Monitoring for Antiretroviral Drug Toxicities

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Class/Agent	Adverse Event	Laboratory	Indication/Screening
NRTIs	Hepatic steatosis/lactic acidosis	Chem7/venous lactate if symptoms	Fatigue/muscle aches, GI symptoms, dyspnea
AZT	Cytopenia	CBC/dif	Baseline, q4-6wks, q3-6 months
DDI	Pancreatitis Cytopenia Hepatotoxicity	Amylase/lipase CBC/diff LFTs	Baseline and symptoms Baseline, q12months Baseline, q12months
D4T 3TC/FTC ABC	Hepatotoxicity	LFTs	Baseline, q12 months
Tenofovir *	Nephrotoxicity Proteinuria Phosphate wasting	Chem 7 U/A Phosphate	Baseline, 3 mo, 6 mo, then q year if stable Please see tenofovir document Please see tenofovir document
Nevirapine	Hepatotoxicity	LFTs	Baseline, prior to dose escalation, 2weeks after escalation, 3 months, then q 6months
Efavirenz	Hyperlipidemia	Fasting lipids	Baseline, 3mo., 6mo., then q year if stable
PIs Indinavir Saquinavir Ritonavir Nelfinavir Fosamprenavir Atazanavir Kaltera Atazanavir	Hyperlipidemia/ lipodystrophy	Fasting lipds	Baseline, 3mo., 6mo, then q year if stable
	Hepatitis/hepatotoxicity	LFTs	Baseline, 3mo., then q 6mo
	Cytopenia	CBC/diff	Baseline, 4-6weeks, then q year
	Diabetes mellitus	Fasting glucose	Baseline, then q year
Indinavir	Nephrolithiasis	Urianalysis/creatinine	Baseline, q 6mo or if hematuria/flank pain
Atazanavir	Jaundice	Bilirubin	Baseline, q 3month LFTs

* See below for document on management of tenofovir associated renal dysfunction.

While the risk of nephrotoxicity with TDF is reported to be very low, some data suggest the possibility of renal impairment in a small number of patients. Our goals are to capture data to shed further light on this question and protect research volunteers’ safety, while at the same time not over-burdening the sites and participants. Harmonization of management across all studies is not necessary. Teams should take a flexible approach, considering the risk/benefit ratio in each setting.
GFR calculations or an equivalent measure of baseline renal function should be part of eligibility criteria. Sites may consider whether the MDRD method, using just age, gender, race, and serum creatinine might be an appropriate tool for this purpose. It is available at http://www.nephron.com. The traditional Cockcroft-Gault GFR calculation is also acceptable although it may be less reliable estimate of GFR in the patients with impaired renal function. In cases of extreme physical wasting, it may be helpful to have a baseline urine creatinine excretion, using a 24 hour urine collection, where this is feasible. This would permit any future concerns about a rise in serum creatinine that might be due to increased body mass to be directly addressed.
Teams should consider including a cushion between minimum eligibility GFR and the calculated creatinine clearance <50 threshold for discontinuing drug. (Note that the latter is based on pharmacologic considerations of the need to reduce dose for reduced GFR, as distinct from toxicity management. In trials where change in dosing is planned for reduced GFR, a different threshold may be appropriate).
For toxicity management, as opposed to entry criteria, teams should consider change in serum creatinine or fall in estimated GFR as a primary indication to more closely monitor a subject and to carefully evaluate possible contributing factors. A confirmed 50% increase in serum creatinine or an absolute increase of 0.5 above baseline is suggested as an appropriate threshold for closer monitoring. Alternate measures, such as a fall in estimated GFR, perhaps by 25 or 30 ml/min/1.73 m2, might be used where appropriate. Nevertheless, a subject whose calculated creatinine clearance decreases below the study threshold for drug discontinuation should have their regimen changed.
Management of hypophosphatemia should begin at severity grade 3 (eg ≤1.4 mg/dL) as specified in the DAIDS toxicity table.
Additional factors that should be considered in reviewing whether a treatment regimen should be changed for a subject include abnormalities in serum bicarbonate (or laboratory equivalent), phosphorous, or potassium, and glycosuria or proteinuria, since these may be earlier signs of renal tubular damage that precede elevated creatinine. Teams are asked to consider the presence of three or more of these findings, in the absence of other causes, as an indication to closely monitor and carefully evaluate whether a renal tubulopathy may be occurring and drug change may be indicated.
Use of potentially nephrotoxic drugs together with TDF should be actively discouraged, especially in cases of any evidence of impaired renal function.
Bone mineral density decrease may be a risk in children and this should be monitored whenever feasible in pediatric studies.

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