Unclear ALT Yes Monthly for first 3 months, then every 3 months EFV: 6 weeks. count, chemistry Full blood count, Creatinine, ALT, AST

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1 Supplementary Table S1: Monitoring strategies Study Time to toxic event Type of AE monitoring Frequency of AE monitoring Symptom* Laboratory Baseline Routine Boulle, 2008 Change NVP: 8 weeks Unclear ALT Monthly for first 3, then every 3 EFV: 6 weeks Bruck, 2008 Liver enzyme AST, ALT Every 8 weeks elevation EFV 20 weeks NVP: 16 weeks Castlenuovo, t stated Full blood count, AST, t stated Every 6 Creatinine, serum lactate Elzi, 2010 t stated t stated t stated t stated t stated Ferradini, 2006 t stated Full blood Forna, 2007 t stated (Medical officer or self-referral) count, chemistry Full blood count, Creatinine, ALT, AST Gaytan, 2004 t stated Every 4 weeks George, 2009 t stated t stated t stated t stated t stated Haddow, 2007 t stated t stated t stated t stated t stated Ibadova, 2010 t stated t stated t stated t stated t stated Jena, 2009 t stated Hb, TLC, platelets, CD4, ALT, AST hemogram, liver function test, renal function test, lipidogram, ECG, and chest x-ray Kampire NS NS NS Kalyesubula, t stated Full blood count, ALT Complete blood count and ALT 2,6,14 and 24 weeks 2, 6, 10 and 14 weeks only ALT Khalili, 2009 t stated Full and differential blood counts, ALT, AST, Alk.P, TBR, Creatinine, BUN, triglycerides, total cholesterol, LDL, HDL, blood fasting sugar, lactate, CPK Kumarasamy, 2008a Kumarasamy, 2008b t stated Hb, liver, and renal function tests t stated Hb, Creatinine, ALT, AST t stated t stated Monthly: blood counts 3, 6, 12 : lipids, fasting blood sugar, liver and renal function, lactate, CPK 2, 4, 8, and 12 weeks if on NVP: liver function Every 3 or as clinically indicated t stated Manfredi, 2006 NVP: 4.2±1.8 EFV: 7.8±2.6 Mankhatitham, t stated Messou, 2010 NVP: 4.8 EFV: 12.8 t stated ALT, AST t stated Full blood count, blood chemistries and AST, ALT, TBR Liver function tests only Creatinine, ALT, AST Creatinine, ALT, AST 6, 12 and 24 weeks Every 6 Modayil, 2010 t stated t stated t stated t stated Monthly for newly registered pts; spontaneous reporting for longer term pts

2 Nunez, 2002 t stated Full blood count, liver (AST, ALT) and kidney function tests, amylase and lipid profile (including cholesterol, triglycerides) Obiako, 2012 t stated Blood chemistry and hematology Every 3 Every 12 weeks; visits for complaints Patel, 2006 t stated ALT t stated Monthly then 3 monthly Ritchie, 2006 t stated t stated ALT, AST (frequency stated) Sanne, 2005 HT: 28 days ALT, AST Monthly Sivadasan, 2009 Rash: 2 weeks ALT, AST 2 weeks, 1 month, then every 3 Srirangaraj, 2010 NVP: 77 days Full blood count, AST, 3 monthly EFV: 118 days ALT, TBR, creatinine (Hb, ALT, TBR, creatinine) Sulkowski, 2002 NVP: 137 days Full blood count, ALT, 4 weeks, then 3 monthly Swaminathan, EFV: 100 days t stated (monthly) AST, TBR Full blood count, liver function (tests stated) [0]Hematologic al analysis, blood glucose levels, and liver and renal function tests 2 weeks for 8 weeks, then 3 monthly Tukei, 2012 t stated Full blood count, ALT, AST Monthly van den Berg- t stated ALT, AST t stated 1 month, then 4 monthly Wolf, 2008 Van Leth, 2004 t stated ALT, AST, TBR 2, 4, 8, 12, 24, 36 and 48 weeks Wester, 2010 Treatment lipodystrophy Chemistry, full blood Monthly for 6 then 2 modifying (every 6 count, lipid chemistry monthly for 6, then 4 toxicity ), monthly NVP: c. 14 days peripheral EFV: c. 40 days neuropathy (every 2 ) Zhou, 2006 t stated t stated t stated t stated t stated * [0]Defined as necessary for the laboratory test to be performed (i.e. routine) AlkP Alkaline Phosphatase ALT Alanine transaminase AST Aspartate amiransferase BUN Blood Urea Nitrogen CPK Creatinine phosphokinase Hb Haemaglobin LDL and HDL Low-density and High-density lipoprotein cholesterol TBR Total Bilirubin TLC Total leucocyte count

