HIV/AIDS

Note: Some medications mentioned in this chapter may not be available on the VHA National Formulary. Consult VA pharmacists for alternatives.

Background

• Dyslipidemia is an important risk factor for CV disease, and occurs in a high proportion of people with HIV infection. As advances in ART extend the life spans of people with HIV infection, it is likely that morbidity and mortality from CV disease will increase. It is important to identify patients' CV risk factors and to reduce those that are modifiable.
• CV risk is associated with:
  • Elevated LDL and TC
  • Low HDL
  • Elevated TG

Of these, elevated LDL is most closely linked to CV risk, and usually is the primary target of therapeutic interventions.

• Dyslipidemia is associated both with HIV infection itself and with ARV medications. Accumulating data suggest that both HIV infection and certain ARV medications may increase the risk of CV disease, independent of their effects on lipids.
• Patients with untreated HIV infection commonly show:
  • ↓ TC
  • ↓ LDL cholesterol
  • ↓ HDL cholesterol
  • ↓ TG
• Patients treated with ARV medications commonly show:
  • ↑ TC, LDL, and TG levels
  • Low HDL
• Dyslipidemia among patients taking ARV medications probably is related to multiple factors, including:
  • Individual patient characteristics
  • HIV infection itself
  • ARV medications
• Certain agents in each of the 3 major classes of ARVs may cause lipid abnormalities.
  • PIs: may markedly ↑ TC, LDL, and TG levels (particularly RTV and RTV-boosted PIs; unboosted ATV does not typically affect lipids)
  • NNRTIs: effects are more variable, particularly with EFV; NVP and ETR are less likely to cause abnormalities. NNRTIs may ↑ TC, LDL, and TG
  • NRTIs: d4T may ↑ TC and TG
  • Fusion inhibitors, CCR5 antagonists, integrase inhibitors: not associated with dyslipidemia
• For patients with CHD or CHD risk equivalents (see below), if possible, select ARV regimen to minimize the risk of dyslipidemia.

Screening

• Check fasting lipids before starting ART.
• Check fasting lipids 1-3 months after starting or changing ARVs.
  • If normal: screen at least once per year
  • If abnormal: monitor closely until LDL goal is achieved

Evaluation

Note: The following recommendations are based on National Cholesterol Education Program (NCEP) guidelines for the evaluation and management of dyslipidemia. These are widely used, but have not been validated in HIV-infected patients.

History

The need for lipid management is based on lipid levels and on risk factors for coronary artery disease events. In the history, focus on factors that suggest CHD, CHD equivalents, or CV risk.

• CHD risk equivalent: considered equal in risk to known CHD
• CHD risk factor: a condition associated with greater risk of serious cardiac events

In addition, consider the factors below:

Assessment Tools

Determine whether intervention is needed according to the patient's lipid values and CHD risks, following these 3 steps. Note that for most patients, LDL is the main indicator of need for lipid-lowering therapy.

• Determine CHD risks (above).
• Determine risk category, LDL goal, and LDL threshold for treatment using Table 1.
  • The NCEP also recommends estimating the patient's 10-year risk of MI using the assessment tool derived from the Framingham Heart Study . Note that this tool does not estimate lifetime risk of MI, which for many patients is substantially higher than their 10-year risk. Intervention to treat lipid abnormalities may be warranted even in patients with a low 10-year risk, to prevent CV events later in life.
• Assess TG risk level using Table 2; determine whether TG-lowering treatment is needed.

Table 1. LDL Cholesterol Goals and Thresholds for Treatment

Risk Category	LDL Goal*	LDL Threshold to Initiate Therapeutic Lifestyle Changes	Consider Drug Therapy
* Non-HDL cholesterol target levels are 30 mg/dL higher than corresponding LDL cholesterol levels. Adapted from National Cholesterol Education Program (NCEP), National Heart, Lung, and Blood Institute, National Institutes of Health. Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). NIH Publication No. 02-5215. September 2002.
Lower risk: No CHD or CHD equivalents and 0-1 risk factor	<160 mg/dL	≥160 mg/dL	≥190 mg/dL (at 160-189 mg/dL, drug therapy optional)
Moderate risk: No CHD or CHD equivalents; ≥2 risk factors and 10-year estimated risk <10%	<130 mg/dL	≥130 mg/dL	≥160 mg/dL
Moderately high risk: No CHD or CHD equivalents; ≥2 risk factors and 10-year estimated risk 10-20%	<130 mg/dL (optional goal: <100 mg/dL)	≥130 mg/dL	≥130 mg/dL
High risk: CHD or CHD equivalent	<100 mg/dL (optional goal: <70 mg/dL)	≥100 mg/dL	≥100 mg/dL

Print table

Other issues:

• Consider drug therapy to decrease LDL (or non-HDL) if TC is >240 mg/dL or HDL cholesterol is <35 mg/dL.
• If TG is >400 mg/dL, the LDL cholesterol calculation is unreliable. Use non-HDL cholesterol as a surrogate target of therapy (non-HDL = TC - HDL); the non-HDL goal is 30 mg/dL higher than the LDL goal.
• If TG is 200-500 mg/dL, LDL is the primary target of initial therapy (see Table 1 for LDL intervention levels); if TG is ≥500 mg/dL, TG may be the initial target of therapy (see below).

