music // Title card reads Back to Basic Toronto, 2014. Dr. Ruper Kaul. HIV does not act alone: The importance of co-morbidities. Rupert Kaul stands alone on the main stage of the Back to Basic conference. An on-screen graphic identifies him as an OHTN Endowed Chair, and Professor, Department of Immunology, Faculty of Medicine, University of Toronto.
Rupert Kaul: I was asked to talk about comorbidities and, again, it’s just going to be a bird’s eye view. What we mean by comorbidities is not focusing directly on the virus, as many of the speakers before me have been talking about, but talking about some of the other things that can go along with that virus that can cause a lot of health issues in people living with HIV. And, sometimes, HIV can cause direct damage.
And, again, when people are going to see their doc, one of the reasons why we like to bring down the level of virus is because that virus can directly damage nerves, brain, kidney… and sometimes the the diseases that we see in there can be directly impacted by bringing down the level of virus. More often, it’s things that go along with the virus that are causing illness in our patients with HIV.
And I’m going to go through each of these in turn as we go through, but that may be low virulent infections that wouldn’t normally cause a problem, that may cause opportunistic infections. It may be virulent infections that do cause health problems, that are very commonly seen in conjunction with HIV. There can be some imbalance in normal bacteria called the microbiome, and there can be other severe non-AIDS illnesses that are much more of a focus over the last couple of years. The traditional comorbidities that we’re talking about, when we’re talking about these co-illnesses are the opportunistic infections.
And I think people know about this. HIV directly infects CD4 cells, as we’ve heard about already. Those CD4 cells are very important in coordinating all kinds of immune responses in our body. So, when you take away those immune responses, infections that normally we would come in contact with on a day-to-day basis but wouldn’t cause any problems now take that opportunity to cause health issues. And they’re called opportunistic infections for that reason. I’m not going to go through them.
You know — what we used to call PCP, now we have to call PJP, this Pneumocystis jiroveci Pneumoniae, thrush, cryptococcal disease can cause meningitis, etc. Many of the opportunistic cancers that we think of as associated with HIV, and that’s particularly lymphomas, particularly kaposi’s sarcoma, are related to infections as well. And so, those cancers are actually caused by infections, and I think that’s on the next slide.
Kaul displays a slide containing a forest plot graph taken from a paper by Grulich, published in Lancet, 2007. The details of the forest plot are unintelligible from the audience, but the values have all fallen to the right of the vertical line.
This next slide is quite a fun study that was actually taking huge numbers of patients in multiple studies and looking at the rates of different kinds of cancers. I’ve only put a few of the pictures on here, but looking at different kinds of cancer rates in people living with HIV, and people living with transplants — who also have immune suppression because of the drugs that we give people — and cancers are increased in all those situations. What you see is, on both these charts, a line going down the middle at one. If the rate of cancers was the same as the general population, and somebody living with cancer or transplants, the boxes would be on that line, on the one. If you were protected against cancer, it would be to the left of that line. And, if you have a higher risk of cancer, those boxes would be to the right of the line. And what you see, obviously, is that many of those boxes are over to the right of the line, both in people living with transplants and people living with HIV.
By far, the highest increased risk is Kaposi’s sarcoma and, again, if your have extremely good eyes, and you’re up at the front, you would be able to see that the risk of Kaposi’s sarcoma is about 3,000 times higher in somebody living with HIV than in the general population. So that’s the most profound difference that we see. Lymphoma is about a hundred. But we also have dramatic increases on the bottom, particularly in cancers that are associated with HPV, that we’re focusing on much more these days. Human papillomavirus is the cause of cervical cancer, obviously, in women. That’s increased in the context of HIV. But also anal cancer, in both men and women. And that’s something that we are looking at increasingly; about how to screen, and how to deal with.
There’s a lot of overlap with other infections that we think of as being very serious virulent infections in their own right. Hepatitis B is a sexually transmitted infection and can be transmitted from mother to child. There’s a lot of overlap with HIV. Hepatitis C, usually transmitted through needles, can be sexually transmitted. And HIV co-infection makes both those viruses do worse. Whether those viruses make the HIV worse is controversial.
Tuberculosis is one of these infections — we read about TB a lot. Not a lot of people in the lay public know about TB. Many people around the world are infected with TB. Only about 10% of people who get TB, who don’t have HIV, will ever get sick from the TB. Most of the time, our immune system can wall that off, and you don’t get sick through your whole life. You die with the TB, but it never made you sick. About 10% of the time, you do get ill. In the old days, when we didn’t have HIV medications, we would see that, each year, about 10% of people with HIV would get sick. So, there’s a much higher rate of getting ill from that tuberculosis, if you have HIV. And there’s a lot of interaction between those two very serious infections.
