SERIOUS, ACUTE AND CHRONIC TOXICITIES CAUSED BY ARV DRUGS

Clinical presentation, laboratory abnormalities and implications for ART management

These toxicities may require therapy modification. Alternative explanations for toxicity should be excluded before concluding that it is caused by the ARV drug.

This table describes management of the ART regimen but does not indicate detailed clinical toxicity management

Possible clinical manifestations (most common ARV drug or drugs associated with the toxicity)	Possible laboratory abnormalities ^a		Implications for ARV drug treatment
Acute serious adverse reactions
Acute, symptomatic hepatitis (NNRTI class, particularly NVP, more rarely EFV; NRTIs or PI class
Jaundice Liver enlargement Gastrointestinal symptoms Fatigue, anorexia May have hypersensitivity component (rash, fever, systemic symptoms), usually occurs within 6–8 weeks May have accompanying lactic acidosis (see below) if secondary to NRTI drug	Elevated transaminases Elevated bilirubin		Discontinue all ARVs until symptoms resolve If possible, monitor transaminases, bilirubin If receiving NVP, it should NOT be readministered to the patient in future Once symptoms resolve, either: – restart ART with substitution to alternative ARV (if on NVP regimen, this is required); or – restart same ART regimen with close observation; if symptoms recur, substitute an alternative ARV ^b
Acute pancreatitis (NRTI class, particularly d4T, ddI; more rarely 3TC)
Severe nausea and vomiting Severe abdominal pain May have accompanying lactic acidosis (see below)	Elevated pancreatic amylase Elevated lipase		Discontinue all ARVs until symptoms resolve If possible, monitor serum pancreatic amylase, lipase Once symptoms resolve, restart ART with substitution of an alternative NRTI, preferably one without pancreatic toxicity ^b
Hypersensitivity reaction (ABC or NVP)
ABC: Combination of acute onset of both respiratory and gastrointestinal symptoms after starting ABC, including fever, fatigue, myalgia, nausea, vomiting, diarrhoea, abdominal pain, pharyngitis, cough, dyspnoea; rash (usually mild) may or may not occur; progressive worsening of symptoms soon after receiving ABC dose, usually occurs within 6–8 weeks NVP: Systemic symptoms of fever, myalgia, arthralgia, hepatitis, with or without rash usually occurs within 6–8 weeks	Elevated transaminases Elevated eosinophil count		Immediately discontinue all ARVs until symptoms resolve NVP or ABC should NOT be readministered to the patient in future Once symptoms resolve, restart ART with substitution of an alternative ARV for ABC or NVP ^b
Lactic acidosis (NRTI class, particularly d4T)
Generalized fatigue and weakness Gastrointestinal features (nausea, vomiting, diarrhoea, abdominal pain, hepatomegaly, anorexia, poor weight gain and/or sudden unexplained weight loss) May have hepatitis or pancreatitis (see above) Respiratory features (tachypnoea and dyspnoea) Neurological symptoms (including motor weakness) Can occure at any time on ART	Increased anion gap Lactic acidosis Elevated aminotransferase Elevated creatine phosphokinase (CPK) Elevated lactate dehydrogenase (LDH)		Discontinue all ARVs until symptoms resolve Symptoms associated with lactic acidosis may continue or worsen despite discontinuation of ART Once symptoms resolve, restart ART with substitution of an alternative NRTI with lower mitochondrial toxicity risk (e.g. ABC or AZT ^b
Severe rash/Stevens – Johnson syndrome (NNRTI class, particularly NVP, less common EFV)
Rash usually occurs during first 6–8 weeks of treatment Mild-to-moderate rash: erythematous, maculopapular, confluent, most often on the body and arms, with no systemic symptoms Severe rash: extensive rash with moist desquamation, angioedema, or serum sickness-like reaction; or rash with constitutional findings such as fever, oral lesions, blistering, facial oedema, conjunctivitis Life-threatening Stevens–Johnson syndrome or toxic epidermal necrolysis (TEN)	Elevated transaminases		If mild or moderate rash, ART can continue without interruption staying at induction dose until rash settles but with close observation, and only increase to maintenance dose once tolerated For severe or life-threatening rash, discontinue all ARVs until symptoms resolve NVP should NOT be readministered to the patient in the future Once symptoms resolve, restart ART with substitution of an alternative ARV for NVP (note: most experts would not change to another NNRTI drug if patient had severe or life-threatening Stevens – Johnson syndrome with NVP) ^b
Severe life-threatening anaemia (AZT)
Severe pallor, tachycardia Significant fatigue Congestive heart failure	Low haemoglobin		refractory to symptomatic treatment (e.g. transfusion), discontinue AZT only and substitute an alternative NRTI ^b
Severe neutropenia (AZT)
Sepsis/infection	Low neutrophil count		If refractory to symptomatic treatment (e.g. transfusion), discontinue AZT only and substitute an alternative NRTI ^b
Chronic late serious adverse reactions
Lipodystrophy/metabolic syndrome (d4T; PIs)
Fat accumulation and/or fat loss in distinct regions of the body: – increased fat around the abdomen, buffalo hump, breast hypertrophy – fat loss from limbs, buttocks and face occurs to a variable extent Insulin resistance, including diabetes mellitus Potential risk for later coronary artery disease		Hyper-triglyceridaemia Hyper-cholesterolaemia; Low high-density lipoprotein (HDL) levels Hyperglycaemia	Substitution of ABC or AZT for d4T may prevent progression of lipoatrophy Substitution of an NNRTI for a PI may decrease serum lipid abnormalities
Severe peripheral neuropathy (d4T, ddI; more rarely 3TC)
Pain, tingling, numbness of hands or feet; inability to walk Distal sensory loss Mild muscle weakness and areflexia may occur		None	Stop suspected NRTI only and substitute a different NRTI that is not associated with neurotoxicityb Symptoms may take several weeks to resolve

a: All laboratory abnormalities may not be observed.
b: See Table 7 (Section 9) for recommended ARV drug substitutions.

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Antiretroviral Therapy for HIV Infection in Infants and Children: Towards Universal Access: Recommendations for a Public Health Approach: 2010 Revision.

ANNEX FSERIOUS, ACUTE AND CHRONIC TOXICITIES CAUSED BY ARV DRUGS

Clinical presentation, laboratory abnormalities and implications for ART management

This table describes management of the ART regimen but does not indicate detailed clinical toxicity management

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