Clinical Researcher—October 2023 (Volume 37, Issue 5)

PEER REVIEWED

Kurt Wolfe, MCR, CCRC

 

 

 

New clinical treatments for diseases are conceived in a laboratory, then tested on animals or through simulations, and finally studied on human beings if deemed promising enough. Moving from point to point in this cycle is rarely a straight line, and costly and time-consuming trial-and- error efforts may be the key strategy for pushing a treatment forward.

This methodology is still the case for the majority of clinical research in today’s environment and, traditionally, studies have been designed without direct input from patient populations. This is becoming less common as researchers recognize that excluding patients from the process of creating effective treatments can lead to misinformation regarding new treatments, risks to generalizability, stigma toward those who are sick, and, overall, less effective treatments.{1} The U.S. Food and Drug Administration (FDA) currently mandates the inclusion of patient voices in study development; however, much earlier during the HIV/AIDS crisis, patient advocacy groups had an effective impact on new drug development and disease burden.{2}

The HIV/AIDS crisis in the United States and throughout the world devastated the gay and queer community and changed the world’s perspective on how clinical research is performed. A historical review of those who experienced the crisis from the beginning and what changes resulted from those events can provide valuable information for how the field of clinical research may continue to evolve. This four-decade retrospective will tell the story of how the HIV/AIDS crisis changed the process of how clinical research can be performed and, most importantly, how patients and patient advocates were able to make those changes to the system “from the outside in.”

Background

During the 1970s and early 1980s, the world of clinical research was adjusting from a recent period of major change following World War II. New regulatory efforts such as the Declaration of Helsinki and the Belmont Report shifted the focus of clinical studies onto prioritizing the safety and well-being of research participants. Placebo-controlled, double-blind, randomized clinical trials were determined to be the gold standard for evaluating the legitimacy of any new medical treatment; however, there were still those critics who questioned the ethics and practicality of denying some study participants a potentially beneficial treatment via placebo.{3,4} These questions, which were typically only debated by physicians and bioethical philosophers, would soon be topics of great concern to the general population.

Even prior to the beginning of the AIDS epidemic in 1981, gay and queer civil rights advocates also joined in with this sentiment of scrutinizing previously established clinical processes. Advocates had spent the better part of the 1950s and 1960s petitioning the medical community to continue research into health concerns related to gay and queer individuals, as well as delisting homosexuality as a “Sociopathic Mental Disturbance” in the Diagnostic and Statistical Manual of Mental Disorders.

The Mattachine Society of Washington D.C. was one such advocacy group that openly organized small demonstrations to challenge the federal government’s employment restrictions for homosexuals, which was a decision based in part on homosexuality being medically considered an illness.{5} This categorization would be removed in 1973 after years of research proved that there was not a significant medical difference between the heterosexual and homosexual populations.{6}

Despite these victories, homosexual men (and LGBTQ+ people in general) were still seen as deviant and even dangerous to many in the American public eye, which would lead them to be particularly vulnerable not only to physical harm from AIDS, but to social and political harm as well.

Part 1: The 1980s AIDS Epidemic

The epidemic moved quickly in June of 1981, as reports to the Centers for Disease Control (CDC) of various opportunistic infections among homosexual men began to increase throughout the United States. Conditions that were often linked to weakened immune systems, such as Kaposi’s sarcoma and Pneumocystis carinii pneumonia were suddenly being seen in an alarming number of previously healthy patients.{4} About a month after the initial reports to the CDC, news organizations began reporting this new “gay cancer.”{7} After hundreds of reported cases within this first year, the name of the condition would change to Gay-Related Immune Deficiency before the CDC eventually settled on Acquired Immune Deficiency Syndrome (AIDS) at the end of 1982.{8}

This decade was one of extreme fear in the U.S., as there were many questions associated with AIDS, such as what caused the condition and how was it spread. This anxiety pushed for a sharp increase in AIDS-related research advocacy from both the medical community and through community grassroots efforts.{9}

One grassroots example took place in 1983 with the publication of a booklet titled How to Have Sex in an Epidemic: One Approach by Richard Berkowitz and Michael Callen. This manual was independently printed and distributed in New York City by Berkowitz and Callen, under the medical advice of Dr. Joseph Sonnabend, as a way to help dispel misconceptions regarding the transmission of AIDS within the queer community. While at the time of publication there was no official medical consensus on the mechanisms of how AIDS was contracted, what was clear to the authors was that the known risk factors associated with AIDS transmission needed to be categorized in a digestible and comprehensive format.

