Author: Susa Coffey, MD
HIV-infected individuals, both those on antiretroviral therapy (ART) and those who are untreated, appear to have higher rates of coronary heart disease (CHD) than HIV-uninfected individuals and higher rates of various risk factors for CHD, including dyslipidemia. As the average lifespan of patients on effective ART lengthens, and as people living with HIV become older, morbidity and mortality from CHD are likely to continue to increase. Thus, identification and reduction of modifiable risk factors for CHD are important aspects of primary care for HIV-infected patients.
Dyslipidemia is a well-described independent risk factor for CHD, and it occurs in a high proportion of persons with HIV infection. Current research suggests that this dyslipidemia is caused by a combination of factors related to HIV disease, ART regimens, and individual patient characteristics. HIV itself causes lipid perturbations, particularly in persons with more advanced immunosuppression; HIV-infected individuals who are not on antiretroviral (ARV) medications often have elevations in triglyceride (TG) levels and decreases in high-density lipoprotein (HDL) as well as in low-density lipoprotein (LDL) cholesterol and total cholesterol (TC). Lipid abnormalities also may be caused by or compounded by ARVs (see chapter Coronary Heart Disease Risk). They may appear or worsen within a few weeks to months after starting ART. With some patients, this may, at least in part, represent a return to pre-illness lipid levels, whereas the ARVs cause the abnormality in other cases.
Not all ART-treated patients experience lipid abnormalities to the same degree. Patients with a personal or family history of dyslipidemia, glucose intolerance, diabetes, obesity, or a combination of these health problems may be genetically predisposed to lipid abnormalities that become evident once ART is initiated.
The use of potent combination ART, particularly the use of protease inhibitors (PIs), has increased the prevalence of abnormally high TG, TC, and LDL levels among HIV-infected patients. In fact, dyslipidemia has been associated not only with certain PIs but also with nonnucleoside reverse transcriptase inhibitors (NNRTIs) and some nucleoside reverse transcriptase inhibitors (NRTIs). In the PI class, ritonavir-boosted PIs (with the exception of atazanavir) are particularly likely to cause marked elevations of TG and LDL levels. NNRTIs also may contribute to increases in TC, LDL, and TG levels although the effects, particularly with efavirenz, are more variable (and efavirenz may increase HDL). Of the NRTIs, stavudine, zidovudine, and perhaps abacavir may increase TC and TG levels. To date, available agents from the integrase inhibitor and CCR5 antagonist classes do not appear to have significant adverse impacts on lipid levels.
The largest prospective study of CHD events related to ARVs (the D:A:D study) showed a small but significant increase in the risk of myocardial infarction among HIV-infected patients treated with ARVs; moreover, the effect increased with cumulative years of ARV exposure. This effect was largely but not entirely associated with increases in LDL cholesterol (see chapter Coronary Heart Disease Risk).
Identification and management of dyslipidemia in HIV-infected patients is an important part of HIV primary care. For patients with CHD or CHD risk equivalents (see below), ART regimens should, if possible, be selected to minimize the risk of hyperlipidemia.
Guidelines for the evaluation and management of dyslipidemia have been developed by the National Cholesterol Education Program (NCEP). These recommendations are based on studies of HIV-uninfected persons and may not be entirely applicable to HIV-infected persons, in whom HIV itself may increase risk of CHD events. Despite this limitation, expert panels generally recommend similar treatment goals when evaluating and managing dyslipidemia in patients with HIV infection. (For recommendations on screening, see chapter Initial and Interim Laboratory and Other Tests.)
The history should focus on factors that suggest CHD, risk equivalents, or risk factors for CHD. Both CHD risks and CHD equivalents should be the focus of lifestyle modification strategies and lipid-normalizing treatment.
Check vital signs with special attention to blood pressure and weight. Calculate BMI (see chapter Initial Physical Examination for information on BMI).
Perform a focused physical examination with particular attention to signs of hyperlipidemia, such as xanthelasma and xanthoma, and to the cardiovascular system.
Determine whether a specific intervention is appropriate based on the patient's lipid values and identified CHD risks, as indicated in Tables 1 and 2.
LDL is the main indicator for treatment, and the main target for lipid-lowering therapy. Hypertriglyceridemia is associated with CHD risk, but thresholds of risk have not been defined precisely, and targets for intervention are not entirely clear (for persons with triglyceride levels of ≥500 mg/dL the triglycerides usually are treated first; see "Treatment," below). Severe hypertriglyceridemia (e.g., TG >1,000 mg/dL) also increases the risk of pancreatitis.
