 |
|
|
| |
Bone, Frailty, and Aging at CROI 2019
|
| |
| |
Todd Brown, MD, PhD
Division of Endocrinology, Diabetes, & Metabolism
Johns Hopkins University
As CROI 2019 is fading in our collective rear-view mirrors, now is good time to highlight some aging-related studies that will have impact on the field and how we treat older men and women living with HIV. I will particularly focus on bone related studies, studies that focus on frailty and impaired physical function, and studies that investigated mechanisms underlying aging in people living with HIV (PLWH).
What happened to Vitamin D Studies? Confessions from a former vitamin D evangelist: In past commentaries about CROI, I also covered vitamin D studies, but the paucity of vitamin D related studies at CROI 2019 preclude any discussion. This cooling off of the vitamin D-mania that we have seen in HIV is a general trend also seen on other areas of medicine. 2019 may turn out to the first year in 2 decades that we have not seen a year-over-year increase in the number of Pubmed-indexed publications about vitamin D. This is due, at least in part, to the lack significant findings in randomized trials testing the effect of vitamin D supplementation on non-skeletal outcomes, such as cancer and cardiovascular disease (eg, PMID: 30415629,
28350929, 30964527) and skepticism even about vitamin D's impact on fracture (PMID: 30964527). While we know we can identify people with low vitamin D levels (notwithstanding ongoing debate about the definition of "deficiency") and we can give them vitamin D to improve vitamin D concentrations, there is sparse evidence that we're helping patients by increasing their vitamin D levels by giving vitamin D supplementation. Clearly, vitamin D is not the panacea that many hoped for a decade ago. My own clinical practice has evolved on this issue. While I used to check 25 OH vitamin D to evaluate the potential etiology of many different signs and symptoms, now I generally restrict testing to those with low bone mineral density (BMD) and those with abnormalities in calcium and phosphate balance. Maybe my list will get longer as the evidence base grows, but for right now, these are the indications that I think are warranted. I also generally don't push vitamin D supplementation for otherwise healthy people and have stopped taking vitamin D supplementation myself.
Bone Studies at CROI:
Fracture and Mortality: The biggest bone story at CROI 2019 was an epidemiologic study linking fracture to mortality in the HOPS study. (http://www.croiwebcasts.org/p/2019croi/30). In this study of over 6800 PLWH over an average of 6 years of follow-up between 2000-2017, there were 506 fractures and 732 deaths. In multivariable analysis, incident fracture was associated with all-cause mortality (Hazard Ratio 1.5, 95% confidence interval 1.2-1.9). Importantly, but not surprisingly, other factors were also independently associated with all-cause mortality such as, low CD4 cell count, HCV co-infections, and other comorbidities including liver, renal, pulmonary, and cardiovascular disease. As we all know, why people die can be very complicated. There are factors that are associated with the mortality event, but also less proximal factors that increase overall risk. What this study tells us is that fracture is one of those factors that may contribute to mortality susceptibility. The big question is whether by preventing fracture through identification of osteoporosis with DXA screening, appropriate institution of bisphosphonates or other medications, or attention to fall prevention will also reduce mortality and help close the mortality gap between HIV+ and HIV- persons. I don't think we'll ever have a definitive answer to that question, but I think it's a decent working hypothesis and one that I bring with me to clinic.
