This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.
Michael S. Saag, MD: Hello. I'm Dr Michael Saag, professor of medicine, infectious diseases, and epidemiology at the University of Alabama at Birmingham Heersink School of Medicine. Welcome to season 2 of Medscape's InDiscussion series on HIV. Today, we're going to discuss COVID and HIV. What do we know? Let me introduce my guest for today, Dr Monica Gandhi, who's professor of medicine and medical director of Ward 86, the HIV clinic at UCSF. She's also a co-director of their Center for AIDS Research. Welcome to InDiscussion, Monica.
Monica Gandhi, MD, MPH: Thank you. Nice to see you.
Saag: Let me start with this question. You have been at the forefront of HIV research for well over two decades now. But you've really dug in deeply into COVID. Briefly describe how that happened and how you've become such an effective spokesperson for COVID in general, but especially with COVID and HIV.
Gandhi: I think that these are the two great viral pandemics of our day. HIV was first described in 1981 and was probably around before then. Now, we are up to 40.3 million deaths from HIV and 38.4 million people living with HIV worldwide. By no means is it over. Then, COVID-19 was a new pandemic. March 11, 2020 was the date that the WHO declared it a global pandemic. And it's not over yet. They really clashed in many ways. COVID outcomes were influenced by HIV status and the other way around. Actually, COVID and COVID responses did lead to setbacks in HIV, which we've all been working hard to try to rectify. Then, when the COVID vaccines came out, we really needed to think about our patients living with HIV and how they were responding to the vaccine. I feel like it is very natural for anyone in HIV thinking about great societal pandemics and their effects to work on COVID-19.
Saag: Right. The biology is sort of similar in a lot of ways, a lot of replication. There are variants that emerge in response to an immune response that attacks the virus. We see that in HIV and a lot of the drugs that we're currently using for COVID are directly descended from HIV, right?
Gandhi: Yes. That was really quite amazing because I feel like there's a real parallel to that. If we look back at azidothymidine (AZT), our first HIV drug, they just pulled it off the shelf from the National Cancer Institute. It wasn't designed specifically for HIV, and it held us for a while. But then there was tailored drug design for HIV. Similarly, molnupiravir, which is the first oral antiviral approved for COVID, was not directed necessarily and tailored and specifically made for COVID-19. It had been looked at for Ebola, for other RNA viruses. Why not try this nucleoside analog in COVID-19? It had some effect. Absolutely. For those who were unvaccinated and at risk for severe infection, molnupiravir led to 30% reduction in hospitalizations and deaths (as shown) in the MOVe-OUT trial.
If you looked at just the immunocompromised population — there was just a recent analysis that just came out — it was an even higher effect. It really helped people who are immunocompromised or at risk for severe disease. To be fair, molnupiravir like AZT is not that powerful. And really, in the vaccinated population, the PANORAMIC study from the UK with molnupiravir showed us that it really didn't change hospitalizations and deaths. I think that's because the vaccines work so well. Fast forward to the next antiviral that we got for COVID-19, Paxlovid, it sounds very familiar, like HIV. It's a protease inhibitor. It was targeted directly for COVID-19. It works better than molnupiravir. The current status with this 5-day boosted ritonavir protease inhibitor at this point is that it is used for vaccinated people who are older, based on observational studies, who are risk for severe disease, and absolutely the unvaccinated are at risk for severe disease.
Saag: That whole idea of boosting came right out of HIV. It's really pretty straightforward for those of us who have been working in HIV just to pivot and start working with COVID and SARS-CoV-2. Let me ask just a couple of straightforward questions. One that comes up a lot is whether people living with HIV are more likely to acquire SARS-CoV-2 or get sick with COVID?
Gandhi: In terms of acquisition, we did an analysis in San Francisco, and people with HIV were less susceptible to getting COVID at the beginning, probably because they were really following public health measures, had lived through one pandemic, and were not going to try to have this exposure in a second pandemic. But in terms of severe outcomes, there was some confusion at the beginning. But I think we've all sort of settled with larger analyses from New York and the WHO and South Africa that, yes, at least if you have more immunosuppressed HIV, so CD4 counts < 200, that does predispose you to more severe COVID outcomes.
Saag: In that regard, people who are not treated for their HIV, have ongoing replication, maybe high viral loads, are not terribly different maybe than an immunosuppressed person who's on some sort of immunotherapy for cancer or for autoimmune disease.
Gandhi: Yes. This is always the population that we worry about. Those with CD4 counts < 200, without controlled viremia, that becomes an immunosuppressed group. Just like you said right now, it is really those who are immunosuppressed that we always have to think about — when do we need to boost and also [give] these oral antivirals.
