Dyslipidemia in the HIV Patient

OVERVIEW: What every practitioner needs to know

The Significance of Dyslipidemia in the HIV-Infected Patient.

The risk of coronary heart disease is increased in human immunodeficiency virus (HIV)-infected patients relative to age- and sex-matched controls from the general population. The risk of myocardial infarction appears to be increased about two-fold in people with HIV infection. Dyslipidemia is a common modifiable risk factor for atherosclerosis in HIV-infected patients that is likely due, in part, to the underlying chronic infection and to antiretroviral therapy.

What Types of Lipid Abnormalities are Common in HIV-Infected Patients?

In untreated, advanced HIV disease, patients typically have low total cholesterol, low low-density lipoprotein (LDL) cholesterol, low high-density lipoprotein (HDL) cholesterol, and hypertriglyceridemia. The proportion of LDL that is the particularly atherogenic, small, dense LDL may be increased in advanced HIV disease. With initiation of antiretroviral therapy, total and LDL cholesterol levels tend to increase if low at baseline, regardless of the type of antiretroviral regimen.

With contemporary antiretroviral regimens, HDL cholesterol generally increases with control of HIV replication. Changes in triglycerides are variable and dependent on the specific antiretrovirals used. Among the most commonly used initial regimens, ritonavir-boosted protease inhibitors and efavirenz often result in some degree of triglyceride elevations. A minority of patients are sensitive to low doses of ritonavir used to boost protease inhibitors and may develop significant hypertriglyceridemia.

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What Basic Lab Tests Should you Order to Assess for Dyslipidemia?

HIV-infected patients should have a standard fasting (8–12 hours) lipid panel sent annually if otherwise stable. Patients initiating antiretroviral therapy who have baseline hypertriglyceridemia should have lipids checked within 1 month of starting therapy. Others should have a lipid panel sent within 3 months. LDL cholesterol is a calculated value in a standard lipid panel, and the calculation is not accurate when triglycerides exceed 400mg/dL (4.6mmol/L). In the setting of hypertriglyceridemia, it is helpful to calculate the non-HDL cholesterol value (total cholesterol—HDL cholesterol) to estimate the quantity of circulating atherogenic lipoproteins.

Are Other Lab Tests Useful?

The clinical utility of measuring either LDL directly, lipoprotein particle size (e.g., by nuclear magnetic resonance), or apoliprotein A or B levels has not been established in HIV-infected patients.

Although high sensitivity C-reactive protein (hsCRP) testing may be useful in some situations in the general population, such as further risk stratifying patients at intermediate risk of coronary heart disease, its role in HIV-infected patients is uncertain. The level of hsCRP appears associated with risk of myocardial infarction in HIV-infected patients. hsCRP may be elevated in the proinflammatory state of uncontrolled HIV infection, but its level may or may not decrease with control of HIV replication. There are no data in HIV-infected patients on whether statin therapy is beneficial in the setting of hsCRP elevation and normal lipids.

What is the Approach to Assessing Risk of Coronary Heart Disease in the HIV-Infected Patient?

HIV-specific guidelines recommend adopting the National Cholesterol Education Program (NCEP) Adult Treatment Panel III approach to assessing and managing dyslipidemia. The intensity of risk-reduction interventions is based on the risk of coronary heart disease, and LDL cholesterol is the primary target of intervention.

The first step in risk stratification is to determine if the patient has a condition called a coronary heart disease (CHD) risk equivalent state, which places the patient at similar risk as someone with known CHD. These conditions include diabetes mellitus, symptomatic carotid artery disease, peripheral artery disease, and abdominal aortic aneurysm.

The consideration of diabetes mellitus as a risk equivalent condition is controversial. Some experts factor in the duration of diabetes (e.g., >20 years) or patient age (e.g., >40 years for men and >45 years for women). Others advocate using the UK Prospective Diabetes Study risk engine to calculate specific risk in diabetic patients, although this has not been validated in HIV-infected patients. Some also include chronic kidney disease to be a risk equivalent state.

