October 21, 2010
This is part of a series of articles summarizing presentations from the 1st International Workshop on HIV & Aging, which took place in Baltimore, Md., from Oct. 4 to Oct. 5, 2010. Jump to the table of contents to see the other articles in this series.
The program was kicked off by Luigi Ferrucci, M.D., Ph.D., who gave the first presentation on frailty. He works in geriatrics and presented general data from previous studies in the aging HIV-negative population. He presented compelling data that showed people lose lean body mass (via a syndrome called "age-related sarcopenia") and strength as they age, and those decreases are correlated to higher mortality. Also, inflammation markers such as interleukin-6 increase with age, and levels of over 2.5 pg/ml in the blood have been linked to disability due to loss of muscle strength and mass. He also added that aging-related inflammation can decrease brain volume and may be implicated in depression and other health issues.
Joseph Margolick, M.D., Ph.D., presented previously published frailty data from the Multicenter AIDS Cohort Study (MACS), an ongoing study that since 1984 has enrolled 6,972 men who have sex with men (MSM) in four U.S. cities. Some of these men got infected with HIV since they enrolled, and have been followed up before and after infection. He presented data on a total of 1,045 men with HIV who were followed. About 75 percent of them had an undetectable HIV viral load.
Margolick and his team attempted to determine whether frailty was more common among HIV-positive gay men than HIV-negative gay men. They defined frailty by creating a "frailty-related phenotype" (FRP) -- i.e., a measurement of the physical characteristics of frailty. The FRP was based on a brief survey that assessed four components of frailty: weight loss ("Since your last visit, have you had unintentional weight loss of at least 10 pounds?"), exhaustion ("During the past four weeks, as a result of your physical health, have you had difficulty performing your work or other activities [for example, it took extra effort]?"), slowness ("Does your health now limit you in walking several blocks?"), and low physical activity level ("Does your health now limit you in vigorous activities, such as running, lifting heavy objects, participating in strenuous sports?"). A participant was considered as having FRP at the visit if the answer to at least three of the four questions was "yes." (The assessment of weakness [e.g., grip strength] was not incorporated into the MACS protocol until October 2005 and therefore could not be used in defining the FRP.)
The FRP thus defined had a prevalence of 4.4 percent among MACS HIV-negative MSM aged 65 years and older, which was similar to the prevalence of frailty observed in the Cardiovascular Health Study for men of similar ages. After adjusting for most important factors, frailty was still higher in HIV-positive men compared to HIV-negative men. In fact, Margolick reported that the frailty of a 55-year-old HIV-positive man may be similar to that of a 65-year-old HIV-negative man. History of unintentional weight loss before the initiation of HAART was strongly associated with frailty.
I caution that the HIV-positive people involved in the MACS study population include many men who were exposed to the more "toxic" antiretroviral drugs of the past, and who were also more prone to have wasting syndrome in the past than we experience nowadays, so the data may not be easily extrapolated to the current era. Also, it would have been nice to have measures of testosterone levels in these men, since low testosterone has been associated with frailty in HIV-negative men, and we see testosterone deficiency rates of 20 percent to 30 percent in aging HIV-positive men even after the introduction of HAART. Basal metabolic rate has also been found to be higher in HIV-positive men compared to HIV-negative men, which means that our bodies are not as efficient at burning food for energy as HIV-negative, healthy people.
No therapeutic intervention data was presented to review the effect of exercise, testosterone replacement, or other factors that may improve frailty in HIV-positive men. I always tell people in my lectures to prevent frailty in their older years by exercising and keeping their testosterone at normal levels now, while they are younger. This will help them build muscle and bone mass that will enable them to prevent disability due to fractures or weakness.
As HIV-negative and HIV-positive people age, their bone density decreases. Post-menopausal women are more prone to have bone loss, but men also have this problem. In HIV, there is bone loss at earlier ages than what is expected in the general population. It seems that the virus itself can cause this problem, which seems to get worse among people who are taking HIV medications. The questions are 1) whether or not bone loss stabilizes with time after someone reaches undetectable viral load and 2) when -- and who -- to test for bone loss.
Todd Brown, M.D., Ph.D., reviewed available data on bone loss in HIV that show increased incidence of osteopenia and osteoporosis. Bone loss seems to be associated with inflammatory responses due to HIV infection and/or by the lack of balance between bone cells that build bone compared to cells that help them be reabsorbed. The SMART study showed that people on HIV medications lose more bone than those who are not being treated. Past history of unintentional weight loss, low body mass index, smoking, low testosterone and other well-known bone loss inducers are also common in HIV-positive people -- just as they are in the general population. It is yet unclear if those who started HIV medications with lower baseline CD4 cells, who have been infected the longest, or who were exposed to the more toxic antiretroviral drugs of the past are at higher risk of bone loss.