For patients who do not have diabetes or preexisting CHD and who have two or more CHD risk factors, calculate the "10-year risk of cardiovascular events" by using the Risk Assessment Tool for estimating the 10-year risk of a major CHD event. Use the risk-estimate tool at the end of this chapter or the online risk calculator at the National Institutes of Health website.
|Risk Category||LDL Goal*||Initiate Therapeutic Lifestyle Changes||Consider Drug Therapy|
|Lower risk: No CHD or CHD risk equivalents and <0-1 risk factor||<160 mg/dL (<4.1 mmol/L)||LDL ≥160 mg/dL (≥4.1 mmol/L)||≥190 mg/dL (≥4.9 mmol/L); at 160-189 mg/dL, LDL drug therapy is optional|
|Moderate risk: No CHD or CHD risk equivalents and ≥2 risk factors, with 10-year estimated risk <10%||<130 mg/dL (<3.4 mmol/L)||LDL ≥130 mg/dL (≥3.4 mmol/L)||≥160 mg/dL (≥4.1 mmol/L)|
|Moderately high risk: No CHD or CHD risk equivalents and ≥2 risk factors and 10-year estimated risk 10-20%||<130 mg/dL (<3.4 mmol/L) (optional goal of <100 mg/ dL)||LDL ≥130 mg/dL (≥3.4 mmol/L)||≥130 mg/dL (≥3.4 mmol/L)|
|High risk: CHD or CHD risk equivalent (see above)||<100 mg/dL (<2.6 mmol/L) (optional goal of <70 mg/dL#)||LDL ≥100 mg/dL (≥2.6 mmol/L)||≥100 mg/dL (≥2.6 mmol/L)|
|Risk Category||Triglyceride Measurement||Initiate Therapy|
|Normal triglycerides||<150 mg/dL|
|Borderline-high triglycerides||150-199 mg/dL|
|High triglycerides||200-499 mg/dL||Start therapeutic lifestyle changes; consider medication if CHD, CHD equivalents, or high risk|
|Very high triglycerides||≥500 mg/dL||Start therapeutic lifestyle changes; consider medication|
The fasting serum lipid panel should be performed at least 8 hours, but ideally 12 hours, after last food and beverage intake. It measures TC, HDL, TG, non-HDL cholesterol with calculated LDL, and TC/HDL cholesterol ratio.
A fasting lipid panel should be checked at baseline, before patients start ART.
Repeat the fasting lipid panel within 3-6 months after ARVs are started, and sooner for patients who have abnormal values at baseline.
Patients with normal lipid values should be rechecked annually. Those with dyslipidemia may need more intensive monitoring (e.g., every 4-6 weeks) until the LDL goal is met, after which monitoring every 4-6 months is adequate.
Treatment of dyslipidemia usually involves a multimodal approach, including diet and exercise in all cases, lipid-modifying medication, and consideration of changes in ARV medication. The primary goal of lipid-lowering therapy is to reduce LDL to target levels. For persons with CHD and CHD risk equivalents, the type and intensity of LDL lowering therapies are adjusted according to LDL baseline levels. Note that other interventions to reduce CHD risk also should be undertaken (e.g., smoking cessation if appropriate).
For patients with serum TG level of >400 mg/dL, the LDL cholesterol calculation is unreliable. In this situation, non-HDL cholesterol (TC minus HDL) can be used as a surrogate target of therapy; the non-HDL goal is 30 mg/dL higher than the LDL goal. For these individuals, dietary intervention is warranted, and drug therapy to decrease LDL (or non-HDL) can be considered if TC is >240 mg/dL or HDL cholesterol is <35 mg/dL. For those with TG levels of 200-500 mg/dL, achieving the LDL cholesterol target is the primary goal, and lowering non-HDL cholesterol levels is a secondary goal (see Table 1 for LDL intervention levels).
The NCEP guidelines recommend that very high TG levels (≥500 ml/dL) be reduced before LDL is treated directly (see "Treatment of hypertriglyceridemia," below).
The LDL levels at which either therapeutic lifestyle change (TLC) or drug therapy should be initiated are shown in Table 1, along with the target goals for LDL cholesterol. The response to therapy should be monitored and therapeutic interventions should be intensified or augmented until lipid targets are met.
TLC, consisting of diet modification and exercise, is fundamental to the management of dyslipidemia for HIV-infected patients.
Target goals for lipid abnormalities are difficult to achieve without prioritizing these behavioral change efforts. Although TLC is hard to maintain, it can yield significant results in reducing CHD risk and improving quality of life. Effective TLC is best achieved with a multidisciplinary team approach. HIV primary care providers should be instrumental in identifying TLC as a treatment priority and providing referrals to nutritionists for dietary counseling, to mental health professionals for assessment of treatable mood disorders, and to social workers, peer counselors, or clinical nurse specialists for assistance with health-behavior changes, self-care strategies, and identification of resources in the community for smoking cessation support and exercise programs. Specific recommendations for TLC goals and behavior change strategies are contained in the Adult Treatment Panel guidelines.
