Management of Medication Toxicity or Intolerance

Hepatic Events

Table 15e. Antiretroviral Therapy-Associated Adverse Effects and Management Recommendations—Hepatic Events
Adverse Effects Associated ARVs Onset/Clinical Manifestations Estimated Frequency Risk Factors Prevention/Monitoring Management
Hepatitis Most ARV drugs have been associated with hepatitis, but there is a strong association between hepatitis and the use of NVP and EFV.

NVP, EFV, ABC, RAL, DTG, and MVC have been associated with hepatitis in the context of HSRs.

NRTIs, especially ZDV, have been associated with lactic acidosis and hepatic steatosis.
Onset: 
  • Acute toxic hepatitis most commonly occurs within the first few months of therapy, but it can occur later.
  • Steatosis presents after months or years of therapy.
  • Patients with HBV coinfection may experience a hepatitis flare with the initiation or withdrawal of 3TC, FTC, TDF, or TAF. Flare may also occur with the emergence of resistance to 3TC or FTC (especially if the patient is receiving only one anti-HBV agent). Note that TDF and TAF have high barriers to resistance when used to treat HBV.
  • Hepatitis may be a manifestation of IRIS if it occurs early in therapy, especially in patients with HBV or HCV coinfection.
Presentation:
  • Asymptomatic elevation of AST and ALT levels
  • Symptomatic hepatitis with nausea, fatigue, and jaundice
  • Hepatitis may present in the context of HSR with rash, lactic acidosis, and hepatic steatosis.
Uncommon HBV or HCV coinfection

Underlying liver disease

Use of other hepatotoxic medications and supplements (e.g., St. John's wort [Hypericum perforatum], chaparral [Larrea tridentata], germander [Teucrium chamaedrys])

Alcohol use

Pregnancy

Obesity

Higher drug concentrations of PIs

For NVP-Associated Hepatic Events in Adults:
  • Female sex with pre-NVP CD4 count >250 cells/mm3
  • Male sex with pre-NVP CD4 count >400 cells/mm3
  • Population- specific HLA typesa
Prevention:
  • Avoid concomitant use of hepatotoxic medications.
  • In patients with elevated levels of hepatic enzymes (>5 times to 10 times ULN) or chronic liver disease, most clinicians would avoid NVP.
Monitoring
For ARV Drugs Other Than NVP:
  • Obtain AST and ALT levels at baseline and at least every 3–4 months thereafter;b monitor at-risk patients more frequently (e.g., those with HBV or HCV coinfection or elevated baseline AST and ALT levels).
For NVP:
  • Obtain AST and ALT levels at baseline, at 2 weeks, 4 weeks, and then every 3 months.
Evaluate the patient for other infectious and non-infectious causes of hepatitis and monitor the patient closely.

Asymptomatic Hepatitis:
  • Potentially offending ARV drugs should be discontinued if ALT or AST level is >5 times ULN.
Symptomatic Hepatitis:
  • Discontinue all ARV drugs and other potentially hepatotoxic drugs.
  • If a patient experiences hepatitis that is attributed to NVP, NVP should be permanently discontinued.
  • Consider viral causes of hepatitis: HAV, HBV, HCV, EBV, and CMV.
Indirect Hyperbilirubinemia ATV Onset:
  • Within the first months of therapy
Presentation:
  • May be asymptomatic or associated with jaundice
  • Levels of direct bilirubin may be normal or slightly elevated when levels of indirect bilirubin are very high.
  • Normal AST and ALT
In long-term follow-up, 9% of children who were receiving ATV had at least one total bilirubin level >5 times ULN and 1.4% of children experienced jaundice. None established. Monitoring:
  • No ongoing monitoring needed.
  • After an initial rise over the first few months of therapy, unconjugated bilirubin levels generally stabilize; levels may improve over time.
Isolated indirect hyperbilirubinemia is not an indication to stop ATV.

Psychological impact of jaundice should be evaluated, and alternative agents should be considered.

