Table 15b. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Dyslipidemia

Body
Adverse Effects Associated ARVs Onset/Clinical Manifestations Estimated Frequency Risk Factors Prevention/ Monitoring Management
Dyslipidemia PIs:
  • All PIs, especially RTV-boosted PIs; lower incidence reported with DRV/r and ATV, with or without RTV.
NRTIs:
  • Lower incidence reported with TDF than with TAF.
NNRTIs:
  • Lower incidence reported with NVP, RPV, and ETR than with EFV.
 Onset:
  • As early as 2 weeks to months after beginning therapy
Presentation
PIs:
  • ↑ LDL-C, TC, and TG
NRTIs:
  • ↑ LDL-C, TC, and TG.
    Significant increase in plasma lipid values was observed in adults switching from TDF to TAF, regardless of third agent or presence of a boosting agent.
NNRTIs:
  • ↑ LDL-C, TC, and HDL-C

Reported frequency varies with specific ARV regimen, duration of ART, and the specific laboratory parameters used to diagnose lipid abnormalities.

10% to 20% of young children receiving LPV/r will have lipid abnormalities.

40% to 75% of older children and adolescents with prolonged ART history will have lipid abnormalities.

Pooled dyslipidemia prevalence of 39.5% reported in a recent meta-analysis.

Increase in serum lipids from baseline also has been noted in adolescents receiving EVG/c/FTC/TAF.

 Advanced-stage HIV disease

High-fat, high-cholesterol diet

Lack of exercise

Obesity

Hypertension

Smoking

Family history of dyslipidemia or premature ASCVD

Metabolic syndrome

Fat maldistribution		 Prevention:
  • Low-fat diet
  • Exercise
  • Smoking-prevention counseling
  • Use of ARVs associated with a lower prevalence of dyslipidemia, such as INSTIs and newer PIs (e.g., ATV, DRV). 
  • When considering a TDF-based or a TAF-based regimen, lipid-lowering beneficial effect of TDF should be weighed against its potential for increased renal and bone toxicities. 
Monitoringa
Adolescents and Adults:
  • Obtain FLP (TC, HDL-C, non-HDL-C, LDL-C, and TG) twice (>2 weeks but ≤3 months apart, average these results). Monitor FLP every 6 months (for abnormal results) or every 12 months (for normal results).
Children (Aged ≥2 Years) without Lipid Abnormalities or Additional Risk Factors:
  • Obtain nonfasting screening lipid profiles at entry into care and then every 6–12 months, depending on the results.
  • If TG or LDL-C is elevated or if a patient has additional risk factors, obtain FLP.
Children with Lipid Abnormalities and/or Additional Risk Factors:
  • Obtain 12-hour FLP before initiating or changing therapy and every 6 months thereafter (more often if indicated).
Children Receiving Lipid-Lowering Therapy with Statins or Fibrates:
  • Obtain 12-hour FLP, LFT, and CK at 4 weeks, 8 weeks, and 3 months after starting lipid therapy.
  • If minimal alterations in AST, ALT, and CK are indicated, monitor every 3–4 months during the first year and every 6 months thereafter (or as clinically indicated).
  • Repeat FLP 4 weeks after increasing doses of antihyperlipidemic agents.
 Assess all patients for additional ASCVD risk factors. Patients with HIV are considered to be at moderate risk of ASCVD.b

ARV regimen changes should be considered, especially when the patient is receiving older PIs (e.g., LPV/r) and/or RTV boosting. Switching to a PI-sparing regimen, a PI-based regimen with a more favorable lipid profile or COBI boosting causes a decline in LDL-C or TG values. However, the lipid-lowering effect for LDL-C is less pronounced than with statin therapy.

Refer patients to a lipid specialist early if LDL-C is ≥250 mg/dL or TG is ≥500 mg/dL.

If LDL-C is ≥130 mg/dL but <250 mg or TG is ≥150 mg/dL but <500 mg/dL, the following staged treatment approach is recommended by the NHLBI guidelines:b
  • Implement diet, nutrition, and lifestyle management for 6–9 months. Consult with a dietician if one is available.
  • If a 6- to 9-month trial of lifestyle modification fails and the patient is aged ≥10 years, consider implementing lipid-lowering therapy after consulting a lipid specialist. 
  • Statin therapy should be considered for patients with elevated LDL-C levels. NHLBI provides recommendations for statin therapy in patients with specific LDL-C levels and risk factors.b
  • Concurrent substitution—preferably to ARVs with no inhibitory or inducing effect on CYP3A4 or OATP1B1 (e.g., INSTI)—also should be considered as appropriate to limit drug-drug interaction potential.
  • Drug therapy can be considered in cases of severe hypertriglyceridemia (TG ≥500 mg/dL). Fibrates (gemfibrozil and fenofibrate) and N-3 PUFAs derived from fish oils may be used.
The long-term risks of lipid abnormalities in children who are receiving ART are unclear. However, persistent dyslipidemia in children may lead to premature ASCVD.
a Given the burden of collecting fasting blood samples, some practitioners routinely measure cholesterol and TG from nonfasting blood samples and follow-up abnormal values with a test done in the fasted state.

b Refer to the NHLBI guidelines: Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. 

Key: ALT = alanine aminotransferase; ART = antiretroviral therapy; ARV = antiretroviral; ASCVD = atherosclerotic cardiovascular disease; AST = aspartate aminotransferase; ATV = atazanavir; CK = creatine kinase; COBI = cobicistat; CYP3A4 = cytochrome P450 3A4; DRV = darunavir; DRV/r = darunavir/ritonavir; EFV = efavirenz; ETR = etravirine; EVG/c = elvitegravir/cobicistat; FLP = fasting lipid profile; FTC = emtricitabine; HDL-C = high-density lipoprotein cholesterol; INSTI = integrase strand transfer inhibitor; LDL-C = low-density lipoprotein cholesterol; LFT = liver function test; LPV/r = lopinavir/ritonavir; NHLBI = National Heart, Lung, and Blood Institute; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; OATP1B1 = Organic Anion Transporter Polypeptide 1B1; PI = protease inhibitor; PUFA = polyunsaturated fatty acid; RPV = rilpivirine; RTV = ritonavir; TAF = tenofovir alafenamide; TC = total cholesterol; TDF = tenofovir disoproxil fumarate; TG = triglycerides