Activity Transcript

Giovanni Guaraldi, MD: Hello. I'm Giovanni Guaraldi. I'm Associate Professor of Infectious Diseases and the chair of the Modena HIV Metabolic Clinic at the University of Modena and Reggio Emilia in Italy. Welcome to this program titled "HIV and Inflammation: Raising Awareness of the Impact of Inflammation on People Living With HIV." Joining me today is Professor Maile Karris, who is an Associate Professor of Medicine at the Division of Infectious Diseases and Global Public Health and Geriatrics and Gerontology at the UC San Diego. Welcome.

Maile Karris, MD: Giovanni, it's such a pleasure to be here with you today.

Dr Guaraldi: Very good. Actually, we have very interesting learning objectives for you today. We will try to increase knowledge regarding the impact of chronic immune dysfunction and inflammation in HIV patients. We will try to go into the relationship between chronic inflammation in people living with HIV and comorbidities, but also aging. And in the last part, we will try to address the interventions used to manage comorbidities associated with inflammation. So with no further ado, I believe at that we need to get into the topic. I will ask my colleague, Maile, what is driving inflammation and which are the cells, the tissues and even the organs that are implicated in this?

Dr Karris: Well, inflammation in people living with HIV is multifactorial and intersecting. Multiple initiators of inflammation include HIV itself, other chronic coinfections, including cytomegalovirus and hepatitis C and hepatitis B. We also know that HIV associated non-AIDS conditions, such as substance use and obesity, also contribute to activation of the innate immune system. And liver fibrosis from HIV medication toxicity, hepatitis and/or alcohol additionally contribute via microbial translocation or leaky gut, as we say.

Dr Guaraldi: Very good. And how does HIV cause inflammation?

Dr Karris: HIV is very interesting in how it causes inflammation. Activated CD4 T-cells, which are the specific HIV target, are easiest to infect compared to other types of resting CD4 T-cells, for example. And they exist in abundance in gut-associated lymphoid tissue, also known as GALT because that organ has to basically keep our gut micro-organisms from invading the body. So there's a lot these activated CD4 T-cells in there. When they're infected with HIV, they are massively depleted specifically in that area and which also causes some destruction of the architecture of the GALT.

So that permanently alters the function of that very large immune organ in our body. And this ultimately then allows that bacterial translocation that we mentioned earlier, as well as reactivation of other viruses like cytomegalovirus. And although HIV causes the depletion of 1 of the arms of the immune system, it also initiates activation of other arms, specifically CD8 T-cell responses and pro-inflammatory macrophages and dendritic cells. So in 1 way, it immunosuppresses, but in another way, our immune system responds to it and causes chronic inflammation related to that. And if antiretroviral therapy is not initiated this ongoing immune suppression and chronic activation just really exhausts the immune system resulting in senescent cells. And Giovanni, what markers do you use to evaluate inflammation?

Dr Guaraldi: Well, you see Maile, actually you explained very well that there are several biomarkers, so that can be assessed whenever you want to address the systemic immune activation. But if I am at the bedside, I realize that the numbers of these biomarkers tend to be very low. Actually, most of these biomarkers, for instance, imagine cytokines like interleukin (IL)-6 or even coagulation markers like D-dimer have been proven to be very effective at the population level to predict comorbidities, cardiovascular events, and even mortality. But let me say at the single patient level, this is not the case. I would like to present this nice study that was on the ICONA cohort by Christina Mussini. Actually it was shown that presumably the most, let's say easy to measure marker associated with inflammation is in fact the CD4:CD8 ratio. Nowadays, in a setting where most of our patients have undetectable viral load and high CD4, CD8 are even more, let's say informative on the CD4:CD8 ratio, as it is shown here in model 2 was independently a predictor of mortality in this cohort.

So we try also to use at a clinical bedside, for instance, in this slide. So from the J-PAL cohort. Remember J-PAL is a cohort of geriatric people that are more than 65 years of age, this was 1092 individuals. We try to understand what were the predictors of having a CD4:CD8 ratio above 1, that is normal. And you see in this situation, actually, this was associated with undetectable viral load, female sex, and nadir CD4 cell count. But if there are in fact some HIV parameters associated with the natural history, it's my turn, Maile, how does the duration of untreated HIV impact inflammation and what are the possible consequences in regard of what can we do at a clinical level?

