This week marks the 40th anniversary of the CDC's June 5, 1981, Morbidity and Mortality Weekly Report describing rare instances of immunocompromised status among 5 homosexual men in Los Angeles. The American Journal of Managed Care® spoke recently with lead author Michael Gottlieb, MD, who was the first to describe what would come to be known as HIV and AIDS.
In June of 1981, Michael Gottlieb, MD, was an assistant professor of medicine at the UCLA School of Medicine, when he and a team from the school, along with investigators from Cedars-Mt. Sinai Hospital in Los Angeles and the CDC’s Epidemiology Program Office, published a brief report in the June 5, 1981, issue of Morbidity and Mortality Weekly Report (MMWR).
This week marks the 40th anniversary of that report, which described a 5-case cluster of Pneumocystis carinii pneumonia, previously seen only in patients with known severe immunocompromised status, among homosexual men in Los Angeles. With the exception of one of the men, who had a history of Hodgkin disease, none were known to have been immunocompromised. The cause of their rapid decline would come to be known as AIDS, and the virus that causes it, HIV.
Today, Gottlieb, lead author on that first MMWR paper to identify HIV/AIDS, is a staff physician at AIDS Project Los Angeles (APLA) Health & Wellness and an associate clinical professor of medicine at the David Geffen School of Medicine at UCLA. The American Journal of Managed Care®(AJMC®) recently spoke with him to discuss the implications of his initial findings, how azidothymidine (AZT; now known as zidovudine) became an agent against this pandemic, appreciating the fear that permeated the field at that time, and vaccine and health equity, among other topics.
This interview has been edited slightly for clarity.
AJMC®: One of your principal conclusions in that first MMWR study was a possible cellular-immune dysfunction. The more extensive report months later in New England Journal of Medicine has been called one of the most prominent in the publication’s history. Did you have an indication of your findings’ implications?
GOTTLIEB: The short answer is, no. The longer answer is that what we were seeing was very different from anything I was aware of. It was very different. It was striking. And it was a distinction from previously known stuff, without being very eloquent. The demographics—5 gay men—in our experience raised the question of a sexually transmitted immune deficiency. But why? There were no known sexually transmitted immune deficiencies.
In the New England Journal of Medicine paper, we raised the possibility of cytomegalovirus, CMV, as the cause. But, of course, that was a chicken-and-egg phenomenon. The patients were excreting cytomegalovirus in their urine because they were immune deficient. So cytomegalovirus was not the cause. We did include a caveat in the discussion to the effect that there could have been some common exposure or undetected viral infection—I’d have to go back and look at it—some undetected microbial agent that could be the cause of the immune deficiency, based on the demographics.
Did I have an indication of the findings’ implications? A sexually transmitted immune deficiency would be a serious public health problem.
AJMC®: Each of the 5 men in your MMWR paper had some form of candidiasis. How important is mucosal immunity to virus prevention, particularly in someone with immunocompromised status?
GOTTLIEB: Well, it’s very important—but it's complicated. Because mucosal immunity is complicated. It involves cells, it involves barriers, it involves local cells that might be susceptible to infection. It involves the presence of antibodies at the site, humoral immunity. It’s always important, but it's virus dependent. In other words, for some viruses, just having antibody in the tissue may be sufficient to prevent infection. But that doesn't seem to be the case for HIV.
HIV has a unique way of initiating infection. The portal of entry, the cells present in the tissue, probably are important in preventing HIV infection at the site of entry. Even today, 40 years later, we're not sure what types of immunity might be necessary to induce to protect against HIV infection. And that's why we still don't have a vaccine.
But if your question pertains to COVID-19, for example, in someone who is immunocompromised, the data so far are kind of conflicting as to whether people with HIV have increased risk of contracting COVID-19. And they are somewhat conflicting with respect to the outcome. It does not appear that our patients with HIV, today at least in Western countries, have a poor prognosis with regard with regard to contracting COVID-19 and suffering serious consequences.
