This article is more than 5 years old. Information may no longer be current.
‘Appropriate eligibility criteria’ must guide selection of HIV-positive individuals for cancer trials
An estimated 36 million people worldwide are living with HIV.
Advances in HIV treatments have resulted in these individuals living longer than they did decades ago; however, they are now at increased risk for other diseases.
Cancer is now the leading cause of death among those with HIV in the United States.
However, patients with HIV often are excluded from cancer clinical trials because of concerns about treatment interactions. Thus, data on the use of newer cancer treatments for these patients are limited, prompting experts to call for increased inclusion of patients with HIV in more cancer clinical trials.
“Otherwise healthy patients with HIV need to be included in more cancer clinical trials in order to inform the development of treatments for these patients,” Thomas S. Uldrick, MD, MS, deputy head of global oncology and associate member of the vaccine and infectious disease division at Fred Hutchinson Cancer Research Center, told HemOnc Today. “Historically, there were concerns over interactions between HIV drugs and cancer drugs, but this was during the time when a lot of the cancer medications were combination regimens and the HIV therapies were extremely toxic. The pharmacology of treatments has changed over the years and this is no longer valid.”
HemOnc Today spoke with Uldrick and Elad Sharon, MD, MPH, medical officer at NCI, about how individuals with HIV traditionally have been excluded from cancer trials, why exclusion criteria may not be warranted, the need for more data from the subgroup of patients with cancer who also have HIV, and the studies underway that are intended to meet this need.
Question: Can you provide some context for why individuals with HIV traditionally have been excluded from cancer trials?
Sharon: This has been a real problem. Some time ago, the NIH recognized this as an issue and began pushing both investigators and our pharmaceutical industry collaborators to try to include patients with HIV in clinical trials. A lot of what has occurred in the past in terms of excluding patients with HIV is more or less focused on a distorted perception of what HIV care is today. HIV care has been revolutionized within the past decade.
Q: Why are exclusion criteria not warranted for these individuals?
Sharon: With highly active antiretroviral therapy (HAART), HIV can be a chronic condition for many patients. It is unfortunate that, for many individuals, this chronic disease is unfairly stigmatized and patients are excluded from trials in the way that other chronic diseases — such as diabetes and heart disease — are not. We have a situation in which this viral infection — which can be controlled very well in the United States with appropriate access to care — unfortunately continues to face such barriers. Many investigators express concern about the potential for drug-to-drug interactions between HIV medications and cancer therapies. However, this should not only be a concern for HIV, it should also be a concern for people with diabetes and hypertension or any chronic condition that requires medical therapy. Many oncologists are simply unaware that there are now dozens of possible regimens for HIV. If infectious disease physicians need to change a patient’s HAART regimen to let a patient go on trial or receive an anticancer therapy, that is not a major problem. In fact, in the real world, it happens all of the time. The other issue seems to be around the idea that HIV-positive patients have inadequate immunity. If their HIV is not controlled, that is certainly true, but HIV-positive patients under good control respond to vaccines and other therapies. There is certainly no reason to think that someone on HAART with a high CD4 count is immunologically deficient.
Uldrick: Historically, people with HIV did not have good options and would die of HIV complications. At the same time, cancer has always been a major manifestation of HIV — largely lymphomas and Kaposi sarcoma. As the treatments for HIV have progressed, it has become easier to treat people with HIV. However, the culture of how we conduct clinical trials has not changed from the era in which we did not have effective HIV medication. The Modernization of Eligibility Criteria project looked at this from a scientific perspective and attempted to figure out what the clinical trial eligibility criteria for HIV patients should be. Much like patients with diabetes or heart disease, we need to simply choose the people who are healthy enough from the perspective of that disease to participate in a cancer study. For the Modernization of Eligibility Criteria project, we tried to come up with criteria to destigmatize HIV and to choose the patients who are healthy enough to participate in a cancer study. We came up with criteria related to opportunistic infections, excluding specific drugs rather than excluding HIV treatment overall.
Q: Can you explain the need for more data from the subgroup of patients with cancer who also have HIV?
Sharon: The FDA has made it clear that, because we have such effective therapies available for many of these patients, there is not as much opportunity to see if we can push the envelope further in terms of treating — or even curing — HIV. One unique advantage in conducting cancer trials for HIV specifically is that we may be able to give agents other than HAART that can further diminish the viral loads of HIV. This certainly is of interest in cancer therapies, such as immunotherapies, where there could be potential for blocking the mechanisms by which the HIV virus escapes immune protection, which deals with issues of latent HIV reservoirs that are inaccessible otherwise. These are the types of things that we can do with HIV-specific cancer trials. On the other hand, when we exclude these patients from trials, we learn nothing. Investigators who ignore HIV-positive patients condemn them to receive second-class therapy.
Uldrick: When looking at past hospital-based and epidemiology-based studies that assessed cancer outcomes among people with HIV, a lot of times people with HIV have done worse than the general population of patients with cancer. There are potentially various reasons for this. Sometimes they do worse because of comorbidities. I think that, for a lot of people, this has been an issue, but there are other provider-based issues and treatment-based issues that weigh into this. It really becomes a matter of treating oncologists being comfortable with managing an HIV patient and developing evidence to support their comfort level. In some cases, there are true drug-to-drug interactions that need to be taken into consideration and it is helpful to sort those out in the perspective of a clinical study.
