30 Years Later: Lessons from Living in a Pandemic

In 1985, in the midst of the budding tragedy that would rapidly morph into the full-blown acquired immunodeficiency syndrome (AIDS) pandemic, Dr. Hiroaki Mitsuya et al reported on the in vitro activity of zidovudine, better known as azidothymidine  or AZT, in the Proceedings of the National Academy of Sciences and thus, heralded the advent of antiretroviral therapy.  When given as monotherapy, AZT lacked durable efficacy, required multiple doses a day, was associated with a multitude of adverse effects; and soon after its introduction, the emergence of AZT-resistant human immunodeficiency virus (HIV) was described.  Yet, despite these significant shortcomings, AZT still conferred a modest, but measurable degree of virologic and clinical efficacy, and afforded a modicum of hope to those infected with the virus.

Even with a cursory glance at the timeline of human development, it is readily apparent that epidemics have punctuated and have significantly  shaped that history: the Antonine Plague in ancient Rome, the Black Death of the Middle Ages, the 1918 influenza pandemic, and in our lifetime, the AIDS epidemic.  Since the initial case reports of AIDS in the early 1980s, the toll of HIV on a global scale, can be measured in millions upon millions of deaths.  Millions more remain chronically infected, and new cases, sadly, abound.  It is, fortunately, somewhat unusual to be able to observe the defining events of a pandemic’s onset and a society’s response to it.  As a medical student in the 1980s, I had the unsettling experience of bearing witness to the U.S. portion of that pandemic in a first-hand, ground-level sort of way.  Infections that would otherwise have been considered rare case reports, emerged seemingly as commonplace as the common cold.  In the absence of an appropriate immune response, opportunistic diseases that affect the lungs, brain; heart, kidneys, skin, intestines - virtually every organ system - afflicted HIV-infected patients either sequentially or simultaneously, manifesting with a corresponding broad spectrum of debilitating local or systemic pathology.  Early in the U.S. AIDS crisis, most of the attention was focused on the infected intravenous drug user and the gay male population; however, in AIDS clinics, it was undeniable that no demographic was unrepresented:  adult—child, female-male, white-non-white, conservative-liberal, gay-straight, rich-poor, believer-atheist, married-single, the convict-the innocent.  No one was spared.  For healthcare workers, accidental occupational needle sticks and blood/blood product exposure meant months of waiting and worrying as to whether that percutaneous exposure might ultimately result in an HIV seroconversion.

On an infectious disease in-patient service, ward rounds consisted primarily of visiting patient after patient infected with HIV.  Many were young individuals in their 20s to 30s, who should otherwise be at the peak of post-adolescent vigor and optimism, but instead, lay with their cachetic, skeletal frames seemingly devoid of muscle, barely covered by skin, and barely strong enough to lift a plastic cup to drink water.  Possibly blind from an AIDS-related retinopathy, overtly disfigured by mucocutaneous Kaposi’s sarcoma and molluscum contagiosum, wearing diapers as a practical, but humiliating means of addressing intractable diarrhea; all of this outright biomedical mayhem was oddly juxtaposed against the tenuous orderliness of a typical antiseptic hospital ward, further heightening the almost surreal nature of the macabre proceedings.  Despite these indignities wrought by the disease, many managed to persevere and maintain a fraction of their usual daily activities, a stark reminder of the strength of the human spirit and the will to live.  To support a life in the advanced stages of AIDS, drug regimens were so extensive that writing refill prescriptions could, by itself, represent a 10 minute exercise, and patients would joke that it might be apropos to prescribe gravy or another condiment to accompany the meal-size handfuls of pills they were required to take several times a day.

At the New England Deaconess Hospital, a tertiary care center in Boston, the infectious disease staff were reminded daily of the nearly unfathomable magnitude of the human cost of AIDS.  During the height of the deadly epidemic, an office was set aside to temporarily house the overflowing stacks of medical records of the deceased, which, in an unpremeditated way, stood like make-shift memorials to the abject suffering and grief meticulously documented within.

To address the AIDS-related chaos, health authorities, academia, and the private drug development sector mobilized their efforts to identify new antiretroviral drugs that might further improve upon the potency and durability of the seminal compound, AZT.  Other medicines in AZT’s drug class, the nucleoside analog reverse transcriptase inhibitors, were sequentially introduced from the late 1980 to mid-1990s.  The added utility of treating with combination therapy was demonstrated in the mid-1990s in clinical trials such as the AIDS Clinical Trial Group 175 Study.   New classes of antiretrovirals - non-nucleoside reverse transcriptase inhibitors, protease inhibitors, cell entry inhibitors, integrase inhibitors were subsequently introduced.  From a perspective that is now decades removed, the HIV drug development process might seem to have been indifferently routine, almost mechanical; akin to nonchalantly accepting the delivery of the next glossy issue in a years-long magazine subscription.  In fact, in the heat of the US pandemic when the virus would invariably demonstrate the ability to develop resistance to the “cutting edge” HIV drug of that early epoch, each antiretroviral therapy conference was met with nearly frantic anticipation by clinicians, patients, and their loved ones, that a new, effective compound might soon be added to the therapeutic options list.  In essence, efficient drug development became an integral part of extending patients’ lives in weeks- to months-long increments.  HIV-infected patients were, in short, trying to somehow stay alive from one drug approval to the next.

Unfortunately, despite the best of supportive care and the best efforts of the pharmaceutical industry, spurred on by infected individuals, friends, family, clinicians, and advocacy groups who exhorted the more rapid development of new HIV drugs, many succumbed to the disease mere weeks or months before a new antiretroviral drug became available.  Such a patient was PF, a talented young artist infected with a drug-resistant virus that whittled his immune cell count down to zero.  With no other active treatment options available and left with a hobbled immune response, he could not weather the onslaught of several serious opportunistic infections and died only months prior to the introduction of the highly active HIV protease inhibitors.  For years after the loss of her only son, lovingly referred by her as “my sweet child,” his grieving mother would send me Holiday cards and reminisce about her lost boy and what might have been were he able to last just a bit longer into the era of more effective antiviral treatment.  The state of HIV treatment is now, thankfully, in a much different place.  However, on a global scale, there are obvious challenges and shortcomings that yet persist.  Moreover, in addition to AIDS, the potential for a wholesale spread of other communicable diseases remains a looming risk in spite of the substantial advancements in antimicrobial drug development.  The spread of antibiotic resistance, emerging infections such as SARS, MERS, Ebola, Dengue fever, the threat of bioterrorism, and the continued toll of long-standing maladies such as malaria, cholera, tuberculosis, and childhood diarrhea are all humbling reminders that there is much more work to be done.  Also, with the approach of the one hundredth anniversary of the 1918 influenza pandemic, during which tens of millions of people died, we are reminded that the potential for the reemergence of another deadly pandemic should remain at the forefront of humanity’s collective consciousness.

How will Society face these challenges?  In addition to the mobilization of important preventive measures, education, and prudent healthcare policy, certainly, ongoing drug development will represent an important facet in the overall response; and companies such as PAREXEL, in partnership with large and small pharma will likely play a pivotal role in this effort.

It is not requisite to experience a healthcare provider’s daily struggles to manage diseases with inadequate treatment options in order to readily understand the importance of drug development.  Rather, one merely needs to cite and remember the trying personal experiences when serious ailments afflicted family and/or friends.  Prescribed treatments either helped advance recovery but, alternatively, in some cases, somehow could have been more effective or better tolerated.  Helping fill the void of the latter situation is the true mission of PAREXEL.