But, there’s a lot of interaction between malaria and HIV. If you have malaria, it gives you higher levels of HIV in your system, makes it more likely that you transmit that HIV to your partner, and, if you have HIV, it makes you more likely to get malaria, and more likely to get severe malaria.
And herpes is a particular interest of mine. We do a lot of work looking at herpes. If you have HIV, you’re more likely to be co-infected with herpes. Most people, actually, who have herpes — herpes 2, or genital herpes — don’t get any symptoms. You’re much more likely to get symptoms if you are co-infected with HIV. And herpes makes you more likely, again, to transmit HIV to your partners. Although, unfortunately, treating that herpes doesn’t have an impact on that risk.
So, recently we’ve been very focused on serious “non-AIDS illnesses” and, by “non-AIDS illnesses,” we’re talking about illnesses that are more common in people living with HIV, but are not part of the traditional spectrum of AIDS as defined by the CDC back in the 1980s. So, that can be a number of things.
So, non-infectious cancers. I’m not going to show, you know, charts again, showing these things, but actually, a number of cancers that aren’t traditionally associated with HIV are more common in the context of HIV. And we’re realizing that, now that people living much longer because of HIV medications, we’re seeing increased rates of some of these other cancers that we hadn’t appreciated in the old days. So, kidney cancer, ovary cancer, testes — there are a number of these cancers, and that may have an impact on how we screen. There may be, in some studies, an increased risk of colon cancer, so we should be doing our 50 years screen. I do see some gray hairs in the audience. Hopefully people are getting their — as I have, getting their 50-year old colon cancer screen.
Heart disease is one of the things that’s been getting a lot of press. So, we are seeing increased risks of heart attacks in our HIV-infected community as they age, at an earlier age than we would expect in the general population.
Neurocognitive disease or HAND. I think there are going to be some talks about many of these things. I’m giving you the bird’s eye view. But HIV-Associated Neurocognitive Disease or HAND is a big focus for Sean, who’s the Scientific Director of the OHTN, and a number of other researchers in Ontario. Osteoporosis. Increased risk of fractures. And, inflammation may be something that is central to all of these. And we do see that, even when somebody’s been on HIV medications for many years, they have higher levels of inflammation in their system than somebody who’s HIV-negative. There are a number of reasons for that. And, again, those are things that will be touched on in some of the sessions outside of this talk. But frequent rates of co-infections is one of them.
Damage to the gut lining — there was a short introduction to that last night in one of the sessions, in terms of how the immune system is working in the gut and how those bacteria are leaking from the gut into the bloodstream — may be a cause. And, one of the things that we really need to do is study what is the cause of that inflammation? What are ways to reduce that inflammation? And will that make people survive longer?
Kaul displays a line graph indicating the mortality rates of people living with HIV compared to the general population. A dotted line, representing the mortality rate before 1996 continually steps upward from the time of infection to 14 years later. A solid line, representing the mortality rate in 2004-2006, charts a much less pronounced path, rising only slightly above a faint line representing mortality rates in the general population.
This is just showing you, as an overview, the — in the bad old days, before 1996, that dotted line on the top — what the chances were that you would — that you would survive, compared to the general population, after a diagnosis of HIV. And you can see that, by 14 years, about 60% of people have died. That may even be an underestimate from the very early years of the epidemic. What you see on the bottom — you may not even be able to differentiate those two from each other — but, you have a solid black line that is the risk of dying if you’re HIV positive in the current setting — so, since 2006 — and the very dotted line that’s very close to the x-axis is your risk of dying in the general population. So, obviously that mortality has really come down compared to the old days. But it’s still not all the way down to the general population. And these non-AIDS illnesses, these comorbidities, are an important driver of that increased increased risk of death.
I love the microbiome. You know, the micro — but we’re all covered with bugs. All parts of us are covered with bugs. That’s, I don’t know how they do the study, but there’s nice studies saying that you actually have more bacteria in your system than you have cells in your system. So that you’re more bacteria than you are a human. And that plays key positive rules — that does not trigger immune responses, as Polly was saying, and they play very important positive roles in our lives, helping us to absorb food, helping us to reproduce, doing many things. But HIV can alter that microbiome. And, if those bugs get into the wrong place, particularly in the bloodstream, they can be one of the drivers of inflammation.
I think one important message should get out there: there’s a lot that we know about how to reduce, for instance, heart attacks. And, clearly, stopping smoking, and the things that we know how to do. We should be doing much better than we are. That comes down to medical practitioners. That comes down to the community. Those are probably the most important things. But we need to know a lot more about what to do from the HIV side as well.
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