Hypertriglyceridemia is associated with CAD risk, but it is unclear whether it is an independent risk factor; hence indications for treatment are less certain than those for cholesterol abnormalities.

Table 2. Classification of Triglyceride Levels

Risk Category	Triglyceride Measurement	Initiate Therapy
Adapted from National Cholesterol Education Program (NCEP), National Heart, Lung, and Blood Institute, National Institutes of Health. Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). NIH Publication No. 02-5215. September 2002.
Normal	<150 mg/dL
Borderline High	150-199 mg/dL
High	200-499 mg/dL	TLC Consider drug therapy for those with CHD, CHD equivalents, high risk of CHD
Very High	≥500 mg/dL	Low-fat diet (<15% of caloric intake); pharmacologic therapy probably will be required Consider drug therapy If severe (>1,000 mg/dL), treat to decrease risk of pancreatitis

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Management

The primary goal of lipid-lowering therapy for most patients is to lower LDL to target levels. The potential benefits of lipid-lowering therapy for HIV-infected patients should be balanced against drug toxicities, as well as the risk of CV mortality relative to HIV-associated mortality.

• If the TG level is very high, it may have to be reduced before LDL is treated directly (see below).
• Low HDL is not usually a primary target of therapy; data are conflicting as to whether raising HDL confers CV benefits.

A multimodal approach to treatment is important:

• Lifestyle modification
• Lipid-modifying medication
• Changes in ARV medication (or other exacerbating medication), if possible
• Management of associated conditions (eg, diabetes)

See Table 1 for LDL levels at which either TLC or drug therapy should be initiated, and for the target goals for LDL cholesterol.

Lifestyle Modification

Lifestyle modification is fundamental to the management of dyslipidemia and should be initiated in all patients with dyslipidemia. Behavioral changes may be difficult for patients, but can yield significant results in improving lipid values and reducing CHD risk.

Encourage patients to:

• Reduce dietary cholesterol and saturated fat (all patients)
• If overweight, lose weight
• Maintain or increase aerobic exercise (all patients)
• Reduce alcohol consumption (especially for those with high TGs)
• Stop smoking, and reduce other CHD risk factors

Medication

See Table 3 and Characteristics of Lipid-Lowering Medications, below, for information about lipid-lowering medications. Therapies should be intensified or augmented until lipid targets are met.

Switching ARVs

• For patients with CHD or CHD equivalents, try to select ARV medications associated with the lowest risk of dyslipidemia.
• For patients with dyslipidemia caused by ARV agents, consider discontinuing lipogenic ARVs if safe and effective alternatives exist.
  • For example, substitute ATV, RAL, or NVP in place of a lipogenic PI or substitute an unboosted PI (eg, ATV or FPV) for an RTV-boosted PI.
  • Replace d4T with TDF, or perhaps ABC*.
• Before making ARV substitutions, consider the possible effect on HIV virologic control and the potential adverse effects of new ARVs.
• In some cases, antihyperlipidemic agents may still be necessary after ARV substitution.

* Data from the D:A:D observational study associated ABC with increased risk of MI; some other studies have not confirmed this association. See References.

Potential ARV Interactions

Interactions with ARVs: Most PIs inhibit the metabolism of most statins and can significantly increase serum statin levels, thus increasing the risk of toxicity, including rhabdomyolysis.

Some combinations are contraindicated. Of the statin drugs, pravastatin is the least affected by most PIs (DRV is an exception). Atorvastatin, if used, must be initiated cautiously and at a low dose. EFV can induce the metabolism of some statins, causing therapeutically significant decreases in their concentrations. See Lipid-Lowering Medications, for further information.

References

• Brunzell JD. Clinical practice. Hypertriglyceridemia. N Engl J Med. 2007;357:1009-17.
• Coffey S. Dyslipidemia. In: Guide for HIV/AIDS Clinical Care. U.S. Department of Health and Human Services, Health Resources and Services Administration. Washington, DC; January 2011.
• D:A:D Study Group, Sabin CA, Worm SW, Weber R, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. 2008 Apr 26;371(9622):1417-26.
• Lloyd-Jones DM, Leip EP, Larson MG. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation. 2006 Feb 14;113(6):791-8.
• National Cholesterol Education Program (NCEP), National Heart, Lung, and Blood Institute, National Institutes of Health. Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). NIH Publication No. 02-5215. September 2002. Accessed December 10, 2008.
• Schambelan M, Benson CA, Carr A, et al. Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA panel. J Acquir Immune Defic Syndr. 2002 Nov 1;31(3):257-75.
• VA/DoD Clinical Practice Guideline Working Group. Management of Dyslipidemia in the Primary Care Setting. Washington, D.C.: Department of Veterans Affairs, Office of Quality and Performance; 2006. Accessed April 7, 2011.