At this stage of the epidemic, neither the medical community nor the federal government had been able to engage in such a clear method of scientific communication with the affected population.{10} Ground-level engagement like this would become the bedrock for federal AIDS prevention initiatives within the next several years, and these programs would help kick-start a community-based approach not just to local public health, but global health as well.{11}

By the mid-1980s, the Human Immunodeficiency Virus (HIV) had been discovered as the culprit that caused an infected individual’s immune system to decline to AIDS.{12} Clinical trials looking to find a treatment for HIV/AIDS began around this time, and among the first notable agents explored was an unsuccessful anticancer drug called zidovudine (AZT). AZT is part of a drug class known as antiretroviral therapy (ART) that prevents HIV from replicating within the infected patient. With ART keeping the virus from overwhelming the body, the immune system is able to recover and remain healthier for longer, reducing the chance that the patient will develop full-blown AIDS. Although AZT was associated with bone marrow toxicity, headaches, nausea, and insomnia, early results were promising at reducing the progression of the disease.{4,13,14}

At this point in the epidemic, there had not been any sort of recognized treatment for AIDS, so when word of the potential aid AZT could provide arrived, the desperate public put an enormous amount of pressure on pharmaceutical governing bodies to get it into the hands of as many patients as possible. The FDA’s regulations over Investigational New Drug (IND) applications made getting this potentially valuable new drug into pharmacies extremely difficult, as unapproved drugs can only be administered on a case-by-case basis after all other treatments have been exhausted. These restrictions prevented the patients who were dying of AIDS from grasping their one lifeline, and this sparked a movement from AIDS advocacy groups to turn their resources toward the FDA.

Efforts made by advocacy groups such as the AIDS Coalition to Unleash Power (ACT-UP) were a major force behind shining a public light on the clinical research process and how more patient-focused rules for how INDs are approved could save the lives of desperate patients. Public outcry and protests brought the concerns of these patients straight to the FDA’s doorstep and, through their knowledge of clinical research processes, advocates helped propose a new pathway to allow unapproved INDs to be received by a broader population. This pathway was known as the “parallel track,” which essentially allowed for unapproved, but potentially helpful, medications to skip Phase III testing and be given to patients in an extensive post-market (Phase IV) surveillance phase.

While controversial at first, the AIDS Clinical Trials Group as well as the National Institute of Allergy and Infectious Diseases, Division of AIDS led by Dr. Anthony Fauci, ultimately concurred that unapproved drugs of this kind could be given to those who needed them without sacrificing patient safety or the legitimacy of ongoing trials.{4,15} This represented a major turning point not just in the history of the AIDS epidemic, but in the field of clinical research, as the scientific community was made to reflect on its practices as a result of direct community involvement. Despite the advancements being made not just in research, but in the clinical processes for HIV/AIDS, by the end of the 1980s there were more than 100,000 reported cases of AIDS in the U.S. alone and a pervasive culture of stigma toward the disease.{4,16}

Part II: The 1990s

The HIV/AIDS epidemic had affected vast swaths of American culture—from famous musicians, artists, and performers, to regular people just trying to live their lives.{17–19} Pharmaceutical companies were scrambling to launch as many different INDs as possible to meet the demand for a variety of treatment options. After a slow start, the Reagan administration’s response to the crisis had finally begun to establish programs to provide needed aid to patients.{20}

The 1990s continued to see steady activism centered on the rights and protections of those affected by the epidemic, and the successful adoption of the parallel track process helped bolster additional changes to the clinical research field. The National Institutes of Health (NIH) established the Office of AIDS Research to further the country’s efforts to provide new HIV/AIDS treatments and prevention methods, while activists continuously pressured the government to allocate the appropriate funds needed to quell the ongoing crisis. Their efforts resulted in the amount of federal dollars dedicated to ending the epidemic nearly quadrupling by the end of the decade.{21}

ACT-UP proponents were very active during this time, famously holding a highly publicized demonstration in New York City’s Grand Central Terminal at rush hour holding signs with messages such as “One AIDS death every 8 minutes” and “Money for AIDS, not for war” (in reference to the U.S. prioritizing tax-payer dollars for the Gulf War in Iraq and Operation Desert Storm). Another notable demonstration was at the home of U.S. Senator Jesse Helms, where activists wrapped his Virginia residence in a 15-foot condom to protest his anti-HIV funding voting record.{22}

Research activists also began to shift their focus to populations still being left out of HIV/AIDS treatment groups. In the previous decade, the most visible and outspoken activist voices were usually white, middle-class, gay men, which left little room for groups of those who were equally affected by the epidemic, such as ethnic minorities, women, and hemophiliacs. The early research also reflected this white, middle-class, gay male majority as they were often seen to be the best fit for clinical trial participation over other groups.