All patients with elevated lipid levels should initiate TLC. If pharmacologic intervention is indicated, statins (hydroxymethylglutaryl coenzyme A [HMG-CoA] reductase inhibitors) are the first-line treatment for most patients. These agents can be effective in reducing TC, LDL, and non-HDL cholesterol levels in HIV-infected patients (see Table 3).
Recommended starting dosages of statins for patients taking PIs are as follows (Note: see "Potential ARV Interactions," below):
Fibrates may be considered as an alternative or adjunct to statins (see "Treatment of hypertriglyceridemia," below, for further information). When given concomitantly, statins and fibrates increase the risk of rhabdomyolysis and must be used cautiously and with careful monitoring). Niacin may be effective as adjunctive therapy, but may worsen insulin resistance and may cause hepatotoxicity. It also causes uncomfortable flushing in some patients; the sustained-release formulations are better tolerated. Ezetimibe (Zetia) appears to be effective in combination with statins for patients whose cholesterol is not controlled adequately with a statin alone, but it has not been shown to decrease CHD events. Bile acid sequestrants generally should be avoided because they may interfere with the absorption of other drugs and may increase TG levels.
|Lipid Abnormality||First Choice||Second Choice||Comments|
|* May have significant interactions with certain PIs; see Table 4.|
|Isolated high LDL, non-HDL cholesterol||Statin||Fibrate||Start with pravastatin* or atorvastatin.* Use low statin dosages and titrate upward; patients taking PIs have increased risk of myopathy.|
|Isolated high TG||Fibrate||Statin, N-3 (omega-3) fatty acids||Start with gemfibrozil or fenofibrate. Combined statin and fibrate may increase myopathy risk.|
|High LDL and TG (TG level 200-500 mg/dL)||Statin||Fibrate||Start with pravastatin or atorvastatin. Use fluvastatin,* rosuvastatin,* gemfibrozil, or fenofibrate as alternatives. Combined statin and fibrate may increase myopathy risk.|
|High LDL and TG (TG level >500 mg/dL)||Fibrate||N-3 (omega-3) fatty acids, niacin, statin||Start with gemfibrozil or fenofibrate. Niacin is associated with insulin resistance. May need to add statin if cholesterol is not controlled adequately.|
Clinicians should note that there are clinically significant drug interactions between most statins and both PIs and NNRTIs (see Table 4). PIs can increase serum levels of most statins significantly, thus increasing the risk of severe statin adverse events such as rhabdomyolysis. Of the statin drugs, pravastatin is the least affected by most PIs (darunavir is an exception) and is the recommended statin for most patients with hypercholesterolemia without hypertriglyceridemia. Atorvastatin, if used, should be initiated at low dosage (10 mg) and titrated slowly upward to achieve target lipid levels (note that atorvastatin may lower TG, TC, and LDL levels). Lovastatin and simvastatin are contraindicated for use by patients taking PIs, and pitavastatin is contraindicated for use by patients taking ritonavir-boosted PIs. These can result in severe statin-related adverse events if prescribed. Other available statins include rosuvastatin and fluvastatin. These have not been as well studied but may be used with most PIs. When statins are given concurrently with interacting PIs, the statins should be started at low dosage and increased incrementally, if indicated; in general maximum dosages should not be used.
NNRTIs decrease levels of most statins (however, etravirine increases fluvastatin levels); higher dosages of statins may be needed to overcome this interaction. Be aware that various formulations and combination products contain these statins; check the generic name of components in new or unfamiliar cardiac prescriptions to determine whether they contain lipid-lowering agents.
Other classes of ARV drugs (NRTI, fusion inhibitor, CCR5 antagonist, and integrase inhibitor) do not have recognized interactions with statins. Other types of lipid-lowering medications generally are not metabolized by hepatic cytochrome P450 and are not affected by ARVs (an exception to this is gemfibrozil, whose levels are decreased by lopinavir/ritonavir, by an unknown mechanism).
