C15 Metabolic problems and cardiovascular complications
The use of effective and durable combination antiretroviral therapy, or highly active antiretroviral therapy (HAART) has allowed us to witness successful long-term control of viral replication and prevention of AIDS-defining complications in people living with HIV/AIDS (PLWHA). However, non-AIDS-related comorbidities began to emerge as a result of direct viral effects with ongoing inflammation and immune activation, antiretroviral therapy (ART), as well as host factors. Such non-AIDS comorbidities at least partly accounted for the shorter life expectancy observed in PLWHA receiving effective HAART, when compared with that in the general population. These comorbidities are cardiovascular diseases and metabolic complications, the latter including insulin resistance and diabetes, hypertension, dyslipidaemia, fatty liver, obesity, and osteoporosis.
Profiles and characteristics of metabolic problems and cardiovascular diseases in PLWHA
Recent large cohort studies consistently showed higher risk of myocardial infarction among PLWHA compared with the general population, although the excess risk associated with HIV infection has been diminishing over time. Mortality after myocardial infarction was also observed to reduce over time in PLWHA, which was predominantly attributed to improved medical interventions for its treatment.
Risk factors for myocardial infarction were evaluated in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study, which involved >90,000 person-years of follow-up in 21 countries from Europe, USA and Australia. Myocardial infarction was associated with older age, male sex, family history of premature coronary heart disease, smoking, diabetes mellitus (DM), hypertension, dyslipidaemia, as well as exposure to protease inhibitors (PIs). The D:A:D study and some other cohort studies and randomised trials also showed that recent abacavir (ABC) and didanosine (ddI) use were also associated with higher risk of myocardial infarction.
Other than the traditional cardiovascular disease risk factors and antiretroviral drugs, viral replication is another significant risk factor for development of cardiovascular diseases. The Strategies for Management of Antiretroviral Therapy (SMART) study showed that when patients were randomised to receive either continuous ART or CD4-guided interrupted therapy, patients with interrupted treatment had higher risk of cardiovascular events and mortality. This is most likely due to the activation of inflammatory and coagulation pathways by active viral replication leading to endothelial damage.
There is evidence that PLWHA have higher risk of other cardiovascular diseases, including ischaemic stroke and peripheral artery disease, as well as heart failure with both preserved and reduced ejection fraction.
Insulin resistance and diabetes
PLWHA have a higher risk of DM than the general population. In the D:A:D study, in a cohort of 16632 patients with median follow-up of 5.2 years, there was an incidence of new onset diabetes of 4.2 per 1000 person-years. In this study, older age, lipodystrophy, higher body mass index (BMI), glucose and triglyceride levels, and recent CD4 counts <200/μL were predictive of new-onset diabetes. Other risk factors accounting for the higher risk of diabetes in PLWHA included hepatitis C co-infection, tuberculosis, and exposure to older generations of nucleoside reverse transcriptase inhibitors (NRTIs) and PIs . Increasing evidence showed intestinal microbiota might play a role in the pathogenesis of diabetes in the setting of HIV infection.
Most studies showed that PLWHA receiving ART had higher prevalence of hypertension than the general HIV-uninfected population. The burden of hypertension in PLWHA is contributed by a variety of factors. Traditional risk factors, like older age, male sex, family history of hypertension, smoking and use of alcohol and recreational drugs, are associated with higher risk of hypertension in PLWHA. Some HIV-related factors, like lipodystrophy and central obesity secondary to the use of ART, and nadir CD4, have been shown to be associated with higher risk of hypertension as well.
Dyslipidaemia is associated with both HIV infection and the administration of various classes of antiretroviral agents. Treatment-naive patients with advanced HIV infection have higher triglyceride and lower total, LDL- and HDL-cholesterol levels. Various classes of antiretroviral agents, including PIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs) and NRTIs, are associated with dyslipidaemia, including hypertriglyceridaemia, elevated LDL-cholesterol, and decreased HDL-cholesterol, as well as increased apolipoprotein B concentration and small, dense LDL lipoproteins. Some 40-70% of patients on PIs have hypercholesterolaemia or hypertriglyceridaemia in several cohort studies. Newer generations of PIs, e.g. atazanavir (ATV) and darunavir (DRV), have less impact on lipid levels, with lower rise in total cholesterol and triglyceride levels. NNRTIs generally cause less adverse impact on the lipid profile than PIs; efavirenz (EFV) and nevirapine (NVP) raise both total and HDL-cholesterol, resulting in no change or a favourable decrease in total HDL-cholesterol ratio. The newer classes of antiretroviral drugs, including integrase inhibitors (INSTI), generally have little effect on lipid concentrations.
