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Musculoskeletal Complications of HIV 

Musculoskeletal Complications of HIV
Chapter:
Musculoskeletal Complications of HIV
Author(s):

Tanvir K. Bell

DOI:
10.1093/med/9780190493097.003.0043
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date: 07 December 2019

Vitamin D deficiency and Effects of Vitamin D

Vitamin D helps set up the matrix for bone. Vitamin D levels have been observed to be low in HIV-infected patients. Vitamin D deficiency can lead to osteomalacia and rickets. Vitamin D appears to play a role in cell death and survival, which is termed autophagy; autophagy is also involved in killing intracellular organisms. Vitamin D may also play a role in autoimmune disease, cancer, cardiovascular disease, and diabetes (Spector, 2011). Vitamin D deficiency is common in both developing and developed countries. Recommendations for screening for vitamin D levels are controversial. The Endocrine Society recommends checking vitamin D levels of people who take AIDS medications (Holick, 2011).

The metabolite of vitamin D that is recommended to be measured in blood tests is 25-hydroxyvitamin D (D2). HIV patients frequently have low vitamin D levels (Dao, 2011). Vitamin D2 is converted to 1,25-dihydroxyvitamin D (D3), the active form of vitamin D, in the kidneys. Sunlight assists in the process of conversion to the active form of vitamin D. Natural foods, including oily fish and egg yolks, and vitamin supplements can augment levels of D2 or D3. Lab tests of 25-hydroxyvitamin D should be checked to determine vitamin D levels for patients. A value less than 30 mg/ml is considered to be low (Holick, 2011).

Antiretroviral agents may influence vitamin D levels when patients are started on therapy. There is consistent evidence that efavirenz may lower vitamin D levels (Conesa-Botella, 2010; Gyllensten, 2006). The mechanism for vitamin D deficiency is inhibition of the enzymes involved in vitamin D metabolism. This is not a class effect of the non-nucleoside reverse transcriptase inhibitors; some studies have also shown that protease inhibitors lower vitamin D levels. Tenofovir disoproxil fumarate (TDF) has been associated with renal calcium and phosphate loss and higher parathyroid hormone levels. Vitamin D supplementation in adolescents with or without vitamin D deficiency at baseline led to lower levels of parathyroid hormone (Havens, 2012).

A multicenter study by the AIDS Clinical Trials Group showed that supplementation with vitamin D and calcium led to less decline in total hip and lumbar spine bone mineral density (BMD) at 48 weeks in subjects who initiated efavirenz/emtricitabine/TDF (Overton, 2015). Switching subjects from efavirenz to boosted darunavir is another strategy that has led to increased vitamin D level (Fox, 2013).

Treatment of Vitamin D Deficiency

It is now common to check vitamin D levels in general medicine practice and for HIV-infected patients. Current recommended allowances for vitamin D are 600 IU for persons aged 1–70 years and 800 IU for individuals older than 70 years (Spector, 2011). If replacement of low vitamin D is warranted, initial supplementation is done with 50,000 IU of vitamin D2 or D3 once weekly for 8 weeks or 600 IU of vitamin D2 or D3 daily to achieve blood levels >30 ng/ml. This should be followed by a maintenance dosage of 1500–2000 IU/day (Holick, 2011).

Recommended Reading

McComsey GA, Tebas P, Shane E, et al. Bone disease in HIV infection: A practical review and recommendations for HIV care providers. Clin Infect Dis. 2010; 51(8):937–946.Find this resource:

Spector SA. Vitamin D and HIV: Letting the sun shine in. Top Antivir Med. 2011; 19(1): 6–10.Find this resource:

Osteopenia, Osteoporosis, and Fractures

Low BMD occurs in HIV-infected patients. Many factors contribute to osteopenia, including HIV, host characteristics, and ART. Osteopenia and osteoporosis may cause morbidity in patients with fragility fractures. As the HIV-infected population ages, osteopenia and osteoporosis have become more prevalent, and fractures have been observed more often in HIV-infected patients.

Risk Factors for Bone Loss

Compared to controls, HIV-infected patients have a 3.7 times higher unadjusted odds ratio for osteoporosis (Brown, 2006). HIV-infected postmenopausal women have greater bone loss compared to HIV-uninfected women. In a longitudinal study of postmenopausal women, HIV-infected women had more than twofold higher rates of annualized bone loss at the lumbar spine and radius. Lower body mass index and TDF were associated with more bone loss as well (Yin, 2012). Some data on bone mineral density in HIV-infected patients may be confounded by low weight in HIV-infected patients.