Saag: So it just tells us to double down on our efforts to get those patients who are drifting in and out of care back engaged in care, and get them on treatment as COVID is emerging. Going back to your first comment, the initial thought or observation was that we didn't seem to see as many cases of COVID for people diagnosed with HIV. It led to the question of, well, maybe some of the antivirals that we're using for HIV therapy are protective against SARS-CoV-2. Has that borne out?
Gandhi: Only with one drug in kind of an associative way. We looked at lopinavir-ritonavir at the beginning because we thought it would work against SARS-CoV-2. There was this big Hong Kong study and it didn't have any effect. This clinical trial of lopinavir-ritonavir is not going to help patients with SARS-CoV-2. That's a HIV drug. Tenofovir keeps on coming up only in the sense that there was a large VA study, not a randomized trial, that was published in October 2022 that at least observationally in the VA Aging Cohort, there was an association with being on tenofovir and less severe disease to SARS-CoV-2. They never got that trial done in Spain, where they were looking to see if tenofovir could be a good prophylactic for SARS-CoV-2. But after controlling for confounders, there was this association that tenofovir could be protective, and there is in vitro data that tenofovir has an effect on SARS-CoV-2 polymerase. The way I say it to my patients is it doesn't change anything. You're on tenofovir anyway for your HIV. If it has an advantage against SARS-CoV-2, all the better. But we're still going to vaccinate you, boost you, and use Paxlovid if we need to.
Saag: Well, let's pick up on the vaccine. That's one thing we don't have in the world of HIV. Despite working on it for 35 years, we don't have an effective HIV vaccine. But really miraculously, starting in March or so of 2020, within 7 or 8 months, we not only developed candidate vaccines, but many were shown to be remarkably effective at preventing symptomatic COVID and certainly preventing hospitalizations and death.
Gandhi: You wrote a beautiful article in JAMA. I just want to tell you that I really appreciated that. It was a very recent article and you really talked about this. I think the miracle of producing safe and effective vaccines that quickly... That is absolutely going to be the savior for future pandemics. Barney Graham predicted this in 2018 in a Nature article; he said, "We had to get the vaccines quickly," and it happened.
Saag: One of the questions that comes up is do these vaccines, and especially the mRNA vaccines, work as well in fully suppressed people with HIV? Do they last as long? What are the guidelines or what are your thoughts about what to say to patients about getting a vaccine and how often they should be boosted and with what?
Gandhi: It's such a good question. Of course, everything is still evolving in some way. But I would say that we and others, because we had a research project to look at this, have actually looked at immune responses in those patients living with HIV to the COVID vaccines. Like we just said, for severe disease in general, those who have low CD4 counts or viremia are less likely to have good responses to the COVID vaccines and will probably need more boosting. But actually, those who are in that immunocompetent category, CD4 counts > 200 and viral loads that are suppressed, seem to have excellent responses to the COVID-19 vaccines. In terms of waning, the media can make things seem really simple, like there's just antibodies and that's all there is. But you and I really have thought about T cells a lot because we're in HIV immunology, we're HIV doctors. The waning aspect really depends on if you're talking about antibodies, which obviously will come down with time vs T and B cells, which are kind of cellular immunity that's induced by the mRNA vaccines and other vaccines. In those two arms, the cellular immunity lasts longer.
If we have to think about boosting those with HIV, I do think we're going toward a strategy. The world is going toward the strategy of boosting yearly those who are still susceptible to severe disease. The US hasn't quite settled on exactly a strategy if they want to boost everyone vs those who are at risk for severe disease. But Canada, the WHO, UK, and Europe are all going toward this idea that the people who are still susceptible and need yearly boosting are those who are on immunosuppressants, those who are older, over 65 years, and those who have multiple comorbidities. And in the immunosuppressant category, I'd include patients with HIV with low CD4 counts.
Saag: I think what we've learned over the past 20 years can actually be applied to the question that you're addressing. It seems that the virus itself, HIV itself, when it's replicating at high levels, that really is the immunosuppressive factor. The virus binds to T cells or receptors and interferes with the function of the immune system. When you knock the virus down to undetectable levels, the immune system, in essence, wakes up and returns to a pretty good degree of normal, especially over 6-12 months. We shouldn't be thinking of a well-suppressed, functional person with HIV as being technically immunosuppressed. I think they behave biologically and immunologically more like an un–HIV-infected individual. If we think about it that way, it really starts to all come together. Maybe the people with HIV who are suppressed are not really a separate category as much. Do you agree with that?
