Better treatments and drugs in the pipeline

Better treatments

Dr. Fiona Lampe from London presented data from a large joint cohort of treatment-naïve patients from England and Canada. This study shows that treatments are becoming more effective. Or are we just learning how to use them better?

The risk of reaching an initial treatment failure over a seven-year period has halved in this analysis. Still, people who were lost to follow-up or stopped therapies due to failure suggests that the treatments used today could be even simpler and less toxic.

Another large cohort from Dr. John Bartlett and colleagues at Duke University showed that treatment responses are getting better as drugs are improved. The meta-analysis collated the results of 48 weeks of data from 64 clinical trials and showed that boosted protease inhibitors and non-nucleoside reverse transcriptase inhibitors work best to bring virus levels down. Boosted PIs work best to increase CD4 cells.

Drugs in the pipeline

There was even good news in the salvage setting for those with highly resistant HIV.

Protease inhibitors

Use of Fuzeon in addition to the experimental protease inhibitors such as Boehringer’s tipranavir or Tibotec’s TMC-114 are working well for those with no treatment options.

In a 24-week analysis of the RESIST study, use of tipranavir compared to comparator protease regimens showed better results, but Fuzeon and tipranavir was the best combination in this study. Tipranavir 500 mg (two capsules) must be used with 200 mg Norvir twice daily with food.

In a subgroup analysis of TMC-114, use of Fuzeon with two nucleoside drugs showed the greatest response in lowering virus levels to less than 50 copies at week 24. The drug is boosted with a lower dose of Norvir than is used with tipranavir. The data for this drug was very impressive, showing up to 1.85 log drop in treatment-experienced patients. (See “New Protease Inhibitor TMC-114” in the March/April issue.)

Non-nukes

TMC-278 is a non-nucleoside reverse transcriptase inhibitor that is active against resistant HIV in laboratory studies thus far. Another Tibotec compound from the DAPY class, this Phase II monotherapy, proof-of-principle study in people who have not been on treatment showed an average 1.2 log drop in HIV. The company is filling its portfolio with drugs that are made to work against both wild type and resistant HIV. Their other compound, TMC-125, is further along in development… watch for larger Phase III studies.

Maturation inhibitors

But we are not out of the woods yet. There are still people who need new therapies from different classes due to drug resistance. And there is always room for safer, less toxic therapies.

One interesting drug target is the later “maturation” stage of HIV replication, where HIV matures and buds out of the infected CD4 cell. Panacos’ compound PA-457 is the furthest along in this new class. In a randomized, controlled single dose study with different doses, the average activity seen was between .3 to .7 log drop. And while this may not sound impressive, it is only one dose, and this drug represents new hope for yet another HIV target for those who have few options. A bonus is this drug will likely only be once daily as well. The company is moving forward with further development. If all goes well, we should see this drug in larger trials by next year.

CCR5 antagonists

There are three CCR5 antagonists running neck-and-neck down the development track in this new exciting field of research. The new drug class blocks the CCR5 co-receptor on the surface of HIV and has reached Phase II trials. Two out of the three drugs will have to be boosted with Norvir. At CROI there was information on how long the compounds block the co-receptor and how that will affect resistance. Other studies are beginning to show cross-resistance in two of the compounds, further complicating the problem of multi-drug regimens used in HIV. Maraviroc is the new name selected by Pfizer for their co-receptor antagonist UK-427,857.

Integrase inhibitors

Everyone has been waiting for the integrase drugs to come to fruition, or at least show any sign that the class will work in HIV at all. Merck is farthest along in the field, even though the audience was informed at CROI that their integrase inhibitor L-870810 is being put on hold due to toxicities in a long-term dosing study of dogs. However, the study showed a hefty 1.7 log viral load drop in a controlled 10-day monotherapy trial and provides hope that the class can work once the toxicity issues are teased out. And fortunately, the company has a back-up compound in Phase II development.

A few investigational agents are being researched to target the reverse transcriptase and protease enzyme in unique ways. There is hope that these new agents will work against drug resistant virus. Stay tuned.

Gene therapy

There were two Phase I gene therapy studies showing safety and persistence of the therapy over time. Although very new in development, it is extremely encouraging to see non-drugs move into this stage of development.

More drug development

New drug classes are no longer a distant wish, but are promising. According to the Treatment Action Group 2005 Antiviral Pipeline (see www.aidsinfonyc.org/tag/tx/pipeline2005.html) there are at least 28 different entry inhibitors, eight integrase inhibitors (all in pre-clinical development), four maturation inhibitors and at least 14 other drugs with various mechanisms of action in the HIV treatment research pipeline. This represents a significant new area of research into new targets to fight HIV.

Time will now only tell if some of the new classes become approved after rigorous clinical trials. There was talk at CROI that some of the new classes may actually out perform the drugs currently in use. Even though this is pure conjecture, it provides hope that there is new energy in HIV research where a few years ago there was disappointment and fear that it was stalled.