A year ago, my longtime friend Jeremy Tjhung, a talented creative director who a few years ago moved back to his native Rochester, New York, after decades in New York City, was diagnosed with non-Hodgkin’s lymphoma (NHL). It’s a cancer that often hits people with weakened immune systems, and before the advent of effective HIV meds in the mid- to late 1990s, it was, along with Kaposi’s sarcoma, the most common cancer in people with HIV, a community that includes both Jeremy and me. Since the advent of effective meds, NHL rates in people with HIV have plunged, and treatment outcomes have improved even when it occurs, although NHL is still one of the most common cancers in HIV-positive folks.
Working with his oncologist, Patrick Reagan, M.D., at Wilmot Cancer Institute in Rochester, Jeremy started treatment immediately after diagnosis, a very traditional cancer “cocktail” regimen called R-CHOP. The cancer receded, but it came back after treatment. He did another cocktail called RICE. The cancer still persisted. In December, he got a T-cell transplant called CAR T, which has only been on the market since 2017. It worked, until it didn’t.
“At that point, I really realized that I was up against a very aggressive disease that even the best of modern science didn’t seem to be keeping under control,” said Jeremy. “My treatment options going forward were going to be limited, and I had to start weighing them carefully.”
In March of this year, he started yet another treatment, called pola+BR, a chemoimmunotherapy combo treatment that the U.S. Food and Drug Administration (FDA) approved in 2019. “It’s called salvage treatment,” he said, using the term for treatment options pulled out when several others fail. He’s on this new treatment until July to see if it works. After that, he said, “There’s still the possibility of a stem-cell transplant, but they have to suppress the cancer to a reasonable level first.”
Of course, there’s always clinical trials, where people can gain access to developing therapies that are not yet on the market. There’s just one catch: Jeremy’s doctor said that his HIV status precludes him from participating in most clinical trials, even though his HIV is well controlled.
“With all the innovation happening right now in cancer treatment, to have a relic of 1980s AIDS-phobic policy be driving scientific decisions makes no sense to me,” he said. “It just seems really outrageously unfair.”
Outmoded Restrictions Are Hurting Folks With HIV Who Have Cancer
Even though 25 years have passed since the approval of effective and simple HIV therapies that have extended the lives and increased the health profiles of people living with HIV, we’re still being excluded from potentially lifesaving cancer trials. It’s especially concerning given that, despite these advancements, people with HIV are still at higher risk for many cancers than the overall population.
Prompted by Jeremy, I dug in. First, I reached out to Palm Springs, California, advocate Jeff Taylor, an HIV and cancer long-term survivor who heads the HIV + Aging Project. I asked: Was Jeremy’s doctor’s concerning forecast on trials true? Short answer: Yep.
“The exclusion of people living with HIV (PLH) in cancer trials is a vexing problem that won’t go away,” Taylor wrote me back. “The National Cancer Institute [NCI, within the federal National Institutes of Health (NIH)] recommends against it, as does the FDA.” In fact, in 2019, the FDA issued new guidance urging drugmakers to loosen restrictions in their cancer trials against not only people with HIV but those with other conditions, including hepatitis B or C or prior or additional cancer or organ problems.
But, according to Taylor, the perception that people with HIV could complicate results often keeps them out of trials. Negative side effects experienced by people with HIV would have to go on a drug label after it’s approved, so they’re excluded.
“And despite their own guidances to the contrary, the FDA can’t/won’t require that companies stop excluding PLH from their registrational trials,” Taylor wrote. “The NCI could do the same, limiting access to drugs in their CTEP program [which oversees drug trials] unless they allow enrollment of PLH.”
“In the meantime,” Taylor wrote of my friend Jeremy, “if he’s got an oncologist who’s willing to go to bat for him, he could challenge the companies excluding PLH from their trials to provide their scientific rationale for doing so. It used to be concerns about drug-drug interactions—but that was almost always with [older-line HIV regimens with] protease inhibitors, and the new integrase-based regimens don’t have any interactions, to my knowledge.”
I had to go deeper into why the exclusions persisted. With the help of Taylor and fellow longtime HIV activist Lynda Dee in Baltimore, I was put in touch with Bob Yarchoan, M.D., who heads the HIV and Malignancy Branch of the NCI.
“It’s a constant battle,” Yarchoan said, to get drugmakers to open up their cancer drug trials to people with HIV, “despite a real effort.” He noted that most trials cosponsored by NCI admit people with HIV with CD4 counts over 350, which is fairly common in people on HIV meds.
