Management of Medication Toxicity or Intolerance

CNS Toxicity

Table 15a. Antiretroviral Therapy-Associated Adverse Effects and Management Recommendations—Central Nervous System Toxicity
Adverse Effects Associated ARVs Onset/Clinical Manifestations Estimated Frequency Risk Factors Prevention/ Monitoring Management
Global CNS Depression LPV/r oral solution (contains both ethanol and propylene glycol as excipients) Onset:
  • 1–6 days after starting LPV/r
Presentation
Neonates/Premature Infants:
  • Global CNS depression (e.g., abnormal EEG, altered state of consciousness, somnolence)
Unknown; rare case reports have been published Prematurity

Low birth weight

Aged <14 days (whether birth was premature or term)
Avoid use of LPV/r until a postmenstrual age of 42 weeks and a postnatal age of ≥14 days unless no other alternatives are available, see Lopinavir/Ritonavir. Discontinue LPV/r; symptoms should resolve in 1–5 days.

If needed, reintroduction of LPV/r can be considered once the patient is outside the vulnerable period (i.e., postmenstrual age of 42 weeks and a postnatal age ≥14 days).
Neuropsychiatric Symptoms and Other CNS Manifestations


 
EFV Onset:
  • For many symptoms, onset is 1–2 days after starting EFV.
  • Many symptoms subside or diminish by 2–4 weeks, but symptoms may persist in a significant proportion of patients.
Presentation (May Include One or More of the Following)
Neuropsychiatric Symptoms:
  • Abnormal dreams
  • Psychosis
  • Suicidal ideation or attempted/completed suicide
Other CNS Manifestations:
  • Dizziness
  • Somnolence
  • Insomnia or poor sleep quality
  • Impaired concentration
  • Seizures (including absence seizures)
  • Cerebellar dysfunction (e.g., tremor, dysmetria, ataxia)
Note: CNS side effects (e.g., impaired concentration, abnormal dreams, sleep disturbances) may be more difficult to assess in children.
Variable, depending on age, symptoms, and assessment method

Children:
  • 24% of patients experienced any EFV-related CNS manifestation in one case series, with 18% of participants requiring drug discontinuation.
  • Five of 45 participants (11%) experienced new-onset seizures in one study of children aged <36 months; two of these participants had alternative causes for seizures.
  • Cases of cerebellar dysfunction have been reported in children with very high EFV plasma levels.
Adults:
  • 30% incidence for any CNS manifestations of any severity.
  • 6% incidence for EFV-related, severe CNS manifestations, including suicidality. However, evidence is conflicting about whether EFV use increases the incidence of suicidality.
  • One case series reported 20 women with ataxia that resolved upon EFV discontinuation, but frequency was not reported.
Insomnia is associated with elevated EFV trough concentration (≥4 mcg/mL)

CYP2B6 polymorphisms that decrease EFV metabolism and cause increased EFV serum concentrations (CYP2B6 516 T/T genotype or co-carriage of CYP2B6 516 G/T and 983 T/C variants)

History of psychiatric illness or use of psychoactive drugs
Administer EFV on an empty stomach, preferably at bedtime.

Prescreen for psychiatric illness; avoid use in the presence of psychiatric illness, including depression or suicidal thoughts. Avoid concomitant use of psychoactive drugs.

Consider using TDM in children with mild or moderate EFV-associated toxicities.
If symptoms are excessive or persistent, obtain EFV trough concentration. If EFV trough concentration is >4 mcg/mL and/or symptoms are severe, strongly consider drug substitution if a suitable alternative exists.