Q: How many NCI studies are underway on this topic?
Sharon: I am a part of the NCI’s Cancer Therapy Evaluation Program and we are the principal U.S. government sponsor of cancer-related clinical trials in the United States. We have about 900 clinical trials that are underway, and we have been trying to include more patients with HIV in clinical trials for the past 2 decades. What we usually do to include HIV-positive patients on most of our trials is implement criteria so that, if a patient happens to have a high enough CD4 count and an undetectable viral load, they can be enrolled on our sponsored clinical trials as long as the patients are not at some other increased risk due to HIV. One trial we are actively recruiting for is the CITN-12 trial. We have not completed all of the cohorts just yet, and we are expanding the study further to look specifically at Kaposi sarcoma patients. We also have a trial with nivolumab (Opdivo, Bristol-Myers Squibb) and ipilimumab (Yervoy, Bristol-Myers Squibb) through our AIDS Malignancies Consortium. There is ongoing work in the NCI’s HIV and AIDS Malignancies Branch in the NCI intramural program under the leadership of Robert Yarchoan, MD. Our goal is to highlight to the investigator community that HIV-positive patients are a subgroup of individuals that should be allowed on trials, especially trials that include immune checkpoint inhibitors given the preliminary results that we saw with CITN-12. There does not appear to be any justification to exclude HIV patients from trials.
Q: What prompted CITN-12?
Uldrick: This research was prompted by my interest as an intramural investigator at the NCI in immune-based mechanisms of carcinogenesis in people with HIV. We know that some cancers are specifically caused by viruses, but there have also been data suggesting that PD-L1 was significantly dysregulated in people with HIV. So, as a scientific question, I was interested in PD-L1 dysregulation as something that may lead to carcinogenesis, but also something that could be targetable and potentially more useful in people with HIV than the general population. The cancers that I was thinking about at the time were Hodgkin lymphoma and lung cancer, and these still remain areas of intense investigation. However, in CITN-12, our next step will be to look specifically at patients with Kaposi sarcoma. We do want to note that, after the initial 17 patients were enrolled in CITN-12, and while still enrolling, we did have one death in a Kaposi sarcoma patient. This death was not due to HIV, but the Kaposi sarcoma herpes virus. Our next step is to assess immunotherapy in patients with Kaposi sarcoma with eligibility criteria that excludes people with evidence of Castleman’s disease.
Q: Can you talk a little about the CITN-12 study protocol?
Uldrick: CITN-12 is a phase 1 study examining the effects of pembrolizumab for patients with HIV and malignant neoplasms that have relapsed, are refractory or have disseminated. Monoclonal antibodies, such as pembrolizumab (Keytruda, Merck), may block tumor or cancer growth in different ways by targeting certain cells. It may also help the immune system kill cancer cells. This was a safety study meant to establish that immunotherapy is safe in people with HIV. This is not to be conflicted with the separate issue of people with HIV generally being excluded from cancer trials. This is a parallel issue, but we decided to look at this across a range of immune dysregulation in people with HIV. This is generally looked at based upon CD4 count. We designed this safety study to look at the use of standard dose pembrolizumab across a range of CD4 counts in people with HIV, and there was a parallel interest in looking at the effect on HIV itself. In going through this process, I learned how important this study was. It actually was one of the first studies to actually look at checkpoint inhibitors in people with HIV as a proof-of-concept that this can actually be done, and that people with HIV can and should be included in these types of studies. Results of the first 17 patients showed that there were no safety signals beyond those seen in studies outside of HIV. The CITN-12 study is a good demonstration of what can be done when using appropriate eligibility criteria to inform patient selection.
Q: Is there anything else that you would like to mention ?
Uldrick: As we see the field of immunotherapy study growing, we see that there are mechanisms of resistance that need to be addressed, especially in solid tumors. In a rapidly changing field such as this, we hope that the CITN-12 study will provide evidence to allow other investigators to include HIV-positive patients in their studies and we, the CITN-12 study group, will continue to focus in the short term on the Kaposi sarcoma cohort. This is a proof of concept that people with HIV who have CD4 counts as low as 100 can be safely treated with checkpoint inhibitors in diseases for which checkpoint inhibitors are already FDA approved. For the growing field of clinical research in immunotherapy, appropriate selection of HIV-positive patients is quite feasible and appropriately selected HIV-positive patients should be included in studies, especially for agents that are under development. It is also important to mention that, when we designed CITN-12, it was not for all HIV-positive patients, but we selected patients who were healthy from the perspective of their HIV, just as any cancer study does for patients with malignancies. – by Jennifer Southall
For more information:
Elad Sharon, MD, can be reached at National Cancer Institute, 9609 Medical Center Drive, MSC 9739, Bethesda, MD 20892; email: sharone@mail.nih.gov.
Thomas Uldrick, MD, can be reached at Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. North, Seattle, WA 98109; email: tuldrick@fredhutch.org.
Disclosures: Sharon and Uldrick report no relevant financial disclosures.