Gandhi: I completely agree with that. In fact, we've done everything in our power to ensure that those living with HIV who are adequately treated are essentially living normal life spans and have the same responses to vaccines. They should really think of themselves, with the amazing therapies that we have for HIV, really kind of in the immunocompetent category. That's what we've been doing for 40 years, working on these amazing HIV treatments. I agree with you. Like you, I treat people with HIV, and I reassure them all the time about the COVID vaccines and their responses to the COVID vaccines, which I think is very adequate and just as good as those who don't have HIV if their CD4 counts are high and their viral loads are suppressed.
Saag: Let's dig in a little bit more to the vaccine and in particular to the bivalent booster. That seems to make a big difference, especially in those people who are truly immunosuppressed older folks in terms of reducing not only the risk for hospitalization and death, but in some ways actually more symptomatic infection. Is that the vaccine that you're recommending now for all the people with HIV that you're taking care of? Do you use the original vaccine much anymore?
Gandhi: I also use the bivalent booster. I wrote a piece in The Lancet ID called "New Boosters Are Here! How Should We Use Them?" It's actually exactly what you say. It's exciting that the mRNA technology can be updated to reflect current variants. To be fair though, with these variants, these subvariants, there's a lot of changes. I don't know if we're going to be able to do this every year, but we did it this time.
Saag: If my memory is correct, in December 2020, we released the original mRNA vaccines and a few others, and for about 7-8 months, it seemed to actually prevent symptomatic COVID. It was rare that you saw any fully vaccinated person, especially 20-28 days after their final boost or their second shot, coming down with any kind of COVID until July 2021. There was that event in Cape Cod where 75% of people who had been vaccinated developed symptomatic COVID, but it was with the Delta variant. It seems like if we get the right construct that actually immunizes against the prevailing variant of the moment, perhaps that will again reduce the chance of symptoms. At least that's my take on it. What are your thoughts?
Gandhi: What you just said is one of the key points right now for these vaccines in the sense that there's a lot of polarization at the moment around COVID vaccines, which you and I, as long-term infectious disease doctors, have found very disturbing because vaccines are the mainstay of infectious disease prevention. Some of that polarization is absolutely centered around the fact that the CDC director and many of us said when we first got vaccinated with the Alpha variants in circulation, that these vaccines are actually not only preventing severe disease and death, but they are preventing symptomatic COVID. In fact, they're blocking transmission because if you don't have any COVID, then you're not transmitting it to others. So they absolutely, without a doubt, did reduce transmission and reduce symptomatic COVID during the phase of the Alpha variant up to the time of the Delta variant with the original ancestral strain of vaccines. It wasn't just because those antibodies worked well against the Alpha variant but also because antibodies were high. Once you get a dose of the vaccine, your antibodies are high for a while, and that can remain true and then change. That's actually what changed with the Delta variant. Vaccines were no longer effective against preventing all infections. There were a lot of mild infections like that Cape Cod incident, but they were still profoundly effective against severe disease and death. Just because the science changes doesn't mean that you don't trust the vaccines, because the vaccines work really well.
Severe disease and death is fundamentally why we even noticed COVID-19 and why we'd be worried about it. So that staying power is there. But if we could update the vaccines to get our antibodies nice and plump against whatever variant is circulating, yes, I think we'd have a lot fewer symptomatic COVID infections. I just don't know if they're going to keep up with it given how fast things move. To be fair, the bivalent took quite a long time to produce, and we'd already been past Delta and BA1, BA2, BA2.1, and BA3; now, we've got BA4 and BA5. I don't know how it's going to end up working, but I know that there are also nasal vaccines that are in development to help us with our immunoglobulin A production, the mucosal antibody in the nose to prevent mild infections. There's one already being rolled out in India, and we're always going to work on next-generation vaccines. The NIH has funded seven centers across the United States that are working right now as we speak on pan–beta-coronavirus vaccines. We need to keep our progress up with COVID-19. I know we're at a phase where the emergency is being wound down by May 11, but I think it's tremendously important for us to keep on stressing that COVID-19 is not an eradicable pathogen. Ongoing progress and work on COVID-19 needs to be funded for the NIH.
Saag: I couldn't agree more. Let me turn back quickly to what we started with about treatment and specifically coming back to people with HIV. Let's say you have a well-suppressed, immunologically relatively normal 50-year-old who tests positive for SARS-CoV-2 and gives you a call within an hour after the test turns positive on day 1 of symptoms. Do you prescribe antivirals for them? Either Paxlovid or molnupiravir. What's your thought process?