Alternatively, consider dose reduction with repeat TDM and dose adjustment (with input from an expert pharmacologist).
RPV Onset:
  • Most symptoms occur in the first 4–8 weeks of treatment.
Presentation
Neuropsychiatric Symptoms:
  • Depressive disorders
  • Suicidal ideation
  • Abnormal dreams/nightmares
Other CNS Manifestations:
  • Headache
  • Dizziness
  • Insomnia
  • Somnolence
Adults:
  • CNS/neuro-psychiatric adverse events of all severity grades were reported in 43% of patients at 96 weeks (most were Grade 1). Depressive disorders of all severity grades were reported in 9% of patients; 1% of patients discontinued RPV due to severe depressive disorders.
Children:
  • Depressive disorders of all severity grades were reported in 19.4% of pediatric patients aged 12–17 years. Severe depressive disorders were reported in 5.6% of patients, including one suicide attempt.
  • Somnolence was reported in five of 36 children (14%).
History of neuropsychiatric illness Monitor carefully for depressive disorders and other CNS symptoms. Consider drug substitution in cases of severe symptoms.
RAL Onset:
  • As early as 3–4 days after starting RAL
Presentation:
  • Increased psychomotor activity
  • Headaches
  • Insomnia
  • Depression
  • Cerebellar dysfunction (e.g., tremor, dysarthria, ataxia)
Children:
  • Increased psychomotor activity was reported in one child.
Adults:
  • Headache
  • Insomnia (<5% in adult trials)
  • Rare case reports of cerebellar dysfunction in adults
Elevated RAL concentrations

Co-treatment with TDF, a PPI, or inhibitors of UGT1A1

Prior history of insomnia or depression
Prescreen for psychiatric symptoms.

Monitor carefully for CNS symptoms.

Use with caution in the presence of drugs that increase RAL concentration.
Consider drug substitution (RAL or coadministered drug) in cases of severe insomnia or other neuropsychiatric symptoms.
DTG Onset:
  • 7–30 days after starting DTG
Presentation
Neuropsychiatric Symptoms:
  • Depression or exacerbation of preexisting depression
  • Anxiety
  • Suicidal ideation or attempted/completed suicide
  • Drowsiness
  • Neurocognitive deficits (lower total competence and school performance)
Other CNS Manifestations (Generally Mild):
  • Sleep disturbances
  • Dizziness
  • Headache
Children:
  • In a retrospective cohort analysis, neuropsychiatric events that resulted in discontinuation occurred in two of 29 (6.8%) children who initiated DTG.
Adults:
  • 2.7% of the neuropsychiatric AEs reported in a large prospective cohort resulted in treatment discontinuation.
  • Higher frequency of neuropsychiatric symptoms reported with DTG than with other INSTIs. A class effect has been suggested.
Pre-existing depression or other psychiatric illness

History of ARV-related neuropsychiatric symptoms

Higher frequency of neuropsychiatric symptoms reported when DTG is coadministered with ABC; however, evidence is conflicting.

UGT1A1*6 and/or *28 polymorphism (reported in patients of Asian descent)
Use with caution in the presence of psychiatric illness, especially in patients with depression or a history of ARV-related neuropsychiatric symptoms.

Consider morning dosing of DTG.
For persistent or severe neuropsychiatric symptoms, consider discontinuing DTG if a suitable alternative exists.

For mild symptoms, continue DTG and counsel patient that symptoms will likely resolve with time.
BIC Onset:
  • 1–63 days after starting BIC (as late as 233 days for schizoaffective disorders)
Presentation
Neuropsychiatric Symptoms:
  • Depression or exacerbation of pre-existing depression
  • Suicidal ideation or attempted suicide
  • Schizoaffective disorders
  • Anxiety
Other CNS Manifestations (Generally Mild):
  • Abnormal dreams
  • Dizziness
  • Insomnia
Data in children and adults come mostly from clinical trials. Overall, the frequency of neuropsychiatric events in BIC and DTG comparator arms appeared similar in adult clinical trials.

Children:
  • 1 child (1%) had Grade 2 insomnia and anxiety that led to drug discontinuation.
Adults:
  • Abnormal dreams, dizziness, and insomnia occurred in 1% to 5% of adults.
  • Suicidal ideation, suicide attempts, schizoaffective disorders, and depression occurred in <1% of adults.
Pre-existing depression or other psychiatric conditions

History of ARV-related neuropsychiatric symptoms
Use with caution in the presence of psychiatric conditions, or in patients with a history of ARV-related neuropsychiatric symptoms. For persistent or severe neuropsychiatric symptoms, consider discontinuing BIC if a suitable alternative exists.