AJMC®: You were principal investigator of the UCLA site of the trial that first investigated AZT for use among patients with severe immune deficiency. Azidothymidine was shown effective in the lab, in that it suppressed HIV replication. Can you tell us how a failed cancer treatment become an investigative, eventually approved, agent against a virus of which little was still known at the time?
GOTTLIEB: It involved the determination to find a treatment. First, there had to be the will to look for something, and then it involved a stroke of luck. That’s really the truth.
Marty St. Clair, a scientist at then Burroughs Wellcome in Research Triangle Park, North Carolina, had an interest in retroviruses and developed a plaque assay in petri dishes with mouse leukemia cells that replicated with reverse transcriptase, the same the enzyme that’s necessary for HIV replication. If you’ll recall, in Françoise Barré-Sinoussi and Luc Montagnier’s initial paper, they show the rise of reverse transcriptase in their culture medium.
St. Clair tested numerous compounds in the library of compounds owned by Burroughs Wellcome, and one of them was AZT. As she tells it—and she’s the best one to tell it—she came to the lab, looked at all the petri plates with agar and cells suspended in them. And there were a bunch of them where there was no lysis of the cells, the cells were surviving, and in all the rest of them, the leukemia virus had chewed up the cells. And she thought she’d made a mistake and not put the chemical in that particular set of petri plates. And her colleagues came in and verified that she had, in fact, done it all correctly. And AZT had protected the cells against destruction.
It was chance that Burroughs Wellcome had acquired this compound, a thymidine analogue, which could have been predicted to inhibit reverse transcriptase. It’s the kind of compound, an antimetabolite—a thymidine analogue—that might work against reverse transcriptase. Indeed, that's what they found. And this was an important proof of principle that you could develop a drug against, or you could find a drug against, HIV.
At this time in history, there was only one antiviral drug on the market, and that was acyclovir cycle for herpes. There were a couple of other minor ones, but there was only one major one and that was acyclovir. And so Burroughs Wellcome was carving out a niche for itself as an antivirals company. And that's why they jumped into this arena.
But as you'll recall, there was no cure for the common cold at that time, and there still is no cure for the common cold. So taking on HIV, a new virus about what about which little was known, was a major challenge.
AJMC®: One reason you gave for joining APLA Health in 2019 was to address the increasing insurance-related costs (premiums, deductibles, co-pays). Costs for antiretroviral treatment (ART) average in the thousands of dollars per month. What are some ways persons living with HIV or those with a new diagnosis can overcome these prohibitive costs that may be preventing them from adhering to their current medication regimens or even initiating treatment?
GOTTLIEB: The first point I would make is that it is a bit of patchwork in the United States, state by state, with respect to what are called ADAP programs, or the AIDS Drug Assistance Program. For example, in California, it’s a very generous ADAP program, where there are no lines of people waiting to get on medication. In some states, at least as of a year or 2 ago, there were lists of people who were unable to get their medicine through ADAP, because the ADAP program was less generous or was less well funded. So for ADAP in California, anyone, even people who have no insurance whatsoever, can access medication through ADAP.
Other ways to access medication are through Obamacare [the Affordable Care Act]. And as a last resort for certain medications, pharmaceutical companies offer assistance programs for access to inexpensive medication, depending on the income level of the patient.
AJMC®: Will there ever be a time when the price points on these medications come down? Is that even possible?
GOTTLIEB: I think the price point on branded drugs is unlikely to come down. Once drugs become generic, the price point does come down. But not as much as it should.
In other words, the price point has come down for developing countries, remarkably. They’re able to provide drugs in developing countries at a very low price point. But in the United States, once the drug becomes generic, the price point tends to be not so far off the brand price. The reason for that isn’t clear to me.
It seems to me that if a drug can be made available in developing countries at a low price point, why does the American consumer pay so much more for the same generic?