For patients who do not have a risk equivalent state, the next step is to count the number of major CHD risk factors (Table I). Those with two or more risk factors should have the Framingham risk score calculated. If the calculated 10-year risk exceeds 20%, the patient is managed aggressively like those with established CHD. Those with 0 to 1 risk factors are generally at low risk (<10%) and do not require calculation of Framingham scores.

The last step is to determine the targeted level of LDL cholesterol based on risk level (Table II).

Table I.

Age (men aged ≥45 years, women aged ≥55 years)

Family history of premature coronary heart disease (male first degree relative aged <55 years, female aged <65 years)

Cigarette smoking

Hypertension (blood pressure ≥140/90mm Hg or on antihypertensive medication)

Low HDL-C* (<45mg/dL [1.17 mmol/L])

*Subtract one risk factor if HDL-C >60 mg/d

HDL-C, high-density lipoprotein cholesterol.

Table II.

Risk category	LDL-C goal(mg/dL)[mmol/L]	LDL-C to initiate lifestyle intervention (mg/dL) [mmol/L]	LDL-C to consider pharmacologic intervention (mg/dL) [mmol/L]
CHD or risk equivalent state	<100 [2.59](<70 [1.81] optional)	≥100 [2.59]	≥130 [3.37] (100–129 [2.60–3.36] optional)
≥2 risk factors and 10-year risk:
10–20%	<130 [3.37](<100 [2.59] optional)	≥130 [3.37]	≥130 [3.37]
<10%	<130 [3.37]	≥130 [3.37]	≥160 [4.15]
0–1 risk factor	<160 [4.15]	>160 [4.15]	≥190 [4.92]

C, cholesterol; CHD, coronary heart disease; LDL, low-density lipoprotein.

What is the Overall Approach to Managing Dyslipidemia in HIV-Infected Patients?

The management algorithm depends on the fasting triglyceride level. For patients with triglyceride levels greater than 500mg/dL (6mmol/L), initial management should focus on triglyceride lowering. For all others, LDL-cholesterol is the initial primary target. Non-HDL cholesterol is an appropriate secondary target when triglyceride levels are greater than 200mg/dL (2.3mmol/L). The non-HDL target is simply the LDL target plus 30mg/dL (0.8mmol/L).

Lifestyle modification is an appropriate first step for virtually all patients. Barring any medical contraindication, patients should be encouraged to engage in at least 30 minutes of aerobic activity on most (if not all) days of the week. Sedentary patients can start with walking. The principles of dietary interventions are summarized in Table III. Referral to a dietician is often appropriate as is encouragement of weight loss in the overweight or obese patient.

A fasting lipid panel should be obtained after 6 weeks of lifestyle intervention. For patients who are not close to or at targeted levels of LDL and triglycerides, more intensive therapy may be indicated as described below.

Table III.

Reduce intake of saturated and trans fats to <7% of calories

Polyunsaturated fat: up to 10% of total calories

Monounsaturated fat: up to 20% of total calories

Total fat: 25–35% of total calories

Carbohydrate: 50–60% of total calories (derived primarily from foods rich in complex carbohydrates, especially whole grains, fruits, and vegetables)

Viscous (soluble) fiber: 20–30g/day

Protein: approximately 15% of total calories

Reduce intake of dietary cholesterol to <200mg daily

Balance caloric intake and energy expenditure to achieve/maintain desirable body weight

Consider plant stanols/sterols (2g/day) for LDL cholesterol lowering

(Adapted from National Cholesterol Education Program Adult Treatment Panel III. JAMA 2001; 285:2486-97.)

LDL, low-density lipoprotein.

Is There a Role for Modifying Antiretroviral Therapy to Manage Dyslipidemia?

Modifying antiretroviral therapy to treat elevated triglycerides and possibly LDL-cholesterol is an option for some patients if on drugs that commonly affect lipids adversely (e.g., certain protease inhibitors). Among the most frequently prescribed protease inhibitors, atazanavir and darunavir tend not to affect lipids dramatically, whereas lopinavir/ritonavir often causes triglyceride elevations. Switching a protease inhibitor to nevirapine, rilpivirine, etravirine, raltegravir, or within the protease inhibitor class to boosted or unboosted atazanavir may improve dyslipidemia.

