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Update from CROI 2016: Bones, Vitamin D, Frailty
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Todd T. Brown, MD, PhD
Associate Professor of Medicine and Epidemiology
Division of Endocrinology, Diabetes, & Metabolism
Johns Hopkins University
CROI 2016 included some important contributions to our understanding of bone disease and frailty. Paddy Mallon from University College in Dublin gave an outstanding plenary entitled: "What exactly does antiretroviral therapy do to bone?". For interested readers who were unable to attend his presentation, I encourage you to check it out online (http://www.croiwebcasts.org/console/player/29685?mediaType=slideVideo&) Here, I'll focus on the presented abstracts regarding bone, vitamin D, and frailty with a particular emphasis on those with potential clinical relevance.
Fracture Epidemiology:
When talking about osteoporosis fracture is THE endpoint to investigate. There have been multiple fracture studies in HIV, but two were presented that shed some additional light on the risk factors for fracture in HIV-infected persons. In the EuroSIDA study (#46), the incidence of fracture and associated risk factors since 2004 were investigated in 11,820 people providing over 86,000 person years (py) of follow-up. During this period, 619 fractures occurred in 496 persons, yielding an incidence of 7.2 (6.6-7.7)/1000 pys, including 132 osteoporotic fractures (fracture at the spine, hip, arm, wrist). In the multivariable analysis, fracture was associated with higher age, lower BMI, white race, and IV drug use as the mode of transmission. Similar to other studies, HCV was independently associated with fracture. It should be mentioned that this HCV effect was independent of the IV drug use effect. Undoubtedly, most of the IV drug users were HCV positive (though these data were not shown). It's notable that low BMI, IV drug use, and HCV were all statistically significant in the multivariable model suggesting that each of these is associated with the risk of fracture in some way, whether it be a direct effect or as a disease marker for some other risk factors which confers the increased risk.
Co-morbid conditions were also significant predictors of fractures, including non-AIDS cancers and recent cardiovascular disease. These findings underscore the important point that co-morbidity begets co-morbidity and multi-morbidity can snowball into clinical events. This is a critical concept as we think about the aging of the HIV-infected population.
A major emphasis in the fracture analysis was the association between ART and incident [new] fracture. Whereas no association was observed with PIs (though these data were not presented, but the issue came up in the Q&A), TDF exposure was associated with fracture when assessed as ever/never exposed or current use/non-use. Cumulative TDF exposure was not associated with increased fracture risk after multivariable adjustment [from Jules: in other words this study found ever being exposed to TDF or if you are currently on it is important , while how many years you've been on TDF didn't matter]. None of the TDF exposures were associated with fracture when the location of the fractures was limited to those generally associated with osteoporosis (i.e spine, hip, wrist, forearm) vs a break in any bone, though this analysis was underpowered because there were very many fewer osteoporotic fractures.
The other important contribution of this analysis was identifying the incidence of osteonecrosis and associated risk factors. This is an understudied area of HIV bone disease, especially given the high incidence of osteonecrosis compare to the general population. The two take-home points from this analysis were: 1) osteonecrosis is more common in those with a history of more advanced HIV disease (not surprising but important), 2) no specific ART was associated with osteonecrosis (previously osteonecrosis had been blamed on PIs). The big limitation for this analysis is that they did not have data on glucocorticoid exposure and alcohol use, two of the major risk factors for osteonecrosis.
A second epidemiologic study of fractures compared the rate of incident fractures in HIV-infected and HIV-uninfected men in the Multicenter AIDS Cohort Study (#699). In this study, we found that the rate of fractures increased with increasing age, as expected, but this increase in fracture risk increased in the HIV-infected men beginning at age 50, but increased the HIV-uninfected men after age 60. Similar results were seen when the site of fracture was restricted to spine, hip, upper arm, and wrist (i.e osteoporotic fractures). Current recommendations regarding osteoporosis screening for HIV-infected men suggests that men should get a DXA scan beginning at age 50 (rather than age 70 as in the general population). These data provide evidence to support this recommendation.