|Rosuvastatin AUC ↑ 213% and ↑ Cmax 600%|
|Darunavir/ ritonavir||Pravastatin AUC ↑ up to 500%|
|Fosamprenavir||May need to ↑ pravastatin dosage|
|Lopinavir/ ritonavir||Rosuvastatin Cmax ↑ 466%|
|Nelfinavir||Possible ↓ in nelfinavir levels||No data|
|Saquinavir||Saquinavir + ritonavir: May need to ↑ pravastatin dosage|
|Tipranavir||Atorvastatin Cmax ↑ >760%||Rosuvastatin Cmax ↑ 123%|
|Nonnucleoside Reverse Transcriptase Inhibitors|
|Efavirenz^||May need to ↑ atorvastatin dosage||May need to ↑ flustatin dosage||May need to ↑ lovastatin dosage||No data||May need to ↑ pravastatin dosage||May need to ↑ simvastatin dosage|
|Etravirine||May need to ↑ atorvastatin dosage||May ↑ fluvastatin levels||May need to ↑ lovastatin dosage||No data||May need to ↑ simvastatin dosage|
Patients with TG levels of 200-500 mg/dL should begin non-drug interventions such as diet modification, reduction in alcohol consumption, aerobic exercise, and smoking cessation. When the TG level is ≥500 mg/dL, a low-fat diet (<15% of caloric intake) is recommended to help prevent pancreatitis, and pharmacologic therapy probably will be required. Patients with CHD or CHD equivalents, those at high risk of CHD, and those with TG levels >200 mg/dL may need pharmacologic therapy.
Fibrates are the first-line drug option for isolated hypertriglyceridemia and are an alternative treatment for combined hypertriglyceridemia and hypercholesterolemia. Fenofibrate or gemfibrozil reduce TG levels effectively in patients on ARVs. Because they are not metabolized by the cytochrome P450 hepatic enzyme system, they do not have significant drug interactions with ARVs. Fibrates are contraindicated for use by patients with renal failure. Recommended dosages of these agents are as follows:
If a fibrate alone is inadequate in reducing TG levels, several options are possible. A statin (notably atorvastatin, which acts on TGs as well as cholesterol) could be added cautiously, although there is an increased risk of skeletal muscle toxicity with concomitant use of a fibrate and a statin. N-3 (omega-3) fatty acid supplements (e.g., fish oils), administered at 1-2 g BID or TID, have decreased TG levels in patients taking ART. Extended-release niacin at 1,500-2,000 mg/day also decreases both TG and TC levels, although its clinical utility is restricted because of associated insulin resistance and flushing.
For patients with CHD or CHD equivalents, ARV medications should, if possible, be selected to minimize the risk of hyperlipidemia. In patients with dyslipidemia caused by ARV agents, data suggest that it may be beneficial to discontinue ARVs known to increase lipids if reasonable alternatives exist. Substituting atazanavir or raltegravir in place of a lipogenic PI or replacing stavudine with tenofovir may improve the lipid profile. Before making ARV substitutions, however, consider carefully the possible effect of the substitution on HIV virologic control and the potential adverse effects of new ARVs. In some cases, antihyperlipidemic agents may be necessary even after ARV substitution.
To calculate the 10-year risk of cardiac events, add up points from the following five tables pertaining to age, HDL, systolic blood pressure, TC, and smoking status (Tables 5.1-5.5). Note that in Tables 5.3-5.5, women's points are in parentheses. After adding points from all of the tables, consult Table 5.6. (Alternatively, an online calculator is available.)
(The Framingham Heart Study risk calculator has not been validated for HIV-positive individuals and may underestimate the risk in this population.)
|Systolic Blood Pressure||Points if Untreated-Men (Women)||Points if Treated-Men (Women)|
|<120||0 (0)||0 (0)|
|120-129||0 (1)||1 (3)|
|130-139||1 (2)||2 (4)|
|140-159||1 (3)||2 (5)|
|≥160||2 (4)||3 (6)|
|Total Cholesterol (mg/dL)||Points for Men (Women)|
|Age 20-39||Age 40-49||Age 50-59||Age 60-69||Age 70-79|
|<160||0 (0)||0 (0)||0 (0)||0 (0)||0 (0)|
|160-199||4 (4)||3 (3)||2 (2)||1 (1)||0 (1)|
|200-239||7 (8)||5 (6)||3 (4)||1 (2)||0 (1)|
|240-279||9 (11)||6 (8)||4 (5)||2 (3)||1 (2)|
|≥280||11 (13)||8 (10)||5 (7)||3 (4)||1 (2)|
|Smoking Status||Points for Men (Women)|
|Age 20-39||Age 40-49||Age 50-59||Age 60-69||Age 70-79|
|Nonsmoker||0 (0)||0 (0)||0 (0)||0 (0)||0 (0)|
|Smoker||8 (9)||5 (7)||3 (4)||1 (2)||1 (1)|
|Point Total||10-Year Risk (%)||Point Total||10-Year Risk (%)|