Drifting Agenda for Federal Treatment Research
Although U.S. government clinical trials for AIDS were once at the forefront of HIV treatment research, during the past few years pharmaceutical sponsors have taken over the job of conducting the most important studies of new anti-HIV medications. The government, which continues to play a central role in operating clinical trials for vaccines, for treating the complications of HIV, and for treating children, has fallen strangely out-of-step in its research of new drugs and strategies for treating and managing HIV in adults. A review of recent government clinical trials targeting HIV infection suggests skewed priorities in the federal research agenda. In particular, the unusual proportion of trials investigating two drugs, Agenerase and Ziagen, both marketed by pharmaceutical manufacturer GlaxoSmithKline, raises questions about the relevance of the government's vision for HIV clinical research and concerns about industry influence.
Federally sponsored clinical trials for HIV/AIDS are conducted under the broad umbrella of the National Institutes of Health (NIH). Within the NIH are several Institutes that study HIV treatments in people. The largest is the National Institute for Allergy and Infectious Diseases (NIAID). Within NIAID, there are a number of programs and trials networks conducting clinical research, such as the HIV Vaccine Trials Network (HVTN), the Pediatric AIDS Clinical Trials Group (PACTG) and others.
The oldest, largest, and best-funded NIAID research program is the Adult AIDS Clinical Trials Group (AACTG), a network of research sites around the country, usually affiliated with important medical centers and universities. The AACTG was organized in 1986 to perform high-quality and rapid testing of emerging AIDS therapies. It was created at a desperate time in the epidemic, with no treatment options in sight and enormous pressure on government to speed up the glacial pace of developing and approving new drugs. By late 1986, a Burroughs Wellcome trial (BW 002) had delivered compelling evidence in record time that AZT could slow disease progression and delay death from AIDS. A few months later, on the basis of this trial, the U.S. Food and Drug Administration (FDA) approved AZT for sale in the U.S.
Within the AACTG, Research Agenda Committees (RACs) direct clinical investigations along three basic lines of inquiry: HIV-disease, the complications of HIV disease, and the immunology of HIV/AIDS. The AACTG has performed clinical trials to investigate new therapies for HIV and its associated infections, to test various hypotheses about the pathogenesis of the virus, and to explore strategies for meeting evolving patterns of disease.
Since its inception, the AACTG has initiated nearly 300 clinical trials, of which 118 have focused on HIV disease and its treatments. Added to the overall number are more than 125 nested substudies designed to investigate highly focused scientific questions using trial subjects enrolled in one of the primary clinical trials. Substudies may originate in one RAC to take advantage of a study population assembled for another RAC's research. For example, immunology researchers may nest a substudy of CD4 phenotype into an HIV trial comparing the impact of two treatment regimens on viral load.
The AACTG: "The Amprenavir/Abacavir Clinical Trials Group"?
This report focuses solely on clinical trials of HIV treatments and treatment strategies originating within the HIV RAC of the AACTG. Ten clinical trials overseen by the HIV RAC are currently open to enrollment and three more trials have closed but are still collecting or evaluating data. In addition, more than a dozen substudies are active.
Six of the ten open trials specify drugs in their protocols; four trials prescribe no drugs. Five of the six trials that specify drugs -- half of all open trials -- are testing two drugs marketed by GlaxoSmithKline (Glaxo): the protease inhibitor Agenerase (amprenavir) and the nucleoside analog Ziagen (abacavir). Of these five trials, three include amprenavir, four include abacavir and two include both. (Comparatively, one of the ten open trials prescribes efavirenz and one other trial offers indinavir. Ritonavir is employed as a metabolic modifier in several trials.) Each of the three trials that have closed but are not yet completed also included amprenavir or abacavir. Glaxo also manufactures AZT, 3TC, and Combivir, a popular coformulation of AZT and 3TC into one pill. Combivir is the largest selling HIV drug in the world.
Amprenavir is a drug molecule that was specifically designed as a protease inhibitor for HIV therapy. The drug has a favorable side-effects profile, achieves therapeutic concentrations in semen and the brain, and is active against viral isolates with diminished susceptibility to other protease inhibitors. Nevertheless, amprenavir is not without drawbacks. Resistance does emerge and some studies have reported a high rate of rash associated with the drug. These issues plus a formulation that requires taking many uncomfortably large pills twice daily have contributed to a lack of enthusiasm among clinicians and a poor level of acceptance among people receiving HIV treatment. Agenerase holds about 2% of the U.S. HIV drug market share (see pie chart, below left).
Initially, abacavir and amprenavir appeared to be attractive second-generation therapies that addressed the need for simpler, less toxic and more potent treatment regimens. One of the first AACTG trials of amprenavir optimistically compared triple combination therapy to amprenavir alone. Abacavir has been studied in a dual combination with amprenavir and as an anchor drug in protease inhibitor-sparing regimens. Several trials have employed the drugs as components of salvage therapy. At least eight non-AACTG trials have studied abacavir at various stages in its development and a similar number of non-AACTG trials of amprenavir have been conducted. In the current round of AACTG trials, amprenavir and abacavir are cast as intensifying agents to forestall early virologic failure or as simple but potent first-line treatments.