CROI: Antiretrovirals, fractures and osteonecrosis in a large European HIV cohort - EuroSIDA........TDF Is Only Antiretroviral Implicated in EuroSIDA Fracture Study - Mark Mascolini - (02/25/16)
CROI:Fractures Occur at a Younger Age in HIV+ Men in the Multicenter AIDS Cohort Study - (03/14/16)
Getting off of TDF…It does a body good (at least the skeleton):
It has been known for some time and is highlighted by the EuroSIDA data above that TDF is bad for the bones. In Gilead 311-1089 (#29), HIV-infected persons virologically suppressed on TDF/FTC + any third agent were randomized to continue their regimen or switch to TAF/FTC + the third agent. About 46% of people were taking a boosted PI. About 85% of the population was male. Over 48 weeks, spine BMD increased by 1.5% in those who switched to TAF vs no change (-0.2%) in those who stayed on the same regimen. Similar results were seen at the hip (+1.1% vs -0.2%, p<0.001). These results suggest that switching to TAF from TDF may be a viable option for patients wishing to improve bone health. It would have been interesting to see what the change in BMD was in those patients with the lowest baseline BMD, i.e. those in whom switching would make the most sense from a bone perspective.
CROI:Switching tenofovir DF to tenofovir alafenamide in virologically suppressed adults....TAF/FTC Noninferior to TDF/FTC, and Safer, in Switch Study
Dual Therapy Simplification:
Another switch strategy would be to simplify the regimen by just taking the TDF out. In the AtLAS-M study (#697), patients who were virologically suppressed on a regimen of boosted atazanavir + 2 NTRI (>75% on TDF) were randomized to either continuing on their regimen or simplifying to dual therapy with ATV/r + 3TC. At 48 weeks, BMD in the femoral neck increased by 1.96% in those who simplified to ATV/r + 3TC and decreased by -1.1% in those who continued on their previous regimen. Similar results were seen at the total hip (+1.58% vs -2.25%, p=0.04). At the lumbar spine, there was no difference in the change in BMD between the two arms. It was not presented how many participants remained virologically suppressed after 48 weeks of follow-up. It also was not presented whether the results differed in those taking vs not taking TDF. Assuming the virologic efficacy of the dual therapy is acceptable, these data would suggest that simplification to ATV/r + 3TC may also be another strategy to improve bone health.
Stopping TDF-containing PrEP:
TDF-containing PrEP is an important tool for HIV prevention. The iPREX study has previously shown that in men who initiated TDF-containing PrEP, BMD decreased by 1-2%. This may not sound like a lot, but if given to people before they reach their peak bone mass this may have important consequences for their fracture risk later on in life. The current analysis (#48LB) investigated whether BMD improves after stopping PrEP. It found that after stopping PrEP, the annualized rate of BMD change was 1.13% at the hip and 1.8% at the spine, such that by the time of re-enrollment in the open label extension (about 18 months after stopping PrEP), BMD was at the level of those participants given placebo. Furthermore, the recovery seemed to be greatest in the youngest participants (< 25 years) who have not yet reached peak bone mass. All in all, these data are encouraging, supporting the notion that the BMD effects of TDF PrEP are reversible, as was also seen in African women in a substudy of VOICE (Mirembe, JAIDS, 2016).
CROI:Recovery of bone mineral density after stopping oral HIV pre-exposure prophylaxis
Young Bones: Infants, Children, & Adolescents: Is TDF bad in utero?
