TDF is particularly associated with loss of BMD

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1 Earn 3 CPD Points online HIV infection and risk of fracture Key messages Antiretroviral therapy (ART) has increased the life expectancy of HIV-infected people, which can now match that of the uninfected population As the HIV-infected population ages, osteoporosis will become a significant factor affecting quality of life Professor Juliet Compston Emeritus Professor of Bone Medicine University of Cambridge School of Clinical Medicine Cambridge UK There is an increased risk of osteoporosis and a modest increase in fracture risk in HIV-infected patients as compared to their non-infected counterparts. Specific associated risk factors are a low CD4 count, ART exposure, particularly to tenofovir (TDF) and co-infection with hepatitis C Most forms of ART are associated with bone loss that occurs in the first year of treatment. This contrasts with the stable bone mass seen in young uninfected adults The long-term significance of this initial bone loss which shows a tendency to return towards baseline over time, is not yet clear, but will unfold as experience with ageing HIV-positive women and men grows TDF is particularly associated with loss of BMD Raltegravir, a new class of ART (an integrase inhibitor), does not cause bone loss and may be associated with a positive effect on BMD Treatment of HIV-positive osteopenic men and women has shown that bisphosphonates improve BMD Bisphosphonates are the only osteoporotic medication with evidence of benefit in this patient group Measures to reduce fracture risk include ensuring adequate calcium and vitamin D intake, and optimising ART where appropriate. Bisphosphonate therapy should be considered for high-risk individuals. This article was made possible by an unrestricted educational sponsorship from MSD, which had no control over content The focal continent for HIV infection is Africa, but there are substantial numbers of HIV-infected people in Asia and the Pacific and also in the developed world of North America, Western and Central Europe. The population of HIV-infected people is very heterogeneous with regard to age, ethnicity, gender and cause of infection, Professor Juliet Compston pointed out at the outset of her presentation. Fully effective modern treatments have extended life expectancy in HIV-infected people and as they age, osteoporosis is emerging as one of the significant comorbidities in this population. The pathogenesis of osteoporosis in HIV-positive individuals is multifactorial in origin and is summarised in Table 1. Trauma should also be added as a cause of bone fracture, particularly in IV drug users. There are four broad classes of antiretroviral (ARV) drugs which include a relatively new class of agents, the integrase inhibitors. The new fixed-dose combinations have revolutionised therapy and improved compliance, Professor Compston noted. The rates of ARV treatment have grown exponentially over the years, with the greatest increase occurring in Africa (Figure 1). This may have an impact on the extent of osteoporosis as these patients are exposed to antiretroviral therapies (ARTs) that adversely affect bone health. February

2 Table 1. Risk factors for osteoporosis and fracture in HIV-positive individuals Low body mass index Hypogonadism ARV therapy Infection inflammation Vitamin D insufficiency Growth hormone deficiency Smoking Alcohol abuse Co-morbidities Renal dysfunction Liver disease Hypertension Dyslipidaemia Cardiovascular disease Diabetes mellitus Cancer Dementia Actual and projected numbers of people receiving antiretroviral therapy in low- and middle- income countries by WHO region and in high-income countries across WHO regions, a Number of people receiving ART Projected trend High income African Region Region of the Americas South-East Asia Region European Region Eastern Mediterranean Region Western Pacific Region Projected trend a Country income classification by the World Bank at the time of the 2011 Political Declaration on HIV and AIDS. Source: Global AIDS Response Progress Report (WHO/UNICEF/UNAIDS) Figure 1. ARV therapy: actual and predicted The adverse effects of the different classes of ART and the potential mechanisms of their actions are currently under investigation. These mechanisms include abnormalities in vitamin D metabolism, increased osteoclast activity and reduced osteoblast recruitment and activity. Probably the agent that has been most studied with regard to its effects on bone is tenofovir (TDF), which results in increased renal excretion of phosphate leading to a Fanconi-like syndrome and severe osteomalacia in some instances. Efavirenz has been associated with altered vitamin D metabolism through the induction of CYP450. Zidovudine has also been shown to increase osteoclastogenesis. 1, 2, 3 2 FEBRUARY 2015