Contributing factors to low BMD in HIV-infected patients are complex. Factors that dispose to osteoporosis which are pertinent to HIV patients include sedentary lifestyle, Caucasian or Asian race, steroid therapy, hepatitis C co-infection, and smoking. Drug use also contributed to bone loss in cohorts of HIV patients receiving outpatient therapy (Young, 2011). Bone loss occurs from the effects of HIV on bone metabolism and cytokine activation. Antiretrovirals can also directly affect bone cells. HIV influences bone formation through upregulating the process of bone resorption and bone formation.

Effects of Antiretroviral Drugs

The overall incidence of BMD loss with antiretroviral initiation is approximately 2–6% during the first 1 or 2 years. Starting ART at higher CD4+ cell counts, as is currently advocated by HIV treatment guidelines, may have beneficial effects on bone health. Pooled analysis of three trials starting therapy in antiretroviral treatment-naive patients showed that subjects with a CD4+ count <50 cells/mm3 had more bone loss compared to those with CD4+ count >500 cells/mm3. Multivariate analysis of this cohort found that older age, female sex, lower body mass index, and higher viral loads were associated with greater BMD decline when subjects were followed for 96 weeks after treatment initiation (Grant, 2013). Bone loss seems to stabilize after the first 2½ years on ART (Bolland, 2011).

The impact of ART on BMD has received increased scrutiny during the past decade. For example, in one study, use of TDF in macaques resulted in decreased bone density and osteomalacia. Tenofovir can cause defects in the matrix of bone by urinary calcium and phosphate wasting through proximal tubule dysfunction. Tenofovir may also influence the role of osteoclasts and osteoblasts (Grisby, 2010). The ACTG 5224 trial, a substudy of ACTG A5202, showed a greater decrease in bone density in the spine and the hip with TDF/emtricitabine versus abacavir/lamivudine (McComsey, 2011). Given the approval of TDF/emtricitabine for pre-exposure prophylaxis, bone effects of this medication in HIV-uninfected patients are a concern. Bone mineral density in the hip and spine decreased modestly after 24 weeks in a study of young men in San Francisco with the average age of 28 years. It did not decrease further after that time, and it reversed when the drug was stopped (Mulligan, 2015). Tenofovir alafenamide, a tenofovir prodrug that leads to decreased plasma tenofovir levels, has been shown to lead to significantly less bone mineral density loss at the hip and spine compared to TDF in antiretroviral treatment-naive patients (Sax, 2015). A single-tablet regimen of emtricitabine/tenofovir alafenamide/elvitegravir/cobicistat (Genvoya) was approved in the United States in November 2015.

Protease inhibitor use and low bone mineral density have been evaluated, with some studies showing a possible relationship (Tebas, 2000). Patients who underwent antiretroviral treatment and protease inhibitor treatment were more likely to have low BMD and osteoporosis compared to controls (Brown, 2006). Efavirenz was shown to lead to less bone loss in the spine compared to ritonavir-boosted atazanavir (McComsey, 2011). Integrase inhibitors may lead to less bone loss compared to protease inhibitors. In HIV antiretroviral treatment-naive patients, raltegravir versus ritonavir-boosted atazanavir or ritonavir-boosted darunavir led to less mean bone loss in the spine and hip (Brown, 2015). Data on bone effects of alternative integrase inhibitors such as dolutegravir and elvitegravir are limited.

Prevalence of Lower Bone Mineral Density in HIV-Infected Patients and Fractures as a Consequence of Bone Loss

Fractures are observed in HIV-infected patients at higher rates than observed in HIV-uninfected individuals. Fragility fracture is a clinical manifestation of osteoporosis and is defined as a fracture from a fall from standing height or less. It usually occurs in the vertebrae, hips, or wrist. Among veterans and postmenopausal women, increased fractures occur in HIV-infected patients compared to HIV-uninfected patients. Compared to outpatients in the National Hospital Ambulatory Medical Care Survey, patients aged 25–54 years in the HIV Outpatient Study (HOPS) cohort had higher fracture rates and relative proportion of fragility fractures. In addition to older age, substance abuse, nadir CD4+ cell count <200 cells/mm3, hepatitis C co-infection, and diabetes were associated with incident fractures (Young, 2011). The Veterans Aging Cohort Study Virtual Cohort (VACS-VC) found a higher risk of fragility fractures in HIV-infected male veterans compared to uninfected male veterans, but this difference was attenuated when the model was adjusted for body mass index (Womack, 2011).

Evaluation for Osteopenia and Osteoporosis

The Osteo Renal Exchange Program recommends evaluating fracture risk for HIV-infected men aged 40–49 years and women aged 40 years or older using the Fracture Risk Assessment Tool (FRAX) calculator, which is accessible on the Internet at http://www.shef.ac.uk/FRAX. (Brown, 2015). DXA scan to measure BMD is recommended in men aged 40–49 years or premenopausal women with a 10-year probability of fracture FRAX score >10%. If the 10-year risk of a major osteoporosis-related fracture on the calculator is ≥20% or a 10-year risk of hip fracture is ≥3%, in countries in which DXA scans are not available, patients should be treated for osteoporosis.