Note that atazanavir must be boosted with ritonavir if tenofovir is used concurrently, since tenofovir lowers atazanavir levels. Patients on the older thymidine analogues stavudine or zidovudine may have improvements in lipids by switching to tenofovir or abacavir. Tenofovir appears to have lipid-lowering effects independent of effects on HIV replication. It is critical to factor in prior treatment experience and known resistance if contemplating a switch in antiretrovirals so that virologic control is not compromised.

Advantages of switching antiretroviral therapy (versus adding lipid-lowering therapy) are avoiding extra pill burden, cost, side effects, and drug–drug interaction issues posed by additional medications. Conversely, the clinical benefit of switching antiretrovirals is unproven.

There can be risk of losing virologic control, and efficacy may be diminished compared to lipid-lowering therapy. Furthermore, there are potential pleiotropic effects of statins beyond LDL lowering, including anti-inflammatory activity and atherosclerotic plaque stabilization, that favor lipid-lowering therapy.

The bottom line is that lipid-lowering therapy is sometimes a better option for managing elevated LDL cholesterol. It is reasonable to consider switching a specific antiretroviral for patients with significant triglyceride elevations that are likely attributable to a specific drug.

How Should Elevated LDL or Non-HDL cholesterol be managed?

For patients who are not at targeted levels of LDL or non-HDL cholesterol after lifestyle modification alone, pharmacologic therapy with a statin is indicated. There are clinically important drug–drug interactions between some statins and antiretroviral drugs that are essential. The following interactions are important to consider when changing antiretroviral regimens since statin exposure may be affected:

For patients on protease inhibitors, lovastatin, and simvastatin are contraindicated, since the levels of these statins may increase dramatically with inhibition of cytochrome P450 isoenzymes by the protease inhibitor (Table IV).

Cases of rhabdomyolysis and death have been reported that were attributed to these interactions.

Atorvastatin and rosuvastatin levels increase modestly when coadministered with protease inhibitors, and these statins appear to be safe at low doses.

Pravastatin levels decrease modestly when coadministered with some protease inhibitors but increase when coadministered with darunavir.

Coadministration of darunavir and pravastin is not recommended.

Data on fluvastatin are limited, but it is not likely to interact significantly with protease inhibitors.

Efavirenz lowers levels of atorvastatin, pravastatin, and simvastatin by about 40 to 60%, which may necessitate higher doses of the statin.

Table IV.

Significant interaction—concurrent use contraindicated	Moderate interaction—initiate at low dose	Low potential for interaction
Lovastatin	Atorvastatin	Fluvastatin
Simvastatin	Rosuvastatin	Pravastatin*

*Pravastatin should be used at the lowest possible dose when combined with darunavir/ritonavir because of increased pravastatin exposure.

(Adapted from Glesby MJ. HIV and cardiovascular risk. New York: Oxford University Press. 2011.)

What Dose of Statin Should I Use?

For patients on a protease inhibitor (or the seldom used non-nucleoside drug, delavirdine), the following starting doses are appropriate:

atorvastatin 10mg daily

fluvastatin 20 to 40mg daily

pravastatin 20 to 40mg daily (should be used at the lowest possible dose (e.g., 10–20mg daily) when combined with darunavir/ritonavir)

rosuvastatin 5mg daily

Statin doses can be titrated upward at 4 to 6 week intervals if LDL reduction is insufficient and the drug is tolerated (including stable liver enzymes). The maximum dose of each statin in the setting of protease inhibitor therapy is not established but should probably not exceed 40mg daily for atorvastatin, 80mg for fluvastatin and pravastatin (except if on darunavir), and 10mg for rosuvastatin.

What if the LDL Cholesterol is not at Goal despite a Statin?

Patients on efavirenz who are not also taking a protease inhibitor may need higher doses of statins. Data are limited on other non-nucleoside reverse transcriptase inhibitors, but the same principle is likely to apply. Simvastatin and lovastatin may be used in patients who are not taking protease inhibitors.