People assigned female at birth with HIV/AIDS in particular had difficulty accessing inclusion into clinical trials, as studies at that time were very unwilling to test on anyone who could possibly become pregnant.{23} ACT-UP helped lead the charge in criticizing government-funded research efforts when it came to the inclusion of women and other underrepresented populations, as well as the International Community for Women Living with HIV (ICW), which focused on prioritizing women’s inclusion not just in the U.S., but across the globe.{24,25}

The number of potential treatment options expanded during this decade and these were being tested in the same way AZT was in the late 1980s. Unfortunately, as more patients began taking ARTs, scientists started to observe viral mutations that resulted in antiretroviral resistances.{13,14} This prompted research into combination therapies, as single-agent regimens were not creating enough impact to prevent the virus from replicating.

Researchers found that utilizing combined regimens with AZT and medications such as dideoxycytidine and Lamivudine resulted in more favorable outcomes than AZT alone. Other effective medications that emerged around this time included nevirapine and didanosine.{13,26} Highly active antiretroviral (HAART) medications also became a standard treatment.{26} The number of reported U.S. cases in this decade would peak at around 400,000 before beginning to decline going into the turn of the century.{27}

 Part III: The 2000s to Today

As the new millennium began, the Clinton administration issued a strong federal response to the still ongoing HIV/AIDS epidemic as a threat not just to national security, but also to global safety.{28} In 2002, the United Nations established a Global Fund to aid countries that were working to reduce their HIV infection rates. Eight of the world’s largest economies released a combined statement regarding the international need for investment in HIV/AIDS funding and resources.{29}

As HIV/AIDS became more widely recognized as a global issue, activists pushed for better access to prevention and treatments for middle to lower income countries that wealthier countries already had. The 21st century saw the networks and alliances created in the previous decades flourish into a robust global health community that utilized patient-centered approaches to treat HIV/AIDS and other infectious agents.{11}

With these treatment advancements, the stigmas associated with being HIV+ had lessened, but were not entirely gone. Many U.S. lawmakers still felt that certain policies should be in place for HIV+ patients in the name of protecting public health. Several U.S. states criminalize not disclosing and infected person’s status to sexual partners. Critics have responded that criminalizing HIV+ individuals in this way can have unforeseen negative consequences, as this sort of policy incentivizes people with HIV to forgo testing and remain unaware of their status to prevent being accused of knowingly spreading the infection. Health experts have found laws of this kind are counterproductive to reducing the number of new infections and discourage participation in new clinical trials.{30}

This first decade of the 2000s saw continued advancement in HIV treatments and prevention. While HAARTs were thought to be the best way forward in the previous decade, the patient burden of multi-pill, high-toxicity, high-drug interaction regimens made properly adhering to these treatments extremely challenging. Focus instead shifted to single-dose, one-pill-a-day combination ART that could reduce viral loads and increase medication adherence. The success of combination ART therapies led to the approval of the first once-a-day, single tablet regimen in 2006.{26}

HIV prevention for men who have sex with men also took a giant leap forward with the approval of the first daily, oral, pre-exposure prophylaxis (PrEP) medications, Truvada and Descovy in 2012 and 2016, respectively, along with a monthly injectable called Cabotegravir in 2021.{31}

Conclusion

Across the world, patients with HIV have access to affordable medications that not only allow them to live long and happy lives, but also prevent the infection from being spread. New incidences of HIV in the U.S. have dropped to around 35,000 cases per year in since the 2010s.{32}

The current HIV treatment philosophy of undetectable equals untransmittable (U=U) focuses on reducing the body’s viral load of HIV+ patients to a point where it is virtually undetectable, which significantly reduces the virus’s ability to spread through sex.{33} These treatments were only possible through the hard work and dedication of activists who were able to affect huge change in a complicated system that has lasted even to today.

This article was submitted as a graduation requirement for the Master of Clinical Research program at the Ohio State University College of Nursing.

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Kurt Wolfe, MCR, CCRC, (kurt.wolfe@osumc.edu) is a Clinical Research Coordinator at The Ohio State University Wexner Medical Center.