Jaundice may result in nonadherence, particularly in adolescents; this side effect should be discussed with patients.
Non-Cirrhotic Portal Hypertension d4T, ddI

The Panel no longer recommends the use of these agents.
Onset:
  • Generally after years of therapy; may occur years after stopping therapy.
Presentation:
  • GI bleeding, esophageal varices, and hypersplenism 
  • Mild elevations in AST and ALT levels, moderate increases in ALP levels, and pancytopenia
Liver Biopsy Findings:
  • The most commonly seen findings include nodular regenerative hyperplasia and hepatoportal sclerosis.
Rare Prolonged exposure to ddI and the combination of d4T and ddI. No specific monitoring Manage complications of GI bleeding and esophageal varices.
a For example, HLA-DRB1*0101 in white people, HLA-DRB1*0102 in South Africans, and HLA-B35 in Thai people and white people.

b Less-frequent monitoring can be considered in children whose clinical status has been stable for >2 years to 3 years (see Clinical and Laboratory Monitoring of Pediatric HIV Infection).

Key: 3TC = lamivudine; ABC = abacavir; ALP = alkaline phosphatase; ALT = alanine transaminase; ARV = antiretroviral; AST = aspartate aminotransferase; ATV = atazanavir; CD4 = CD4 T lymphocyte; CMV = cytomegalovirus; d4T = stavudine; ddI = didanosine; DTG = dolutegravir; EBV = Epstein-Barr virus; EFV = efavirenz; FTC = emtricitabine; GI = gastrointestinal; HAV = hepatitis A virus; HBV = hepatitis B virus; HCV = hepatitis C virus; HLA = human leukocyte antigen; HSR = hypersensitivity reaction; IRIS = immune reconstitution inflammatory syndrome; MVC = maraviroc; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; the Panel = Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV; PI = protease inhibitor; RAL = raltegravir; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; ULN = upper limit of normal; ZDV = zidovudine

References

General Reviews

  1. Aurpibul L, Bunupuradah T, Sophan S, et al. Prevalence and incidence of liver dysfunction and assessment of biomarkers of liver disease in HIV-infected Asian children. Pediatr Infect Dis J. 2015;34(6):e153-158. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25970117.
  2. Huntington S, Thorne C, Newell ML, et al. Pregnancy is associated with elevation of liver enzymes in HIV-positive women on antiretroviral therapy. AIDS. 2015;29(7):801-809. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25710412.
  3. Kovari H, Sabin CA, Ledergerber B, et al. Antiretroviral drugs and risk of chronic alanine aminotransferase elevation in human immunodeficiency virus (HIV)-monoinfected persons: the data collection on adverse events of anti-HIV drugs study. Open Forum Infect Dis. 2016;3(1):ofw009. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26925429.
  4. Navarro VJ, Khan I, Bjornsson E, Seeff LB, Serrano J, Hoofnagle JH. Liver injury from herbal and dietary supplements. Hepatology. 2017;65(1):363-373. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27677775.
  5. Sonderup MW, Wainwright HC. Human immunodeficiency virus infection, antiretroviral therapy, and liver pathology. Gastroenterol Clin North Am. 2017;46(2):327-343. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28506368.
  6. The National Institute of Diabetes and Digestive and Kidney Diseases. Clinical and research information on drug-induced liver Injury. 2019. Available at: https://livertox.nlm.nih.gov.
  7. Anadol E, Lust K, Boesecke C, et al. Exposure to previous cART is associated with significant liver fibrosis and cirrhosis in human immunodeficiency virus-infected patients. PLoS One. 2018;13(1):e0191118. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29346443.
  8. Kaspar MB, Sterling RK. Mechanisms of liver disease in patients infected with HIV. BMJ Open Gastroenterol. 2017;4(1):e000166. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29119002.
  9. Melvin AJ, Warshaw M, Compagnucci A, et al. Hepatic, renal, hematologic, and inflammatory markers in HIV-infected children on long-term suppressive antiretroviral therapy. J Pediatric Infect Dis Soc. 2017;6(3):e109-e115. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28903520.
  10. Cai J, Osikowicz M, Sebastiani G. Clinical significance of elevated liver transaminases in HIV-infected patients. AIDS. 2019;33(8):1267-1282. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31008799.
  11. Tadesse BT, Foster BA, Kabeta A, et al. Hepatic and renal toxicity and associated factors among HIV-infected children on antiretroviral therapy: a prospective cohort study. HIV Med. 2019;20(2):147-156. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30474906.