There are no clinical endpoint studies in HIV-infected patients of any lipid-lowering therapies. Extrapolating from studies of primary prevention of CHD in the general population, there is no clear role for adding a second agent to a statin. Although the cholesterol absorption inhibitor ezetimibe lowers LDL-cholesterol further when added to a statin in HIV-infected patients, there is no proven clinical benefit in the general population. Adding niacin to a statin may lower LDL-cholesterol further, but this is unproven. Bile acid sequestrants (cholestyramine, colestipol, colesevelam) could theoretically affect the absorption of antiretrovirals and should be avoided.

Switching within the statin class to a more potent statin (e.g., rosuvastatin, atorvastatin) may be an option for patients who are on a less potent statin (e.g., pravastatin). Drug–drug interactions must be kept in mind. Along these lines, patients on efavirenz and possibly other non-nucleoside reverse transcriptase inhibitors may have reduced statin exposure due to induction of cytochrome P450 and may require higher doses of statins.

How Should Hypertriglyceridemia be Managed?

For most patients, lifestyle modification should be attempted first and consists of dietary counseling (ideally by a dietician) and exercise. Excessive alcohol use can contribute to hypertrigylceridemia and may also need addressed. Optimizing glycemic control in diabetic patients may also help lower triglyceride levels. When triglyceride levels exceed 1,000mg/dL (11mmol/L), pharmacologic intervention should be introduced concurrently with lifestyle modification since there is a risk of pancreatitis.

For patients with fasting triglycerides less than 500mg/dL (5.6mmol/L), LDL-cholesterol and non-HDL-cholesterol lowering with a statin is of primary importance if indicated.

For patients with fasting triglyceride levels greater than or equal to 500mg/dL (5.6mmol/L), options for medical management include:

fibrate drugs (gemfibrozil, fenofibrate, bezafibrate [in Canada, Europe])

fish oil (2–4g daily of the sum of eicosapentaenoic acid [EPA] plus docosahexaenoic acid [DHA] omega-3 fatty acid content)

extended release niacin (starting at 500mg at bedtime with escalation every 4 weeks to 2,000mg as tolerated)

switching antiretroviral regimens

As triglyceride lowering is achieved, LDL cholesterol will generally increase. If LDL cholesterol is not a goal, consideration can be given to adding a statin to fenofibrate (the fibrate of choice with regard to risk of myositis if combining with a statin), fish oil, or niacin.

What about the Patient with Isolated Low HDL-C?

Low levels of HDL cholesterol often travel with elevated triglyceride levels as part of the metabolic syndrome but can be seen in isolation. Patients with untreated advanced HIV infection typically have improvements in HDL cholesterol levels with control of HIV replication. Those already on antiretroviral therapy pose a greater challenge.

It is important to ask about anabolic steroid use (prescribed or purchased at the gym or elsewhere), as these agents can lower HDL cholesterol levels, dramatically in some cases. Encouraging physical activity, weight loss if appropriate, and smoking cessation are all important. Dietary measures may also help. Saturated fats should be minimized and foods rich in n-3 (omega-3) polyunsaturated fatty acids encouraged. Sources of the latter include certain cold water fish (e.g., herring, mackerel, salmon, sardines), nuts (e.g., almonds, peanuts, pecans, walnuts), and oils (e.g., canola, flaxseed, olive oil). Mild to moderate alcohol consumption (up to two drinks daily) may raise HDL cholesterol levels, but the risks may outweigh the benefits in patients with underlying liver disease, such as hepatitis C virus infection, or those prone to addiction.

The role of pharmacologic therapy is uncertain, but options include extended release niacin, fibrates, or potentially rosuvastatin in patients at high risk of CHD. Switching the antiretroviral regimen to a nevirapine-based regimen, if treatment history and resistance profile permit, could result in increases in HDL cholesterol levels, although the clinical significance of such increases is uncertain.

When Should I Refer to a Lipid Specialist?