CROI: BREAKING BONES IS BAD: INCIDENT FRACTURE AND MORTALITY IN THE HIV OUTPATIENT STUDY - 45% Increased Mortality Associated with Fracture - (03/06/19)
PrEP and Bone: The DISCOVER study showed that TAF/FTC was as effective as TDF/FTC for the prevention of HIV infection (http://www.croiwebcasts.org/p/2019croi/104), although the overall rate of infection among the 5300+ participants was very low in both arms (15 in TDF/FTC, 7 in TAF/FTC) and most of those infections were either infected at baseline or had very low on study drug levels. One of the key safety outcomes was the effect on bone mineral density. The BMD substudy of 383 participants over 48 weeks showed decreases in BMD in the TDF/FTC arm (lumbar spine -1.2%, hip -0.99%) and no significant change in the TAF/TDF arm (LS: +0.55%, Hip:+0.88%)(both between group p<0.001). A concern about examining mean or median changes is that these types of analyses ignore the tails of the distribution where the greatest changes occur. The authors performed a second analysis of these data examining the proportion who had a >=3% decrease in BMD over the 48 weeks. This degree of change is greater than the error of the DXA machine and may be clinically significant (though this is definitely a debatable point). At the lumbar spine, the proportion with 3% or greater BMD loss was 27% in the TDF/FTC arm and 10% in the TAF/FTC arm. Similar results were seen at the hip (18% vs 4%). As we have seen in studies in PLWH, TAF clearly has less of an effect on BMD compared to TDF. For this reason, it will be a particularly attractive option for persons desiring PrEP who are at increased risk of fracture because of their age, BMD, or other risk factors. It should be noted that the BMD decreases on TDF-containing PrEP are generally reversible upon discontinuation. Also, since PrEP exposure may not be long term and is likely to be less expensive than TAF, for the majority of people TDF-containing PrEP is a safe, effective, cost-effective option to prevent HIV infection.
CROI: THE PHASE 3 DISCOVER STUDY: DAILY F/TAF OR F/TDF FOR HIV PREEXPOSURE PROPHYLAXIS - (03/06/19)
Bone in Women and Children: There were two studies in special populations that need highlighting. First, Thompson et al presented a combined analysis of 7 studies focusing on women who were randomized to TAF/FTC or TDF/FTC for ART initiation or, among those women who were virologically suppressed on TDF/FTC and switched to TAF/TDF or remained on TDF/FTC (https://www.croiconference.org/sites/default/files/posters-2019/1430_Thompson_0519.pdf). Two studies (n=260 women) focused on treatment naïve persons initiating ART and five studies examined virologically suppressed women (n=519), both over 96 weeks. In the treatment naïve women, the net difference between TAF and TDF groups was 2.3% (TAF: -0.3%; TDF -2.6%) in the spine and 2.6% at the hip (TAF:-1.3%; TDF: -3.9%). In the virologically suppressed women, the difference was 2.8% at the spine (TAF: 1.7%; TDF: -1.1%) and 2.5% at the hip (TAF: -0.8%; TDF: 1.7%). There was no explicit comparison to the TAF vs TDF BMD changes in the men, but based on the information presented in the poster, the TAF-TDF % changes were of similar magnitude, with perhaps the exception of the lumbar spine in those who were virologically suppressed (2.8% in women vs 1.8% in men). However, this apparent difference seems to be driven by the greater decreases in the TDF arms among women vs men, rather than greater increases in the TAF arms. Differences in BMD changes by sex is important since there is evidence that BMD decreases faster in women vs men in PLWH (PMID: 29140875). We also don't know from this analysis what the baseline risk of fracture was either from baseline BMD or other risk factors. One of the most important risk factors for fracture is age and these women were relatively young (∼38 y for the treatment naïve women and ∼47 y for the virologically suppressed). The magnitude of the benefit on fracture prevention with avoidance of TDF is dependent on the baseline underlying risk for fracture (i.e., those with the greatest underlying risk stand to benefit the most).