Gandhi: You know, my thought process is based on age, actually. Remember the EPIC-HR study? It was the only randomized study that really showed efficacy of Paxlovid, but it was among unvaccinated patients who were at risk for severe disease. That's the EPIC-HR randomized study. We've never actually studied Paxlovid in vaccinated patients in a randomized way. But I think the best study is in The New England Journal of Medicine looking at Israeli data to say, "Well, who, if you're vaccinated, benefits?" It was very well done controlling for all confounders, a study that showed that those over 65 years, regardless of vaccination status, really benefited from getting Paxlovid in terms of the risk for hospitalization and death. I make it clean and simple for myself unless they have multiple comorbidities. The patient that you just described is doing well. Like we said, this is an immunocompetent patient, so I would wait. I would prescribe if they were 65 or older, but a 50-year-old, I would let them have their course with COVID and not get Paxlovid. I haven't seen the data that would suggest anything would change for that patient who's young.
Saag: Well, let's say the patient had diabetes and had some degree of hepatitis C–induced cirrhosis that has been treated and is now cleared, that's someone who you might use Paxlovid or molnupiravir.
Gandhi: Exactly. If the patient is at risk for severe disease despite vaccination, I am going to give them Paxlovid. That means comorbidities. Age. Immunosuppressants.
Saag: Very clear. As I anticipated, this time has gone by very quickly. I'd like to take the remaining couple of minutes and just turn on the microphone for you to look into your crystal ball and tell us where are we headed overall with regard to COVID over the next year or 2? Your best guess.
Gandhi: I just wrote a book called Endemic for Mayo Clinic Press that is trying to look at infectious disease history and say, "Where is COVID going to go?" The only reason I would say that is because this idea that it can't be eradicated is really sad, but it can't. It's in 30 animals, so we can't kill all those animals. There is not a way to eradicate this pathogen. That means that we have to think of it as a respiratory pathogen that we're always working on, like influenza, like metapneumovirus, like parainfluenza, like everything that we live with. Actually, if we think about those other viruses, we don't even have great vaccines. We don't have any vaccines for parainfluenza. We're getting one for respiratory syncytial virus (RSV); so I think of it like this, that any non-eradicable pathogen will always need vaccines and treatments to keep it under control. COVID, for me, has given us the power of thinking about antiviral treatments for RNA viruses that we never were very good with. HIV is a retrovirus, and we did a great job with antiviral treatments there. We don't have great antiviral treatments for RSV or parainfluenza or these other viruses. I'm hoping this is going to launch a field of no RNA virus should kind of go untreated. We should have treatments for all of them, better treatments for COVID. More are going to come. We have to think about how to refine our vaccines for the future because if something can't be eradicated, it always needs constant work.
Saag: That's right. I think the public is kind of getting used to that
Well, this has been wonderful. We've been talking today with Dr Monica Gandhi from the University of California, San Francisco, about COVID-19 and HIV. What we've learned is that for people who are fully suppressed with their HIV, that we should basically think about those individuals as not being different than any other person in the community who otherwise has a normal immune system. We should be vigilant, especially for people who are older or have chronic comorbid conditions. Everyone should be vaccinated. Ideally, now with the bivalent vaccine. The vaccines will be given about every year. We're still going to be working that out. What we can expect in the future is that this virus will remain with us and that we're going to learn to live with it, unfortunately. But because of the tools that science has given us in terms of treatment, in terms of vaccines, in terms of understanding the normal epidemiology, we're going to be able to manage this and live with it successfully. Nobody wants it but there's a lot of other respiratory viruses that we deal with annually, and this is just another one added to the mix. Thank you for tuning in today. If you haven't already done so, please take a moment and download the Medscape app to listen and subscribe to this podcast series on HIV. This is Dr Michael Saag for InDiscussion.
Listen to additional seasons of this podcast.
Resources
Coronavirus Disease 2019 (COVID-19)
Molnupiravir, an Oral Antiviral Treatment for COVID-19
Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients
A Trial of Lopinavir-Ritonavir in Adults Hospitalized With Severe Covid-19
Tenofovir Disoproxil Fumarate and Coronavirus Disease 2019 Outcomes in Men With HIV
Development of COVID-19 Vaccines–An Unanticipated Moon Shot Achieved at Warp Speed
Emerging Viral Diseases From a Vaccinology Perspective: Preparing for the Next Pandemic
A Bivalent Omicron-Containing Booster Vaccine Against Covid-19
New Boosters Are Here! Who Should Receive Them and When?
Nirmatrelvir Use and Severe Covid-19 Outcomes During the Omicron Surge
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Cite this: When Viral Pandemics Collide: Vaccinating, Boosting and Caring for Patients Diagnosed With HIV During the Time of COVID - Medscape - Apr 11, 2023.
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