AJMC®: Today’s younger generation knows of HIV as a treatable condition and does not know of the fear that surrounded HIV and the stigma experienced by those early patients. Can you discuss how that fear was experienced in the scientific community, or even expressed by scientists themselves?
GOTTLIEB: I think you have to go back to the very beginning. Young people, as you point out, do not appreciate the amount of fear, in general, that was out there among people who perceive themselves to be at risk for this disease. You only have to watch certain films to get an idea. I think that the best way for them to get an idea of what the atmosphere was like is to watch films like “Philadelphia,” “How to Survive a Plague,” “The Dallas Buyers Club,” “The Normal Heart,” and “Angels in America” to know what AIDS was like in the early 80s.
With regard to the scientific community, I have heard stories from researchers—and I have my own story—of experiencing an illness, which appeared to be viral, with fever and profound fatigue that lasted for months early on in the HIV epidemic. Paul Volberding, MD, in San Francisco has related a story of experiencing fear that he was going to bring HIV home to his family from the clinic. That all came on maybe a little bit later, maybe prior to the HIV test, probably 1983, 1984. The HIV test came about in 1985.
But early on, at the very beginning, we had no fear. We were perhaps naïve, but we carried on as usual. We did not take universal precautions. We didn't gown up, we didn't glove up, we took blood without gloves. That was probably out of error. And it was just dumb luck that there weren't a lot of health care worker infections in the very earliest days.
In the lab, once we knew it was this virus, once HIV was discovered, it seemed the pattern of transmission seemed to be the same as that of type B hepatitis. We were pretty reassured by that and doubted that it was transmitted by any kind of aerosol or droplet—because hepatitis B is not transmitted by that route.
My wife at the time, her niece was having heart surgery in New York City as a child, and I advised the parents to donate blood for the child and not to take a chance on banked blood. It was probably 1982, 1983 and 83. Once the HIV test came out, and we all—researchers in the scientific community—took the test, I think there was a collective sigh of relief.
AJMC®: In 1996, Peter Duesberg asserted that HIV does not cause AIDS despite scientific evidence to the contrary. What message do you have for those who continue to deny that HIV and AIDS exist?
GOTTLIEB: Disinformation and a false narrative did not originate recently. Peter Duesberg and his colleagues were ahead of the time in disseminating misinformation and a false narrative, for unclear motives. Duesburg and the AIDS deniers did a huge amount of damage and undoubtedly cost peoples’ lives.
People win the Nobel Prize for doing a very specific thing in the laboratory, which does not make them a global expert on anything other than that specific thing that they did. It does not, necessarily. Some may be polymaths who are brilliant in all aspects. But most have done a very specific thing for which they were well rewarded.
Peter Duesberg is flat wrong. One has only to look at the success of ART in changing HIV from a death sentence to a manageable condition with projected longevity for young people that approximates what their lifespan would have been without HIV. The only thing different is the fact that they are treated with medication that addresses HIV specifically and not any other virus or factor in their lives.
My message to them is to stop it.
AJMC®: What ideal circumstances need to be present to develop a safe vaccine that both prevents new HIV infection and reduces viral load in the blood? In light of drugs that enable persons living with HIV to reach undetectable levels, is such a vaccine possible?
GOTTLIEB: I think you’re talking about 2 different kinds of vaccine. One vaccine that prevents new infection and a vaccine that reduces viral load in the blood are 2 different animals. The first is a preventive vaccine. The second is a therapeutic vaccine. The characteristics are probably going to be very different.
A therapeutic vaccine, the hope would be that it would substitute for medication or that you could use less medication—if you could somehow stimulate the immune system to be more effective against an existing HIV infection. A preventive vaccine would act at the mucosa and prevent the early steps by which HIV can establish infection. Whether it infects the dendritic cells or local CD4 cells at the mucosal level, it would have to interfere with the steps that initiate infection.
One important lesson is the success of pre-exposure prophylaxis [PrEP] with medication. People at risk for HIV can take antiretroviral medicine every day. It’s remarkably effective at preventing new HIV infections. We don't know exactly how that works, but it probably has to do with a tissue level of drug.
