As Cure Search Intensifies, Questions Arise
By Rowena Johnston, Ph.D.
May 19, 2011— As HIV/AIDS researchers intensify their search for a cure and begin trials to test the most promising new interventions in HIV-positive patients, questions abound about how best to approach these trials. What are the best non-human models for determining whether an intervention may work in people? How can researchers ensure that human trials are conducted ethically? And what are the best ways to measure the impact of these interventions? These and other questions were discussed at a workshop on cure-related clinical research in Baltimore, April 20–21, organized by amfAR, the Treatment Action Group, Project Inform, and the AIDS Policy Project.
Models for Testing Possible Cures
Before a cure intervention even makes it to clinical testing, it is first identified, characterized, and tested in the test tube, and often also in an animal model. One question facing researchers is which of these models best predicts clinical outcome.
Since no intervention that can be replicated has yet been shown to cure an HIV-infected person, it is difficult to know what looks promising in a test tube. Test-tube models—including one developed by amfAR Krim Fellow Alberto Bosque—involve cells that have been either taken from a patient (primary cells) or grown for many generations in lab conditions (cell lines). Primary cells more closely mimic cells that are the targets for interventions aimed at curing HIV, but they can be laborious to acquire and work with. Cell lines are readily available and easily standardized, but they can develop characteristics over time that make them less comparable to cells within a patient’s body. Even within primary cell models, several permutations have been developed by different research groups, and it is still unclear which of these models can most accurately predict an intervention’s outcome.
Within animal models there are similar uncertainties. Primates are generally considered state-of-the-art, but even these do not exactly mirror human HIV infection, and their cost is considerable. Several research groups have developed different primate models of HIV infection, but it remains unknown which of these will prove most informative in the search for a cure. Other researchers—including amfAR fellow Dr. Paul Denton—have developed mouse models of HIV infection, which have the advantage of costing significantly less than primates. But so far none has conclusively demonstrated those characteristics that currently constitute a barrier to curing human infection.
Current Clinical Trials
Clinical trials that are currently under way or about to begin are testing a wide range of strategies, from gene therapy to pharmacological and immunological approaches.
Dr. Carl June of the University of Pennsylvania described a gene therapy intervention in which immune cells known as CD4+ T cells are extracted from patients and genetically modified to delete the CCR5 protein from their surface. This renders the cells almost entirely resistant to HIV infection. Researchers then infuse the cells back into the patient in the hope that they will reproduce and replace the HIV-susceptible immune cells in the patient’s body, causing the HIV infection to die out.
On the pharmacological front, Dr. Steven Deeks from the University of California at San Francisco described a clinical trial that has emerged from the amfAR Research Consortium on HIV Eradication (ARCHE). Another ARCHE researcher, Dr. Robert Siliciano, had previously identified disulfiram—a drug used to treat alcoholism—as a potential means of flushing HIV out of infected cells, where it could then be targeted by antiretroviral therapy. The two researchers teamed up to launch a small clinical trial in January and are now receiving funding through ARCHE.
Finally, Dr. Rob Murphy of Northwestern University described the ERAMUNE trials, which are testing two different immune interventions. In Europe, patients will receive the immune hormone IL-7, while those in the U.S. will get a DNA vaccine. In each case, researchers are hoping that boosting or supplementing immune function will help to clear persistent virus from infected patients.
The Ethics of Cure Research
Dr. Bernard Lo of the University of California at San Francisco outlined some of the ethical questions raised by cure-directed trial interventions. One of them concerns the standard practice in any clinical trial of paying subjects for their time and inconvenience—payments that are generally commensurate with risk. In a cure-related trial involving several procedures, these payments can add up to a substantial sum that may become a significant source of income and therefore exert undue influence on the patient’s decision to take part in the trial. Patients may also enroll in a trial to secure access to clinical care they would not otherwise receive, or because their prognosis is so dire they feel they have nothing to lose. Despite these concerns, researchers noted that it might be unfair to deny patients the opportunity to take part in a clinical trial that may benefit them or others like them.
Ensuring that the patient is giving informed consent in a cure-related trial can be challenging due to the complexities of the science involved and the difficulty of explaining it clearly and concisely. Suggestions for improving the process included face-to-face discussion of the consent form between the doctor and the prospective participant, and the development of questions to assess the patient’s comprehension of the key concepts.
Determining acceptable levels of risk is another concern. To test whether an attempt at curing HIV has succeeded, it will often be necessary to withdraw antiretroviral therapy, which can sometimes leave the patient worse off than before the trial. Patients make decisions about risks in discussions with their doctors, and standards for different trials are set by institutional review boards, as well as by the FDA. But opinions on what level of risk is acceptable vary widely, and questions persist. What if a patient is willing to assume additional risk? Should society limit individuals’ options in order to protect them?
Dr. Lo concluded that the answers to many of these conundrums are trial-specific and must be addressed during the planning phase of any trial.
Once an intervention has reached the clinical testing phase, researchers must measure what changes, if any, are occurring that may signal progress toward a cure. It is generally accepted that the viral reservoir—which consists of virus that persists despite treatment—constitutes the main barrier to curing HIV. Most researchers believe that virus within CD4+ T cells constitutes the main reservoir, but there is disagreement about the extent to which other cell types, such as macrophages or stem cells, might also play a role. Additionally, it is possible that certain anatomical sites play a more important role than others in harboring the virus.
One of the most daunting challenges is working out how best to measure the minute levels of virus present in patients who are already responding well to treatment and the tiny but potentially significant changes in virus levels as the amount of virus approaches zero. The gold standard is IUPM, or infectious units per million, a technique developed more than a decade ago by amfAR ARCHE researcher Dr. Robert Siliciano. But the procedure is so costly and time consuming that it is not practical to conduct on a widespread basis.
In spite of the challenges that lie ahead, there was a general sense of optimism among the researchers attending the workshop. The exciting progress that has been made in identifying many of the key questions surrounding a potential cure offers hope that many of these questions will be resolved in the near future. Collaborative efforts such as ARCHE are helping to find the answers.
Dr. Johnston is amfAR’s vice president and director of research.