New Targets, New Drugs, Failed Trials and the Need for More Information
Among these agents, the PI atazanavir (Reyataz) has garnered the most attention. Atazanavir appears to be effective in both treatment-naive and, when boosted with ritonavir, in some treatment-experienced patients. Atazanavir is dosed once daily, well tolerated, and has remarkably little effect on serum cholesterol or triglycerides. Each of these features clearly distinguish it from the majority of approved PIs. Care must be taken when using atazanavir with other HIV agents, notably tenofovir. Also, it cannot be used at present with anti-acid agents (studies are underway), including proton pump inhibitors such as Prilosec or H2 blockers such as Pepcid AC, Zantac or Tagamet.
The other PI approved this year is the pro-drug of amprenavir (Agenerase). Called Lexiva (fos-amprenavir), this formulation greatly reduces the pill burden and gastrointestinal side effects of amprenavir. Lexiva has demonstrated impressive effectiveness in advanced (low CD4, high viral load) patient populations. Lexiva has been tested in treatment-naive and experienced patients, and can be used either once or twice daily with or without ritonavir boosting. (All treatment-experienced patients should use it twice daily and with ritonavir.)
A new nucleoside analogue was approved this year as well. Emtriva (FTC or emtricitabine) is a NRTI much like lamivudine (3TC or Epivir). It has an identical resistance pattern, safety profile, and like 3TC can be dosed once daily. It will soon be combined with tenofovir (Viread) into a combination pill much like Combivir.
Several important clinical trials have improved our understanding of the most effective combinations of antiretroviral therapy. Combinations containing three NRTIs, so called triple nukes, have been found to be inferior to three drug combinations using at least two classes of antiretroviral agents.
In an important study that was terminated early, the triple nuke combination of AZT, 3TC and abacavir (all in one drug, Trizivir) was found to be significantly less effective than an efavirenz (Sustiva)-based regimen in treatment-naive patients. While Trizivir clearly still has a place among the drugs used to treat HIV, it is also clearly not as effective when used as the whole regimen and not part of anti-HIV therapy.
Two other seemingly potent triple nuke regimens fared far worse than Trizivir in studies. Unlike Trizivir, the performance of these combinations was so dismal that they should never be used as sole treatment. The combination of tenofovir, abacavir and lamivudine was dramatically less effective than the combination of efavirenz with abacavir and lamivudine. Didanosine (ddI or Videx) when used with tenofovir and lamivudine was effective in only one of the 30 patients who received this combination. Clearly more work is needed to understand why these otherwise effective agents failed so miserably.
Drug of Choice
The guidelines for treatment of HIV infection issued by the Department of Health and Human Services for the first time listed combinations of agents to be used in the treatment of naive patients. This recommendation was based on the evaluation of these combinations in clinical trials. Among the preferred combinations are those of:
Recommended among the PIs is:
This is not to say that other triple drug combinations are not effective, but rather that these combinations have not shown the same effectiveness, safety and durability as the preferred combinations.
Drugs on the Horizon
Several important agents are in advanced (Phase III) clinical trials. These include the PIs tipranavir and TMC-114. Both agents are felt to be effective in those patients harboring significant PI-resistant virus. If these agents prove effective they should become available in expanded access in 2004 and 2005.
Clinical trials are of course the means by which new agents are tested for effectiveness and safety. It is also the venue for testing against the current standard of care agents. Participation in clinical trials is a very important part of the learning and discovery process, especially for HIV agents.
It is of vital importance that participants in clinical trials be of a diverse racial/ethnic and sexual mix. By participating in clinical trials we can not only speed along the process of drug development and approval, but learn valuable lessons about how the drugs work in different patient populations. If a clinical trial meets your particular needs, consider participation. You can avail yourself of important treatment options, but also assist all clinicians and researchers in the HIV field by providing crucial clinical information. In turn, you'll be helping people with HIV around the world.
Dr. Stephen L. Becker is with Pacific Horizon Medical Group in San Francisco, and on the faculty of the University of California, San Francisco.
Special thanks to Gilead Sciences for supporting Dr. Becker's work on the 8th Annual HIV Drug Guide.
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