Table 17a. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Central Nervous System Toxicity

LPV/r oral solution which contains both ethanol (42.4% v/v) and propylene glycol (15.3% w/v) 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 when the patient is outside the vulnerable period (i.e., postmenstrual age of 42 weeks and a postnatal age ≥14 days).

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

Avoid use of EFV for initial ARV treatment in children and adolescents to prevent EFV-associated CNS side effects. See What to Start: Regimens Recommended for Initial Therapy of Antiretroviral-Naive Children.

In situations where EFV treatment may be indicated, consider the following:

• 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

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 5 of 36 children (14%).

Adults

• CNS/neuropsychiatric 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 because of severe depressive disorders. Higher frequency of depression and dizziness reported when coadministered with DTG.

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
• Self-harm thoughts, 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 2 of 29 (6.8%) children who initiated DTG.
• Significantly higher frequency of self-harm or suicidal thoughts reported in children in the ODYSSEY trial receiving DTG (23%) compared to SOC ARVs (5%). They were transient, self-resolved, and did not lead to treatment changes.

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.

Preexisting depression or other psychiatric illness

History of ARV-related neuropsychiatric symptoms

Higher frequency of overall neuropsychiatric symptoms reported when DTG is coadministered with ABC, and of depression and dizziness when DTG is coadministered with RPV. However, evidence is conflicting for ABC association.

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 likely will 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 preexisting depression
• Suicidal ideation or attempted suicide
• Schizoaffective disorders
• Anxiety

Other CNS Manifestations (Generally Mild)

• Sleep disturbances
• Dizziness
• Insomnia

Children

• One child (1%) had Grade 2 insomnia and anxiety that led to drug discontinuation in clinical trials.

Adults

• Overall, the frequency of neuropsychiatric events in BIC and DTG comparator arms appeared similar in adult clinical trials.
• 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.
• A recent study reported a 3.3% short-term BIC-related discontinuation rate due to neuropsychiatric AEs after ART switch in a large cohort of adults with HIV in routine clinical practice setting.

Preexisting 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 likely will resolve with time.

CAB

Presentation

Neuropsychiatric Symptoms (Generally Mild or Moderate, Occasionally Serious)

• Mood disorders, including depression and suicidal ideation or attempt
• Anxiety disorders

Other CNS Manifestations

(Generally Mild or Moderate)

• Sleep disorders
• Dizziness
• Headache
• Somnolence

Children

• Insomnia was reported in 1 of 8 adolescents in the ongoing MOCHA trial.

Adults

• 2–4% pooled incidence reported in Phase 3 trials for CNS AEs, including sleep disorders, dizziness, and headache.
• Less than 2% incidence reported for depressive disorders, including suicidal ideation, in Phase 3 trials, with comparable incidence in CAB and control groups.

Preexisting depression or other psychiatric conditions could be contributing factors, but causal links have not clearly been identified.

CAB exposure did not differ between subjects with or without CNS or neuropsychiatric manifestations.

Monitor individuals for depressive symptoms or self-injurious thoughts or behavior, especially if prior history of such.

Promptly evaluate severe depressive symptoms, self-injurious behavior, or other CNS symptoms for a possible relationship with CAB, and assess risks and benefits of continued CAB treatment.

If CAB is discontinued—

• Counsel the individual about prolonged residual CAB levels in the blood for 52 weeks or longer, and monitor frequently for symptom resolution.
• Ensure that a new suppressive regimen is started within 30 days of last injection.