The prevalence of osteoporosis, as well as fractures, in HIV-infected individuals is more than three times greater when compared with HIV-uninfected controls.84,85
Reasons for decreased bone mineral density (BMD) in PLWH can be split into the following mechanisms:
Immune dysregulation and chronic inflammation; Yong et al. studied risk factors of fragility fractures in a matched case control study in patients with HIV and found that a low CD4+ cell count, use of corticosteroids, and anti-epileptic medications were strong predictors for fragility fractures.86 Furthermore, multiple studies have linked chronic inflammation with low BMD.87
Traditional risk factors for decreased BMD; low Vitamin D, tobacco smoking, excessive alcohol use, and increased use of selective serotonin re-uptake inhibitor (SSRI) have all been associated with low BMD.88,89 These risk factors for osteoporosis are more prevalent in PLWH.89
ART causing bone disease; TDF is the antiretroviral agent with the most potent decrease in BMD, especially at the start of therapy.90 Efavirenz has also been linked to bone disease because it has been shown to decrease vitamin D levels.90
HIV ASSOCIATED NEUROCOGNITIVE DISORDERS (HAND)
HAND is inclusive of a range of neurocognitive disorders related to HIV from asymptomatic cognitive disability to HIV dementia, an AIDS-defining diagnosis that was commonly encountered prior to the advent of effective ART.91 This complex neurocognitive disorder is probably the result of multiple factors, including inflammation with possible atherosclerotic consequences, as well as concomitant abuse of drugs, aging, and potential neurotoxicity of ART drugs.92
Potential mechanisms driving HAND in PLWH will be described within the same three categories:
Immune dysregulation and chronic inflammation; systemic and CNS inflammation seem to play a central role in the pathophysiology of HAND.93
Traditional risk factors for HAND; aging, atherosclerosis, thrombosis, mental illness (depression, anxiety, post-traumatic stress disorder, psychosis, etc.), HCV, and drug use are all linked to HAND and are all more prevalent in PLWH.94
ART causing neurocognitive disorder; when analyzing the effect of ART on neurologic function, it is essential to differentiate separate drug toxicity (i.e., efavirenz) from lack of CNS drug penetration which could potentially cause persistent HIV related CNS damage.95
An obvious interaction between these factors would be chronic inflammation from HIV infection, leading to atherosclerosis with subsequent strokes and ischemic damage, which, in turn, would cause neurologic disease.96
HOW TO COMBAT CHRONIC INFLAMMATION IN PLWH
Many investigators have studied different interventions to decrease the inflammatory response in PLWH.97-107 These interventions can be divided into two groups. The first is using different antiretroviral agents, while the second is using other alternative methods in order to manipulate immune dysregulation and alleviate chronic inflammation.97-107
Group 1: ART Intervention
This group can further be divided into three subcategories based on differing treatment methodology:
- The first method calls for adding another antiretroviral agent to an already suppressive regimen in an effort to decrease inflammation.97 This approach has generally been unsuccessful.97
- The second approach is switching patients who are virologically controlled to a different ART regimen while measuring markers of inflammation.98-100 The SPIRAL trial used this method in patients who had undetectable HIV VL on a boosted Protease inhibitor (PI) and then randomly switched them in a 1:1 fashion to Raltegravir (RAL).98 At 48 weeks after the randomized switching from a boosted PI to RAL, results showed significant changes in several cardiovascular biomarkers that could not be completely explained by lipid changes alone.98 Other RAL switch studies from both non-nucleoside reverse transcriptase inhibitors (NNRTIs) and enfuvirtide (an HIV fusion inhibitor) that measured inflammatory biomarkers also favored the RAL switch arm.99,100 It is worth noting, however, that none of these studies had a clinical endpoint.98-100
- A third method aimed to discover ideal antiretroviral treatments for suppressing chronic inflammation in PLWH is a head-to head trial of different ART regimens in patients that are naïve to treatment. Hileman et al. examined markers of inflammation and monocyte activation in a randomized controlled blinded study of single tablet regimen of cobicistat / elvitegravir / emtricitabine / TDF versus efavirenz / emtricitabine/TDF.101 They concluded that the elvitegravir-containing regimen had a greater decrease in sCD14, hs-CRP, and Lp-PLA2 levels compared to the efavirenz-containing regimen.101
Group 2: Non-Antiretroviral Intervention
There have been a variety of promising studies suggesting alternate therapies to treat chronic inflammation. Multiple published trials revealed that rosuvastatin showed benefit in reducing inflammation markers and immune activation.102-104 Wooten at al. examined the effect of healthy diet and exercise on inflammation in PLWH with undetectable VL and dyslipidemia.105 In this study, these interventions effectively reduced plasma Lp-PLA2 mass.105 Villar-Garcia et al. conducted a double-blind, randomized, placebo-controlled trial of Saccharomyces boulardii in 44 patients with viral loads of <20 copies/ml for at least 2 years. These researchers found that this fungus was very effective at decreasing microbial translocation and inflammation parameters.106 Another innovative approach at non-ART intervention was a 12-week, single-arm, open-label study, whereby Sereti et al. tested the efficacy of IL-7 adjunctive therapy on T-cell reconstitution in peripheral blood and gut mucosa in 23 ART suppressed PLWH with incomplete CD4+ recovery. They observed that administration of r-hIL-7 improved the gut mucosal abnormalities of chronic HIV infection, as well as attenuated the systemic inflammatory and coagulation abnormalities associated with said gut disease.107 Although promising, these non-ART interventions are still investigational.
A practical clinical approach to the management of PLWH should take into account the following:
- Early ART with complete suppression of HIV VL108 has been shown to best minimize the degree of chronic inflammation, immune activation, and microbial translocation by maintaining a functional immune system, while at the same time, limiting the amount of immune dysregulation.
- The prevention and treatment of co-infection is critical for the control of chronic inflammatory processes in PLWH. Counseling about the importance of continued condom use, following vaccination protocols for HPV, HAV, HBV, influenza, and pneumococcus, providing appropriate cancer screening, and treating HCV and HBV would significantly decrease immune activation in this patient population.
- We must always be wary of the adverse effects of certain antiretroviral regimens and continue to explore the use of newer and potentially less toxic agents that may better suppress chronic inflammation by not contributing towards other co-morbidities. Furthermore, non-ART interventions such as proper diet and exercise should be emphasized as part of our armamentarium against immune dysregulation.