12/1/17: WORLD AIDS DAY: RECALLING THE CRISIS NEARLY 40 YEARS AGO: Deaths Due to Opportunistic Pneumonia

AIDS

 

 

 

 

 

The AIDS epidemic, which so baffled, horrified, and traumatized people in its emergence, is far from over. Last year, 1 million people died worldwide from AIDS-related illnesses—nearly a third from tuberculosis—according to the Joint United Nations Programme on HIV/AIDS; and 1.8 million became newly infected with the Human Immunodeficiency Virus (HIV).

In 2016, 36.7 million people worldwide were living with the virus that causes AIDS.

The good news in this long-running health crisis is that antiretroviral therapy exists to treat, and to prolong the lives of, people infected with HIV. As of June 2017, 20.9 million people living with HIV were accessing this therapy—an increase from 17.1 million in 2015 and 7.7 million in 2010. The combination-drug therapy prevents the virus from replicating or making copies of itself, but it doesn’t eliminate HIV.

I well remember the emergence of AIDS: Like millions of others, I avidly read newspaper articles about the mysterious disease that was killing young people, eagerly awaiting news of breakthroughs about its cause and treatment.

I also talked with my father, who, during the early stage of the epidemic, became president of the Merrell Dow Research Institute and, as such, responsible for Merrell Dow’s research worldwide. (Merrell Dow came about when Dow Chemical acquired a controlling interest in the pharmaceuticals division of Richardson-Merrell Inc. (RMI), my father’s then-employer. Dad didn’t want to work for Dow, but he was offered authority he couldn’t refuse.)

The following is an edited excerpt from my book, “Starting With Serotonin: How a High-Rolling Father of Drug Discovery Repeatedly Beat the Odds” about the early years of the AIDS epidemic and the role my father played. As usual I omit the endnotes and highlight my father’s comments in italics. (The book may be purchased on Amazon or at improbablebooks.com/purchases.html.)

The excerpt, which I present in two parts because of its length, provides insight into how Big Pharma can operate when the need for life-saving treatment is acute. It also illustrates (in tomorrow’s installment) how the associative mind of a physician-scientist intent on discovering new therapeutic drugs works. In neither case is money the object.

***

It was in 1978 that physicians at several hospitals in New York City and Los Angeles first noticed an unusual number of previously healthy, young adults suffering from Pneumocystis (P.) carinii pneumonia (PCP). PCP is a life-threatening “opportunistic” lung infection, which means it is caused by a pathogen that takes advantage of conditions in the human body that are not normally present.

PCP occurs almost exclusively in people with preexisting immunosuppressive disorders: It exploits weakened immune systems.

As the PCP cases accumulated, medical authorities discerned that, rather than being anomalous, these patients actually had a new disease, one that decimated their bodies and killed them within months or, at most, a year or two.

Epidemiologically identified as young men who were homosexuals, bisexuals, or parenteral drug abusers, the patients also often had an “unusually aggressive and multifocal form” of Kaposi’s sarcoma, which is a cancer that produces purplish skin blemishes.  Three years after the initial reports, the U.S. Centers for Disease Control in Atlanta officially alerted physicians to a new syndrome of “Kaposi’s sarcoma and Pneumocystis pneumonia among homosexual men.”

Although suspected of being a fungus [which it is], P. carinii was then considered a protozoan. It is ubiquitous in human beings, but it only triggers disease in susceptible people. Originally described in malnourished children in orphanages, then in patients with neoplastic disease and organ transplants, P. carinii pneumonia is characterized by a fever, a dry cough, weight loss, progressive dyspnea (difficulty in breathing), tachypnea (rapid breathing), and, ultimately, respiratory failure.

In 1982, the new sarcoma-PCP syndrome received its name: Acquired Immunodeficiency Syndrome. Two years later, scientists identified its cause as an emergent retrovirus, the Human Immunodeficiency Virus. HIV is an enveloped (coated) retrovirus, which loosely means that it contains RNA and is re-created by the enzyme, reverse transcriptase. [The antiretroviral drugs inhibit the enzyme.]

***

Early in the AIDS epidemic, PCP afflicted about 60 percent of all patients and was the most common cause of their deaths.

 [These patients] lacked resistance, said Sjoerdsma. They would get all kinds of secondary infections, like candidiasis in their mouths and throats, what you call thrush.

Pentamidine, long used to treat African trypanosomiasis (sleeping sickness), was the first drug used effectively against PCP. Unfortunately, it also induced allergic or toxic responses in half of all patients treated, AIDS and non-AIDS patients, alike.

Subsequently, the antibacterial combination product, trimethoprim-sulfamethoxazole (TMP-SMX), developed by the legendary George Hitchings at Burroughs Wellcome, provided relief to non-AIDS patients, but it produced toxicity in half of all AIDS patients treated. The latter experienced fever, hypersensitivity rashes, hepatitis, and life-threatening leukopenia. (Longtime BW director Hitchings was a prolific drug inventor, with whom my father, who called him “an irascible guy,” clashed. Hitchings definitely was not generous in sharing credit for drug breakthroughs with those who deserved credit.)