Peak bone mass (at age ∼25-30) is a major determinant of bone mass later on in life, so it's important for later fracture risk prevention that peak bone mass be optimized. It is known that children living with HIV (CLWH) may have a lower peak bone mass compared to their HIV-uninfected peers (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157938/). At CROI, Shiau et al presented data from the CHANGES study in South Africa in which bone parameters in 171 children with HIV were compared to 99 controls without HIV (age ∼10 years)( 1430_Shiau_0816.pdf) . Instead of using DXA, this study used peripheral quantitative CT (pQCT), which, as a 3D measurement of bone, is not as affected by bone size compared to DXA (a 2D measurement). In addition, pQCT can resolve trabecular and cortical bone and gives a measurement of bone strength (polar strength strain index (SSI)). The main finding of the study was that SSI at the tibia was lower in the CLWH compared to controls. In addition, among the males (but not the females), trabecular BMD was lower in those with HIV compared to those without. In an analysis restricted to the CLWH, lopinavir/ritonavir treated children had lower trabecular and cortical BMD than those receiving efavirenz. The big questions are whether these differences will be clinically significant as these children age and what specific interventions can be implemented to potentially mitigate fracture risk in the future.
Falls and Fractures: Falls increase markedly as people age and are a major source of morbidity and mortality, including fracture. In a study in the VA, Womack et al investigated the risk of fracture among over 34,000 persons who had had a previous serious fall, 31% of whom were PLWH. (https://www.croiconference.org/sessions/serious-injury-after-fall-are-those-hiv-greater-risk-uninfected). The major finding was that fracture among fallers was more common in PLWH compared to those without HIV, particularly among those >50 years old. This study provides evidence to focus on fall prevention among older PLWH as a strategy to prevent fracture (and possibly mortality given the results of the study above). In clinic, a simple question that is helpful to ask patients is whether they are worried about falling in their everyday life. Worry about falling is a potent predictor of future falls and its presence may prompt referral to physical therapy to improve strength and balance and other fall risk prevention strategies. Other potential modifiable risk factors for fracture in this study of fallers were polypharmacy, alcohol use, opioid use, muscle relaxants, benzodiazepines, cardiovascular medications, proton pump inhibitors, mental health medications, steroids, and hypoglycemics. It's unclear however whether these medications directly led to fracture risk, or rather the associations seen in the study were related to the underlying condition being treated by these medications or some other confounding factor.
Frailty and Physical Function Impairment and its Relationship to Cognitive Impairment: Physical and cognitive impairment are often conceptualized separately. When we do studies, we often investigate a frailty phenotype, which focuses on physical function, and, in other studies, cognitive impairment, but in reality, these two problems are inter-related and have interactive and perpetuating effects. For example, cognitive impairment leads to decreased physical activity, leading to increase in frailty which increases isolation, leading to worse cognition, and the downward cycle continues. At CROI, we saw a few studies which linked physical and cognitive impairment which is an important area of research, since breaking this downward spiral is critical to healthy aging. In the ALIVE study (a cohort of injection drug users in Baltimore; 1430_Piggott_0418.pdf), frailty (using the Fried Phenotype) and HIV infection were associated with impairments in information and motor processing, which in turn were associated with mortality. In addition, frailty and global cognitive impairment (< 1 SD below the mean in two or more cognitive domains) were independently associated with mortality. In a separate analysis in the HAILO study (the long term observational study in the AIDS Clinical Trial Group; 1430_Masters_0703.pdf), neurocognitive impairment (at least 1 z-score > 2 SD below mean or multiple z-scores at least 1 SD below mean) was associated with the development of a slow gait over 3 years, independent of other risk factors. Taken together, these findings suggest an important influence of impairments of physical function on cognitive function (and vice versa) and hints at their important interactive effects over time.
Exploring Mechanisms of Aging in PLWH: No one really knows why we age. We all can recognize aging when we see it, but the underlying mechanisms are multiple, interactive, and tough to pin down. There are a host of articles that describe these "Pillars of Aging" and are definitely worth checking out ( PMC3836174; PMC4852871). There were several studies at CROI which investigated some of these mechanisms which may underlie aging in PLWH.
