By any immunology standards, scientists at the University of California San Francisco (UCSF) are embarking on a complicated research project—a $1 million study of organ transplants in HIV-infected patients. “Since the advent of highly active anti-retroviral therapy (HAART) for HIV infection about three years ago, patients' life expectancy has increased, leaving them susceptible to death from non-HIV-related causes, including end stage organ disease,” says project leader Peter Stock, explaining why transplants for such patients have become more feasible.

The study marks a resurgence of interest in organ transplants for HIV-infected patients, which were attempted in the 1980s but were discontinued after it became clear that patients with HIV had poorer chances of survival than did non-infected persons. Although it remains to be demonstrated conclusively, this no longer seems to be the case. Stock says that UCSF plans five transplants over the next six months, and adds that his program is moving faster than expected because of a strong response from the patient community.

Six HIV-infected patients have already received kidney transplants since 1997 at the Starzl Center in Pittsburgh, according to chief of transplantation surgery John Fung, and other centers that have expressed interest in resuming organ transplants for this population group include Mount Sinai in New York and the University of Maryland.

The immunological complexity of the experimental situation is clear in the different views held by specialists involved. John Fung notes that drugs like tacrolimus and cyclosporine, used to prevent graft rejection, will also affect the immune systems of HIV-positive patients, as they inhibit T-cell activation, the process that drives cells from a resting to a mitotic state, when they are susceptible to virus-mediated killing. “The idea that some of these drugs may help the immune system, even though they suppress it, sounds contradictory, but at a theoretical level there might be a benefit,” Fung says.

However, Mike McCune, who will examine the immunological data from the UCSF study, admits that ideas like this are controversial. Although he does expect that “the transplanted organs will confer benefit,” he has no expectation that the immunosuppression will ameliorate the HIV-related disease.

The study plans to examine new drug interactions in light of the altered pharmacological environment in which today's HIV patients live. Patients in the UCSF study will be on cyclosporine augmented by steroids to suppress graft rejection, plus stable HAART regimens to keep their HIV in check. These drugs interact with both the cytochrome p450 system and the P-glycoprotein multidrug efflux pump, located in the liver and gut. “We expect that the immunosuppressant will affect plasma concentrations of the anti-retrovirals, but it is also likely that the protease inhibitor and non-nucleoside anti-retrovirals will affect metabolizing enzymes and transport proteins in such a way as to increase the levels of cyclosporine as well,” says Leslie Floren, who is in charge of pharmacology for the study.

The National Institutes of Health has taken an active interest in the trials. According to Bill Duncan, associate director of the National Institute of Allergic and Infectious Disease (NIAID), who has organized meetings on the topic over the last six months, “a feeling of consensus has grown up that the various transplant centers can share data [and work together]”.

The investigators hope that by establishing proof of the principle that liver and kidney transplantation is appropriate for HIV-positive patients, they will be able to persuade insurers to pay for the procedures. “HIV is a contraindication for transplantation in most Medicare and Medicaid programs. But that's based on very old literature, and we are trying to show that you can get a transplant and be on antiviral programs and still have a pretty good outcome,” says Fung.

In other clinical trials news…

The National Institutes of Health has launched a new clinical trials database aimed at the general public carrying information on over 4,000 federal and private medical studies at more than 47,000 locations nationwide. ClinicalTrials.gov provides information on the location of trials, their design and purpose, criteria for participation, and some disease and treatment information. The data-base is available at http://clinicaltrials.gov/.