HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity

As Deeks and Phillips note there is indeed emerging data on a link
between bone disease, specifically osteoporosis and osteopenia, and HIV
infection.[1] This data further highlights the complex interactions
between lifestyle, disease and pharmacological factors in this patient
group.

A recent meta analysis of 20 studies demonstrated that HIV infected
patients had a 6.4 fold increased odds of reduced bone mineral density
(BMD) compared with HIV negative controls and 3.7 fold increased odds of
osteoporosis.[2] Controls were matched for age and BMI with an increased
incidence of smoking and amenorrhea noted in HIV infected patients.

This difference in BMD had largely been attributed to chronic
inflammation caused by HIV however recent in vitro studies have
demonstrated that HIV envelope glycoprotein gp120 is capable of directly
promoting osteoblast apoptosis as well as osteoclast proliferation, fusion
and activation, via up-regulating TNF alpha, leading to unopposed bone re-
absorption.[3, 4]

This meta analysis also demonstrated that antiretroviral therapy
(ART) itself may also directly promote bone demineralisation. When
comparing patients treated with ART against ART naive individuals those
receiving ART had a 2.5 fold increased risk of a reduced BMD and 2.4 fold
increased risk of osteoporosis. This effect was more prevalent in patients
treated with protease inhibitors (PI), with an odds ratio of a reduced BMD
of 1.5, and of osteoporosis 1.6, fold higher compared to patients treated
with an alternative class of antiretroviral drug.

The mechanism by which ART, specifically PI, result in reduced BMD
remains to be elucidated. Emerging studies suggest this may be a drug, not
class, effect. In vitro the protease inhibitors ritonavir and saquinavir
have been demonstrated to inhibit IFN gamma associated TNF alpha receptor
associated factor 6 (TRAF6) degradation, in effect working synergistically
with gp120 promotion of osteoclast activity.[4] This effect was not
demonstrated in the PIs indinavir and nelfinavir which have not clinically
been linked to bone loss.

Longitudinal studies of HIV positive patients initiating ART are
needed to delineate the impacts of lifestyle, disease and pharmacological
therapy on BMD in this patient group as well as clarify the heterogeneous
actions of different classes of ART. What is clear however is that we must
take a holistic approach to HIV management, reducing traditional risk
factors, managing HIV as well as being aware of the iatrogenic effects of
therapy.

[1] Deeks SG & Phillips AN. HIV infection, antiretroviral
treatment, ageing and non-AIDS related morbidity. BMJ 2009;338:a3172. (31
January)

[2] Brown TT & Qaqish RB. Antiretroviral therapy and the
prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS
2006; 20:2165-2174.

[3] Gibellini D, De Crignis E, Ponti C, Cimatti L, Borderi M, Tschon
M, Giardino R & Re MC. HIV-1 triggers apoptosis in primary osteoblasts
and HOBIT cells through TNF alpha activation. Journal of Medical Virology
2008 80:1507-1514.

[4] Fakruddin JM & Laurence J. Interactions among human
immunodeficiency virus (HIV)-1, interferon-gamma and receptor of activated
NF-kappa B ligand (RANKL): implications for HIV pathogenesis. Clinical
Experimental Immunology 2004 137:538-45

Competing interests:
None declared