Metabolic Complications of HIV Infection

Case Patient 3

Initial Presentation and History

A 45-year-old male with a history of HIV infection diagnosed 10 years ago, on TDF/FTC/efavirenz (trade name Atripla) for the last 7 years, presents with a left femoral neck fracture after he missed the pavement and fell on his left hip. His history is significant for IV drug abuse for 10 years prior to diagnosis of HIV, and he has been on methadone for the last 6 years.

• Is HIV infection associated with increased prevalence of osteopenia and osteoporosis and increased risk of fractures?

With recent advancements in antiretroviral therapy and improved survival of the HIV-infected population, osteoporosis and increased fracture risk have become important causes of morbidity and mortality. Osteoporosis is a skeletal disorder characterized by compromised bone strength, which predisposes to an increased risk of fracture. The World Health Organization defines osteoporosis as a bone mineral density (BMD) measurement by dual X-ray absorptiometry (DXA) at the spine, hip, or forearm that is more than 2.5 standard deviations below that of a "young normal" adult (T-score < –2.5) or a history of one or more fragility fractures. Fragility fractures result from mechanical forces that would not ordinarily result in fracture, such as fall from standing height [40]. Osteopenia is characterized by low BMD (T-score between –1.0 and –2.5) and can be a precursor to osteoporosis.

Several observational, retrospective, and prospective studies have shown lower bone density and an increased risk of fractures in the HIV-infected population compared to age-, race- and sex-matched HIV-negative adults. In a large meta-analysis of pooled prevalence data on 884 HIV-infected patients compared with 654 HIV-uninfected age- and sex-matched controls [72], overall, HIV-infected patients had a significant 6.4-fold increased odds of reduced BMD and a 3.7-fold increased odds of osteoporosis compared to the control population. This meta-analysis also compared ARV-treated subjects to ARV-naive subjects and showed that ARV-treated subjects (n = 824) had a higher prevalence of reduced BMD compared with ARV-naive subjects (n= 202; odds ratio 2.5, 95% CI 1.8–3.7). The odds of osteoporosis was increased 2.4 times (95% CI 1.2 – 4.8) in ARV-treated subjects compared with ARV-naive subjects. None of the studies adjusted for potentially important confounding factors, such as age or duration of HIV infection. PI-treated patients (n = 791) were also found to have a higher prevalence of reduced BMD compared with PI-untreated patients (n = 410; OR 1.5, 95% CI 1.1–2.0). The odds of osteoporosis in PI-treated patients (n = 666) was also 1.6-fold greater (95% CI 1.1–2.3) than those not treated with PI (n = 367).

Low bone density has also been reported in HIV- positive premenopausal women irrespective of ARV status. In a recent study of 89 premenopausal women (mean age, 37 years) predominantly of African origin with HIV infection, osteopenia and osteoporosis were prevalent in one-third of these women, irrespective of ARV use and were associated with low BMI [73]. In a sub-study of the INSIGHT trial evaluating prevalence of and risk factors for low BMD in untreated HIV infection, performed at several sites across 6 continents involving 424 subjects, osteopenia was present in a third of this relatively young predominantly non-white ART-naive population (mean age 34 + 10 years) with normal CD4 cell counts, while only 2% had osteoporosis. Factors independently associated with lower BMD at the hip and spine were female sex, Latino/Hispanic ethnicity, lower BMI, and higher estimated glomerular filtration rate. Longer duration of HIV infection was also associated with lower hip BMD. Current or nadir CD4 cell count and HIV viral load were not associated with low BMD [74].

Many studies have reported increased fracture prevalence in the HIV population. In a retrospective study of fracture prevalence in a large US health care system, a significantly higher rate of fractures was reported in HIV-infected men and women compared to non-HIV-infected controls (2.87 vs. 1.77 fractures per 100 persons, P < 0.001). The difference in the increased fracture prevalence was greater in HIV positive men compared to women (3.08 vs. 1.83; P < 0.001). Vertebral, wrist and hip fractures were more prevalent in men compared to vertebral and wrist fractures only in women. Fracture prevalence was higher in both Caucasian females and males and only in African-American women [75].

In the HIV Outpatient Study (HOPS) [76], age-adjusted fracture rates in the HIV population were noted to be 1.98 to 3.69 times higher than rates in the general population. The HOPS was an open prospective cohort study of HIV-infected adults who were followed at 10 US HIV clinics. Rates of first fractures at any anatomic site from 2000–2008 were assessed among 5826 active HOPS patients (median age 40 years, 79% male, 52% Caucasian, and 73% exposed to ART). Among persons aged 25–54 years, both fracture rates and relative proportion of fragility fractures were higher among HOPS patients than among outpatient controls. Older age, substance abuse, nadir CD4+ cell count <200 cells/mm, HCV infection and DM were associated with incident fractures [76].