Each individual’s threshold for referral is different. If a patient has not responded adequately to lifestyle intervention and therapy with two lipid-lowering agents, it may be time to seek the help of a preventive cardiologist, endocrinologist, or other lipid expert.

Is the Framingham Risk Calculation Accurate in HIV-Infected Patients?

The Framingham equations predict risk of coronary heart disease endpoints reasonably well in HIV-infected patients, although risk may be underestimated modestly in smokers and overestimated modestly in nonsmokers. HIV-specific risk stratification tools have been developed but are not fully validated.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Ashen, MD, Blumenthal, RS. “Clinical practice. Low HDL cholesterol levels”. N Engl J Med. vol. 353. 2005. pp. 1252-60. (Although not specific to HIV, this excellent review article highlights strategies to managing low HDL cholesterol.)

Aslangul, E, Assoumou, L, Bittar, R. “Rosuvastatin versus pravastatin in dyslipidemic HIV-1-infected patients receiving protease inhibitors: a randomized trial”. AIDS.. vol. 24. 2010. pp. 77-83. (In this randomized trial of 88 HIV-infected patients on ritonavir-boosted protease inhibitors, rosuvastatin 10mg daily more effectively lowered LDL cholesterol and triglycerides compared with 40mg daily of pravastatin. Both drugs were well tolerated.)

Calza, L, Manfredi, R, Colangeli, V, Tampellini, L, Sebastiani, T, Pocaterra, D, Chiodo, F. “Substitution of nevirapine or efavirenz for protease inhibitor versus lipid-lowering therapy for the management of dyslipidaemia”. AIDS. vol. 19. 2005. pp. 1051-8. (This is the only published randomized comparison of switching antiretrovirals versus adding lipid-lowering therapy. Patients with mixed hyperlipidemia on a protease inhibitor were randomized to change the protease inhibitor to nevirapine or efavirenz versus adding pravastatin or bezafibrate. The strategy of adding a lipid-lowering agent was more effective at lowering total and LDL cholesterol and triglycerides.)

Chow, D, Chen, H, Glesby, MJ. “Short-term ezetimibe is well tolerated and effective in combination with statin therapy to treat elevated LDL cholesterol in HIV-infected patients”. AIDS. vol. 23. 2009. pp. 2133-41. (The addition of ezetimibe to ongoing statin therapy in this cross-over study of HIV-infected patients with baseline LDL cholesterol >130mg/dL resulted in additional LDL cholesterol lowering of approximately 20% at 12 weeks.)

Cohen, CJ, Andrade-Villanueva, J, Clotet, B. “Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, noninferiority trial”. Lancet. vol. 378. 2011. pp. 229-37. (Similar to the ECHO trial, in this randomized comparison of rilpivirine versus efavirenz [each with two investigator selected nucleoside reverse transciptase inhibitors], changes in total cholesterol, LDL cholesterol, and triglycerides at week 48 favored rilpivine, but HDL cholesterol increased more with efavirenz. The change in total cholesterol:HDL cholesterol ratio did not differ between treatment arms.)

Dubé, MP, Stein, JH, Aberg, JA. “Guidelines for the evaluation and management of dyslipidemia in HIV-infected adults receiving antiretroviral therapy. Recommendations of the HIV Medical Association of the Infectious Diseases Society of America and the Adult AIDS Clinical Trials Group”. Clin Infect Dis. vol. 37. 2003. pp. 613-27. (These HIV-specific guidelines are an adaptation of the National Cholesterol Education Program Adult Treatment Panel III approach, factoring in drug–drug interactions and other HIV-specific issues.)

Dubé, MP, Wu, JW, Aberg, JA. “Safety and efficacy of extended-release niacin for the treatment of dyslipidaemia in patients with HIV infection: AIDS Clinical Trials Group Study A5148”. Antivir Ther. vol. 11. 2006. pp. 1081-9. (This small single arm study of HIV-infected patients with elevated triglycerides or non-HDL cholesterol demonstrated that extended-release niacin was well tolerated up to 2,000mg daily and reduced total cholesterol and triglycerides.)

“Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)”. JAMA. vol. 285. 2001. pp. 2486-97. (This is a concise summary of the National Cholesterol Education Program Adult Treatment Panel III guidelines.)

Fichtenbaum, CJ, Gerber, JG, Rosenkranz, SL. “Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047”. AIDS. vol. 16. 2002. pp. 569-77. (This study in healthy volunteers demonstrated clinically significant interactions between protease inhibitors and certain statins and serves as the basis for recommended and contraindicated statins.)

Friis-Møller, N, Thiébaut, R, Reiss, P. “Predicting the risk of cardiovascular disease in HIV-infected patients: the data collection on adverse effects of anti-HIV drugs study”. Eur J Cardiovasc Prev Rehabil. vol. 17. 2010. pp. 491-501. (The authors developed HIV-specific risk equations from a subset of patients in the D:A:D Study and validated them in the remaining study cohort. The models included age, sex, systolic blood pressure, smoking status, family history of CHD, diabetes, total and HDL cholesterol, and exposure to the HIV drugs indinavir, lopinavir/ritonavir, and abacavir. The models performed better than the Framingham equation but require validation in different HIV-infected populations.)

Gallant, JE, DeJesus, E, Arribas, JR. “Tenofovir DF emtricitabine, and efavirenz versus zidovudine, lamivudine, and efavirenz for HIV”. N Engl J Med. vol. 354. 2006. pp. 251-60. (This study randomized treatment-naive patients to tenofovir-emtricitabine or zidovudine-lamivudine, each with efavirenz. Fasting total cholesterol and LDL cholesterol increased less in the tenofovir arm, whereas HDL cholesterol increased more in the zidovudine arm. There was no difference in changes in triglycerides.)

Gallant, JE, Staszewski, S, Pozniak, AL. “Efficacy and safety of tenofovir DF versus stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial”. JAMA. vol. 292. 2004. pp. 191-201. (In this randomized comparison of tenofovir versus stavudine [each combined with lamivudine and efavirenz], changes in total cholesterol, directly measured LDL cholesterol, HDL cholesterol, and triglycerides all favored tenofovir.)

Gazzard, B, Duvivier, C, Zagler, C, Castagna, A, Hill, A, van Delft, Y, Marks, S. “Phase 2 double-blind, randomised trial of etravirine versus efavirenz in treatment-naïve patients: 48 week results”. AIDS. vol. 25. 2011. pp. 2249-58. (In the SENSE trial, 157 treatment naive patients were randomized to etravirine or efavirenz, each combined with two investigator selected nucleoside reverse transcriptase inhibitors. Grade 3 or higher elevations in total cholesterol [1 vs 8%], LDL cholesterol [3 vs 10%]), and triglycerides [0 vs 3%] were less frequent in the etravirine arm compared with the efavirenz arm.)

Gerber, JG, Kitch, DW, Fichtenbaum, CJ. “Fish oil and fenofibrate for the treatment of hypertriglyceridemia in HIV-infected subjects on antiretroviral therapy: results of ACTG A5186”. J Acquir Immune Defic Syndr. vol. 47. 2008. pp. 459-66. (In this trial, HIV-infected patients with hypertriglyceridemia were randomized to 3g of fish oil twice daily or 160mg of fenofibrate for 8 weeks. Those with triglycerides greater than 200mg/dL at week 8 received dual therapy from weeks 10 to 18. Both fish oil and fenofibrate lowered triglycerides significantly, and combination therapy yielded further reductions and was safe.)

Gerber, JG, Rosenkranz, SL, Fichtenbaum, CJ. “Effect of efavirenz on the pharmacokinetics of simvastatin, atorvastatin, and pravastatin: results of AIDS Clinical Trials Group 5108 Study”. J Acquir Immune Defic Syndr. vol. 39. 2005. pp. 307-12. (This study in healthy volunteers demonstrated that coadministration of efavirenz lowers exposure to atorvastatin, pravastatin, and simvastatin.)