Dr Karris: I really like how you asked that question. Because I think it is important to discern between duration of HIV infection and duration of untreated HIV infection. Certainly it is this ongoing HIV viremia rather than the duration of HIV infection that is leading to the ongoing inflammation that we often see in people living with HIV. Once a person living with HIV is undetectable, immune activation and inflammation starts to decrease. But I did say in an earlier slide that very early on in HIV infection, there's this destruction of the GALT. Actually, the inflammation doesn't quite go back to normal. So people living with HIV, unless they get started on antiretroviral therapy really early, say like a couple of months from their point of infection, never quite achieve the levels of these markers of inflammation that we see in HIV seronegative persons.

So differences still do exist. Although, you can certainly minimize inflammation by getting on antiretroviral therapy (ART) early and staying on ART. And there's also some really interesting data to suggest that achieving 100% adherence also is impactful. So actually there's several papers now published reporting differences in people that say that they are 100% adherent vs 85% to 99% vs less than 85%. This was 1 of the original papers. It was evaluating biomarkers of inflammation in participants of the Multicenter AIDS Cohort Study, which is a large cohort study here in the US, and it really demonstrated differences in inflammatory biomarkers based on what people reported their adherence was. If you look, you can see kind of these squares in yellow. So those were the people that were reporting less than 85% adherence. The squares are the triangles are persons that reported anywhere between 85% to 99%. And when you compared those biomarker levels to people who were saying, they are 100% adherence, there are some clear differences in inflammation. So certainly, adherence matters. And Giovanni, I'd really like to hear what your thoughts are on how chronic inflammation and immune dysfunction can impact the pathogenesis of comorbidities in people living with HIV.

Dr Guaraldi: Well, that's a long story. I think we can concentrate on something. I found this very recent review, very interesting piece. Please concentrate on the central of the design of the circle. You understand that you already mentioned that there are various triggers of inflammation that are reported to contribute to low grade chronic inflammation, but I would now concentrate on the fact that fat alteration in particular can have, let us say an important role with regard of the inflammatory process. And so I want to quote this important paper that was published in the Lancet Diabetes and Endocrinology few years ago. Actually what is shown here is that it's not all the fat, there's what we call ectopic fat. For instance, the fat present at the divisional level, the hepatic fat at the epicardial level, even the liver fat is associated with atherogenic dyslipidemia, insulin resistance, thrombotic state and inflammatory state.

Apparently this fat is a true endocrine organ, which produces inflammatory markers and cytokines. And this is associated with the natural history of many comorbidities, but in particular, is the cardiovascular disease. And so we know that is really important to study fat in order to study the inflammatory process. And so actually I tried to think of my professional life in the past 30 years, actually I'm old enough to remember the wasting syndrome. I was working in Africa as a junior doctor and at that time, HIV was called the slim disease because actually it was the weight loss that was one of the early signs for diagnosis. At that time, they didn't have HIV testing and it was weight loss that contributed to the diagnosis of AIDS.

Okay. But after of course we had drugs, but with the early highly active antiretroviral therapy (HAART) period, actually all the lipodystrophy story came out. And due to toxicity of early antiretroviral therapy, most of the patients didn't really change that much, their weight, but rather actually decrease the fat in the periphery. But at the same time an ongoing process was starting and it's still all there. That is what we call the lipohypertrophy central fat accumulation. In this situation, we had some weight gain, not that severe as what we experienced now in the new clinical manifestation of weight gain and obesity epidemic. And so what is happening? Why somehow this anthropometric changes are telling us the changing the natural history of HIV disease across these 30 years of history? Well, I would like to stress that the fact that there is a crossroad between metabolism and inflammation, and actually if you see this figure, you understand that in that metabolic organs, including the liver, the brain, the pancreas, and especially the adipose tissue, there are resident macrophages, which interact with the stromal cell in the regulation of nutrient availability. And this is the good metabolic homeostasis.

But when this equilibrium goes wrong, these cells can produce mediators. For example adipokine, that may cause systemic inflammation and metabolic alteration, and the result is this so-called immune metabolic disorder. And so I would really like to address the fact that metabolism and inflammation really tell the same story in people living with HIV. And because of this, well, it may be something good because nowadays, assessing metabolism is not just assessing blood glucose or cholesterol level in a test tube, but rather I can develop this idea of immune metabolic disorder that can be measured at an organ level. And of course the organ level is the liver. And I can address the metabolic activity of the liver with a transient elastography. Using this I can measure noninvasively for instance the fat quantity or the level of fibrosis that may be the result of the inflammatory process associated with tissue adipose concentration. And I will end up to the definition of non-alcoholic fatty liver disease (NAFLD).