In the PHACS study, HIV-exposed, uninfected infants born to mothers who received TDF had lower bone mineral content compared to infants born to mothers who received non-TDF regimens (Siberry, CID, 2015). This was an observational study, so TDF-exposure was not randomized. In addition, women started on ART both before and during their pregnancy. In P1084 (#36), HIV-infected women were randomized to one of 3 ART regimens: 1) ZDV (plus single dose NVP and TDF/FTC tail), 2) ZDV + 3TC + LPV/r, 3) TDF + FTC + LPV/r. ART initiation started during pregnancy most often in the 2nd trimester or later. No difference were seen in the infant lumbar spine bone mineral content (BMC) between the arms. However, when examining the whole body BMC, the investigators found something unexpected. Contrary to their hypothesis, there was no difference between infant BMC in the triple ART therapies with and without TDF. However, BMC was significantly lower in infants whose mothers were randomized to the two LPV/r-containing triple therapy arms vs the ZDV only arm. It's not clear whether the observed effect in the triple therapy arms was due to LPV/r itself or the fact that the women were started on suppressive ART so late in their pregnancy with resulting effects on the fetal skeleton. We know that ART-initiation impacts BMD regardless of regimen, but whether ART-initiation also affects bone health in the developing fetus, even when HIV-uninfected, is not clear. What's clear from this study though is that TDF given to the mother [during pregnancy] did not have the impact on infant BMC as expected, allaying some safety concerns.
CROI:P1084s: Impact of maternal tenofovir disoproxil fumarate (TDF) use on HIV-exposed newborn bone mineral content - (03/14/16)
CROI:Duration of in utero exposure to tenofovir and linear growth in the first year of life
Is a switch from LPV/r to EFV good for the bones in perinatally infected children?
The NEVEREST 3 study enrolled children who started on LPV/r-containing ART before age 3 and randomized them to continue their LPV/r containing ART or switch to EFV. The CHANGES study investigated the BMC in LPV/r treated vs EFV treated children a median of 2.1 years after the switch. The investigators compared height-adjusted BMC Z-scores in the HIV-infected children compared to HIV-uninfected controls while on treatment, and found that whole body, but not spine height-adjusted BMD Z-scores was lower in the HIV-infected children compared to the HIV-uninfected controls. The investigators then compared BMC in the LPV/r and EFV groups and found that those who remained on LPV/r had lower height-adjusted Z-scores vs those who had switched to EFV, suggesting a beneficial effect of switch to EFV on bone health. Furthermore, the longer time a participant had been on EFV, the higher the BMC, consistent with a continued salutary effect. LPV/r has been implicated in bone loss and fracture in adult HIV populations. From these data, it seems that a switch off on LPV/r to EFV would be a good strategy to help reach peak bone mass in perinatally infected children. Whether a switch to other 3rd agent would have similar beneficial effects requires further study.
CROI:Efavirenz Is Associated With Higher Bone Mass in South African Children With HIV....after switching to EFV from LPV/r - (03/14/16)
Prevention of ART Associated Bone Loss:
Perhaps the biggest bone story at CROI this year was a randomized clinical trial to determine whether a single IV dose of the bisphosphonate, zoledronic acid could attenuate bone loss related to the initiation of ART (#47). As mentioned above, ART initiation is associated with about a 2-6% decrease in BMD over the first 96 weeks, with the largest decreases observed with TDF containing ART, which is characterized by a marked increase in bone turnover. We know that vitamin D/calcium can attenuate bone loss in persons starting TDF/FTC/EFV by approximately 50% (Overton, Annals of Internal Medicine, 2015). Other strategies have not been tested.
Zoledronic acid is a particularly attractive strategy in that a single infusion has long term effects on suppressing bone turnover (it is dosed yearly for treatment of osteoporosis). In this study, 63 HIV-infected persons without osteoporosis were randomized to receive a 5 mg dose of zoledronic acid or placebo prior to initiating ART with TDF/FTC/ATV/r. BMD and markers of bone turnover were examined over 48 weeks. As expected, markers of both bone formation and bone resorption increased markedly in the placebo group, but remain unchanged in the zoledronic acid group, resulting in a 65-73% reduction in bone resorption relative to placebo. The BMD data were impressive. Whereas the placebo group showed the expected decrease in spine BMD by ~5% at week 48, the zoledronic acid group showed an improvement, leading to an 11% relative increase in the lumbar spine. Similar results were observed at the total hip and femoral neck. According to the authors, no major adverse events were observed.