Four or five years ago, he told me, CTEP did an analysis of trials, finding that policies on inclusion of people with HIV were “all over the place.” He said the CTEP researchers made an effort to go into each of the studies and that they need to up their game when it comes to including people with HIV.
“They recommended that people with HIV should be included unless there was a reason to exclude,” he said. One reason could be a presumed interaction between the study drug and certain HIV meds. Of course, he added, “The companies would come up with a variety of reasons to exclude.”
And Yarchoan echoed Taylor, saying that drug companies are terrified of side effects in drug trials because they can sink approval of a new drug. Drugmakers, he said, want to get populations for their studies that are likely to tolerate the new drug—and they worry that trial outcomes in people with HIV will make a drug look bad.
Additionally, he said, many Pharma researchers are older folks who remember a darker era of AIDS, when people with the disease didn’t tolerate cancer drugs well at all.
“Sometimes, early impressions really stay with people,” he said.
Ariela Noy, M.D., an oncologist who specializes in lymphomas and AIDS-related cancers at New York City’s Memorial Sloan Kettering Cancer Center, said that the exclusion of people living with HIV continues to be frustrating.
“I am constantly sitting in meetings saying, ‘Um, is there a good reason why people with HIV are excluded from this trial?’ And they say, ‘No, but the manufacturer wanted it that way,’ and I say, ‘That’s not a good reason—we should push back.’”
Moreover, she said, research shows that HIV-negative cancer patients often have CD4 counts that are lower than 350, which is usually the required minimum in the rare cases where people with HIV are allowed into cancer trials. “Why are we asking people with HIV to jump through hoops that other cancer patients don’t have to? It’s biological racism,” she said—particularly because people with HIV tend to be disproportionately Black and Brown and/or LGBTQ.
Some Progress, but Not Enough
Despite a gloomy general picture, “I don’t know if the situation is quite as bleak as [some] say,” said Yarchoan, noting that in the past decade—particularly since an influential paper coauthored in 2008 by Rich Little, M.D., another NCI honcho—some drugmakers have been allowing folks with well-managed HIV into some trials.
But how many? On the positive side, one study published last year and coauthored by Little found that among trials for a certain kind of cancer therapy that has emerged in the past decade called immune checkpoint blockade (ICB), the percentage of studies that included people with HIV went from a mere 16% to 70% after CTEP urged them to do so. This suggests that intense advocacy around this issue yields results.
But very likely not enough yet. Another study last year found that of about 1,000 cancer trials listed on clinicaltrials.gov, the national clearinghouse for medical studies, nearly 73% excluded people with HIV categorically, while only about 7% of trials allowed people with HIV if they met such criteria as having undetectable HIV and a minimum CD4 count. By cancer type, rates of HIV exclusion ranged from 60.9% for kidney cancer and 85.7% for cervical cancer (far more common in women with HIV than women in general) to 85.2% for cancers (such as NHL) affecting the blood, bone marrow, and lymph nodes.
I decided to do an informal investigation of my own. In mid-March, using clinicaltrials.gov, I searched currently or imminently enrolling trials for treatments for four cancers common in people with HIV—NHL, anal, cervical, and lung—sponsored by five big cancer drugmakers: Merck, Bristol Myers Squibb (BMS), AstraZeneca, AbbVie, and Bayer. I wanted to determine which trials categorically excluded people with HIV, which allowed people with HIV under certain conditions, and which presumably allowed people with HIV unconditionally because there was no mention of “HIV” or “human immunodeficiency virus,” my search terms, in the trial protocol. (Keeping in mind, of course, that trials have discretion to exclude individuals for reasons not outlined in the protocol.)
It’s important to note that trial protocols describe HIV differently. With that in mind, I considered the exclusion of “active HIV infection” to be an across-the-board exclusion, but considered such terms as “uncontrolled” or “unmanaged” HIV to be a conditional exclusion.
For Merck, I found that 4 of 7 NHL trials, 1 of 2 anal cancer trials, 13 of 16 cervical cancer trials, and 37 of 53 lung cancer trials seemed to categorically exclude people with HIV.
For BMS, 11 of 14 NHL trials, 0 of 5 anal cancer trials, 6 of 10 cervical cancer trials, and 13 of 30 lung cancer trials categorically excluded people with HIV.