For mild symptoms, continue BIC and counsel patient that symptoms will likely resolve with time.
Key: ABC = abacavir; ARV = antiretroviral; BIC = bictegravir; CNS = central nervous system; CYP = cytochrome P; DTG = dolutegravir; EEG = electroencephalogram; EFV = efavirenz; INSTI = integrase strand transfer inhibitor; LPV/r = lopinavir/ritonavir; PPI = proton pump inhibitor; RAL = raltegravir; RPV = rilpivirine; TDF = tenofovir disoproxil fumarate; TDM = therapeutic drug monitoring; UGT = uridine diphosphate-glucuronosyltransferase

References

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  24. Nachman S, et al. IMPAACT P1066: raltegravir (RAL) safety and efficacy in HIV infected (+) youth two to 18 years of age through week 48. Abstract no. TUAB0205. Presented at: 19th International AIDS Conference. 2012. Washington, DC.
  25. Napoli AA, Wood JJ, Coumbis JJ, Soitkar AM, Seekins DW, Tilson HH. No evident association between efavirenz use and suicidality was identified from a disproportionality analysis using the FAERS database. J Int AIDS Soc. 2014;17:19214. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25192857.
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  28. Puthanakit T, Tanpaiboon P, Aurpibul L, Cressey TR, Sirisanthana V. Plasma efavirenz concentrations and the association with CYP2B6-516G >T polymorphism in HIV-infected Thai children. Antivir Ther. 2009;14(3):315-320. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19474465.
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  36. Todd S, Rafferty P, Walker E, et al. Early clinical experience of dolutegravir in an HIV cohort in a larger teaching hospital. Int J STD AIDS. 2017:956462416688127. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28118801.
  37. van Dijk JH, Sutcliffe CG, Hamangaba F, Bositis C, Watson DC, Moss WJ. Effectiveness of efavirenz-based regimens in young HIV-infected children treated for tuberculosis: a treatment option for resource-limited settings. PLoS One. 2013;8(1):e55111. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23372824.
  38. Variava E, Sigauke FR, Norman J, et al. Brief report: late efavirenz-induced ataxia and encephalopathy: a case series. J Acquir Immune Defic Syndr. 2017;75(5):577-579. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28520619.
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  40. Walmsley S, Baumgarten A, Berenguer J, et al. Dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: week 96 and week 144 results from the SINGLE randomized clinical trial. J Acquir Immune Defic Syndr. 2015. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26262777.
  41. Waters L, Fisher M, Winston A, et al. A Phase IV, double-blind, multicentre, randomized, placebo-controlled, pilot study to assess the feasibility of switching individuals receiving efavirenz with continuing central nervous system adverse events to etravirine. AIDS. 2011;25(1):65-71. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21099666.
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Management of Medication Toxicity or Intolerance

CNS Toxicity

Table 15a. Antiretroviral Therapy-Associated Adverse Effects and Management Recommendations—Central Nervous System Toxicity
Adverse Effects Associated ARVs Onset/Clinical Manifestations Estimated Frequency Risk Factors Prevention/ Monitoring Management
Global CNS Depression LPV/r oral solution (contains both ethanol and propylene glycol as excipients) Onset:
  • 1–6 days after starting LPV/r
Presentation
Neonates/Premature Infants:
  • Global CNS depression (e.g., abnormal EEG, altered state of consciousness, somnolence)
Unknown; rare case reports have been published Prematurity

Low birth weight

Aged <14 days (whether birth was premature or term)
Avoid use of LPV/r until a postmenstrual age of 42 weeks and a postnatal age of ≥14 days unless no other alternatives are available, see Lopinavir/Ritonavir. Discontinue LPV/r; symptoms should resolve in 1–5 days.