There are several cohorts that are starting to show an increasing trend of fractures in people living with HIV. Brown reminded us that the latest bone guidelines recommend doing bone scans on HIV-positive people in they have a fracture; if they have traditional risk factors; or if they are 50 years of age or older. To assess who should be prescribed bone density-enhancing drugs, it is also recommended to calculate risk of fractures using the FRAX equation after measuring bone density with DEXA. (To learn more about bone density and screening in people with HIV, read or listen to this January 2010 interview with Brown and Ben Young, M.D., Ph.D.)
It is unfortunate that Brown did not have time to discuss different interventions to increase bone density. As far as I know, there is only one small study that has studied an intervention in HIV-positive people with bone loss. It provided all 44 volunteers 500 mg of calcium plus 400 IU of vitamin D per day, and also gave some volunteers one weekly dose of alendronate (Fosamax) for 96 weeks. Both arms had mild increases of bone density, with the Fosamax + calcium + vitamin D arm having the highest improvement.
But increases, when they occur, are slow, so it is always better to prevent bone loss than to try to reverse it once it has progressed to critical levels. Resistance exercise, calcium, vitamin D and several medications can help increase bone strength. But it seems that HIV-positive people also have vitamin D deficiencies that may prevent proper calcium absorption to build stronger bones.
Judith Currier, M.D., is a good friend of the HIV community and a top clinician in Los Angeles. She reviewed the data on vitamin D deficiencies, which have been linked to bone loss and other health-related issues. This is probably the hottest vitamin in HIV research in the present. It is made by the body after our skin is exposed to sufficient amounts of sunshine, but the liver and kidneys need to transform it into the "active" form, known as 25-OH vitamin D, which is the form that helps our bones and immune system.
Vitamin D may be involved in increasing the ability of immune cells to kill invaders in our bodies. It also seems to help those with tuberculosis have less severe disease symptoms and progression. It can also mediate inflammation by decreasing tumor necrosis alpha levels. In addition, a review of seven past studies in HIV-negative people, five of them found a correlation between low vitamin D levels and higher cardiovascular risk (although the studies were not very similar, so it is difficult to compare apples and oranges).
The general population commonly suffers from vitamin D deficiencies, especially now that most of us try to avoid the sun to minimize skin cancer. People with darker skin, those who live in northern latitudes, those in winter time and the elderly tend to have more vitamin D deficiency. And HIV in itself, as well as the medications used to treat it, seem to also be risk factors.
It is not completely clear if low vitamin D in HIV -positive people is due to inflammatory responses caused by HIV. Emerging data point to the likelihood that HIV-positive people using Sustiva (Stocrin, efavirenz) may have lower vitamin D levels due to this drug's acceleration of the degradation of the vitamin in the liver (it lowered vitamin D levels by 4.5 percent in 26 weeks). Other small studies have shown than Viread (tenofovir) may also affect the metabolism of vitamin D into its active metabolite in the kidneys.
Dr. Robinson from Ontario, Canada, presented some data that may indicate those with lipoatrophy have more vitamin D deficiencies due to changes in skin thickness. I am not convinced about this, however; I think that longer HIV infection was probably the most important factor in those who had lipoatrophy and vitamin D deficiency.
No one has really determined what "vitamin D deficiency" really means, but most clinicians agree that keeping blood levels of 25-OH vitamin D over 30 nanograms/ml may be appropriate to ensure proper amounts of vitamin D. No one knows what the optimum dose of a vitamin supplement should be, nor do we know for sure who should be tested for vitamin D deficiencies. In light of emerging data, however, a growing number of doctors are ordering vitamin D blood level tests in their patients, and are also recommending vitamin D supplements for those who are deficient -- typically 1,000 to 2,000 IU of vitamin D per day, although retesting is needed to determine if a dose adjustment is needed over time. It is a cheap supplement and one that may not harm people even at higher doses, although a recent study in HIV-negative women who were prescribed megadoses of vitamin D in on-again, off-again cycles suffered more fractures than HIV-negative women who were not.
There is a large study looking at the long-term effects of vitamin D plus fish oils in 20,000 HIV-negative people to see if fractures and other health issues are improved by these supplements. However, results will not be available until five years from now.