European HIV treatment activists, the European AIDS Treatment Group (EATG), are demanding that a worldwide trial of Pfizer’s investigational CCR5 antagonist, maraviroc (UK-427,857) in HIV-positive treatment-naïve individuals “be changed or stopped” since it is unnecessarily putting people with HIV who have severe immune suppression at risk. However, leading US activists are critical of the EATG’s position, claiming that it “fails to offer a balanced view,” and that it “is not an opinion shared by all HIV treatment activists.” Pfizer argues that the study “includes appropriate checks and balances to protect patient safety” and say that it and other stakeholders “believe our position is well considered.”
Pfizer’s A4001026 trial is a combined PhaseIIb/III study to define the dose, preliminary efficacy and safety of maraviroc in participants who have never taken treatment before, and whose HIV is thought to be susceptible to maraviroc via a test for R5-tropic virus (i.e. HIV that is attracted to a cell’s CCR5 receptor). It is one of three maraviroc studies currently enrolling worldwide. A4001028 will give the drug, plus the best available HAART regimen (often called an ‘optimised background regimen’), to people whose R5-tropic HIV has resistance to at least one drug in three of the four current anti-HIV drug classes. A third, smaller study, A4001029, will give maraviroc plus ‘optimised’ HAART to people who have both R5- and X4-tropic virus, to see what happens.
The EATG, which had been in discussions with Pfizer regarding its trial designs, has no problem with the other two studies, but it is greatly concerned that the 1026 trial’s inclusion criteria may be placing vulnerable people recently diagnosed with HIV at unnecessary risk.
The inclusion criteria allow individuals to enter the trial regardless of their CD4 count and viral load. This includes people with CD4 counts below 200 cells/mm3 and viral loads over 100,000 copies/ml who are at greater risk of disease progression, and who could benefit from currently available treatment options. It is often the case that individuals with advanced HIV disease who have never previously taken treatment have only recently been diagnosed with HIV and/or AIDS, and may not be in the best position to make informed treatment decisions.
“Pfizer has said it will informally recommend a limit of over 100 [CD4 cells],” Nikos Dedes, Chair of EATG’s European Community Advisory Board (ECAB) tells May’s issue of AIDS Treatment Update, “but we want it stated in the protocol so that less-informed physicians don’t enrol vulnerable patients…We don’t see that there’s any medical rationale to put people with 80 CD4 cells on these regimens. These days we have drugs that work for most people, so why be in such a hurry? Make it people who would not be endangered by one ineffective regimen, say with CD4 counts of 250-350.”
US activists disagree
However, Bob Huff, Editor of New York-based GMHC Treatment Issues, tells aidsmap that the “EATG fails to offer a balanced view of this controversial issue. This is not an opinion shared by all HIV treatment activists.
“The opinions about whether this trial is ethical are based on individual beliefs about ethics, not on a careful consideration of the specifics of the drug and the science,” he says. ”In fact, [most countries’] regulatory agencies have assumed their responsibility and decided to approve the current trial design. They did not do so in ignorance or without careful consideration of the EATG position.”
He points out that existing standard-of-care treatments are unacceptable to many people due to toxicity and do not assure sustained viral suppression. He also notes that it is important to acquire safety data in all populations that will ultimately be exposed to a new drug. "Due to close, expert monitoring and the attention of trial staff, patients in clinical trials often have better outcomes than patients treated [according to] guidelines", he notes.
Jules Levin, founder of the New York-based National AIDS Treatment Advocacy Project (NATAP), has also criticized the EATG. "It's unfortunate for patients, HIV research and for AIDS drug development that such an uninformed and harmful effect has occurred by a group of individuals, the European activists," he wrote in a message on an HIV treatment discussion group board following the EATG's announcement.
Maraviroc is an investigational compound that has so far only been tested in 63 HIV-positive people at eight different doses for 10 days. In that study, one person was inadvertently enrolled who had X4-tropic virus that should have been detected, and did not respond to the drug. X4-tropic virus emerged near the end of the dosing period in another two individuals. X4-tropic virus ‘went away’ in one of these two participants after the drug was stopped, but the other person still had a mixed R5- and X4-tropic virus population 40 days later.
David Haerry, ECAB Co-Chair, says that since there are so few clinical data on maraviroc, “it is totally unacceptable to treat naïve patients with severe immune suppression and high viral loads with a drug combination containing an investigational drug whose potency and ideal dose are still unknown”. Haerry adds that people who do not respond to the drug, either due to potency or adverse events, will have their physical and psychological wellbeing impacted and future treatment options may be reduced.
Pfizer says that “individual patient safety is paramount to Pfizer, and study 1026 has been designed to ensure patients receive excellent medical care…[The study design means that] future treatment options with the most potent of antiretrovirals - efavirenz (Sustiva), boosted protease inhibitors and tenofovir (Viread) - are preserved.
“Pfizer believes a thorough evaluation of maraviroc is required in a population representative of individuals initiating HIV therapy today. Such an evaluation in a well-controlled trial setting with clear individual patient stopping rules in the protocol, not only will yield valuable data to guide appropriate future use of this potential new medicine by clinicians, but also addresses individual patient safety within the trial.”
Pfizer is one of three pharmaceutical companies currently in a race to produce the first CCR5 antagonist, which would be the first oral anti-HIV drug to prevent HIV from entering cells. Schering-Plough and GlaxoSmithKline also currently have CCR5 antagonists in clinical trials, and activist and community consultations with these companies have gone much more smoothly.
When Pfizer was asked by aidsmap why it was necessary to include treatment-naïve patients in a study of a drug that has previously only been tested in 63 HIV-positive people, a spokesperson stressed the scientific and humanitarian issues involved.
“Typically, about 85% of treatment-naïve patients are R5-tropic [i.e. candidates for a CCR5 antagonist], compared to just 50% of heavily treatment experienced patients,” says Pfizer. "It is therefore possible that the response to an R5 antagonist may be different between these two populations, even when patients from both populations are confirmed to have R5-tropic virus before initiating treatment. As such, starting exclusively in treatment-experienced patients may not predict outcome in treatment-naïve patients.
“Secondly, transmission of resistance to at least one of the currently available drugs has been reported as being from 10% – 26% in treatment-naïve patients. Furthermore, existing drugs, although life-saving for HIV patients, are not ideal in their toleration profile….Therefore, new mechanisms without cross resistance and with different (better) toleration profiles are needed for treatment naive patients. The most appropriate place for CCR5 antagonists may well be in the treatment naive population.”
However, ECAB’s Nikos Dedes counters that “the development of new ARV drug classes is essential to treat experienced patients in need of effective salvage regimens. But in the case of naïve patients, new drug classes are less urgent given the number of effective treatment options available.” The EATG strongly feels that “pressure and requests for the fast development of investigational compounds in the name of patients with no options or other competitive considerations cannot justify putting naïve patients’ health at unnecessary risk.”
The maraviroc trial in treatment-naïve individuals is currently enrolling, or has approval to start, in Australia, Belgium, Canada, Italy, Mexico, Netherlands, Switzerland, the United Kingdom and the United States, but not currently in France, Germany or Spain, where state regulatory authorities have taken ECAB’s concerns seriously. Applications are pending in several other countries.
The May issue of NAM’s newsletter, AIDS Treatment Update, will examine the issues surrounding the CCR5 antagonist controversy in more detail. AIDS Treatment Update is available free* to individuals affected by HIV. Professionals and voluntar
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