BMD is measured by DXA scan. Osteopenia and osteoporosis are defined based on T-score, which measures individual BMD by DXA and assesses the number of standard deviations compared to a young population average (30 years old), adjusted for gender and race. The World Health Organization (WHO) diagnostic criteria for categories of osteopenia and osteoporosis are listed in Table 43.1. A Z-score measures BMD compared with those of individuals of the same age, weight, ethnicity, and gender. A Z-score is preferred for individuals younger than age 50 years, and a score of –2 or less is abnormal. Experts recommend DXA scans be done in HIV-infected men aged 50 years or older, postmenopausal women, patients on chronic glucocorticoid therapy, patients with a history of fragility fracture, and those with a high risk of falls. DXA should also be done in men aged 40–49 years and premenopausal women with a FRAX score >10% (Brown, 2015).

Table 43.1 WHO Classification of Bone Mineral Density

Classification

T Score

Normal

Above –1

Osteopenia

Between –1 and –2.5

Osteoporosis

At or below –2.5

Severe osteoporosis

Osteoporosis with one or more fragility fractures

Many studies have evaluated markers of bone turnover and biomarkers and cytokines to better determine etiologies of bone loss. Markers of bone turnover include C-telopeptide, N-telopeptide, osteoprotegerin, and RANKL. Interleukin-6 and tumor necrosis factor-α‎ are potent stimulators of osteoclast activity (Brown, 2006). Higher adiponectin, a hormone produced from adipocytes, and lower osteoprotegerin were associated in lower BMD in ART-naive HIV-infected individuals (Brown, 2013).

Treatment

In many trials, including an ACTG trial, alendronate has been demonstrated to be safe and effective for treatment of low BMD when diagnosed by DXA scan in patients with HIV infection (McComsey, 2007). Alendronate 70 mg weekly is usually used. Bisphosphonates are considered the first line of therapy.

Adverse effects of bisphosphonates include esophagitis. Bisphosphonates should be taken while sitting upright, without food and with water. A rare but debilitating consequence of bisphosphonate therapy is osteonecrosis of the jaw. Subtrochanteric fractures or atypical femoral shaft fractures can occur with long-term use. The optimal duration of therapy is uncertain. Benefit past 3 years of therapy is unclear. Further guidance may be available in the future. DXA scans should be followed up 1 or 2 years after initiating therapy.

If possible, underlying risks that contribute to osteoporosis should be modified. These include changing sedentary lifestyle, vitamin D level augmentation, and smoking cessation. Good bone health may be facilitated with adequate intake of vitamin D and calcium. Vitamin D levels may be checked and need to be supplemented. It is recommended that HIV-infected patients consume 1000–1500 mg of calcium per day. Increased weightbearing exercise, smoking cessation, and decreased alcohol consumption are also recommended (McComsey, 2010). Another strategy for augmenting bone health in patients with osteoporosis or bone fractures is switching antiretroviral drugs to raltegravir- or tenofovir alafenamide-containing regimens.

Recommended Reading

Brown TT, Hoy J, Borderi M, et al. Recommendations for evaluation and management of bone disease in HIV. Clin Infect Dis. 2015; 60(8):1242–1251.Find this resource:

McComsey GA, Tebas P, Shane E, et al. Bone disease in HIV infection: A practical review and recommendations for HIV care providers. Clin Infect Dis. 2010; 51(8):937–946.Find this resource:

Muscle Disorders

Muscle disorders can be debilitating in HIV-infected patients. Myopathies can have a range of presentation from myalgias to rhabdomyolysis. HIV-associated myopathy and HIV-associated polymyositis are rare. This entity is slowly progressive, symmetrical proximal muscle weakness. Diagnosis is made by elevated CK, electromyography characteristics, and muscle pathology. Pathologic evaluation will show inflammatory infiltrates of CD8+ T cells and macrophages surrounding major histocompatibility complex-1-expressing muscle fibers. Treatment is with immunomodulatory regimens, including corticosteroids and intravenous immunoglobulin. HIV-associated myopathy can occur as part of the immune reconstitution inflammatory syndrome (Robinson-Papp, 2009). Myalgia and elevated CK can occur from other etiologies in HIV-infected patients, including exercising. Cocaine use and trimethoprim–sulfamethoxazole use have been associated with rhabdomyolysis.