If needed, reintroduction of LPV/r can be considered once the patient is outside the vulnerable period (i.e., postmenstrual age of 42 weeks and a postnatal age ≥14 days).
Neuropsychiatric Symptoms and Other CNS Manifestations


 
EFV Onset:
  • For many symptoms, onset is 1–2 days after starting EFV.
  • Many symptoms subside or diminish by 2–4 weeks, but symptoms may persist in a significant proportion of patients.
Presentation (May Include One or More of the Following)
Neuropsychiatric Symptoms:
  • Abnormal dreams
  • Psychosis
  • Suicidal ideation or attempted/completed suicide
Other CNS Manifestations:
  • Dizziness
  • Somnolence
  • Insomnia or poor sleep quality
  • Impaired concentration
  • Seizures (including absence seizures)
  • Cerebellar dysfunction (e.g., tremor, dysmetria, ataxia)
Note: CNS side effects (e.g., impaired concentration, abnormal dreams, sleep disturbances) may be more difficult to assess in children.
Variable, depending on age, symptoms, and assessment method

Children:
  • 24% of patients experienced any EFV-related CNS manifestation in one case series, with 18% of participants requiring drug discontinuation.
  • Five of 45 participants (11%) experienced new-onset seizures in one study of children aged <36 months; two of these participants had alternative causes for seizures.
  • Cases of cerebellar dysfunction have been reported in children with very high EFV plasma levels.
Adults:
  • 30% incidence for any CNS manifestations of any severity.
  • 6% incidence for EFV-related, severe CNS manifestations, including suicidality. However, evidence is conflicting about whether EFV use increases the incidence of suicidality.
  • One case series reported 20 women with ataxia that resolved upon EFV discontinuation, but frequency was not reported.
Insomnia is associated with elevated EFV trough concentration (≥4 mcg/mL)

CYP2B6 polymorphisms that decrease EFV metabolism and cause increased EFV serum concentrations (CYP2B6 516 T/T genotype or co-carriage of CYP2B6 516 G/T and 983 T/C variants)

History of psychiatric illness or use of psychoactive drugs
Administer EFV on an empty stomach, preferably at bedtime.

Prescreen for psychiatric illness; avoid use in the presence of psychiatric illness, including depression or suicidal thoughts. Avoid concomitant use of psychoactive drugs.

Consider using TDM in children with mild or moderate EFV-associated toxicities.
If symptoms are excessive or persistent, obtain EFV trough concentration. If EFV trough concentration is >4 mcg/mL and/or symptoms are severe, strongly consider drug substitution if a suitable alternative exists.

Alternatively, consider dose reduction with repeat TDM and dose adjustment (with input from an expert pharmacologist).
RPV Onset:
  • Most symptoms occur in the first 4–8 weeks of treatment.
Presentation
Neuropsychiatric Symptoms:
  • Depressive disorders
  • Suicidal ideation
  • Abnormal dreams/nightmares
Other CNS Manifestations:
  • Headache
  • Dizziness
  • Insomnia
  • Somnolence
Adults:
  • CNS/neuro-psychiatric adverse events of all severity grades were reported in 43% of patients at 96 weeks (most were Grade 1). Depressive disorders of all severity grades were reported in 9% of patients; 1% of patients discontinued RPV due to severe depressive disorders.
Children:
  • Depressive disorders of all severity grades were reported in 19.4% of pediatric patients aged 12–17 years. Severe depressive disorders were reported in 5.6% of patients, including one suicide attempt.
  • Somnolence was reported in five of 36 children (14%).
History of neuropsychiatric illness Monitor carefully for depressive disorders and other CNS symptoms. Consider drug substitution in cases of severe symptoms.
RAL Onset:
  • As early as 3–4 days after starting RAL
Presentation:
  • Increased psychomotor activity
  • Headaches
  • Insomnia
  • Depression
  • Cerebellar dysfunction (e.g., tremor, dysarthria, ataxia)
Children:
  • Increased psychomotor activity was reported in one child.
Adults:
  • Headache
  • Insomnia (<5% in adult trials)
  • Rare case reports of cerebellar dysfunction in adults
Elevated RAL concentrations

Co-treatment with TDF, a PPI, or inhibitors of UGT1A1

Prior history of insomnia or depression
Prescreen for psychiatric symptoms.

