4.1. Cardiovascular Disease

13, PLWH are at increased risk of developing cardiovascular disease (CVD) compared to the general population and this risk appears to persist despite effective virological suppression [ 6 7 ]. While the risk of death associated with CVD is reducing in the general population, recent data on mortality from the United States suggests it may be increasing in PLWH [ 8 ], although this has not been observed in other cohort studies [ 9 ]. However, CVD is estimated to account for 11–30% of mortality in PLWH [ 10 11 ] and while there is a relatively high prevalence of traditional CVD risk factors in populations of PLWH, this does not adequately account for the observed higher prevalence [ 12 14 ].

Chronic inflammation has been linked to the development of CVD in PLWH with those not on ART with detectable virus more likely to develop CVD than those who are on effective, fully suppressive ART [ 7 15 ]. Higher circulating markers of inflammation, such as hsCRP and IL6, are associated with increased prevalence of, and worse outcome with, CVD in PLWH [ 16 17 ]. It has also been shown that vascular inflammation occurs earlier in PLWH despite effective ART [ 18 ] with PLWH more likely to develop high risk atherosclerotic plaques compared to HIV negative controls matched for age and traditional risk factors [ 19 ]. Antiretroviral therapy reduces but does not normalise the circulating inflammatory markers suggesting a persistent chronic inflammatory state despite ART, the causes of which will be discussed below.

The role of ART in the development of CVD in PLWH remains the subject of debate. While there is little doubt that ART, by reducing HIV viremia and inflammation, reduces the overall risk of CVD [ 7 ], certain antiretroviral medications, such as the nucleoside reverse transcriptase inhibitor (NRTI) abacavir and some protease inhibitors (PI), have been associated with an increased risk of CVD in some studies [ 20 ] but is not a consistent observation, with uncertainty remaining as to magnitude of additional risk attributable to ART exposure.

Current use, or use in the last six months of abacavir has been associated with an increased risk of myocardial infarction (MI) [ 21 ]. This association, although repeatedly observed in a number of observational cohort studies, has not consistently been observed in randomised, clinical trials and at least two meta-analyses [ 22 23 ]. Despite this, guidelines recommend considering alternatives to abacavir in PLWH with established CVD or presence of multiple risk factors [ 24 25 ].

It is known that certain antiretroviral regimes can alter traditional risk factors, including induction of dyslipidaemia and in this way, may contribute to CVD risk. The non-nucleoside reverse transcriptase inhibitor efavirenz has been shown to increase total cholesterol, LDL and HDL levels when compared to a regimen containing an integrase inhibitor [ 26 ] while the nucleotide reverse transcriptase inhibitor tenofovir disoproxil fumarate (TDF) appears to reduce atherogenic lipids through a mechanism that remains unclear [ 27 ]. Despite these effects on lipids, however, exposure to neither efavirenz or TDF modified CVD risk when adjusted for alterations in lipid levels [ 28 29 ]. Cumulative exposure to NRTI has also been linked to development of insulin resistance [ 30 ]. First generation protease inhibitors such as indinavir and saquinavir, although rarely used currently, are also known to affect serum lipid concentrations, with cumulative exposure associated with additional CVD risk [ 31 ]. More recent protease inhibitors, such as atazanavir and darunavir, used frequently in contemporary clinical practice, are associated with less dyslipidaemia but there is emerging data that darunavir exposure is also associated with an increased risk of MI [ 32 ]. As these data emerge, clinicians treating PLWH are better able to limit the impact of ART on CVD risk by avoiding use of specific ART drugs in PLWH at higher risk of CVD.

Like in the general population, risk calculators for CVD are used to help identify PLWH who would benefit from primary preventative therapies such as HMG Co-Enzyme A reductase inhibitors or ‘Statins.’ However, CVD risk calculators have not been validated in cohorts of PLWH and are thought to underestimate actual risk of CVD in this cohort [ 33 ]. In addition, use of statins, although shown to reduce both serum lipid levels and development of high risk coronary plaque features, in both HIV negative and positive populations [ 34 ], is often limited in PLWH by significant interactions with concurrent ART. Pitavastin, a recent addition to the statin family, does not utilise the cytochrome p450 system for metabolism and therefore reduces the number of potential drug-drug interactions with ART. It has been shown to be efficacious in PLWH with dyslipidaemia and is currently being studied as an intervention to prevent the development of CVD in PLWH who are deemed low to moderate risk based on traditional CVD risk factors [ 35 36 ]. Other therapeutics targeting inflammation in PLWH are also being developed such as Canakinumab, a novel anti-IL1b monoclonal antibody, which has shown some promising early results [ 37 ].