Fatty liver disease
With the availability of cure and long-term control of chronic viral hepatitis infections, non-alcoholic fatty liver disease (NAFLD) is becoming the predominant cause of chronic liver disease in PLWHA, and is reported to be present in 28% to 48% of PLWHA in the modern HAART era. Risk factors associated with NAFLD included higher BMI and waist circumference, DM, hypertension, and high triglyceride and cholesterol levels. Importantly, NAFLD can lead to steatohepatitis and liver fibrosis, which were present in 42% and 22% of HIV-monoinfected individuals respectively, as shown in a recent meta-analysis.
Obesity and lipodystrophy
Body composition abnormalities were present in 40-50% of PLWHA. Lipodystrophy (loss of subcutaneous fat and a relative increase in central fat) was predominantly associated with the use of thymidine analogues in the early ART era. This condition has been associated with atherogenic lipid profile and insulin resistance, as well as a higher cardiovascular risk.
More recently, obesity and visceral adiposity are increasing in prevalence among PLWHA receiving HAART. Up to two-thirds of PLWHA are overweight or obese. Excessive weight gain and increase in visceral abdominal fat were common after initiation of HAART, particularly in those with the lowest pre-treatment CD4 count. Hypertrophied adipocytes and activated macrophages in adipose tissues stimulate the production of pro-inflammatory cytokines and increase oxidative stress. Not surprisingly, obesity is associated with multimorbidity, including cardiovascular diseases, liver disease and cognitive decline in PLWHA.
Higher prevalence of osteopaenia and osteoporosis has been described in PLWHA compared with the general uninfected population. Overall 20-50% of PLWHA were reported to have osteopaenia or osteoporosis. As decrease in bone mineral density (BMD) leads to increased risk of fragility fractures, the problem of osteoporosis and the resulting morbidity and mortality in the ageing population of PLWHA awaits to be seen. In fact, recent studies have shown that PLWHA had 30-70% higher fracture rates than the general population. Reduced BMD in PLWHA is likely a result of interplay among traditional osteoporosis risk factors, HIV infection, and antiretroviral agents. Chronic cytokine activation may play a role in osteoporosis in PLWHA, by promoting osteoblast apoptosis and increasing osteoclastic activity. Among PLWHA, lower BMI, smoking, and longer duration of HIV infection were associated with lower BMD. Observational studies showed that initiation of HAART resulted in decrease in BMD by 2-6% in the first two years, which usually became stabilised or improved while on established HAART. Regarding specific antiretroviral agents, patients on tenofovir disoproxil fumarate (TDF) had been shown to have significantly greater decreases in BMD than those on other NRTIs.
Screening for metabolic and cardiovascular diseases
Prior to initiation of HAART, all PLWHA should be assessed for metabolic and cardiovascular risk factors,[Algorithm 15] including smoking history, physical activity, past history of hypertension, DM, dyslipidaemia, ischaemic heart disease, cerebrovascular disease and peripheral artery disease, and family history of premature coronary heart disease. Measurement of body weight, BMI, waist circumference, blood pressure, fasting glucose, and fasting lipid profile (total, LDL-, HDL-cholesterol, triglycerides) should be performed at the time of HIV diagnosis prior to initiation of HAART, and at least annually afterwards. Ten-year risk for atherosclerotic cardiovascular disease should be calculated. Convenient risk calculators for PLWHA are available at https://www.chip.dk/Tools-Standards/Clinical-risk-scores. Measuring surrogate markers of cardiovascular diseases, including high-sensitivity C reactive protein, apolipoprotein B, and coronary artery calcium score, may aid management decisions for the prevention of cardiovascular diseases.
According to the latest American Diabetes Association definition, DM is diagnosed when fasting glucose is ≥7 mmol/L, or 2-hour plasma glucose during a 75g oral glucose tolerance test is ≥11.1 mmol/L, or HbA1c is ≥6.5%. Patients are considered to have increased risk of diabetes (or prediabetes) if their fasting glucose is 5.6-6.9 mmol/L, or 2-hour plasma glucose during an oral glucose tolerance test is 7.8 -11.0 mmol/L, or HbA1c is 5.7-6.4%. According to the World Health Organization criteria, overweight and obesity are defined by BMI greater than 23 kg/m2 and 27 kg/m2 respectively in Hong Kong Chinese population. The International Diabetes Federation defines waist circumference ≥90cm in males and ≥80cm in females in Chinese as central obesity.