NAFLD is defined as the excessive hepatic fat accumulation in more than 5% of our adipocytes. Well, this may be a risk factor, but actually in particular, in people living with HIV, this may promote fibrosis, ballooning, and inflammatory cell migration. And this will end up with the bigger issue of non-alcoholic steatohepatitis (NASH) that is full-blown disease condition that had been associated with multiple comorbidities, of course, the cardiovascular disease, but also the cardiac hypertrophy, the congested gut-associated lymphoid tissue (GALT) failure, but also arrhythmias and in particular arterial fibrillation and also chronic kidney disease, but even some kinds of cancer. And so I believe that this idea of moving from, let's say inflammation to immune metabolic condition is a clinical process that will help us to study how the comorbidity, issue is changing across at the aging process of people living with HIV. And so Maile, I ask you what does the literature tell us about the risk of chronic diseases because of chronic inflammation?

Dr Karris: Absolutely. I like how you really laid out the changing face of HIV. And certainly that is very true and, really, thankfully for the advances that we've made in antiretroviral therapy accomplished because of the joint efforts of the community and clinicians and researchers, there has been a steadily narrowing lifespan gap, comparing people living with HIV and HIV seronegative persons. So we're certainly closing that lifespan gap.

People living with HIV today are expected to live a near normal lifespan. And that's amazing. However, we unfortunately have not made similar progress in closing the comorbidity gap or life without non-HIV comorbidity years. So we do know that people living with HIV tend to accumulate other medical conditions earlier and in excess of HIV seronegative persons. And some of that work, Giovanni, you've done and contributed to our knowledge of that. But if we break it down, not all comorbidities are present in excess in older adults, or people living with HIV. Conditions like hepatitis C, maybe due to some overlapping acquisition risk with HIV, others like anemia, osteoporosis, and kidney disease may be associated with antiretroviral therapy, but many excess comorbidities appear to bundle under what we call metabolic syndrome. Things like hypertension, dyslipidemia, diabetes, and cardiovascular disease as presented here in this rate graph. Giovanni, how does inflammation impact our aging patients?

Dr Guaraldi: Well, I think what you're asking me is 1 step forward. Now it's, let us say, well established that inflammation and that immune metabolic alteration may impact comorbidities as you told me. But unluckily the complexity is not just because patients have got single comorbidities, but because they have altogether, what we call multimorbidity. Nevertheless, this is not even enough because of the complexity of aging is not just because we accumulate diseases. We move from single comorbidities to multimorbidity, but then we end up with geriatric syndrome and among all the most important is frailty. And so you see, I would like to show this vicious circle in which you understand the pathway of frailty pathogenesis are many, and are all associated with dysregulated inflammation in HIV.

Okay. This is a very complex framework to understand that the development of frailty and you see that there are back and forth mechanisms related comorbidities, related fatigue, related wasting and sarcopenia and the related obesity and lipodystrophy. And so all these are actors, that produce frailty and frailty producers in this condition. And for this reason, I think nowadays it is important to recognize that frailty, which is conceptualized as a measure of biological age, is somehow associated with the immune metabolic condition. And so let me show you this paper that we were able to publish last year, in which we try to address if there was any association between liver steatosis what we call NAFLD and especially NAFLD with fibrosis was associated with frailty and actually here we measure frailty with the frailty index.

And so in this table, you can see that in fact, NAFLD with fibrosis was very much correlated with many comorbidities, but also narrow cognitive impairment, vitamin D insufficiency, type 2 diabetes or osteoporosis and so on and so forth. But actually when we try to look what was, let us say the predictors of frailty, what we ended up with was that, frailty may have been predicted by the complexity of multimorbidity, but frailty was independently predicted by fibrosis and the steatosis. And so somehow this returned me to an idea that frailty is like a big umbrella which is not, comorbidities on the top of the other comorbidities, but it's a big umbrella in which multimorbidity contributes, but also NAFLD contributes in the development of this condition. And so, well, we said many things, but I believe now we need to get into the clinic. And so I'm in the clinic tomorrow morning and Maile, I would like to ask you, what's the best practice for comorbidities management in people aging with HIV now?

