Table 2.

Clinical trial evaluation of hepatic toxicity and incidence for non-nucleoside reverse transcriptase inhibitors.

Reference	Drug(s)	No. of Study Patients	Hepatic Evaluation	Overall Incidence of Cases/100 Persons Exposed	Study Design	Patient Population
Sulkowski 2002 [10]	Efavirenz	312	Combined Grade 3 and 4 Grade 3: AST/ALT 5.1–10× ULN Grade 4: AST/ALT > 10× ULN	8	Prospective	Treatment-naive; 40% HCV-positive; 52% concurrent protease inhibitor use
van Leth 2004 2NN [11]	Efavirenz	400	Combined Grade 3 and 4 Grade 3: AST/ALT 5.1–10× ULN Grade 4: AST/ALT > 10× ULN	4.5	Prospective	Treatment-naive; 10% HCV-positive; 4% HBV-positive
Girard 2012 DUET-1 and DUET 2 (96 Week Pooled Data) [12]	Etravirine	599	Grade 3: AST/ALT 5.1–10× ULN Grade 4: AST/ALT > 10× ULN	Grade 3: 4.4 Grade 4: 3.9	Prospective	Treatment-experienced; 12% HBV- and/or HCV-positive
Molina 2011 ECHO [13]	Rilpivirine	346	Combined Grade 3 and 4 Grade 3: AST/ALT 5.1–10× ULN Grade 4: AST/ALT > 10× ULN	AST: 2 ALT:1	Prospective	Treatment-naive; 3% HBV-positive; 2% HCV-positive
Cohen 2011 THRIVE [14]	Rilpivirine	340	AST/ALT 5.1–10× ULN	2	Prospective	Treatment-naive; 4% HBV-positive; 5% HCV-positive
Nelson 2012 [15]	Rilpivirine	686	Combined Grades 1–4 Grade 1: AST/ALT 1.25–2.4× ULN Grade 2: 2.5–4.9× ULN Grade 3: 5–9.9× ULN Grade 4: ≥ 10× ULN	2.2	Prospective	Treatment-naive; 8.4% HBV- and/or HCV-positive
Molina 2020 DRIVE-FORWARD [16]	Doravirine	383	AST/ALT ≥ 5× ULN	ALT: 1 AST: 2	Prospective	Treatment-naive
Orkin 2020 DRIVE-AHEAD [17]	Doravirine	363	AST/ALT 5–9.9× ULN	ALT: 0.8 AST: 0.6	Prospective	Treatment-naive; 3% HBV- and/or HCV-positive
Johnson 2019 DRIVE-SHIFT [18]	Doravirine	447	ALT/ALT ≥ 3× ULN plus bilirubin ≥ 2× ULN and alkaline phosphatase < 2× ULN	0	Prospective	Treatment-experienced; 3% HBV- and/or HCV-positive

Abbreviations: ALT, alanine transaminase; AST, aspartate aminotransferase; HBV, hepatitis B virus; HCV, hepatitis C virus; ULN, upper limit of normal.