For PLWHA with abnormal liver function tests, common causes, including viral hepatitis, alcoholic liver disease, and drug-induced liver injury, should be excluded. Ultrasound is the preferred diagnostic imaging for NAFLD. Non-alcoholic steatohepatitis is diagnosed by liver biopsy, showing steatosis, hepatocyte ballooning, and lobular inflammation.[Further reading A]
Dual-energy X-ray absorptiometry (DEXA) scan is performed to measure BMD, and should be considered for at-risk patients, including post-menopausal women, men ≥50 years, and patients with history of low impact fracture, clinical hypogonadism, or oral corticosteroid use. Osteoporosis is defined as T score <-2.5, and osteopaenia as T score between -2.5 and -1.0 in post-menopausal women and men younger than 50 years old. BMD is regarded below the expected range for age in pre-menopausal women and men younger than 50 if Z score is -2.0 or lower. If BMD is reduced, secondary causes should be excluded, e.g. smoking, excessive alcohol use, vitamin D deficiency, steroid use, hyperparathyroidism, hyperthyroidism, malabsorption, hypogonadism, autoimmune disease, diabetes, and chronic liver disease. For patients with osteopaenia, their 10-year fracture risk can be calculated using WHO Fracture Risk Assessment Tool (FRAX) https://www.sheffield.ac.uk/FRAX/tool.aspx?country=20.
Management of metabolic problems and cardiovascular diseases [Algorithm 15]
Management of these comorbidities in PLWHA generally follow the recommendations for the general population. Smoking is the most important modifiable cardiovascular risk factor among HIV-infected patients. Cessation of smoking results in reduction in cardiovascular risk by up to 50%. Therefore, counselling on smoking cessation is essential. Patients can be referred to specialist smoking cessation clinics in Hong Kong (Details on referral to public services can be found at https://www.taco.gov.hk/t/english/quitting/quitting_scc.html).
Counselling on diet should stress limiting energy intake from total fats and sugars, increase consumption of fruit and vegetables, as well as legumes, whole grains and nuts. Adult PLWHA should be encouraged to engage in at least 150 minutes moderate-intensity aerobic physical activity (or at least 75 minutes of vigorous-intensity aerobic physical activity) throughout the week. Aerobic activity should be performed in bouts of at least 10 minutes duration. Muscle-strengthening activities should be done involving major muscle groups on 2 or more days a week.
Management of cardiovascular diseases
For patients diagnosed with cardiovascular diseases, modification of cardiovascular risk factors by lifestyle modification and pharmacological therapy are essential. Addition of anti-platelet agent, beta-blocker, and statin is often necessary. Cardiologist referral for patients with established or suspected coronary heart disease is recommended. Percutaneous coronary intervention and coronary artery bypass graft can be performed safely and effectively in PLWHA with stable immune status and reasonable life expectancy.
Although some antiretroviral agents have been shown to be associated with higher myocardial infarction risk, interruption of antiretroviral therapy is not recommended as a measure to reduce cardiovascular events, as explained above by the SMART study. In fact, current evidence supports early initiation of continuous HAART in PLWHA to reduce cardiovascular morbidity and mortality. However, specific antiretroviral agents associated with higher cardiovascular risk, e.g. lopinavir-ritonavir (LPVr) and ABC, should be avoided and switched to alternative agents.
Management of diabetes mellitus
Management of diabetes in PLWHA is similar to the uninfected population. Self-monitoring of blood glucose should be encouraged. Lowering HbA1c to <7% has been shown to reduce microvascular complications and macrovascular diseases. HbA1c should be monitored at least twice per year for patients who have met treatment goals, and quarterly for those who have not. Of note, discrepancy between HbA1c and an individual’s true mean glycaemia may occur in situations affecting red cell turnover, e.g. macrocytosis associated with older generations of NRTI and ABC. Patients should be regularly assessed for any diabetes-related complications. Screening for nephropathy should be done at least annually by measuring urine albumin excretion and serum creatinine. Foot examination and screening for retinopathy and distal symmetric polyneuropathy should also be performed regularly.
Lifestyle intervention includes nutrition therapy of glycaemia and weight management emphasising portion control and healthy food choices, e.g. carbohydrate intake from foods higher in fibre and lower in glycaemic load, diet rich in monounsaturated and polyunsaturated fats, and alcohol in moderation. Regular moderate-to-vigorous intensity aerobic physical activity and resistance exercise are also recommended. Currently, metformin is recommended as the first-line drug treatment for patients with type 2 diabetes unless contra-indicated. One or more additional anti-hyperglycemic agents should be added if treatment goals are not met. Choices include sulphonylureas, thiazolidinediones, dipeptidyl peptidase 4 inhibitors, sodium glucose co-transporter 2 inhibitors, glucagon-like peptide 1 receptor agonist, and insulin. The choice should depend on drug-specific and patient factors. Caution should be exercised when there is drug interaction with anti-retroviral drugs. A notable example is dolutegravir (DTG), which increases concentration of metformin.