3 Meta-analysis of the risk of osteoporosis, defined as a T-score -2.5, in HIV-infected patients as compared to matched controls across this heterogeneous population, has shown a significant overall increase in risk of osteoporosis in infected cohorts (odds ratio of 3.6). 4 Also, HIV-infected patients on ART were significantly more likely to have osteoporosis than HIV-infected non-treated patients. Interesting data are emerging from a South African study 5 showing that untreated HIV-positive black women have a similar BMD to uninfected black women. The effects of ART in these women are currently being followed up in a longitudinal study. What is clear now from a number of studies is that most forms of ART are associated with bone loss, Professor Compston noted. The bone loss is transient, occurs mainly in the first year with a 2-6% loss of BMD in the hip and spine. This is contrary to what one would expect in a relatively young adult population. In the ASSERT study 6, both ART treatment arms - the one containing TDF, the other without - showed a quite rapid bone loss and an increase in markers of bone turnover. The bone loss occurred within the first 24 weeks and over the next 60 weeks showed a tendency to return towards initial baseline levels. The TDF-treated groups showed a much greater overall bone loss, which reached statistical significance. The clinical implications of this bone loss in essentially young adults are still unknown. When switching from nucleoside reverse transcriptase inhibitor (NRTI) therapy to a fixed-dose combination with TDF, even further bone loss occurred. 7 A newer ART, raltegravir, has been studied with regard to BMD in comparison to TDF and this therapy has not shown any adverse effect on bone. 8 Raltegravir has been shown in small studies to have a beneficial effect on BMD, Professor Compston noted. It does however have a slightly reduced action of viral suppression than other forms of ART. The important clinical issue of the initial BMD loss and subsequent return to baseline stability is how this impacts on the risk of all fractures and fragility fractures in HIV-positive individuals. Data support the view that the fracture rate is increased in ART-treated HIV-positive individuals. A recent meta-analysis 9 showed that both the risk of all fractures and of fragility fractures is statistically increased in this population. Predictive risk factors for fractures in HIV infection Some predictive risk factors have been identified, which can be helpful in determining fracture risk and the need for protective therapy (Table 2). Over and above traditional risk factors, there are three HIV-related factors which add to fracture risk. These are a low CD4 count, ART exposure to two types of treatment (TDF and the protease inhibitors) and, lastly, co-infection with hepatitis C. Table 2. Predictive risk factors for fracture in HIV-positive individuals Traditional risk factors Age Low BMI Tobacco use Alcohol or substance abuse Glucocorticoids Proton pump inhibitors Anticonvulsants Co-morbidities Non-black or white race Factors specific to HIV infection Low CD4 counts ART exposure»» TDF»» Protease inhibitors Co-infection with hepatitis C It is particularly co-infection with hepatitis C that greatly increases risk of fracture, Professor Compston pointed out. This has been shown in a very recent study, where the presence of both hepatitis C and HIV raises the risk of fracture February

4 to levels higher than that of only HIV or only hepatitis C infection. 10 With regard to vitamin D status and HIV infection, we are not quite sure whether there is an increased risk of vitamin D insufficiency or deficiency in HIV and in ART-treated HIV-positive individuals. What has been shown is that efavirenz treatment results in a greater risk of vitamin D deficiency. From a clinical viewpoint it is important to think about osteomalacia and Fanconi Syndrome as a cause of low BMD in a TDF-treated patient. Fanconi Syndrome is very rare; it is a disorder of renal proximal tubules with reduced reabsorption of phosphate, glucose and amino acids, also of calcium, potassium, uric acid, protein, sodium and water. Clinical presentation includes polydipsia, polyuria, dehydration, asthenia, rickets (children) or osteomalacia (in adults). Is it important to treat bone disease in HIV-infected individuals? It is important to assess the individual patient in terms of fracture risk, as the HIV-infected population is heterogeneous and frequently young. The Europeon AIDS Clinical Society (EACS) has published guidelines for screening for bone disease in HIV-positive individuals (www. eacsociety.org Table 3) and has proposed a useful clinical approach to fracture prevention (Table 4). Table 3. EACS guidelines 2014: Screening for bone disease in HIV-positive individuals Consider DXA if 1 of following: Postmenopausal women Men 50 years Previous low trauma fracture High risk of falls Clinical hypogonadism Oral glucocorticoid use 5mg/day prednisolone equivalent > 3 months Use FRAX with BMD if DXA indicated In others use FRAX if > 40 years old and progress to DXA if indicated FRAX may underestimate fracture risk in HIVpositive individuals Table 4. EACS guidelines 2014: Approach to fracture prevention Assess falls risk Ensure adequate calcium and vitamin D intake Consider bisphosphonate therapy in postmenopausal women and men aged >50 years if previous fragility fracture, low BMD, high fracture probability Consider optimising ART in high-risk individuals Treatment decisions in premenopausal women and younger men should be made by a bone specialist Bisphosphonates are the only agents with evidence of benefit in treating HIVpositive individuals. In a double-blind randomised study 11 alendronate therapy (once weekly) with vitamin D and calcium showed a significant benefit in BMD score without adverse effects, although black race was associated with a smaller benefit in overall BMD T-score. Also, a study of intravenous zoledronate given in two doses/year to HIV-infected men showed improvement in BMD T-score of lumbar spine and total hip 12 which lasted for a five-year period. The issue of diagnosis and management of vitamin D deficiency in HIV-infected individuals is a fairly controversial area. The EACS guidelines on vitamin D are useful, but not practicable in all countries, while, the EACS approach to fracture prevention is very useful and is practical in most environments, Professor Compston concluded. 4 FEBRUARY 2015