Dr Karris: Yeah. You and I are both infectious disease physicians, but I think we both realized that it's really best to care for people living with HIV if we move past HIV premises. So we really do need to go beyond, the viral suppression and co-infections and STDs, and we need to be providing excellent primary care. So there are some HIV specific concerns, for example, treating and monitoring hepatitis B and C infection. HIV doctors are really familiar with things like HIV and antiretroviral associated metabolic conditions like testosterone deficiency and osteopenia. But we also need to be optimally managing things like diabetes, cancer screening, we're pretty good at anal cancer and cervical cancer. And I think we're also fairly great at a screening for hepatocellular carcinoma, but we also need to be encouraging our patients to pursue their general cancer screening, prostate, lung, breast, colon, of course, vaccinations.

As we are infectious disease doctors we should definitely be encouraging our folks to be vaccinated, particularly COVID, there is some data that suggests that people living with HIV that had a very low CD4 nadir were more likely to get ill with COVID. That was most recently presented at a conference. And of course, mental health and substance use, those things are ongoing issues. They impact the quality of life and the form comorbidities of the people we care for. We need to be better coordinators also of multispecialty care. But as our population ages, again, because the face of HIV is changing, we should consider switching to different models of care, for example, geriatric models of care. And here in the US, I really embraced the five Ms. So that really stands for mind or mentation, how are patients thinking. Mobility, their ability to function independently and complete their independent activities of daily living. Multimorbidity like we have been talking about, and medications.

You need to be deprescribing as much as we possibly can. And focusing on what matters most to a lot of our patients. It's difficult when we try to complete the traditional screening, because sometimes it could be pages of things that we need to be doing for our older adults with HIV. And they struggle with getting to appointments, but talking to them about, okay, this is the screening that is important to me. I think you need this. What is important to you? And how can we help you to achieve these screens, is a huge value. Additionally, I do strongly believe that we should also be targeting modifiable factors. So let's think about the things that impact a lot of different comorbidities a lot of different aspects of life, things that are changeable or modifiable, and let's really focus and address those early on and through their lives.

So, 1 thing that impacts a lot of different comorbidities is weight gain. And weight gain has a lot of different reasons for why people, especially people with HIV are gaining weight. We know substance use can be contributing, diet or even access to healthy foods. Many of the people that we care for don't have the money to go to the grocery store and buy fresh vegetables and fruits and whole grains. Sometimes all they can afford are canned goods. And so they may not even have access to healthier types of foods. A lack of exercise, which could be due to a variety of factors, including whether or not they feel like they are living in a safe environment. I have patients that have said, I don't feel comfortable even walking around outside because my neighborhood is unsafe. And then of course, things like depression and whatnot. So these are multifactorial things that can contribute to weight gain.

Dr Guaraldi: You see, Maile, actually, I believe that in recent years, there has been a big worry, especially in people living with HIV regarding what was the contribution of  integrase strand transfer inhibitor (INSTI) switching with weight gain. And of course, this is a hot topic. I said before, the importance of the measurement of weight and especially ectopic fat with regard of the inflammatory process. Nevertheless, I would like to show you this data that we presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in which we tried to understand what was the different contribution of traditional and HIV related factors with regard of weight gain. And we used a population in which there was a 5% weight gain at the time of switching to INSTI. As a statistical approach, we used this so-called, population attributed factor that somehow helped to quantify the proportion of weight gain that could be eliminated if that particular risk factor was not present.

And that, contrary to my expectation, the event switch to INSTI turns out to be nonsignificant when I was able to describe in detail the physical activity of my patient and we use a standardized questionnaire and the measure of meds. I believe that INSTI and switch to INSTI play a role, but the relative contribution disappears compared to other factors like, initial body mass index (BMI), high CD4, CD8 and in particular sedentary life. Somehow suggesting the need that first of all, we need to empower the patient, to educate, because a sedentary life is really what we need to fight in order to avoid weight gain at any time of the natural history of HIV disease.

Dr Karris: I 100% agree with you. And here in the US, we have several lifestyle programs. For example, a classic one is the Center for Disease Control Lifestyle Change Program, also known as the Diabetes Prevention Plan, or DPP. Now, this program incorporates a lifestyle coach that provides education and really encourages people to pursue exercise, join gyms and things of that sort. Eat healthier. And it also couples it with a support group. So you also get that social support as you're making these positive changes in your life. But the really interesting thing about the DPP, we've got about a decade of research using this intervention that demonstrates that people lose weight. There's a decreased incidence of sleep apnea, probably because of the weight loss, decreased incidence of diabetes, and one study it even outperformed metformin to prevent the development of diabetes and prediabetics, reduce risk of cardiovascular disease and metabolic syndrome, improve general health and physical function, decrease pain, and improve quality of life. And yet only about 1% of all eligible persons in the US have ever accessed this program.

