The last 20 years have seen an unprecedented rate of progress in the management and prevention of HIV. The disease has transitioned from the modern-day plague of the late 1990s, into something that many people regard as a chronic illness. In the wake of increased access to anti-retroviral therapy (ART) and a wide range of new and inventive prevention strategies, in 2014 UNAIDS set the global 90-90-90 target. By 2020, they aim for 90% of people living with HIV (PLWH) to be aware of their diagnosis, 90% of those diagnosed to be on ART, and 90% of those taking ART to be virally suppressed.
Despite these encouraging gains, there are still significant barriers to achievement of the 90-90-90 goal. Although Africa carries the largest burden of disease, there are currently two million people living with HIV across Europe, with the rate of new diagnoses increasing each year. Late diagnosis, with its associated impact on morbidity and mortality, continues to be a significant concern, particularly in Eastern Europe.1 However, there are other comorbities that further complicate the pattern of morbidity and mortality among those living with HIV, particularly as this population continues to age.
When discussing overarching morbidity and mortality among almost any population, it is difficult to ignore the impact of cardiovascular disease (CVD). CVD refers to a group of disorders of the heart and blood vessels, the most common of which are coronary heart disease and cerebrovascular disease, but which also incorporates peripheral arterial disease, rheumatic heart disease, congenital heart disease and deep vein thrombosis and pulmonary embolism.1 CVD remains the most common cause of death worldwide, with a particularly high prevalence being evident across Europe.2 In 2016, the European Society of Cardiology found that CVD accounted for 45% of all deaths, with nearly 40% of those deaths occurring prematurely (under the age of 75).3
Increased CVD risk is recognised amongst PLWH seemingly due to a multifactorial interaction between high CVD risk factor prevalence, ART effect and HIV-associated inflammation and immune activation. As the life expectancy of those who are living with HIV approaches that of the general population, it is important to examine the impact that cardiovascular disease may have on this group, both in terms of management of HIV in the presence of CVD as a comorbidity, and in terms of prevention of any additional risk conferred by the virus itself or a lifetime of ART.
CVD risk factors
Risk of CVD is conferred via a myriad of factors; including diet, smoking and alcohol, physical activity, comorbidities such as diabetes, and even low birth weight. Smoking, in particular, is a major cause for concern across Europe; this modifiable behavioural risk factor accounts for 20% of CVD in European men.3 Prevention and management of CVD therefore requires a combination of pharmacological, behavioural and structural interventions, particularly in vulnerable and high-risk groups.
Traditional risk factors in the context of HIV
Recent data from the Data collection on Adverse Effects of Anti-HIV Drugs (D:A:D) study, a worldwide cohort of 49,731 individuals living with HIV under active follow-up, showed CVD to be one of the most common causes (11%) of death, over a ten-year follow up period between 1999 and 2011, following the other leading causes of AIDS-related deaths (29%), non-AIDS cancers (15%) and liver disease (13%).4 Compared with the general population Triant et al found a significantly higher prevalence of CVD risk factors (p<0.001) in PLWH; smoking (38% vs 18%), dyslipidaemia (23% vs 18%), hypertension (21% vs 16%) and diabetes (12% vs 7%).5 Smoking prevalence was comparable to the D:A:D baseline statistics (35%); however, there was a lower prevalence of hypertension (16%) and diabetes (3%), reflecting the differing demographics of data sources. Smoking has been associated with an increased morbidity and mortality in PLWH, with a twofold increased risk of myocardial infarction among people who were current or ex-smokers compared with non-smokers.6 Smoking therefore presents itself as a clear target for preventative measures. Prevalence of substance misuse also remains high in PLWH compared withthe general population demonstrating the complex lifestyle of many individuals and may contribute further to increased CVD risk.
HIV infection is known to disrupt lipid metabolism giving rise to increased triglycerides, total and low-density-lipoprotein (LDL) cholesterol and decreased high-density-lipoprotein (HDL) cholesterol. The use of ART has also been shown to cause dyslipidaemia. Older nucleoside reverse transcriptase inhibitors (NRTIs), stavudine and zidovudine, non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavarinz, and protease inhibitors (PIs) cause raised LDL and triglycerides and thus a concern of increased CVD risk associated with them.7
D:A:D cohort data has revealed ten-year CVD prevalence trends to have reduced over time, more than that in the general population.4 Improved CVD prevention methods, including lipid-lowering medication and lifestyle moderation, as well as decreased use of the high CVD risk-associated ART are possible reasons for this effect.4
HIV as a risk factor
HIV is an independent risk factor for CVD. A recent meta-analysis found the relative risk (RR) of CVD to be 61% higher in PLWH compared with matched HIV-negative counterparts, when traditional risk factors were factored for.7 While the exact mechanism of HIV as a risk factor remains to be understood, there is a growing body of evidence proposing an interplay between a pro-inflammatory state and immune activation.8 A combination of ongoing background low-level HIV viral replication despite viral suppression in PLWH as well as CMV co-infection, adaptive immune system damage and microbial translocation are all referred to in the literature.9 A large Italian cohort showed CMV seropositivity rates to be high among PLWH.10 When compared with CMV-negative HIV positive counterparts, CMV was an independent risk factor for non-AIDS defining events, in particular cerebrovascular and cardiovascular events, supporting an association.10 It is thought to have a role in both chronic inflammation and T-cell activation.9 Gut permeability is increased in PLWH and, as a result, microbial translocation occurs with systemic release of pro-inflammatory products. These are thought to have a role in endothelial activation and therefore increased CVD risk.9 The pathogenesis of HIV as a CVD risk factor and the balance of inflammation versus immune contribution remains to be fully understood.