These results suggest that a single dose of zoledronic acid may be an effective preventive measure to avoid ART-associated bone loss. The major limitations to this trial were the relatively short follow-up, the use of a single ART regimen, and small size. The authors are following these participants up to 144 weeks so we will have a better sense of the long term effects. A single dose of zoledronic acid can suppress bone turnover markers for at least 2 years (Grey, J Bone Mineral Research, 2014; Negredo, HIV Medicine, 2015). It could be that immune reconstitution associated with ART initiation had occurred sufficiently by the time the zoledronic acid effects have waned that the ART-associated bone loss will not be observed. Only the long-term data will be able to tell us this.
As it stands now, a single dose of zoledronic acid would be reasonable in my view in HIV-infected persons at moderate/high risk for fracture by virtue of age, BMD or other risk factors prior to ART initiation. However, it should be noted that this is not the population that was studied. Cost and toxicity will limit the application of this strategy to other populations. While no important toxicities were reported in this study, in the pivotal trials for zoledronic acid in post-menopausal women, about 20% got an acute phase reaction after the first dose [self-limited flu-like symptoms (fever, chills, muscle aches) over 2-5 days]. If this strategy were applied to large swath of the HIV-infected population initiating ART, these toxicities would be seen.
Vitamin D:
The offerings regarding vitamin D were somewhat meager this year. Allison Eckard presented two posters (#826, #859) describing the results of a randomized trial in which 61 HIV-infected youths, ages 8-25 years were randomized to standard vitamin D dosing (18,000 IU =~600 IU/d), medium dose supplementation (60,000 IU =~2000 IU/d), and high dose supplementation (120,000 IU =~4000 IU/d) over a 12 month period. During this interval, cellular markers of T-cell activation decreased, with the largest decreases in the high dose group, although the between arm comparisons were not statistically significant. From a bone perspective, spine Z-score increased in the combined medium and high dose supplement groups (p=0.005), whereas no change was observed in the standard dose group. However, the between group p-value was not statistically significant. At the hip, BMD increased similarly in both groups (the standard & medium/high dose groups), either reflecting a similar effect of vitamin D supplementation regardless of dose or the normal natural history of bone accrual in adolescents/young adults. Taken together these studies are suggestive but not definitive regarding the effects of vitamin D supplementation on immune and bone outcomes in younger HIV-infected persons. Larger studies would be needed to confirm these findings with adequate power.
In a secondary analysis of a placebo-controlled RCT investigating the effect of vitamin D (4000 IU) + calcium (1000 mg) daily in HIV-infected persons initiating ART with TDF/FTC/EFV (#700), we examined whether the change in total 25 D, bioavailable vitamin D, and vitamin D binding protein differed by race. There has been concern that in those with darker skin, total vitamin D levels may not provide adequate insight into a person's vitamin D status since VDBP (Vit D binding protein) is generally lower in blacks. The bioavailable vitamin D might be a better measure. At baseline (i.e time of ART initiation), total vitamin D levels were lower in black vs non-blacks, but bioavailable vitamin D levels were similar. In those randomized to vitamin D and calcium, the change in total 25 D was similar by race, but the change in bioavailable 25 D was greater in blacks vs non-blacks. These findings suggest that vitamin D dynamics in response to vitamin D supplementation may differ by race. While it is well known that total 25D levels are generally lower in blacks, the clinical significance is unclear and bioavailable 25 D may be a more accurate measure of vitamin D status compared to total vitamin D. This is important since the assessment of vitamin D status and guidelines for supplementation uses total vitamin D regardless of race. Further work is needed to test this hypothesis.
