CORVID-19

Pandemic Fears: What the AIDS Battle Should Teach Us About COVID-19

By ANISH KOKA, MD

As the globe faces a novel, highly transmissible, lethal virus, I am most struck by a medicine cabinet that is embarrassingly empty for doctors in this battle.  This means much of the debate centers on mitigation of spread of the virus.  Tempers flare over discussions on travel bans, social distancing, and self quarantines, yet the inescapable fact remains that the medical community can do little more than support the varying fractions of patients who progress from mild to severe and life threatening disease.  This isn’t meant to minimize the massive efforts brought to bear to keep patients alive by health care workers but those massive efforts to support failing organs in the severely ill are in large part because we lack any effective therapy to combat the virus.  It is akin to taking care of patients with bacterial infections in an era before antibiotics, or HIV/AIDS in an era before anti-retroviral therapy.  

It should be a familiar feeling for at least one of the leading physicians charged with managing the current crisis – Dr. Anthony Fauci.  Dr. Fauci started as an immunologist at the NIH in the 1960s and quickly made breakthroughs in previously fatal diseases marked by an overactive immune response.  Strange reports of a new disease that was sweeping through the gay community in the early 1980’s caused him to shift focus to join the great battle against the AIDS epidemic. 

The first reported cases of AIDS were reported in the United States in the 1981 Morbidity and Mortality Weekly Report.  5 young men, all previously healthy and all active homosexuals were found to have Pneumocystis carinii pneumonia, a disease that prior had been restricted to the severely immunocompromised.  An avalanche of clinical reports subsequently woke the nation to a disease that appeared to have a predilection for the gay community.  The remarkable subsequent successes of medical therapies that followed to make AIDS a manageable disease to grow old with are now a matter of history, but in the early years this success seemed anything but inevitable.

The charge leveled against the establishment of the day by a public becoming aware of the tragedy of young, previously healthy individuals dying by the thousands was that there was an attempted cover up of a ‘dirty’ disease in a community America would rather not talk about.  But from the first description of the disease by the medical community, the activity in the research industry (both public and private) was intense.  It took 2 years for two labs to simultaneously identify the HIV virus that appeared responsible for the development of AIDS.  Elaborating the mechanism by which the virus destroyed the body’s immune system lead to the discovery of potential therapies. 

The first drug therapy with the most promise was AZT, or azidothymidine.  Remarkably this wasn’t a drug that was developed from scratch, it had been developed in the 1960’s by a US researcher to battle cancer.  The drug failed in mice and was set aside.  The problem with the drug wasn’t that it was ineffective, but that it was a solution without a problem. The drug was targeted to retroviruses that affected humans, but at the time of its development, there were no important retroviruses infecting humans.

The HIV virus turned out to be the problem AZT had been in search of.  HIV’s genetic information lives in a single strand of RNA that requires an enzyme called reverse trancriptase to transform into a double stranded DNA which then integrates into the host cell.  AZT is a thymidine analogue that works by selectively inhibiting the reverse transcriptase enzyme.  The company that had AZT, Burroughs-Wellcome, used the agent successfully in an animal model of a retrovirus surrogate, but that was not a specific model for HIV infection.  Fortuitously, the National Cancer Institute (NCI) had a model of immune cells (CD4) that they had developed to use as an antiviral assay for potential HIV therapies.  AZT was one of a promising group of drugs Burroughs-Wellcome sent to the NCI. The in-vitro results were impressive.  The HIV virus was unable to infect the CD4 cells in the presence of AZT.

The year was 1985.  It had taken four years since the first clinical report of the disease by the CDC to find a promising drug.  The time was intense.  There were 20,000 reported cases, and as many as a million people believed infected but asymptomatic.  Doctors were helpless, serving as witnesses to the eventual progression to death, rather than agents that could alter the the natural history of the disease. 

AIDS hospices were set up.  It was a terrible time, encapsulated by a haunting picture taken of AIDS activist David Kirby as he lay near death, cradled in his father’s arms.  It turns out that diagnosing a disease with no cure is its own desperate malady. 

Identifying a drug that works in a lab was progress, but at the time, the FDA’s usual timeline for a drug to be judged safe and effective enough to be used in patients was 8-10 years.  Under intense pressure, the FDA fast-tracked everything. A phase 1 trial where the drug was injected into healthy volunteers to test for safety suggested symptoms at high doses, but a tolerable safety profile.  The next step mandated by the FDA was a double blind randomized control trial in patients with AIDS.  This meant half of the patients in the trial would get a placebo drug, while the other half would get AZT.  The trial was terminated early when 19 patients died in the placebo arm, but only 1 died in the AZT arm.  The study was published in the New England Journal of Medicine in 1987, six years after the first clinical report of AIDS, and rapidly approved by the FDA panel in the same year.

The trial was criticized for its early termination, and the entire fast-track process was challenged by skeptics who felt the FDA shouldn’t have bent to the wishes of activists.

Fauci was asked about pressure from activists and responded positively.

No, actually it is difficult to say what was the right or wrong thing to do. It was a situation where there was only one drug available–it was not like trying out one amongst many antibiotics–and the activist community and the constituents were suffering. They demanded that they have access to anything that could give them even a little hope. Pressure was put on the FDA. They responded appropriately for rapid expedited approval of AZT, making drugs available that normally would not have been available for years and years.”