Patients with diabetes should be screened for hypertension and dyslipidaemia. Blood pressure target should be set at <130/80 mmHg, especially for those with other risk factors for cardiovascular disease. Hypertension in patients with diabetes should be treated, preferably with either an angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker. Statin should be added for prevention of atherosclerotic cardiovascular disease.
Management of hypertension
Lifestyle intervention that helps to improve blood pressure includes reducing sodium and increasing potassium intake, and increasing physical activity. Secondary causes should be excluded if clinically indicated. Anti-hypertensive drug treatment should be initiated in those with average blood pressure ≥140/90 mmHg, or ≥130/80 mmHg in those with established cardiovascular disease or high risk of cardiovascular disease. Caution should be paid for any drug-drug interactions DDI between anti-hypertensive and antiretroviral agents, in particular NNRTIs and PIs.
Management of dyslipidaemia
If dyslipidaemia is diagnosed, secondary causes should be screened for, and these include obesity, DM, hypothyroidism, nephrotic syndrome, liver disease, excessive alcohol intake, and use of hormonal treatment. Lifestyle intervention should involve a dietary pattern that emphasises intake of vegetables, fruits, whole grains, legumes, healthy protein sources (low-fat dairy products, low-fat poultry (without the skin), fish/seafood, and nuts), and non-tropical vegetable oils, and limits intake of sweets, sugar-sweetened beverages, and red meat.
In patients with ART-induced dyslipidaemia, a modification of HAART regimen to include more “lipid-friendly” anti-retroviral drugs should be considered, if virological suppression can be maintained. Switching patients on ritonavir- or cobicistat-boosted regimens and EFV to raltegravir (RAL), DTG, bictegravir (BIC) and rilpivirine (RPV) have been shown to improve lipid profiles. [Further reading B]
Statins remain the cornerstone of lipid-lowering therapy in PLWHA. In patients with established atherosclerotic cardiovascular diseases, severe primary hypercholesterolemia (LDL cholesterol ≥4.9 mmol/L, or diabetes with LDL cholesterol ≥1.8 mmol/L, statin should be initiated to reduce LDL cholesterol. Statin should also be considered in other adults with 10-year atherosclerotic cardiovascular disease risk ≥7.5%, especially if other risk factors are present. Ezetimibe and PCSK9 inhibitors can be considered in high-risk individuals when fail to achieve target LDL-cholesterol levels with maximally tolerated doses of statin. Attention has to be paid to DDI between statin and various anti-retroviral drugs, including PI and NNRTI. PIs, which are CYP 3A4 inhibitors, increase concentrations of certain statins. Pravastatin, atorvastatin and rosuvastatin are the recommended statins to be used with PIs; simvastatin is contra-indicated with PIs.
Management of fatty liver disease
Weight loss by lifestyle modification is currently the mainstay of treatment for PLWHA with NAFLD. A 10% reduction in body weight has been shown to improve hepatic necroinflammation. Alcohol consumption should be discouraged, and control of diabetes and other metabolic complications are also important elements of management. In patients with biopsy-proven steatohepatitis, vitamin E and pioglitazone have been shown to improve NAFLD activity score on liver biopsy, although long-term use of these drugs have to be balanced against its associated risks.
Management of lipodystrophy
As no treatment has been proven to reverse lipodystrophy completely, avoiding or prophylactic switching from the use of stavudine (d4T) and zidovudine (ZDV) to alternative NRTIs (ABC or tenofovir) is the key to prevention of development of lipodystrophy. After development of lipoatrophy, switching from the thymidine analogues to alternative NRTIs or NRTI-sparing regimens only result in partial reversal of the problem. In some studies, pioglitazone and uridine supplement had been shown to partially increase subcutaneous limb fat, while recombinant human growth hormone, human growth hormone-releasing-factor analogue and metformin had been shown to reduce visceral fat. Reconstructive intervention, e.g. injection of fillers (e.g. poly-L-lactic acid) to improve facial lipoatrophy, and surgical removal of buffalo humps, can be contemplated in selected patients.
Management of osteoporosis
Patients should be advised to have adequate dietary calcium and vitamin D intake, regular weight-bearing exercise and avoid smoking and excessive alcohol. Secondary causes of reduced BMD, if found, should be managed accordingly. Pharmacological treatment should be considered for patients with history of fragility fracture, post-menopausal women or men ≥50 years with confirmed osteoporosis by BMD measurement, or  patients with osteopaenia and a 10-year risk for all osteoporotic fracture ≥20% or hip fracture ≥3%. Bisphosphonates have been shown to improve BMD in HIV-infected patients with osteopaenia or osteoporosis, and should be considered as first-line therapy in HIV-infected patients.
Algorithm 15. Prevention and management of cardiovascular risk factors in PLWHA
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