kaletra + two NRTIs. People interested in the study can call 1-800-323-4204 for more information.
While these viral load reductions are impressive, the study was very small and short-term. Other studies are needed to determine whether the drops in viral load can be sustained over time. Activists will also be pushing for drug interactions studies between D-D4FC and other existing drugs to ensure its usefulness as part of combination therapy.
The company developing the drug shared data from test tube studies showing that D-D4FC may be active against virus resistant to AZT, 3TC and other NRTIs. It is too early to draw conclusions about the resistance and cross-resistance patterns of D-D4FC, however. Nearly every new drug promises activity against drug resistant virus -- only larger studies will tell if this holds true over time. A larger study will begin recruiting 180 treatment-experienced people later in 2004.
All four drugs (tipranavir, TMC-114, capravirine and D-D4FC) were developed with the goal of suppressing drug-resistant HIV. Together, they represent three of the four classes of approved drugs. Though not a revolutionary step forward, they nonetheless offer hope to people who will need them.
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