He went on to note that the British were able to complete a long term 3 year study of AZT that could never have been completed in the United States that showed no long term benefit.  Apparently AZT blessed patients with a brief reprieve, not a long term cure.  The investigators at the time had no way of knowing that the HIV virus mutated in response to the initial single agent therapy and eventually became resistant to the drug.  The initial doses used were also very high, and caused patients a number of well described side effects. Investigators since have learned to use lower doses of the drug to avoid the toxicities that plagued patients in the early years. 

Many in the scientific community were upset with the early approval of AZT, and prominent critics emerged comparing the drug to aspirin, as well as alleging financial interest in the drug approval.  The activists in the United States that pressured the scientific community were eventually proven right. The desperation of the dying patients in the early years is well represented in the movie starring Matthew McConaughey – The Dallas Buyers Club.  Unwilling to be randomized to the placebo arm of the AZT trial, the character played by McConaughey flees to Mexico, only to be prescribed a cocktail of vitamins by an unlicensed expatriate US doctor.  The movie butchers the actual history by constructing the well-worn conspiracy narrative of a pharmaceutical company terminating a trial early to foist a dangerous drug (AZT) onto the public.  What’s correct is that the community wanted hope in the form of some drug, and every day that a therapy was delayed was paid in lives lost.  Ultimately the public pressure to get AZT out into the community was the right decision.  A longer trial may very well have been negative, and subsequent non-approval may very well have confined the use of the drug to Mexican black market clinics and unlicensed doctors until the biology of the virus was better understood.  There would have been no winners in that scenario.

There are important lessons to heed as the global biotech community races to cure doctors of their impotence when faced with a patient dying of the COVID-19 virus.  Once a drug proves promising in-vitro, the same FDA will stand guard.  Randomized control trials are planned to test these drugs for efficacy against the novel coronavirus.  The emergency will certainly lubricate the timeline of approval  just as it did with the AIDS epidemic, but a great deal of caution is to be advised in designing and interpreting trials where the patients range from mild symptoms with recovery with no intervention, to severely ill in intensive care units. Use a novel therapy too late, and a drug effective when used earlier may look ineffective.  Used too early in the process, and any positive effect may be washed away by the mild natural history of the disease in most.

Part of the discomfort for the medical community lies in an aversion to dead ends in these battles.  But as any detailed analysis of medical progress will clarify – the forward march of science is messy.  Thalidomide, the drug responsible for the FDA as we now know it, eventually found use in patients with multiple myeloma.

The current approach is also paternalistic to the extreme.  Patients dying of their disease may choose to enter a randomized control trial where they have a 50% chance of being placed on a “sugar pill”.  But I question the ethics of denying patients an active drug unless they choose to enter this flip-of-a-coin lottery.  As Fauci himself noted, the AIDS fight taught the NIH the importance of working with the community.

“When the gay activists were demonstrating, predominantly against the FDA but also against the NIH, and being very strident in their criticism, I challenged them. I said, “Okay, come on in, sit down, and let’s talk about it. What is it that you want?” That was when we developed relationships with them that are now very productive. We have activists who are important members of our advisory councils. We consult back and forth with them all the time. AIDS changed the way we do business at NIH in that, when appropriate, the constituencies play a major role in some of the policy and decision-making processes. You cannot just cave in and let people tell you how to do science the wrong way, but there is a lot you can learn from understanding how the disease is affecting a particular population, somewhat removed from the bench, and removed from the “ivory towers” that we have here.”

Science turns out to be an imperfect war waged with many casualties.  Patients aren’t soldiers to be conscripted into this war.  If people are to die, they deserve agency if they are to be part of the scientific enterprise. Patients and their doctors deserve the right to choose paths that end up being dead ends.  Our job as doctors shouldn’t be to lean into the dichotomonia of positive and negative randomized control trials that frequently guides FDA approval. The AIDS struggle shows the chinks in the armor of the regulatory framework that keeps us safe, but in doing so risks keeping us from effective therapies.  While it shouldn’t take grave threats of the scale of AIDS and COVID19 to lower barriers to treatments, it would be stupidity on the scale of the current pandemic to not adapt regulatory barriers to the problems faced.

What the world needs months ago is a therapy for patients stricken with COVID19.  This would completely alter the public health response.  No need to self quarantine, little need to test the mildly symptomatic since most get better, and cruises would become great again.  A COVID-19 illness would prompt the same response as someone found to be actively ill with tuberculosis – not fun for close contacts, but no chance 16 million people would wake up in Italy to a quarantine.

The story of AIDS is a story of human ingenuity that should inspire hope for the COVID-19 pandemic.  Effective therapies will take time. Patients will die, but the deaths will not be in vain. Skeptics will rightly cast doubt on claims of success. They will be right most of the time. Regulatory frameworks will be appropriately challenged by the desperate. Conflicts of interest will be raised to question data.  The process will be messy and documented in a hypercritical manner by the Monday-morning journalists of the day. It will seem hopeless. But we will prevail despite the long odds because in the end, it will be those that remember the patients at the center of the storm that will show us the way forward.

It is always darkest just before the dawn.

Anish Koka is a cardiologist in practice in Philadelphia. He can be reached on Twitter @anish_koka

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