CROI:Racial Differences in Bioavailable Vitamin D and Response to Supplementation: A5280 ...... Bone, Vit D, EFV+Truvada & Blacks - (03/09/16)
CROI:Vitamin D Supplementation Decreases Immune Activation and Exhaustion in HIV+ Youth...high dose did best & increased Vit D levels best too - (03/17/16)
CROI:Effects of Vitamin D Supplementation on BMD and Bone Markers in HIV+ Youth - (03/14/16)
Aging:
There were several important descriptive studies related to the aging HIV-populations. This CROI saw the first data from the ACTG observational cohort, called HAILO (HIV Infection, Aging, and Immune Function Long-Term Observational Study)(#719, #721). The study enrolled HIV-infected persons > 40 years who had received their initial ART regimen through an ACTG treatment trial. At the entry visit, tests of physical function and questionnaires were completed such that the presence of frailty could be ascertained. Frailty was defined as the presence of ≥ 3 of the 5 criteria: weight loss, exhaustion, weakness (by grip strength), slowness (by walk speed), and low physical activity. Of the 1016 enrolled, 6% were classified as frail and 38% were considered pre-fail (1 or 2 of 5 criteria present). In the multivariable analysis, the factors associated with frailty were lower education, Medicaid/Medicare insurance, smoking, obesity, and neurocognitive impairment. HCV and renal disease tended to be associated with frailty, but these were not statistically significant (p=0.06 for both). Somewhat surprisingly, use of NNRTI as the 3rd drug compared to PI was associated with an increase in the prevalence of frailty.
The investigators also examined factors associated with a slow walk speed (≤ 1 m/sec) and found that non-white race, low education, Medicare/Medicaid insurance, greater weight change with ART-initiation, low physical activity, and renal disease were all significantly associated. Of the ART factors examined any prior use of d4T or ddI was associated with an increased prevalence of slow walk speed.
While the overall prevalence of frailty was low which was not surprising given the relatively young age of the cohort, some of the associations found are novel and may suggest avenues which may lead to strategies which may be helpful for risk stratification or targeted interventions.
In another analysis from HAILO (#721), the prevalence of impairment of independent activities of daily living (IADL) was determined based on self-reported impairment in 8 categories. The most frequent impairments were reported for housekeeping, transportation, and shopping. Overall, 6% reported impairment in 2 or more IADLs, and 11% reported impairment in 1 IADL. Compared to a similar questionnaire done in general population (NHANES), the prevalence of IADL impairment was markedly higher among the HIV-infected participants, particularly in the lower ager categories. In the multivariable analysis, the presence of frailty and neurocognitive impairment were important predictors of IADL impairment. These data suggest that even during middle age, IADL impairment is common among HIV-infected persons, which will only grow in importance as the population ages.
CROI:Frailty is associated with NNRTI-based Initial ART and Modifiable Risks in ACTG 5322 - (02/29/16)
CROI:Factors Associated with Limitations in Daily Activity Among Older HIV+ Adults - (02/29/16)
HIV patients over 75 years:
Indeed, when the oldest populations of HIV-infected persons are examined, a very high burden of comorbidities is observed. In the DatAIDS study group (#709), 430 HIV-infected persons 75 (Geriatric group) and over were compared to 12,748 HIV-infected persons between 50-75 years (Elderly group). Although perhaps not surprising, the prevalence of almost all comorbidities (except depression) was markedly higher in the Geriatric group vs the Elderly group, including diabetes, hypertension, hyperlipidemia, CVD, osteoporosis, neoplasia, and chronic kidney disease. In the Geriatric group, 14% had ≥ 4 comorbidities compared to 4% in the elderly group. These data underscore the very high comorbidity burden in the oldest HIV-infected persons, which has very important implications for the lifespan and health-span of those aging with HIV.
CROI:Aging with HIV: Emerging importance of chronic comorbidities in patients over 75 - (02/29/16)
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