The Lineup of HIV Treatment Research at the AACTG
A) Five Trials Not Using Either Amprenavir or Abacavir.
Two of the ten open HIV RAC trials are investigating pharmacologic or scientific questions. One trial, AACTG 317, which began in 1998 and is set to close soon, has been evaluating the effects of birth control hormones on AZT metabolism. A recently opened trial, A5077, is comparing changes in viral loads in the blood and other non-blood compartments before and after initiating HAART.
Trial number A5076, which opened in late 2000, is a treatment strategy trial comparing the selection of a second regimen after virologic failure with and without guidance from phenotypic drug susceptibility test results. A salvage strategy trial, A5086, is designed for heavily pre-treated individuals experiencing virologic failure. This study compares a strategy of immediately switching to a regimen selected with the aid of resistance test results to one of temporarily stopping all treatment for a period of time before starting the new regimen. Another salvage therapy trial, A5055, is investigating two dosing schedules of indinavir boosted with ritonavir for individuals who have failed amprenavir, nelfinavir, or saquinavir.
B) Five Trials Using Either Amprenavir or Abacavir
AACTG 371 is a trial of an intensive regimen of antiretroviral therapy administered to recently infected individuals during primary infection that will assess if viral load levels can remain suppressed following a planned discontinuation of therapy. Each treatment arm will receive amprenavir boosted with ritonavir and either abacavir or abacavir placebo. One arm will receive amprenavir/ritonavir plus abacavir with no other nucleosides. This trial opened in early 1998 and as of May 2001 had enrolled 32 of the targeted 120 subjects. AACTG 371 has eight substudies attached to it.
A newly-opened salvage trial, A5061, is investigating the strategy of treatment intensification for individuals starting to experience virologic failure. Trial subjects will add either abacavir or amprenavir/ritonavir to their current failing regimens. A similar trial, A5064, which opened in 1999, is comparing intensifying the failing regimen with abacavir or placebo. So far 15 patients have enrolled into this 80-person trial.
Another newly opened trial, A5095, expects to enroll over 1,100 previously untreated individuals into three treatment arms, each containing abacavir or abacavir placebo. The abacavir is administered as a component of Glaxo's triple combo, Trizivir. Participants will also receive efavirenz or placebo. These individuals may also be simultaneously enrolled into a separate Glaxo-sponsored study looking for genetic markers associated with abacavir hypersensitivity.
One final HIV RAC trial currently enrolling is only accepting HIV-negative individuals. This 90-person study, A5043, will investigate pharmacokinetic interactions between amprenavir, efavirenz, and other HIV drugs. Subjects in this study are paid $1,000 for their participation.
Past AACTG Studies of Amprenavir and Abacavir
As of May 1, 2001, three AACTG HIV trials involving amprenavir or abacavir, AACTG 372, 384, and 400, are closed to enrollment but have not yet been completed. AACTG 384 successfully enrolled nearly 1,000 patients, but AACTG 400 was closed due to poor accrual after only 21 of 300 expected subjects had enrolled during a three year period.
Four additional HIV RAC trials, now completed, have also studied the Glaxo drugs. One of these studies, AACTG 347, compared amprenavir plus AZT/3TC to amprenavir alone. A subsequent study, AACTG 373, compared amprenavir plus AZT/3TC with other treatment regimens for people who had previously received amprenavir, primarily individuals from AACTG 347. A salvage protocol, AACTG 398, added amprenavir to other protease inhibitors or placebo in combination with abacavir, efavirenz and adefovir. Finally, AACTG 368 investigated abacavir combined with efavirenz and indinavir for individuals who had participated in an earlier AACTG trial involving indinavir.
If at First You Don't Exceed . . .
Amprenavir and abacavir may be expected to continue playing significant roles in the government's HIV treatment research agenda. Looking ahead to HIV RAC protocols still in the planning stages, amprenavir is proposed as part of a salvage trial comparing fixed-dose with concentration-adjusted doses of protease inhibitors. Custom monitoring and adjusting of doses to assure sufficient protease inhibitor blood levels may have an important role to play in reducing virologic breakthroughs due to individual metabolic variations. Kaletra, tenofovir, and DAPD are also slated to appear in several of these proposed trials. Outside of the HIV RAC, Trizivir has been proposed as the primary antiviral regimen in a trial of cyclosporin originating with the Immunology RAC.
A water-soluble pro-drug of amprenavir, currently called GW-433908, may allow improved amprenavir blood levels with a much smaller pill burden by virtue of being metabolized to the active form in the intestines. This new version of amprenavir has been selected as the protease inhibitor in one arm of a proposed three-arm protocol for salvage therapy and is also being considered for other protocols in the conceptual stage. At least one protocol in development proposes to investigate the safety and activity of abacavir administered with mycophenolate mofetil, an immunosupressive anti-cancer agent that may improve the competitive advantage of abacavir's active metabolite within cells.
It's unclear if the current imbalance in AACTG treatment research is due to outdated priorities that attained bureaucratic momentum, an absence of critical thinking about these priorities, or lack of vision within the leadership. At the very least, AACTG's leaders have demonstrated a poor sense of propriety regarding apparent conflicts of interest between government and industry.
This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.