Several ART regimens have been associated with increased CVD risk; however, the SMART study has shown clear benefits of ART outweighing the risks.11 In the SMART study, PLWH were randomised to receive continuous or interrupted ART, and a significant reduction in morbidity and mortality in the continuous treatment arm was seen and as a result the trial was prematurely stopped.11 Given ART is known to cause dyslipidaemia the study group, investigators were expecting a 15% lower CVD risk in those in the treatment interruption group. However, against expectations, dyslipidaemia was actually reduced by continuous ART. We also recognise abnormal fat distribution as a result of ART use, with typically increased abdominal fat, which, in turn, is a risk for the metabolic syndrome. Islam et al found in their recent meta-analysis that individuals on a PI based regime had higher risk of CVD compared with those on a PI-sparing regime (p<0.001).8 PIs have been associated with both dyslipidaemia and increased risk of myocardial infarction and stroke.7
Controversy has surrounded the NRTI, abacavir, since 2008 when the D:A:D group showed it to be associated with an increased risk of MI. The dataset has been revisited following studies both supporting and refuting these findings. The most recent review of the data shows a strong association of abacavir with increased risk of MI after adjusting for confounding factors.12 The association cannot be ignored and wehave to interpret the findings with caution and manage patients according to the guidelines.
Prevention and management of CVD in HIV
Given that the high prevalence of CVD in Europe is often attributed to a certain lifestyle, CVD prevention among PLWH will always involve managing the behavioural risk factors that mediate CVD risk across the continent. Smoking cessation, in particular, is likely to have a significant impact on CVD incidence among those living with HIV. A 2011 study found that the IRR of acute myocardial infarction among people living with HIV decreased from 2.32 within the first year of cessation to 1.49 after three years, indicating a demonstrable cardiovascular benefit to smoking cessation, even in the presence of the increased risk conferred by HIV infection and ART.6 However, there remains a paucity of data on the design and effectiveness of behavioural prevention programmes that have been specifically tailored to HIV-positive populations, indicating that it may currently be difficult for individual physicians to find evidence-based prevention strategies that take the diverse and complex needs of HIV-positive patients into account.
Even assessing the risk of CVD in patients living with HIV can present obstacles in the clinical setting. Due to the absence of certain HIV-related parameters, the existing Framingham risk score has been found to under-predict cardiovascular risk in certain HIV-positive sub-groups, including women, former smokers and diabetics.7 In 2010, models created using data from the D:A:D study were used to create a more appropriate risk screening calculator; however, it is likely that the efficacy of HIV-specific screening tools will improve as we gain a better understanding of biological factors such as inflammatory and immunologic markers.13 Recent European guidelines for managing CVD in people living with HIV have taken these findings into account; the 2016 British HIV Association (BHIVA) guidelines recommend the use of the QRISK2 scoring system, with a caveat that this may lead to underestimation of risk, while the European AIDS Clinical Society (EACS) recommends the use of the Framingham calculator in conjunction with the D:A:D risk tool.14,15
Modification of behavioural factors, however, will not be effective in the absence of judicious use of pharmacological interventions; both with regards to the prevention of biological risk factors and the avoidance of anti-retrovirals that increase the likelihood of CVD. As always, the selection of an effective ART regime remains the first priority, as viral suppression is the most important determinant of overall morbidity and mortality, as well as preventing the inflammatory changes associated with an HIV viraemia. With this in mind, based on the evidence surrounding anti-retrovirals and CVD risk, the BHIVA guidelines recommend that abacavir, didanosine and lopinavir should be avoided in patients with a high CVD risk, unless removing these drugs will compromise HIV control.14 Pharmacological control of risk factors such as hypertension, diabetes and dyslipidaemia are also important, however anti-retroviral therapy poses several obstacles with regards to drug–drug interactions.
A particular concern is the effect of cytochrome p450 inhibition, as caused by administration of PIs (particularly ritonavir) and the NNRTI, efavirenz. Several of the more commonly used statins, particularly simvastatin, lovastatin and atorvastatin, are susceptible to interactions via this enzymatic pathway, meaning that co-administration of these particular statins and certain PIs is contraindicated.7 The potential for interaction between anti-retrovirals and drugs aimed at tackling hypertension, dyslipidaemia and glycaemic control is something that must always be considered when attempting to mitigate cardiovascular risk in patients living with HIV, and physicians may therefore find it helpful to consult the comprehensive HIV drug-interaction database that has been compiled by the University of Liverpool (www.hiv-druginteractions.org), or other similar treatment guidelines, when prescribing.
Evidence shows increased CVD risk in PLWH but how this manifests clinically is largely unknown. With ever-increasing ART coverage, starting individuals on treatment sooner and using newer, more lipid-friendly agents may alter what we observe in this population over the next decade. When seeing patients with HIV it is important to aggressively manage CVD risk factors: in particular, strongly encouraging smoking cessation and supporting people with managing change.
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10 Lichtner M et al. Cytomegalovirus coinfection is associated with an increased risk of severe non-AIDS-defining events in a large cohort of HIV-infected patients. J Infect Dis 2015;211:178–86.
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