Management of Medication Toxicity or Intolerance

Dyslipidemia

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

Higher abnormal fasting serum lipids have been observed in ART-naive adults who received EVG/c/FTC/TAF than in those who received EVG/c/FTC/TDF.

Increase in serum lipids from baseline has also 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
  • When possible, use ARVs associated with a lower prevalence of dyslipidemia. These include INSTIs and newer PIs (e.g., ATV, DRV).
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 there are minimal alterations in AST, ALT, and CK, 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-month 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
  • 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; 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; PI = protease inhibitor; PUFA = polyunsaturated fatty acid; RPV = rilpivirine; RTV = ritonavir; TAF = tenofovir alafenamide; TC = total cholesterol; TDF = tenofovir disoproxil fumarate; TG = triglycerides

References

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  20. Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, Phase 3, non-inferiority trials. Lancet. 2015;385(9987):2606-2615. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25890673.
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  23. Melvin AJ, Montepiedra G, Aaron L, et al. Safety and efficacy of atorvastatin in human immunodeficiency virus-infected children, adolescents and young adults with hyperlipidemia. Pediatr Infect Dis J. 2017;36(1):53-60. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27749649.
  24. Jao J, Yu W, Patel K, et al. Improvement in lipids after switch to boosted atazanavir or darunavir in children/adolescents with perinatally acquired HIV on older protease inhibitors: results from the Pediatric HIV/AIDS Cohort Study. HIV Med. 2018;19(3):175-183. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29159965.
  25. Echecopar-Sabogal J, D'Angelo-Piaggio L, Chaname-Baca DM, Ugarte-Gil C. Association between the use of protease inhibitors in highly active antiretroviral therapy and incidence of diabetes mellitus and/or metabolic syndrome in HIV-infected patients: A systematic review and meta-analysis. Int J STD AIDS. 2018;29(5):443-452. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28956700.
  26. Echeverria P, Bonjoch A, Puig J, Ornella A, Clotet B, Negredo E. Significant improvement in triglyceride levels after switching from ritonavir to cobicistat in suppressed HIV-1-infected subjects with dyslipidaemia. HIV Med. 2017;18(10):782-786. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28671337.
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  28. Cid-Silva P, Fernandez-Bargiela N, Margusino-Framinan L, et al. Treatment with tenofovir alafenamide fumarate worsens the lipid profile of HIV-infected patients versus treatment with tenofovir disoproxil fumarate, each coformulated with elvitegravir, cobicistat, and emtricitabine. Basic Clin Pharmacol Toxicol. 2019;124(4):479-490. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30388308.
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  30. Taramasso L, Tatarelli P, Ricci E, et al. Improvement of lipid profile after switching from efavirenz or ritonavir-boosted protease inhibitors to rilpivirine or once-daily integrase inhibitors: results from a large observational cohort study (SCOLTA). BMC Infect Dis. 2018;18(1):357. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30064371.
  31. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Circulation. 2019;139(25):e1046-e1081. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30565953.

Management of Medication Toxicity or Intolerance

Dyslipidemia

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

Higher abnormal fasting serum lipids have been observed in ART-naive adults who received EVG/c/FTC/TAF than in those who received EVG/c/FTC/TDF.

Increase in serum lipids from baseline has also 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
  • When possible, use ARVs associated with a lower prevalence of dyslipidemia. These include INSTIs and newer PIs (e.g., ATV, DRV).
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 there are minimal alterations in AST, ALT, and CK, 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-month 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
  • 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; 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; PI = protease inhibitor; PUFA = polyunsaturated fatty acid; RPV = rilpivirine; RTV = ritonavir; TAF = tenofovir alafenamide; TC = total cholesterol; TDF = tenofovir disoproxil fumarate; TG = triglycerides
Updated
Reviewed
Apr. 14, 2020

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