So it's there, it's covered by insurance, but very few people are actually accessing it. Similarly, the Ornish Lifestyle Medicine Program also known as the Intensive Cardiovascular Rehab. It's a very similar program except really focused more on cardiovascular outcomes rather than diabetes, weight loss. This program incorporates a vegan, low fat, whole grains diet, regular exercise, social connection, meditation, and relaxation. And very similar findings to the DPP, including a decrease atherosclerotic plaques. So this alone compared to people who are on medications, further decreased atherosclerotic plaque. So these interventions work.

The other thing I think that can be very valuable, so, we as doctors work we're used to diagnosing and prescribing things. It's kind of what we got trained to do, but we can prescribe lifestyle intervention. So there was a great paper by Montoya and Christine Erlandson in which they developed an exercise prescription that we can be using for our patients. And I started to do this and I follow up on it. I also do a lot of social prescriptions in persons that I've identified as particularly lonely. And I also follow up on them when they come and visit me. So this is another thing that we as doctors can do and should be doing for a lot of our older adults that are living with HIV. So only a small portion of eligible persons are participating in these lifestyle programs. And there's lots of reasons for that. So I think healthcare disparities, at least in the US, is a clear reason why only a small proportion of people are actually doing these things.

Now, there's some adaptions that we can also make and has a feasibility and the maintenance of some of these programs. And I want to just briefly mention one of those adaptions here. So we recently performed a study that used recorded mindfulness lessons to evaluate its impact on people living with HIV, who are experiencing depression, anxiety, and loneliness. And this is a randomized controlled trial. And we found that people who are randomized to just listening to these prerecorded programs, it wasn't even interactive. We just gave them the program and said, please listen - a program a day would be fantastic, in that period of time, people who did this had significant decreases compared to people who did not participate in their depression scores, their anxiety scores, and loneliness. So this is something that could probably be very feasibly implemented to help a lot of our older folks that are struggling with things like depression, anxiety and loneliness. Giovanni, what's your approach?

Dr Guaraldi: You see I think that we agree on most of what's said so far because we want to be practical. And we understand that we need to prevent, but also to treat inflammation, treating and preventing comorbidities, but also treating and preventing frailty.

Imagine nowadays we speak of same day therapy, but also definitely the fact that we've got better drugs. And so here I depicted this issue in which of course what we want for all people living with HIV is to achieve the third 90 or over the United Nations (UN) goal or that he's achieving undetectability. But this has been done in the past with drugs that maybe were gero-inducers, because the toxicity associated with these drugs was a somehow accumulating deficit producing comorbidities.

Nowadays we are in the process to consider the contemporary antiretroviral therapy, senomorphic drugs, drugs that may change their senescence and even revert the senescence of aging cell. And so let me conclude with this image. We know that the main stream for treating HIV is the model of the 90-90-90-90 goal that is at the fourth 90, the fourth 90 is achieving good health related quality of life. Let me say achieving healthy living and a healthy aging with HIV. And so if all what we said makes sense, I believe that the metabolic health is a component of the fourth 90. And so let us conclude and try to give some remark. First of all, what we said is that that HIV leads to a dysregulation of the immune system, which trigger inflammation, isn't it?

Dr Karris: Absolutely. Antiretroviral therapy certainly decreases the HIV viral load. Doesn't 100% completely eliminate replication. So there's always a little bit of low level viral replication. We know as long as it's low and people are taking their meds, it probably doesn't have a consequence in terms of development of resistance, but it can lead to a chronic inflammatory state. And I think that highlights the importance of achieving and maintaining a hundred percent adherence if possible.

Dr Guaraldi: And we also try to explain the association between inflammation and metabolic derangement. And we know that increasing the risk of chronic diseases is really associated with this immune metabolic process going on in people living with HIV. And that is what we want to treat.

Dr Karris: And as a clinician, a lot of these comorbidities really can be addressed with good primary care, early cancer screening, lifestyle interventions, vaccinations and early diagnosis and treatment of comorbidities.

Dr Guaraldi: And so thank you all of you listening to this webinar and thank you for participating in this activity. Please continue to answer the question that follow and complete the evaluation. Thank you so much.

This is a verbatim transcript and has not been copyedited.