Hepatic Events and NRTIs

  1. The European Pregnancy and Paediatric HIV Cohort Collaboration, (EPPICC) study group in EuroCoord. Safety of zidovudine/lamivudine scored tablets in children with HIV infection in Europe and Thailand. Eur J of Clin Pharm. 2017;73(4):463-468.

Hepatic Events and NNRTIs

  1. Phillips E, Bartlett JA, Sanne I, et al. Associations between HLA-DRB1*0102, HLA-B*5801, and hepatotoxicity during initiation of nevirapine-containing regimens in South Africa. J Acquir Immune Defic Syndr. 2013;62(2):e55-57. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23328091.
  2. Sonderup MW, Maughan D, Gogela N, et al. Identification of a novel and severe pattern of efavirenz drug-induced liver injury in South Africa. AIDS. 2016;30(9):1483-1485. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26959511.
  3. Bienczak A, Denti P, Cook A, et al. Determinants of virological outcome and adverse events in African children treated with paediatric nevirapine fixed-dose-combination tablets. AIDS. 2017;31(7):905-915. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28060017.

Hepatic Events and NRTIs plus NNRTIs

  1. Wu PY, Cheng CY, Liu CE, et al. Multicenter study of skin rashes and hepatotoxicity in antiretroviral-naive HIV-positive patients receiving non-nucleoside reverse-transcriptase inhibitor plus nucleoside reverse-transcriptase inhibitors in Taiwan. PLoS One. 2017;12(2):e0171596. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28222098.

Hepatic Events and PIs including Indirect Hyperbilirubinemia

  1. Strehlau R, Donati AP, Arce PM, et al. PRINCE-1: safety and efficacy of atazanavir powder and ritonavir liquid in HIV-1-infected antiretroviral-naive and -experienced infants and children aged ≥3 months to <6 years. J Int AIDS Soc. 2015;18:19467. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26066346.
  2. Rutstein RM, Samson P, Fenton T, et al. Long-term safety and efficacy of atazanavir-based therapy in HIV-infected infants, children and adolescents: the pediatric AIDS clinical trials group protocol 1020A. Pediatr Infect Dis J. 2015;34:162-167. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25232777.
  3. Crutchley RD, Guduru RC, Cheng AM. Evaluating the role of atazanavir/cobicistat and darunavir/cobicistat fixed-dose combinations for the treatment of HIV-1 infection. HIV/AIDS. 2016;8:47-65. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27022304.
  4. Cotton MF, Liberty A, Torres-Escobar I, et al. Safety and efficacy of atazanavir powder and ritonavir in HIV-1-infected infants and children from 3 months to <11 years of age: the PRINCE-2 study. Pediatr Infect Dis J. 2018;37(6):e149-e156. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29206747.
  5. European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) Study Group in EuroCoord. Safety of darunavir and atazanavir in HIV-infected children in Europe and Thailand. Antivir Ther. 2016;21(4):353-358. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26561496.
  6. Leger P, Chirwa S, Nwogu JN, et al. Race/ethnicity difference in the pharmacogenetics of bilirubin-related atazanavir discontinuation. Pharmacogenet Genomics. 2018;28(1):1-6. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29117017.
  7. Sevinsky H, Zaru L, Wang R, et al. Pharmacokinetics and Pharmacodynamics of Atazanavir in HIV-1-Infected Children Treated With Atazanavir Powder and Ritonavir: Combined Analysis of the PRINCE-1 and -2 Studies. Pediatr Infect Dis J. 2018;37(6):e157-e165. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29206748.

