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DRUG THERAPY Failure of HIV Therapy Pits Researchers vs. Drug MakerPharmaceutical companies often sponsor independent clinical trials by academic researchers to add credibility to claims they make about their products. But when the results are unfavorable, researchers may find themselves at odds with their sponsors. A group from HSPH, led by Stephen Lagakos, the Henry Pickering Walcott professor of biostatistics and head of the department, and James Kahn of the University of California, San Francisco, have reported the results of a large-scale clinical trial of a potential HIV therapy, a trial that found no discernible benefit in its primary measure of efficacy. The research team has published the results in the Nov. 1 JAMA despite attempts by the company sponsoring the study to block publication and withhold data.
Stephen Lagakos and HSPH team members Heather Gorski and Deborah Weng Cherng (not pictured) found that their analysis of data on HIV-1 Immunogen put them at odds with their sponsor. The trial tested a drug called HIV-1 Immunogen, or Remune, a therapeutic vaccine designed to boost immune responses in patients infected with HIV. It is a disabled form of HIV that produces viral antigens but cannot cause infection. The trial terminated early, failing to find any clinical benefit in the compound. Antiretroviral therapy, a series of drugs designed to attack HIV's progression, has made it possible to extend the lives of patients by reducing overall viral load to manageable levels. But the drugs are expensive and have toxic side effects, and there has been only limited success in crippling the virus enough to let patients get off the drugs once they start. Researchers are looking for ways to reduce the time patients must take the drugs and find ways to increase their efficacy and cost-effectiveness by combining them with other strategies. HIV-1 Immunogen was originally designed by Jonas Salk as a way to boost the body's immune system. Although the drug is not potent enough to work as a vaccine against the virus, it was hoped that it could complement other therapies and help shift the reliance away from antiviral agents. Exposing the body to HIV proteins, especially early in infection, might give the immune system a head start in combating the virus. Some initial studies suggested that the therapy could elicit immune responses, but there was no clear evidence of clinical effect. The double-blind, randomized, placebo-controlled trial looked at a large population of HIV-infected patients, most of whom also received antiretroviral therapy. The patients varied in viral load but none had developed major symptoms or conditions associated with AIDS. The primary clinical measure was disease progression or death, and the secondary factors measured were the amount of virus in the blood, numbers and percentages of CD4+ T cells, and body weight. About three years after the trial was initiated, an independent Data Safety and Monitoring Board following the study recommended that it be terminated seven months early. They found no indication that the therapy was providing a clinical benefit and, Lagakos said, "it was highly unlikely that if we were to continue this study, anything would change." There were no statistically significant differences between the Remune and placebo groups in terms of mortality, viral load, percent of CD4+ T cells, or body weight. There was a small but statistically significant difference favoring Remune in terms of absolute number of CD4+ T cells. Because it is designed to expose the immune system to viral antigens, the drug was expected by some to have a better effect in patients with better immune function, and further studies may support that potential role. However, this trial found that a group of patients with undetectable viral loads at the study's start—those considered most likely to benefit—did not show an improvement. Lagakos said it was at this point that differences emerged between investigators and their sponsor over interpretation of the data. Months went by, and the sponsor had refused to release final data about the patients to the researchers unless they agreed to include the company's own analysis in the publication of the study's findings. It also demanded to be able to approve any publications. Lagakos and his colleague James Kahn of UCSF decided to move ahead with publication despite the company's efforts to block it with legal action. Relationship TherapyJAMA has used the paper, in conjunction with a study on conflict of interest policies at research universities, to question whether science and industry really can work together. Lagakos does not believe that this case should be viewed as a sign that industry-sponsored clinical trials do not work. "I've had numerous interactions with pharmaceutical companies, and until now they've been very positive," he said.Although the companies themselves may have a conflict of interest, he said, it is in their interest to have their products evaluated by an unbiased group in order to appear more credible. "The perception is generally going to be better if a study is conducted by an independent group of investigators." Lagakos said this particular case is an aberration, but it does raise serious issues about the withholding of information. "Patients and doctors really should have the facts in front of them," he said. This study deals a blow to Remune as a potential immune stimulator, but the drug still may prove valuable in other studies and under different conditions. Immune modulators are difficult to predict because of the complexity of the immune response, and researchers are looking for alternative ways to use Remune as a way to reconstitute the immune system in conjunction with other therapies. Lagakos also emphasizes that the study should not reflect poorly on other immunologic strategies currently being investigated. The prospect of using therapeutic vaccines for HIV has been gaining ground, especially as the possibility of finding a preventative vaccine or any resounding cure remains distant. Norman Letvin, HMS professor of medicine, who has been working on therapeutic HIV vaccines, said that HIV-1 Immunogen may not be effective as a vaccine strategy because it does not specifically target the killer T cells that researchers believe are crucial to fighting HIV. —Courtney Humphries |
