AIDSWEEKLY Plus, Monday, 12 May 1997
Daniel J. DeNoon, Senior Editor

The use of suboptimal treatments in clinical trials is both wrong and dangerous, a leading AIDS researcher argues.

In an extraordinary article in the journal Science, Joep M.A. Lange of the University of Amsterdam blasted the short- sightedness of clinical trial planners, the self-defeating requirements of regulatory agencies, and the greed of drug companies ("Current Problems and the Future of Antiretroviral Drug Trials," Science, 1997;276:548-50).

"Suboptimal therapies are still being used," Lange wrote. "This is a severe problem that deserves far more attention and regulation than it actually gets."

Lange's argument is based on the conviction - not shared by all AIDS clinicians - that the only acceptable treatment for HIV infection (in patients physically and mentally ready for such treatment) is the use of combination regimens that maximally suppress viral burden. In today's world, this generally means the use of a protease inhibitor in combination with two reverse-transcriptase inhibitors (RTIs).

With maximal virus suppression, Lange expects to prevent or at least greatly delay the emergence of drug-resistant HIV strains. When one or more drugs in a potent combination must be changed due to intolerance, patient preference, or other reasons, a new drug can be substituted safely.

But with suboptimal virus suppression, as is seen when with sequential monotherapy, the virus achieves resistance to each of the drugs in turn. Because of cross resistance - and a limit to the number of available antiretroviral medications - such a strategy severely limits a patient's future treatment options.

Lange listed several reasons he believes account for the continuing use of suboptimal therapy.

"This may be because of economic considerations, the need to treat patients who have already undergone multiple therapies, patient intolerance of the drugs, poor compliance, or physician ineptitude, to name a few common reasons," he wrote.

But he can think of no excuse for permitting the use of suboptimal therapies in clinical trials.

"In clinical trials, the least we can do for patients who are willing to help advance knowledge is to try to treat them according to the highest current standard," Lange wrote. "Yet even today, suboptimal regimens are still being evaluated for many reasons."

He explored four of these reasons.

The first is the accidental use of suboptimal therapies in trials of drugs whose in vitro efficacy fail to translate to clinical efficacy. The famous failure of soluble recombinant CD4 stands as the most famous example.

"The risk of such accidents may be minimized by doing the appropriate groundwork," Lange suggested.

Secondly, regulatory requirements often call for monotherapy data, and for new agents to demonstrate clinical superiority over outdated standards of care.

Lange pointed to the Abbott 247 trial in which more than a thousand participants with long histories of antiretroviral drug use and low CD4 counts were randomized to receive either the protease inhibitor ritonavir or a placebo in addition to their ongoing RTI regimen. After six months, the ritonavir group had a 43 percent reduction in mortality.

"For practical reasons and from a regulatory perspective, this is the most efficient trial design, but it is also the best way to select for resistance to the invaluable protease inhibitor," Lange wrote.

"I believe that it would have been in the best interest of the patients if, instead of ritonavir being added to the drugs they were already taking, the patients had been switched to non-cross-resistant nucleoside analog RT inhibitors simultaneously with the beginning of ritonavir treatment."

Lange would permit only a brief period of monotherapy testing, as the ability of a drug to reduce viral replication is usually obvious within a few days of treatment.

He also called for universal adoption of rapid conditional approval of drugs, a policy adopted by the U.S. but not by the European Community. The financial gain from such approval could be balanced by a requirement for drug company-financed postmarketing testing.

The third reason cited by Lange for the use of suboptimal therapy in clinical trials results from trial planners "ignoring the biology of the disease."

As an example, he pointed to the Quattro trial sponsored by the U.K. Medical Research Council. This trial began in 1995 and is scheduled for completion in 1997. The trial has three arms comparing simultaneous quadruple therapy to sequential monotherapy with the same drugs and to simultaneous therapy with two of the four drugs; all treatment arms include lamivudine (3TC).

