Anti-HIV Therapy Update

July 2004

This article is part of The Body PRO's archive. Because it contains information that may no longer be accurate, this article should only be considered a historical document.


New drugs similar to those already approved are in the research pipeline; yet only one, tipranavir (from Boehringer Ingelheim), may get Food and Drug Administration (FDA) approval in 2004. Drugs of new classes and different modes of action are discussed elsewhere in this issue of PI Perspective but they will not be in wider use for two years or more.

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).


Tipranavir has a different chemical structure than other currently available protease inhibitors, which may allow it to work against virus that is resistant to other drugs in this class. It is being studied in people who are taking anti-HIV drugs for the first time as well as in people who have been heavily treated and may have drug resistance.

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.


Like tipranavir, TMC-114 (from Tibotec/Johnson & Johnson) is a protease inhibitor which may have activity against virus that has become resistant to other protease inhibitors. Recently, researchers reported on the completion of a small human study and a test tube (in vitro) resistance study. The goal of the small study was to assess safety and compare the anti-HIV activity of three different doses of TMC-114. Each dose (300 mg twice daily, 600 mg twice daily or 900 mg once daily) was combined with a 100 mg ritonavir booster.

The dosing schemes and viral load responses at the end of two weeks (14 days) follow:

  • TMC-114 300 mg + ritonavir 100 mg twice daily = 1.2 log reduction

  • TMC-114 600 mg + ritonavir 100 mg twice daily = 1.5 log reduction

  • TMC-114 900 mg + ritonavir 100 mg once daily = 1.3 log reduction

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.


Capravirine (from Agouron/Pfizer) is a non-nucleoside reverse transcriptase inhibitor (NNRTI), which belongs to the same class as efavirenz and nevirapine. Early data suggest that it may be active against virus that has become resistant to other NNRTI drugs. It was also found to be quite potent, producing up to 2 log drops in virus when dosed at 1,400 mg twice daily. Development of capravirine was stalled when animal studies suggested that the drug might cause heart problems. A review of data from a small human study with close heart monitoring did not reveal heart-related side effects. Development is now proceeding.

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.


D-D4FC (Reverset, from Pharmaset) is a nucleoside analog reverse transcriptase inhibitor (NRTI). Results from a small short-term study of people who have not taken anti-HIV drugs before suggest it may have potent anti-HIV activity. Taken as a single agent therapy (monotherapy, not together with other anti-HIV drugs) over a ten-day period at three different doses, D-D4FC produced the following drops in viral load:

  • an average 1.67 log reduction in people on the 50 mg once daily dose,

  • an average 1.74 log reduction in people on the 100 mg once daily dose, and

  • an average 1.77 log reduction for people on the 200 mg daily dose.

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.


It is likely that the novel HIV treatment strategies discussed elsewhere in this publication will take at minimum several years before they are more widely available to people living with HIV. Some of those strategies are in their scientific infancy and will take even longer. In the meantime drugs like those discussed in this article offer promising alternatives to people who will need new drugs in the near future.

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.

Bottom Line on Anti-HIV Therapy Update


  • New protease inhibitor, likely to be approved in 2004.

  • May be active against virus resistant to other PIs.

  • Must be boosted with ritonavir.

  • Low to moderate side effects so far.


  • New protease inhibitor, currently in small studies.

  • May be active against virus resistant to other PIs.

  • Must be boosted with ritonavir.


  • New NNTRI, entering large studies this year.

  • May be active against virus resistant to other NNRTIs.


  • New NRTI, still in small studies.

  • May be active against virus resistant to other NRTIs.

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