Myopathy can also be a complication of ART. Zidovudine has classically caused HIV treatment-associated myopathy. CK levels are often checked when patients are on zidovudine, which is now less commonly used. Inhibition of DNA polymerase-γ‎ in mitochondria has been implicated as a possible mechanism, and thus drugs that inhibit this enzyme, including stavudine, also cause myopathy. Elevated CK has been seen in HIV-infected patients on many other antiretrovirals, including protease inhibitors. Raltegravir use has been associated with muscle symptoms and elevated CK and, rarely, rhabdomyolysis. Grade 2–4 CK elevations reported in the BENCHMARK 1 and 2 trials were similar for raltegravir versus placebo when combined with optimized background regimen at 9% versus 6%, respectively (Issentress (raltegravir) package insert, https://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf). Postmarketing evaluation in Italy among 496 patients showed that 5.2% of patients on raltegravir had muscle symptoms, and of these, 1.4% discontinued raltegravir (Madeddu, 2015). Data characterizing muscle symptoms and CK for newer integrase inhibitors such as dolutegravir and elvitegravir are lacking. When patients develop myopathy or rhabdomyolysis on a suspected HIV medication, consideration should be given to stopping that drug.

Questions and Answers

This chapter in Fundamentals of HIV Medicine has accompanying questions that can be answered for continuing medical education (CME) credit. To access these questions, visit www.cmeuniversity.com and enter course ID 11635 in the “Find Post-test/Evaluation by Course” field. Access to CME credit expires April 2018.

Recommended Reading

Robinson-Papp J, Simpson DM. Neuromuscular diseases associated with HIV-1 infection. Muscle Nerve. 2009; 40(6):1043–1053.Find this resource:

References

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Brown TT, Chen Y, Currier J, et al. Body composition, soluble markers of inflammation, and bone mineral density in antiretroviral therapy-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr. 2013; 63(3):323–330.Find this resource:

Brown TT, Hoy J, Borderi M, et al. Recommendations for evaluation and management of bone disease in HIV. Clin Infect Dis. 2015; 60(8):1242–1251.Find this resource:

Brown TT, McComsey GA. Osteopenia and osteoporosis in patients with HIV: A review of current concepts. Curr Infect Dis Rep. 2006; 8:162–170.Find this resource:

Brown TT, Moser C, Currier J, et al. Changes in bone mineral density after initiation of antiretroviral treatment with tenofovir disoproxil fumarate/emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir or raltegravir. J Infect Dis. 2015; 212(8):1241–1249.Find this resource:

Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: A meta-analytic review. AIDS. 2006: 20(17):2165–2174.Find this resource:

Conesa-Botella A, Florence E, Lynen L, et al. Decrease of vitamin D concentration in patients with HIV infection on a non-nucleoside reverse transcriptase inhibitor-containing regimen. AIDS Res Ther. 2010; 7:40.Find this resource:

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Havens PL, Stephensen CB, Hazra R, et al. Vitamin D3 decreases parathyroid hormone in HIV-infected youth being treated with tenofovir: A randomized, placebo-controlled trial. Clin Infect Dis. 2012; 54(7):1013–1025.Find this resource:

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McComsey GA, Kendall MA, Tebas P, et al. Alendronate with calcium and vitamin D supplementation is safe and effective for treatment of decreased bone mineral density in HIV. AIDS. 2007; 21(18):2473–2482.Find this resource:

McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir–lamivudine or tenofovir disoproxil fumarate–emtricitabine along with efavirenz or atazanavir–ritonavir: AIDS Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis. 2011; 203(12):1791–1801.Find this resource:

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Overton ET, Chan ES, Brown TT, et al. Vitamin D and calcium attenuate bone loss with antiretroviral therapy initiation: A randomized trial. Ann Intern Med. 2015; 162(12):815–824.Find this resource:

Robinson-Papp J, Simpson DM. Neuromuscular diseases associated with HIV-1 Infection. Muscle Nerve. 2009; 40(6):1043–1053.Find this resource:

Sax PE, Wohl D, Yin M, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: Two randomised, double-blind, phase 3, non-inferiority trials. Lancet. 2015; 385(9987):2606–2615.Find this resource:

Spector SA. Vitamin D and HIV: Letting the sun shine in. Top Antivir Med. 2011; 19(1):6–10.Find this resource:

Tebas P, Powderly WG, Claxton S, et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS. 2000; 14(4):F63–F67.Find this resource:

Womack JA, Goulet JL, Gilbert C, et al. Increased risk of fragility fractures among HIV-infected compared to uninfected male veterans. PLoS One. 2011; 6(2):e17217.Find this resource:

Yin MT, Zhang CA, McMahon DJ, et al. Higher rates of bone loss in postmenopausal HIV-infected women: A longitudinal study. J Clin Endocrinol Metab. 2012; 97(2):554–562.Find this resource:

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