(This is an online version of the Framingham risk calculator used in the National Cholesterol Education Program Adult Treatment Panel III guidelines. Enter values for age, sex, total and HDL cholesterol, smoking status, and systolic blood pressure to calculate the 10-year risk of myocardial infarction or coronary death. The Framingham calculations are reasonably accurate in HIV-infected patients but may underestimate risk in smokers and overestimate risk in nonsmokers.)

Kiser, JJ, Gerber, JG, Predhomme, JA, Wolfe, P, Flynn, DM, Hoody, DW. “Drug/drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers”. J Acquir Immune Defic Syndr. vol. 47. 2008. pp. 570-8. (This study in healthy volunteers demonstrated an unexpected increase in rosuvastatin exposure when co-administered with the combination protease inhibitor lopinavir/ritonavir with attenuation of LDL-C lowering.)

Law, MG, Friis-Møller, N, El-Sadr, WM. “The use of the Framingham equation to predict myocardial infarctions in HIV-infected patients: comparison with observed events in the D:A:D Study”. HIV Med. vol. 7. 2006. pp. 218-30. (This study compared rates of myocardial infarction predicted by the Framingham equation with observed rates from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study. Overall, the Framingham equation was reasonably accurate at predicting events.)

Mallolas, J, Podzamczer, D, Milinkovic, A. “Efficacy and safety of switching from boosted lopinavir to boosted atazanavir in patients with virological suppression receiving aLPV/r-containing HAART: the ATAZIP study”. J Acquir Immune Defic Syndr. vol. 51. 2009. pp. 29-36. (This randomized, controlled trial demonstrated that switching from lopinavir/ritonavir to atazanavir/ritonavir resulted in reductions in total cholesterol and triglycerides but not LDL cholesterol or HDL cholesterol.)

Martínez, E, Larrousse, M, Llibre, JM. “Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: the SPIRAL study”. AIDS. vol. 24. 2010. pp. 1697-707. (This randomized, controlled trial demonstrated that switching from ritonavir-boosted protease inhibitors (primarily lopinavir and atazanavir) to the integrase inhibitor raltegravir resulted in reductions in triglycerides, total, LDL, and HDL cholesterol with favorable changes in the total:HDL cholesterol ratio.)

Molina, JM, Cahn, P, Grinsztejn, B. “Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial”. Lancet. vol. 378. 2011. pp. 238-46. (In this head-to-head comparison of rilpivirine with efavirenz [each with tenofovir/emtricitabine] in treatment naive patients, changes in total cholesterol, LDL cholesterol, and triglycerides at week 48 favored rilpivirine. HDL cholesterol increased significantly more with efavirenz, however, and the change in total cholesterol:HDL cholesterol ratio did not differ between treatment arms.)

Riddler, SA, Smit, E, Cole, SR. “Impact of HIV infection and HAART on serum lipids in men”. JAMA. vol. 289. 2003. pp. 2978-82. (This is a study of stored blood samples from 50 men with documented seroconversion to HIV demonstrated low total, HDL, and LDL cholesterol levels in untreated HIV infection relative to their preinfection levels. Total and LDL cholesterol levels increased with treatment of HIV but to levels that would be expected based on preinfection levels plus age-related increases. HDL cholesterol remained low with treatment of HIV in this study, although this may be a function of the now outdated antiretroviral regimens used then.)

Tungsiripat, M, Kitch, D, Glesby, MJ. “A pilot study to determine the impact on dyslipidemia of adding tenofovir to stable background antiretroviral therapy: ACTG 5206”. AIDS. vol. 24. 2010. pp. 1781-4. (This small cross-over study demonstrated that adding tenofovir to a stable antiretroviral combination in the setting of controlled HIV replication led to reductions in total, LDL, and non-HDL cholesterol.)

(This is a downloadable risk calculator for patients with type II diabetes mellitus based on the UK Prospective Diabetes Study. Enter values for age, sex, ethnicity, duration of diabetes, smoking status, history of atrial fibrillation, hemoglobin A1c value, systolic blood pressure, and total and HDL cholesterol. Lab values must be converted to International System of Units units. This calculator has not been validated specifically in HIV-infected patients.)

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