Reducing medical comorbidities associated with long-term HIV infection: beyond optimizing antiretroviral therapy regimens

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Non-AIDS-related comorbidities, such as cardiovascular disease [1,2], liver disease [3], kidney disease [1,4], and non-AIDS defining malignancies [2], occur in persons with HIV in greater number [1,5] and at an earlier age [6,7] than in persons without HIV. Although the reasons behind this finding are poorly understood, multiple causes have been proposed, including inflammation [8], immunodeficiency [9], direct viral effects [10], and lifestyle [11–13] factors. Although highly effective and well tolerated antiretroviral therapy (ART) regimens have led to significant reductions in some HIV-associated comorbidities and poor clinical outcomes [14,15] and have increased life expectancy [7,16], the side-effect profiles of ART can also cause and exacerbate preexisting comorbidities, such as dyslipidemia, renal dysfunction, and low bone mineral density [17–19]. As a result, the clinical management of long-term HIV infection has become focused on optimizing medication regimens to minimize the development of comorbidities seen commonly in persons with HIV.
This issue of ‘AIDS’ reports results from a randomized clinical trial that evaluated the efficacy and impact on lipid profiles of switching from a boosted protease inhibitor to dolutegravir in patients at high risk for cardiovascular disease [20]. The authors have demonstrated that switching to dolutegravir was noninferior for maintenance of HIV viral suppression, safe, and resulted in a significant improvement in total cholesterol and lipid fractions [low-density lipoprotein cholesterol, non-high-density lipoprotein (HDL) cholesterol, total cholesterol/HDL cholesterol ratio and triglycerides]. This study has important implications for the choice of ART regimen in patients with HIV who have dyslipidemia and/or are at increased risk for cardiovascular disease. However, as the authors note, there is no existing evidence showing that lowering lipids alone will reduce cardiovascular risk in persons with HIV; other important risk factors, such as smoking and hypertension, must also be considered.
In recent years, multiple studies have improved our understanding of the adverse effects of ART and newer agents have been developed with improved side-effect profiles. Similar to the use of integrase strand transfer inhibitors (such as raltegravir and dolutegravir) in persons with dyslipidemia and cardiovascular disease, tenofovir alafenamide fumarate is now recommended as a comparable agent to tenofovir disoproxil fumarate to reduce kidney and bone toxicities [21], though it is not as favourable for lipids [22,23]. However, as more antiretroviral drugs with fewer and decreased side-effects are introduced into practice, the impact of further optimizing ART on reducing medical comorbidities will be modest. Therefore, we must also focus our approach to reducing medical comorbidities in persons with HIV on understanding the causes of non-ART-related comorbidities and how to prevent them from occurring in the first place.
Apart from the effects of ART, the component causes behind the increased risk of medical comorbidities among persons with HIV, particularly cardiovascular disease, have not been extensively investigated. An on-going study, the Randomized Trial to Prevent Vascular Events in HIV [24,25], is the largest clinical trial to date evaluating HIV-related cardiovascular disease. It is designed to determine whether using statins in people who are taking ART and do not have previously diagnosed heart disease will reduce the risk of major cardiovascular events in this population. Although statins have been shown to be effective as primary and secondary prevention of cardiovascular events in the general population [26,27], studies have not focused specifically on persons with HIV. Similarly, therapeutic strategies like polypills that combine several agents with cardiovascular prevention benefits [28,29] should also be extended to persons with HIV. Polypills may have a greater benefit in HIV patients as they would address the multiple components of cardiovascular risk in HIV simultaneously with a single tablet.

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