For AstraZeneca, 3 of 6 NHL trials, no anal cancer trials, 3 of 5 cervical cancer trials, and 26 of 49 lung cancer trials excluded people with HIV.
For AbbVie, 2 of 5 NHL trials and 2 of 11 lung cancer trials excluded people with HIV. (I found no trials for anal or cervical cancer.)
For Bayer, 2 of 4 NHL trials and 1 of 3 lung cancer trials excluded people with HIV. (I found no trials for anal or cervical cancer.)
I then reached out multiple times via email and phone to these five drug companies, asking them to tell me, if not their exclusion reasons for every single trial, then at least their overall thinking about why they exclude when they do. I also asked if internal conversations about loosening exclusions on people with HIV had occurred in recent years, and if they could give me any sense of what percentage of current trials excluded PWH versus, say, five or 10 years ago—as well as if they had set any targets for lowering exclusion rates in the years ahead. I was looking for as much specificity as possible.
I was disappointed.
AbbVie and AstraZeneca never replied. Merck, BMS, and Bayer wrote back thoughtful replies saying that broadening trial access to people with HIV (and other conditions), when it appeared safe, was top of mind for them—and that, yes, they were aware of the 2019 FDA guidance and other professional papers urging them to do so—but giving no exact metrics about how much they had done so in recent years or aimed to do so in coming years.
On March 26, Merck replied:
As a company focused on oncology and infectious diseases, we remain deeply driven to make a positive impact for people living with HIV. We applaud the FDA for its thoughtful recommendations regarding the inclusion of people living with HIV in cancer clinical trials. The guidance is in line with how we have been approaching our oncology clinical trials and our teams have already factored the FDA’s guidance into our planning.
Our top priority is the safety of the people enrolled in Merck oncology clinical trials and we carefully review inclusion and exclusion criteria on an ongoing basis. The inclusion of people living with HIV in our clinical trials has been thoughtfully considered by our early-stage and late-stage oncology clinical research teams. Broadening the inclusion criteria, where it is supported from a safety perspective, is top of mind, and we have been able to do so in many cases after evaluating additional safety data.
We’ve made important strides in updating our protocol templates, and most of our early-stage studies already allow for inclusion of people living with HIV. We are in the midst of re-evaluating our current eligibility criteria with respect to people living with HIV in our late-stage studies. The majority of Merck’s late-stage clinical trials evaluate KEYTRUDA, an anti-PD-1 therapy, either as a single agent or in combination with other cancer therapies. KEYTRUDA is an immunotherapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells and was first approved in the U.S. in 2014. During early development, there were unknowns about the potential impact of inhibiting the PD-1 axis in individuals with T-cell dysfunction and patients with chronic viral infections. In order to generate additional data evaluating the safety of KEYTRUDA in patients living with HIV, we provided study drug to a trial started in February 2016 by the NIH (NCT02595866). Initial results of this ongoing trial have been presented.
We are continuing to evaluate this area and will plan to thoughtfully broaden our inclusion criteria for people living with HIV when the science affirms that it is safe to do so. Beyond the inclusion and exclusion criteria, we recognize there is more work to be done, particularly in the United States, to create equitable access to our clinical trials, and we are pursuing new ways to recruit and engage a diverse population of clinical trial participants. As a company committed to delivering breakthrough innovations that extend and improve the lives of people with cancer, we recognize that enrolling diverse populations in our clinical programs is critically important to ensuring the thorough evaluation of the safety and efficacy of our medicines.
On March 26, BMS replied:
Early immuno-oncology related clinical trials have historically excluded HIV-positive individuals due to potential safety concerns and uncertainties regarding patients with possible compromised immune systems. However, with more experience, evolving data, a better understanding of HIV and a desire to be more inclusive, starting in late 2020 Bristol Myers Squibb made modifications to HIV-related study inclusion criteria based on recent FDA guidance in an effort to expand enrollment of HIV-positive patients in our oncology trials. As a result, immuno-oncology studies under Bristol Myers Squibb are becoming increasingly more inclusive for people living with HIV. These modifications are also expected to be explored in studies for patients with hematological malignancies as well.
Additionally, cell therapy specific cancer trials have historically excluded HIV-positive individuals due to safety concerns over HIV-associated immunosuppression and CAR T cell function. However, as the field continues to evolve, along with our understanding of the potential to utilize CAR T safely in individuals with HIV, we are hopeful that future cell therapy cancer trials may also become more inclusive for people living with HIV.