HIV and Hepatitis B/C Coinfections

  1. Gowda C, Newcomb CW, Liu Q, et al. Risk of acute liver injury with antiretroviral therapy by viral hepatitis status. Open Forum Infect Dis. 2017;4(2):ofx012. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28470014.
  2. Phung BC, Sogni P, Launay O. Hepatitis B and human immunodeficiency virus co-infection. World J Gastroenterol. 2014;20(46):17360-17367. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25516647.
  3. European Paediatric HIVHCV Co-infection Study Group in the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) in EuroCoord. Coinfection with HIV and hepatitis C virus in 229 children and young adults living in Europe. AIDS. 2017;31(1):127-135. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27898593.
  4. Neukam K, Mira JA, Collado A, et al. Liver toxicity of current antiretroviral regimens in HIV-infected patients with chronic viral hepatitis in a real life setting: The HEPAVIR SEG-HEP Cohort. PLoS One. 2016;11(2):e0148104. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26848975.
  5. Pokorska-Spiewak M, Stanska-Perka A, Popielska J, et al. Prevalence and predictors of liver disease in HIV-infected children and adolescents. Sci Rep. 2017;7(1):12309. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28951598.
  6. Scott JA, Chew KW. Treatment optimization for HIV/HCV co-infected patients. Ther Adv Infect Dis. 2017;4(1):18-36. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28357062.
  7. Sohrab SS, Suhail M, Ali A, Qadri I, Harakeh S, Azhar EI. Consequence of HIV and HCV co-infection on host immune response, persistence and current treatment options. Virusdisease. 2018;29(1):19-26. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29607354.

Nodular Regenerative Hyperplasia and Noncirrhotic Portal Hypertension

  1. Parikh ND, Martel-Laferriere V, Kushner T, et al. Clinical factors that predict noncirrhotic portal hypertension in HIV-infected patients: a proposed diagnostic algorithm. J Infect Dis. 2014;209(5):734-738. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23911709.
  2. Scherpbier HJ, Terpstra V, Pajkrt D, et al. Noncirrhotic portal hypertension in perinatally HIV-infected adolescents treated with didanosine-containing antiretroviral regimens in childhood. Pediatr Infect Dis J. 2016;35(8):e248-252. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27167116.
  3. Sood A, Castrejon M, Saab S. Human immunodeficiency virus and nodular regenerative hyperplasia of liver: A systematic review. World J Hepatol. 2014;6(1):55-63. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24653794.

 

Management of Medication Toxicity or Intolerance

Hepatic Events

Table 15e. Antiretroviral Therapy-Associated Adverse Effects and Management Recommendations—Hepatic Events
Adverse Effects Associated ARVs Onset/Clinical Manifestations Estimated Frequency Risk Factors Prevention/Monitoring Management
Hepatitis Most ARV drugs have been associated with hepatitis, but there is a strong association between hepatitis and the use of NVP and EFV.

NVP, EFV, ABC, RAL, DTG, and MVC have been associated with hepatitis in the context of HSRs.

NRTIs, especially ZDV, have been associated with lactic acidosis and hepatic steatosis.
Onset: 
  • Acute toxic hepatitis most commonly occurs within the first few months of therapy, but it can occur later.
  • Steatosis presents after months or years of therapy.
  • Patients with HBV coinfection may experience a hepatitis flare with the initiation or withdrawal of 3TC, FTC, TDF, or TAF. Flare may also occur with the emergence of resistance to 3TC or FTC (especially if the patient is receiving only one anti-HBV agent). Note that TDF and TAF have high barriers to resistance when used to treat HBV.
  • Hepatitis may be a manifestation of IRIS if it occurs early in therapy, especially in patients with HBV or HCV coinfection.
Presentation:
  • Asymptomatic elevation of AST and ALT levels
  • Symptomatic hepatitis with nausea, fatigue, and jaundice
  • Hepatitis may present in the context of HSR with rash, lactic acidosis, and hepatic steatosis.
Uncommon HBV or HCV coinfection

Underlying liver disease

Use of other hepatotoxic medications and supplements (e.g., St. John's wort [Hypericum perforatum], chaparral [Larrea tridentata], germander [Teucrium chamaedrys])

