International Workshop on Aging and HIV - Day 2
Well, the weather in DC has turned a bit cooler today, but it definitely feels like autumn. Today will cover more of an operational, implementation approach to the research on HIV and Aging.
Key Learnings from day 2.
Geroscience and epigenetics, or the study of cellular and genetic factors that may drive the aging process. Can we identify the specific factors that control aging and identify ways to affect then to slow the aging process?
Inflammation drives a constant level of immune activation. This inflammation is driven by background replication of the HIV virus and may be affected by CMV infection as well.
There was a discussion across multiple presenters on how to measure the impact of inflammation and frailty and identify the relative risk of HIV aging progression. The CD4/CD8 ratio appears to be a better predictive tool than just the CD4 alone of viral load.
Those with a history of low CD4 prior to starting effective ART are likely to have a CD4/CD8 ratio under 1.0 and are unlikely to ever see a full recovery of immune function and need to be monitored appropriately due to higher risk.
There is a study (AACTG 5426 IPACE-HIV) on how to treat inflammation.
Polypharmacy and deprescription is important and needs to be a key part of the treatment process.
My observation is that while implementation science is discussed it is still far from integrated into the processes either on the clinical or research teams
Session Notes.
Following a brief session on mentorship targeting the many young researchers in the room, we went straight into a session on geroscience and epigenetics. This is the field that does research into our “biological clocks” and how we can measure and influence aging in the body at a cellular or genetic level. The goal is to slow the aging process and delay the onset of chronic diseases. So what is it about HIV that changes the way and rate of cellular aging? Can genetic engineering influence the rate at which these changes occur? The MACS study showed form 2-5 years of aging acceleration. Looking for ways to influence aging based on the impact of old virus residual material in the human genome in DNA to reverse epigenetic age acceleration using reverse transcription or other interventions. the primary way to influence or slow aging is - diet and exercise.
The next study looked at the chronic, low-level immune activation and inflammation and its causal effect on frailty driven by CMV infection. It appears that protection against frailty may be mediated by the T Cell response to CMV.
The next presenter looked at fidelity to exercise prescriptions among older PLWH. The HEALTH study is intended to train older adults to develop exercise habits through assignment to high or moderate intensity exercise programs. The study was able ot show participants were able to meet the target participaiton and heart rate goals.
Functional health outcomes in older women with HIV who often report lower quality of life scores compared to PLWH as a whole. Most women in the study identified comorbidities rather than HIV specific issues when asked about quality of life impact. Stress appears to drive low mental health scores.
ViiV sponsored a series of discussions on interventions with frailty.
The first session discussed the methodology behind how inflammation is related to aging and frailty and whether thee are interventional approaches to mediate the effects. Frailty and sarcopenia seem to be related to a couple of changes in cytokines in the body over time. How chronic inflammation affects the metabolites (genes, proteins, etc) in the body are being studied to understand the pathway of translating changes into aging. In mice, tryptophan seemed to be a consistent player. Reducing tryptophan in the diet can extend lifespan. Elevated tryptophan and metabolite levels were correlated to higher levels of frailty. Modulating this pathway can be studied for potential treatments.
The next session was studying the use of inflammation markers to detect the level of frailty in older PLWH. Inflammation is strongly associated with the comorbidities associated with accelerated aging in PLWH. This may be associated to ongoing background viral replication, even when virus is suppressed. Increased inflammatory markers IL-6 and TNFR1 are associated with the level of frailty. Again the combination of IL-6 and CMV are associated with worsened functional capacity. The CD4/CD8 ratio is a better marker of immune reconstitution than just CD4 count. The worse your ratio, the more likely you are to have impaired function. The ability to reconstitute this is related to the nadir CD4 and age when ART is used to drive reconstitution. CD4/CD8 ration < 1, especially is CD4 <350 is an indicator of frailty risk.
We then moved on to prevention and treatment of frailty. The approach is driven by the level of frailty; robust, pre-frailty and frail. Exercise and nutrition are key here along with anti-inflammation medications (ART). Moderate to intense exercise was shown to be directly related to improvement in CD4/CD8 ratio and improvement in outcomes. Can we use geroscience approaches to mediate the accelerated aging in PLWH? Senotherapeutics can target cellular senescence. Some trials in process. (ACTG 5426 IPACE-HIV) More studies are needed to evaluate the use of anti-inflammatory treatments.
Those long term survivors who had a low nadir (lowest ever) CD4 count prior to introduction of effective ART are unlikely to ever fully reconstitute their immune response. You may see a return of higher CD4 counts and undetectable viral load but a low (< 1.0) CD4/CD8 ratio is likely to remain. These people need to be monitored for accelerated aging, frailty, CVD and other comorbidities.
We then moved to a session on Polypharmacy and deprescribing. As Lon term HIV survivors and people aging with HIV we often have multiple comorbidities that leads to a full medicine cabinet. The risks of polypharmacy (5 or more prescribed medications) require ongoing attention to drug-drug interaction, especially in the presence of over the counter medications and natural remedies. Drug-Drug interactions (DDI) risk is much higher in boosted ART regimens. The efficacy of most ART regimens is not different in old vs young PLWH. Anticholinergic medications are not recommended to elderly PLWH due to higher risk of neurocognitive impairment and falls. REcommendations are to keep a list of medications (prescribed and OTC) to be reviewed at each visit. Check appropriateness for PLWH elderly and DDI. A list of medications targeted for deprescribing is available (insert slide) Also medsafer.com.
A study showed that PLWH have 10% more drug interactions than those without HIV. A comparison of DDI at the VA showed that DTG/3TC had the lowest number of interactions while 4 drug regimens had the highest (likely due to boosted drug regimens)
In a study of hospitalization, no direct HIV related issues were identified as risk factors, but smoking and frailty were significant predictors.
After lunch we moved into a community symposium sponsored by NMAC and the DC CFAR
The DC Cohort run by CFAR identified key factors in getting to viral suppression; treatment for opioid use, medication dispensing review and enhanced adherence support.
Implementation science is the study of methods to increase to uptake of evidence based science into clinical practice. A presentation described the inclusion of geriatrics in an HIV clinical setting, the SILVER program in Brighton, UK. HIV services coordinates care across many subspecialties to address the many comorbidities in aging PLWH. A visit to the clinic is a 40 minute session with the HIV physician, geriatrician, HIV nurse and pharmacist. This is more than a physical exam, but includes mental health, frailty, bone density and quality of life discussions. Patients are referred to the clinic based on an annual assessment of each HIV patient in the clinic.
One outstanding question is whether the Ryan White medical case management services could be leveraged to a) include geriatrics and b) serve as the coordinator of care for those PLWH who are not served by and integrated care model. A follow on is how to address long term care as PLWH age.