Monitor carefully for CNS symptoms.

Use with caution in the presence of drugs that increase RAL concentration.
Consider drug substitution (RAL or coadministered drug) in cases of severe insomnia or other neuropsychiatric symptoms.
DTG Onset:
  • 7–30 days after starting DTG
Presentation
Neuropsychiatric Symptoms:
  • Depression or exacerbation of preexisting depression
  • Anxiety
  • Suicidal ideation or attempted/completed suicide
  • Drowsiness
  • Neurocognitive deficits (lower total competence and school performance)
Other CNS Manifestations (Generally Mild):
  • Sleep disturbances
  • Dizziness
  • Headache
Children:
  • In a retrospective cohort analysis, neuropsychiatric events that resulted in discontinuation occurred in two of 29 (6.8%) children who initiated DTG.
Adults:
  • 2.7% of the neuropsychiatric AEs reported in a large prospective cohort resulted in treatment discontinuation.
  • Higher frequency of neuropsychiatric symptoms reported with DTG than with other INSTIs. A class effect has been suggested.
Pre-existing depression or other psychiatric illness

History of ARV-related neuropsychiatric symptoms

Higher frequency of neuropsychiatric symptoms reported when DTG is coadministered with ABC; however, evidence is conflicting.

UGT1A1*6 and/or *28 polymorphism (reported in patients of Asian descent)
Use with caution in the presence of psychiatric illness, especially in patients with depression or a history of ARV-related neuropsychiatric symptoms.

Consider morning dosing of DTG.
For persistent or severe neuropsychiatric symptoms, consider discontinuing DTG if a suitable alternative exists.

For mild symptoms, continue DTG and counsel patient that symptoms will likely resolve with time.
BIC Onset:
  • 1–63 days after starting BIC (as late as 233 days for schizoaffective disorders)
Presentation
Neuropsychiatric Symptoms:
  • Depression or exacerbation of pre-existing depression
  • Suicidal ideation or attempted suicide
  • Schizoaffective disorders
  • Anxiety
Other CNS Manifestations (Generally Mild):
  • Abnormal dreams
  • Dizziness
  • Insomnia
Data in children and adults come mostly from clinical trials. Overall, the frequency of neuropsychiatric events in BIC and DTG comparator arms appeared similar in adult clinical trials.

Children:
  • 1 child (1%) had Grade 2 insomnia and anxiety that led to drug discontinuation.
Adults:
  • Abnormal dreams, dizziness, and insomnia occurred in 1% to 5% of adults.
  • Suicidal ideation, suicide attempts, schizoaffective disorders, and depression occurred in <1% of adults.
Pre-existing depression or other psychiatric conditions

History of ARV-related neuropsychiatric symptoms
Use with caution in the presence of psychiatric conditions, or in patients with a history of ARV-related neuropsychiatric symptoms. For persistent or severe neuropsychiatric symptoms, consider discontinuing BIC if a suitable alternative exists.

For mild symptoms, continue BIC and counsel patient that symptoms will likely resolve with time.
Key: ABC = abacavir; ARV = antiretroviral; BIC = bictegravir; CNS = central nervous system; CYP = cytochrome P; DTG = dolutegravir; EEG = electroencephalogram; EFV = efavirenz; INSTI = integrase strand transfer inhibitor; LPV/r = lopinavir/ritonavir; PPI = proton pump inhibitor; RAL = raltegravir; RPV = rilpivirine; TDF = tenofovir disoproxil fumarate; TDM = therapeutic drug monitoring; UGT = uridine diphosphate-glucuronosyltransferase
Updated
Reviewed
Apr. 14, 2020

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