These patients were being treated with this combination treatment of Hitchings’s: TMP-SMX. It’s called Bactrim® [a Roche product] or Septra®  [Burroughs Wellcome]. That would work in this PCP, but a lot of AIDS patients would get a reaction to the sulfa. . . . We thought at that time it was conceivable that the PCP organism was a protozoan type of infection. We had nothing more to go on than that.

Molecular parasitologist Daniel V. Santi, of the University of California-San Francisco, approached Sjoerdsma about trying DFMO, a celebrated antiprotozoan compound that my father had developed while employed by RMI, in emergency AIDS cases, and he readily agreed to a trial.

Between July 1983 and July 1984, nine AIDS patients with severe P. carinii pneumonia, whom UC-SF doctors had evaluated as being unresponsive or intolerant to both TMP-SMX and pentamidine and as having a survival expectancy of at least two weeks, received experimental DFMO from Sjoerdsma’s operation.

After just one day of treatment, two of the subjects stopped all supportive measures and died within 72 hours; a third elected to resume pentamidine therapy and experienced a slow and incomplete recovery. Of the remaining six, all finished six to eight weeks of DFMO therapy with favorable results. The drug cleared their lung infection.

***

The outcome with the first patient was auspicious.

Patient No. 1, a 34-year-old gay man, entered the hospital after two weeks of progressive dyspnea and a non-productive cough. Upon physical examination, doctors detected mucosal candidiasis in his mouth and throat; and a chest X-ray showed bilateral “infiltrates,” shadows in his lungs that indicated infection. A transbronchial biopsy confirmed P. carinii pneumonia.

Patient No. 1 underwent the standard breathing/oxygen tests and lung scans and initially received TMP-SMX. After nine days on the sulfa drug, however, he developed a diffuse erythematous (red and inflamed) rash and became febrile, and his doctors switched him to pentamidine. Pentamidine cleared the infiltrates some, and both the man’s rash and fever diminished, but on Day 7, his temperature spiked, and another X-ray revealed a spread of infection. The man’s arterial blood gas values worsened—meaning his oxygen content and pressure declined—and on Day 8, a bronchoscopy showed a persistent pneumonia.

Patient No. 1’s treating physician, Dr. Jeffrey A. Golden, reinstituted TMP-SMX therapy, which precipitated an immediate drop in the man’s blood pressure. Golden only had one option left: DFMO.

After four days of taking Sjoerdsma’s DFMO, which was known as the Resurrection Drug, because of the miraculous effect it had on patients dying of West African trypanosomiasis, Patient No. 1 was breathing much easier, and his temperature was normal. Within a week, a marked improvement appeared in both his chest pictures and his arterial blood gas values. On Day 11, he checked out of the hospital. After 30 days, Patient No. 1 remained free of dyspnea, on exertion, and had a normal chest X-ray. All other scans and tests were negative, and a biopsy showed no evidence of PCP. After seven weeks, he arbitrarily decided to terminate treatment.

The sad footnote to Patient No. 1’s story is that, a year later, he entered a community hospital with fulminant P. carinii pneumonia, rapidly deteriorated, and died.

PCP infections commonly recurred in AIDS patients. Because of the man’s stunning recovery in the UC-SF study, however, physicians treating near-dead PCP-stricken AIDS patients began to appeal to Sjoerdsma for a supply of DFMO on a “compassionate” basis.

They had low oxygen saturations. They were ready to go. We’d get these frantic calls: “Could you send us some?”

Again, Sjoerdsma responded without hesitation, asking John L.R. Barlow, Merrell Dow director of clinical research, to set up an open emergency protocol. Barlow advised all physicians who contacted him to apply a six-week IV-oral DFMO regimen. After observing a favorable response in 70 percent of the first 53 patients, 12 of whom had been on ventilator support, he pronounced DFMO an “acceptable effective therapy” for AIDS-associated P. carinii pneumonia.

We took people whose physicians thought they were going to die. Many of them had gotten the sulfa drug treatment and gotten untoward reactions. We started treating them when they were desperate cases, and our endpoint was, did they leave the hospital alive or not? . . . I saw some of these patients. They were really pathetic. Just skeletonized. There was nothing you could do. They just died. . . . Discharge was our endpoint, and we got fairly impressive results.

Paul Schechter, a clinical pharmacologist who worked under Sjoerdsma, also treated African AIDS patients with DFMO, but to no avail.

“To make a long story short,” Schechter said, “PCP doesn’t exist in Africa. In the United States, it was responsible for most deaths in early AIDS. In Africa, it was cryptococcosis it was not PCP.” Cryptococcosis  is a systemic fungus infection also known as Busse-Buschke disease.

I continue and finish this excerpt tomorrow. Please check back. Thank you.

Ann, 12/1/17

 

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