At the start of the trial, it had already been demonstrated that HIV rapidly develops resistance to 3TC and to the non-nucleoside RT inhibitors (NNRTIs) included in the trial when viral replication is not minimized. Moreover, previous trials had cast doubt on the efficacy of sequential therapy.

"In light of all the available data on viral dynamics, the prognostic value of viral load, resistance development, and the superiority of various triple-therapy regimens over less suppressive regimens, I am amazed at the design and continuation of such a trial," Lange wrote.

Finally, Lange blasted drug companies for restricting combination testing of promising drugs. Companies may require investigators to use other drugs of their own manufacture, or they may prohibit combination testing with specific drugs made by competitors.

"Investigators around the world are experiencing this type of restriction," Lange claimed. "Necessary trials are delayed or cannot be done because of it. There is also a tendency to rapidly and widely publicize positive data and to delay or refrain from publication of studies with a negative outcome.

"All of this is wrong and disgraceful and is not in the long-term interests of the pharmaceutical companies themselves. ... Burning up therapeutic options prematurely is not only very cynical, but in the end, self defeating."

Lange called for anti-trust-like legislation to prohibit clinical trials from the exclusive use of "incestuous" drug combinations. He also called for regulatory agencies and medical journals to require publication of all relevant data.

What can clinical trials do if they can use only maximally suppressive therapies? Lange supplied a list of avenues for investigation:

* How durable and robust are the antiviral effects of various regimens that maximally suppress HIV?

* Can the regimens affect virus sanctuaries such as the central nervous system and long-lived cells?

* What are the regimens' toxicities in the short and long terms?

* How do regimens compare in terms of patient compliance, quality of life, and cost efficiency?

* What level of immune reconstitution can be seen with each regimen, and can immune-based therapies improve these regimens?

* Do various regimens that maximally suppress HIV differ in terms of clinical endpoints and survival?

* Can prophylaxis against opportunistic infections eventually be withdrawn, and if so, when?

"In my view, now that adequate monitoring tools are available, 'strategic trials' to answer questions such as when to start, when to change, and when to stop are obsolete," Lange wrote. "Except for long-term nonprogressors, who are exceedingly rare, from a medical perspective there is no good reason not to start antiretroviral therapy as soon as the HIV infected patient is mentally ready for it."

In an accompanying article, Science writer Jon Cohen reported on conversations with a number of AIDS workers regarding Lange's arguments ("AIDS Trials Ethics Questioned," Science, 1997;276:520-3).

"The biology is really screaming at us to get everyone to undetectable levels [of HIV], but there is more to medicine than biology," Michael Saag of the University of Alabama, Birmingham, told Cohen.

Saag has recommended initiation of a clinical trial to test "strategic timing of antiretroviral therapy (START)." The START strategy would give patients a list of treatment options, and would switch regimens when viral load increased beyond a set point.

Such a trial would necessarily be long and complex; the AIDS Clinical Trials Groups (ACTG) recently rejected Saag's plan. According to Cohen, the ACTG instead will attempt to achieve similar results by meta-analysis of all relevant data from its clinical trials.

Robin Weiss of Chester Beatty Laboratories, London, U.K., defended the Quattro trial design that Lange so bitterly condemned. He admitted to Cohen that combination therapy yields a greater initial decline in viral load, but he said that the long-term efficacy of this approach was questionable.

"It is pure speculation whether a year later or two years later these patients [who receive aggressive combination therapy] are going to have a lower [HIV] load than those patients given drugs sequentially," Cohen quoted Weiss as saying. "It's just a rationale, and it's turning into a dogma. Quattro might give answers."

Robert Yarchoan of the National Cancer Institute also spoke to Cohen; he has long been involved in the design of AIDS clinical trials.

"If you really take a hard line and say everyone should be on triple therapy and drive the virus down to zero and everything else is amoral, then you get into a situation of how do you test new drugs," Cohen quoted Yarchoan. "I don't have the answer."

But Yarchoan agreed with Lange that the U.S. Food and Drug Administration must reexamine rules that lead drug companies to test their new agents against the worst existing therapy.

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