On March 26, Bayer replied:
Bayer is committed to the goal of ensuring our clinical trials are inclusive and represent the diversity required to best ensure all patients’ needs are addressed. To accomplish this, we work continuously with clinicians, research scientists, vendors, and partners in patient engagement to ensure that our purpose of “Science for a Better Life” touches every life, regardless of race, sex/gender, ethnicity, age or any other characteristic that may present a barrier to clinical trial participation.
Bayer does not routinely test for HIV to exclude patients from oncology clinical trials. Where risks are not well characterized, particularly in cases in which the mechanisms of action and/or combinations and drug interactions may not be fully elucidated, exclusion of patients with known HIV and other conditions are considered on a protocol-by-protocol basis depending on the specific agent.
Importantly, Bayer is committed to expanding eligibility of our trials and is looking at multiple groups traditionally excluded from trials with the goal of being more inclusive than has been possible in the past. Such groups include not only people living with HIV, but also patients with brain metastases, male breast cancer patients in BRCA studies, and other groups.
So What’s Next for This Issue?
Thankfully, the HIV community is not the only one trying to get drugmakers to open up their cancer trials to people with HIV and other chronic conditions; groups such as Friends of Cancer Research and the American Society of Clinical Oncology (ASCO) are also chipping away.
And chipping away sounds like the right way to put it. “We’ve learned over the years we’ve had to work hard to get some of our industry [drugmaker] partners to agree to this, and that’s putting it mildly,” Little said on a call with me. “More than half of trials are completely industry-sponsored,” with no government co-sponsorship to lean on the drugmakers about this issue, “and they can do whatever they want.”
Noy agreed, saying that at Memorial Sloan Kettering, she and colleagues are working on small trials of cancer therapies specifically in people with HIV to show that such inclusions are safe, would not mess up drugmakers’ data, and would hopefully show effectiveness outcomes comparable to those of cancer patients without HIV. She urges patients with HIV and lymphomas (and their oncologists) who think they might benefit from such trials to reach out to her.
As for Little, he and colleagues are submitting yet another abstract about the issue to an upcoming ASCO conference, updating the situation since 2018. “But even when you have people like us who recognize the importance of doing this, it’s going to be a long-term process,” he said. “The culture of designing trials has been a cut-and-paste job for decades, and getting [eligibility] right for specific studies needs to be reprioritized by people who write and review the protocols.”
One thing that could help? More activism on this from people living with HIV and other chronic illnesses who either have been or may someday be excluded from potentially lifesaving trials.
“There’s not a hugely loud, strong community voice on cancer clinical trials, like there is with HIV in general,” said Tom Uldrick, M.D., M.S., who heads the global oncology program at Fred Hutch, a major cancer research center in Seattle, and who has coauthored many papers on this topic with Little and others. “Many [cancer] doctors are still under the impression that all trials exclude people with HIV and may not be referring people adequately to existing studies.”
Noy said that the issue really needs someone famous or powerful with both HIV and cancer to come forward and talk publicly about being excluded from trials. “I hate to say that, because I don’t wish that on anyone,” she said, “but it’s true.”
What Happens Now for Those Who Are Affected?
As for right now, As for right now, if you have a patient or client living with HIV who is facing a need for cancer drug trials, it’s important to let oncologists know that HIV exclusion in cancer trials is far from universal, even if still prevalent, and to have them dig hard into trial protocols to read the HIV fine print. If they’re really at a loss, they can also reach out to some of the key experts like Little, Uldrick, and Noy.
The above-mentioned Friends of Cancer Research is also a good resource.
“It’s really hard to figure out exactly the right trials that include people with HIV,” said Noy, “so make sure your oncologist calls someone whose clinical expertise is in this area.”
As for my friend Jeremy, I’m glad that his sparking me to work on this story ended up getting him looped in with some of the docs mentioned here, so that if indeed he does need to go into clinical trials in the months ahead, he and his oncologist will be connected to the full range of options—of which, it turns out, there are several that allow people with HIV, partly because NHL is such an HIV-associated cancer.
“I feel like I’ve entered the second trimester of this journey,” says Jeremy. “We’ve exhausted some options and are considering others. I’ve come to realize this can be a multiyear journey. In my first year, I was super-compliant and did whatever the doctors said. But now the term ‘living with cancer’ is a lot more meaningful, and my eye is much more on the horizon.”