Alcohol use

Pregnancy

Obesity

Higher drug concentrations of PIs

For NVP-Associated Hepatic Events in Adults:
  • Female sex with pre-NVP CD4 count >250 cells/mm3
  • Male sex with pre-NVP CD4 count >400 cells/mm3
  • Population- specific HLA typesa
Prevention:
  • Avoid concomitant use of hepatotoxic medications.
  • In patients with elevated levels of hepatic enzymes (>5 times to 10 times ULN) or chronic liver disease, most clinicians would avoid NVP.
Monitoring
For ARV Drugs Other Than NVP:
  • Obtain AST and ALT levels at baseline and at least every 3–4 months thereafter;b monitor at-risk patients more frequently (e.g., those with HBV or HCV coinfection or elevated baseline AST and ALT levels).
For NVP:
  • Obtain AST and ALT levels at baseline, at 2 weeks, 4 weeks, and then every 3 months.
Evaluate the patient for other infectious and non-infectious causes of hepatitis and monitor the patient closely.

Asymptomatic Hepatitis:
  • Potentially offending ARV drugs should be discontinued if ALT or AST level is >5 times ULN.
Symptomatic Hepatitis:
  • Discontinue all ARV drugs and other potentially hepatotoxic drugs.
  • If a patient experiences hepatitis that is attributed to NVP, NVP should be permanently discontinued.
  • Consider viral causes of hepatitis: HAV, HBV, HCV, EBV, and CMV.
Indirect Hyperbilirubinemia ATV Onset:
  • Within the first months of therapy
Presentation:
  • May be asymptomatic or associated with jaundice
  • Levels of direct bilirubin may be normal or slightly elevated when levels of indirect bilirubin are very high.
  • Normal AST and ALT
In long-term follow-up, 9% of children who were receiving ATV had at least one total bilirubin level >5 times ULN and 1.4% of children experienced jaundice. None established. Monitoring:
  • No ongoing monitoring needed.
  • After an initial rise over the first few months of therapy, unconjugated bilirubin levels generally stabilize; levels may improve over time.
Isolated indirect hyperbilirubinemia is not an indication to stop ATV.

Psychological impact of jaundice should be evaluated, and alternative agents should be considered.

Jaundice may result in nonadherence, particularly in adolescents; this side effect should be discussed with patients.
Non-Cirrhotic Portal Hypertension d4T, ddI

The Panel no longer recommends the use of these agents.
Onset:
  • Generally after years of therapy; may occur years after stopping therapy.
Presentation:
  • GI bleeding, esophageal varices, and hypersplenism 
  • Mild elevations in AST and ALT levels, moderate increases in ALP levels, and pancytopenia
Liver Biopsy Findings:
  • The most commonly seen findings include nodular regenerative hyperplasia and hepatoportal sclerosis.
Rare Prolonged exposure to ddI and the combination of d4T and ddI. No specific monitoring Manage complications of GI bleeding and esophageal varices.
a For example, HLA-DRB1*0101 in white people, HLA-DRB1*0102 in South Africans, and HLA-B35 in Thai people and white people.

b Less-frequent monitoring can be considered in children whose clinical status has been stable for >2 years to 3 years (see Clinical and Laboratory Monitoring of Pediatric HIV Infection).

Key: 3TC = lamivudine; ABC = abacavir; ALP = alkaline phosphatase; ALT = alanine transaminase; ARV = antiretroviral; AST = aspartate aminotransferase; ATV = atazanavir; CD4 = CD4 T lymphocyte; CMV = cytomegalovirus; d4T = stavudine; ddI = didanosine; DTG = dolutegravir; EBV = Epstein-Barr virus; EFV = efavirenz; FTC = emtricitabine; GI = gastrointestinal; HAV = hepatitis A virus; HBV = hepatitis B virus; HCV = hepatitis C virus; HLA = human leukocyte antigen; HSR = hypersensitivity reaction; IRIS = immune reconstitution inflammatory syndrome; MVC = maraviroc; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; the Panel = Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV; PI = protease inhibitor; RAL = raltegravir; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; ULN = upper limit of normal; ZDV = zidovudine
Updated
Reviewed
Apr. 14, 2020

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