In early steps, an infection may start, but it’s stopped in its tracks by the presence of medication at the portal of entry. So I think that here are possibly some lessons for the vaccine folks from the success of pre-exposure prophylaxis with medicine.
Is such a vaccine possible? Well, that’s a therapeutic vaccine. Sure, it’s possible. But of course, once a person has HIV and they're on medication, their immune system can be reconstituted—but it's not normal, it doesn't normalize. Folks with HIV on medication are very immune competent, but it is not a totally normal immune system; there’s still dysregulation caused by whatever damage happened early in the infection.
In the gut, for example, 90% of lymphoid cells in the gut disappear in the first weeks of HIV infection. So years later, the immune system is still isn't normal. You have to have a therapeutic vaccine that is very potent, that can overcome the residual immune deficiency that patients have. That’s different from a preventive vaccine, which you would be giving to folks who are not HIV infected.
AJMC®: What are some lessons to be learned from the early years of the AIDS epidemic that you believe are must-knows for future infectious disease clinicians?
GOTTLIEB: Infectious disease clinicians can be an important voice in supporting the public health infrastructure. Infectious disease clinicians go off; they get this wonderful training; they read Mandel, the book; they take their boards; they go out and they focus just on patients. Public health to them sometimes is a nuisance.
The public health people call them and say, “Your patient has a positive syphilis test,” and the infectious disease doctor replies, “Okay, I’ll do it. I'll get him in, I’ll treat it.” But support for public health infrastructure in this country is insufficient. One only has to look at the HIV epidemic and SARS and COVID-19 to know that.
Maybe the 2 pandemics will send the message to those who are responsible to beef up public health infrastructure. Infectious disease clinicians can be part of that effort as advocates.
I don’t think infectious disease clinicians held a great deal of prejudice. Yes, there was prejudice, but 2021 and 1980 are a long time apart. There's been softening of attitudes over these 40 years. Stigmatizing or blaming a patient or blaming a group of people for disease is unfair. Prejudice is unfair.
There's an outbreak of a disease in Wuhan, China, and blaming all people of Asian ancestry for that, on the part of the public, is absurd. But it’s gone on for centuries. As you know, syphilis was the French disease. Even though it originated elsewhere, it became known as the French disease. HIV early on was characterized as a gay disease, but not by infectious disease clinicians.
It was by the public that didn't want to see it as their problem. They were so frightened of it that they wanted to believe that it was going to be contained in a certain population of people—unfortunately an already highly stigmatized group of people.
For infectious disease clinicians, I think HIV/AIDS has taught them some lessons, in terms of their politics, frankly. I think most people who've trained in this era are now familiar with the lifestyles of gay men and are more comfortable with them. That perhaps is one of the silver linings of all this: Sexual health and LGBT health are more mainstream than they were 40 years ago.
There will still be people who will object and who will refuse to treat, but an LGBTQ person wouldn't want to be treated by those people. And if they sense that, they should simply look elsewhere.
The good news today for younger people is that there is life after HIV, even if they’re diagnosed. There are also lots of options. It is no longer a death sentence.
PrEP is underutilized. PrEP is primarily utilized by White gay men. In the absence of a vaccine, there's a great need to make PrEP available to underserved populations, to people of color. The impediments to doing that really need to be worked on.
Of course, the epidemic goes on globally. There's been some success, remarkably, in providing HIV medication in developing countries. The HIV epidemic was a major message about health equity and set the stage for institutions, like the Gates Foundation, to create global health initiatives. And that's commendable.
Today, we're facing the same sorts of issues with vaccine equity. But the example of HIV, I think there was a compelling moral argument for providing medication to underserved countries, where at one time some people said, “Oh, people in Africa can’t take pills. They don't have clean water.” And yet adherence in developing countries is outstanding.
History has proved the naysayers wrong.