5 References 1. Parsonage MJ, Wilkins EG, Snowden N, et al. The development of hypophosataemic osteomalacia with myopathy in 2 patients with HIV infection receiving tenofovir therapy. HIV Med 2005; 6(5): Gyllensten K, Josephson F, Lidman K, et al. Severe vitamin D deficiency diagnosed after introduction of antiretroviral therapy including efavirenz in a patient living at latitude 59 degrees north. AIDS 2006; 20(14): Pan G, Yang Z, Ballinger SW, et al. Pathogenesis of esteopenia/osteoporosis induced by highly active antiretroviral therapy for AIDS. Ann NY Acad Sci 2006; 1068: Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a metaanalytic review. AIDS 2006; 20(17): Hamill MM, Ward KA, Pettifor JM, et al. Bone mass, body composition and vitamin D status of ARV, naïve, urban, black South African women with HIV infection, stratified by CD4 count. Osteoporosis Int 2013; 24(11): Stellbrink HJ, Orkin C, Arribas JR, et al. Comparison of changes in bone density and turnover with abacavirlamivudine versus tenofovir-emtricitabine in HIV infected adults: 48 week results from the ASSET study. Clin Infect Dis 2010; 51(8): Haskelberg H, Holy JF, Amin J, et al. Changes in bone turnover and bone loss in HIV-infected patients changing treatment to fenofovir-emtricitabine or abacavirlamivudine. PLos One 2012; 7(6): e Bedimo RJ, Drechsier H, Jain M, et al. The RADAR study: week 48 safety and efficacy of raltegravir combined with boosted DARunavir compared to tenofovir/emtricitabine combined with boosted darunavir in antiretroviral-naïve patients - Impact on bone health. PLos One 2014; 9(8): e Shiau S, Broun EC, Arpadi SM, et al. Incident fractures in HIV-infected individuals: a systematic review and metaanalysis. AIDS 2013; 27(12): ONeill TJ, Rivera L, Struchkov V, et al. The effect of HIV-hepatitis C co-infection on bone mineral density and fracture: a meta-analysis. PLOS One 2014; 9(7): e McComsey GA, Kendall MA, Tebas P, et al. Alendronate with calcium and vitamin D supplementation is safe and effective for the treatment of decreased bone mineral density in HIV. AIDS 2007; 21(18): Bolland MJ, Grey AB, Home AM, et al. Annual zoledronate increases bone density in highly active antiretroviral therapy-treated human immunodeficiency virus-infected men: a randomised controlled trial. J Clin Endocrinol Metab 2007; 92(4): Other CPD accredited reports in the field of Osteoporosis are available at denovo Medica s Women s Health programme. CPD How to earn CPD points online: Visit click on Accredited CPD/CEU programmes, click on registration, submit your details and progress to the Modules page. Choose a module, and follow the steps. Your CPD certificate will be ed to you shortly. Disclaimer The views and opinions expressed in the article are those of the presenters and do not necessarily reflect those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by relevant control authorities. Published by 70 Arlington Street, Everglen, Cape Town, 7550 Tel: (021) I info@denovomedica.com February