Mitochondrial Dysfunction: Since the early HAART era, mitochondrial dysfunction has been a major area of investigation in HIV-related comorbidities, especially related to nucleoside analogue-associated toxicity. Mitochondrial dysfunction is also thought to be a major mechanism underlying the aging process in the general population and it is hypothesized that impairments in mitochondrial function in PLWH from previous thymidine analogue use or chronic inflammation may exacerbate aging-related outcomes. Mitochondrial genetics may contribute to mitochondrial dysfunction in the setting of stressors. In the HAILO study, we investigated mitochondrial genetic haplogroups and frailty among PLWH of European ancestry and found that those with the H haplogroup were more likely to be frail (1430_Erlandson_0702.pdf). How these haplogroups relate to mitochondrial function and whether there's heterogeneity in various tissues (eg muscle, brain, fat, macrophages, T-cells, etc) are unclear. Using a different approach to assessment of mitochondrial function, investigators from the University of Colorado compared the mitochondrial function from muscle biopsies in response to exercise in PLWH and HIV-uninfected controls (1430_Jankowski_0701.pdf). At baseline (prior to starting an exercise program), PLWH had higher voltage dependent anion channel 1 expression (hypothesized to be an adaptation to the increased flux of metabolites between the mitochondria and cytoplasm) and lower complex 3 activity, compared to the HIV-uninfected controls. With institution of a 12 week exercise program, mitochondrial markers (C5, manganese superoxide dismutase, PGC1, C4) increased in the HIV-uninfected controls, but did not change among the PLWH, suggesting a differential mitochondrial response to exercise by HIV serostatus. It's unclear if these differences by HIV serostatus would narrow if the exercise program continued past 12 weeks or if exercise type/intensity may make a difference in muscle mitochondrial function. Exercise is one of the only proven interventions to improve physical and cognitive dysfunction in older individuals, so understanding how exercise response may be different by HIV serostatus is of critical importance.
Inflammation and Epigenetic Aging: Modifications in gene expression through epigenetic changes, such as DNA methylation are thought to be a major mechanism underlying the aging process. Certain DNA methylation patterns have been called an epigenetic clock, which has been found to be accelerated among PLWH (PMC4621253). One potential factor that may lead to increase in epigenetic changes is systemic inflammation. In a study using the National NeuroAIDS Consortium, Sundermann et al investigated whether polymorphisms related to systemic inflammation (IL-6, IL-10, TNF-a) were related to epigenetic changes in occipital lobe tissue (1430_Sundermann_0633.pdf). Accelerated aging was defined a z-score value of DNA methylation compared to age-matched controls. In this population, single nucleotide polymorphisms related to IL-6 and IL-10 (but not TNF-a) were related to accelerated aging by the epigenetic clock. These data provide further evidence that systemic inflammation may influence the underlying mechanisms related to aging in PLWH.
Immunosenescence and CMV Infection: Senescent immune cells are a major source of inflammatory mediators in the general population and have been hypothesized to be an important mechanism of aging. Immunosenescence has also been observed among PLWH. Castilho compared markers of cellular senescence or cellular exhaustion on CD4 and CD8 cells in older (>50y) and younger (30-39 years) people with and without HIV, matched for age, race, and sex (1430_Castilho_0255.pdf). Older adults with HIV had higher levels of senescent and exhausted T-cells. Among those without HIV infection, cellular senescence was related to CMV infection. Nearly all the PLWH in the study were CMV positive, which precluded an evaluation of the independent effects of CMV and HIV on cellular senescence. The importance of CMV infection in aging is also supported by an analysis in the UPBEAT cohort showing that T-cell senescence was associated with a lower CD4:CD8 ratio and CMV positivity (1430_McGinty_0257.pdf) and a case-control study in the ACTG showing that CMV DNA positivity measured in PBMCs was related to an increased risk of non-AIDS events (1430_Gianella_0253.pdf). These findings all provide strong rationale for investigating the effects CMV treatment may affect cellular senescence and aging-related outcomes.
Disclosures: The author has served as a consultant to Gilead Sciences, ViiV Healthcare, Merck, Theratechnologies, and EMD-Serono.
|
| |
|
|
|
|
|