3 Supplementary Table S2: Risk of bias Study Baseline characteri stics balanced (details) Unbiased reporting of outcomes Loss to follow up <2 Allocation concealment reported (for RCTs) Minimal follow up time (may exclude early discontinuations) Differential follow up by drug Overall risk of bias Boulle, 2008 N/A Low Bruck, N/A Low Castlenuovo, N/A Moderate Elzi, N/A Low/moderate Ferradini, N/A Low/moderate Forna, N/A Low Gaytan, Low/moderate George, N/A Low/moderate Haddow, N/A Low/moderate Ibadova, High Jena, N/A Low Kalyesubula, -- N/A Low/moderate Khalili, N/A Low/moderate Kampiire, N/A Moderate Kumarasamy, 2008a -- N/A Low/moderate Kumarasamy, 2008b N/A -- Low/moderate Manfredi, N/A Low/moderate Mankhatitham, Low/moderate Modayil, N/A Low/moderate Nunez, 2002 Low/moderate Obiako, N/A Low/moderate Patel, 2006 N/A Low Richie, N/A Low/moderate Sanne, 2006 Low Sivadasan, N/A Low/moderate Srirangaraj, N/A Low/moderate Sulkowski, N/A Moderate/high Swaminathan, -- Low/moderate Tukei, N/A -- Low/moderate van den Berg-Wolf, 2008 Low/moderate Van Leth, 2004 Low Wester, 2010 Low/moderate Zhou, N/A Low/moderate 1. Imbalanced for sex, CD4, and viral load 2. Imbalanced for disease stage 3. Imbalanced for HCV co-infection N/A, applicable

4 Supplementary Table S3: GRADE review - Adults Quality assessment of patients Effect Quality Importance of Design Risk of bias Inconsistency Indirectness Imprecision Treatment discontinuation 18 randomised trials and risk of serious 3 cohort Hepatotoxicity - overall (assessed with: symptom and laboratory monitoring) 23 randomised trials and risk of very serious 4 cohort Hepatotoxicity - severe (assessed with: symptom and laboratory monitoring) 16 randomised trials and risk of serious 5 cohort Skin - any (assessed with: symptom and laboratory monitoring) 19 randomised trials and risk of serious 6 cohort Skin - severe (assessed with: symptom and laboratory monitoring) 15 randomised trials and risk of very serious 7 cohort Severe hypersensitivity reaction (assessed with: symptom and laboratory monitoring) 9 randomised trials and cohort risk of 8 CNS - overall (assessed with: symptom monitoring) 13 randomised trials and cohort risk of CNS - severe (assessed with: symptom monitoring) 11 randomised trials and cohort risk of Neurology (assessed with: symptom monitoring) 10 randomised trials and risk of serious cohort Lipid changes (assessed with: symptom and laboratory monitoring) 7 randomised trials and cohort Other Relative Nevirapine Efavirenz considerations (95% CI) ne 613/ /6291 OR 2.18 (1.86 to 2.56) 535/ /4706 OR 2.51 (2.04 to 3.1) 249/ /9221 OR 3.25 (2.54 to 4.17) 707/ /3886 OR 1.80 (1.51 to 2.17) 217/ /2714 OR 3.68 (2.50 to 5.39) 272/ /2220 OR 2.18 (1.63 to 2.90) 285/ /2269 OR 0.31 (0.26 to 0.38) 22/ /1619 OR 0.29 (0.18 to 0.46) serious 9 196/ /1592 OR 0.88 (0.66 to 1.17) risk of serious 10 serious 11 serious / /1693 OR 0.85 (0.59 to 1.23) Absolute 53 more per 1000 (from 39 more to 69 more) 72 more per 1000 (from 51 more to 97 more) 23 more per 1000 (from 16 more to 32 more) 32 more per 1000 (from 19 more to 46 more) 30 more per 1000 (from 16 more to 47 more) 36 more per 1000 (from 19 more to 56 more) 115 fewer per 1000 (from 102 fewer to 125 fewer) 27 fewer per 1000 (from 20 fewer to 31 fewer) 6 fewer per 1000 (from 17 fewer to 8 more) 4 fewer per 1000 (from 11 fewer to 6 more)

5 1 Only 1 RCT reported allocation concealment 2 Baseline prognostic factors balanced; non-differential loss to follow up. 3 4 reported odds ratios in the opposite direction to the estimate, but only 1 of these was statistically significant. However, a further 5 reported odds ratios with confidence intervals consistent with either an increase or a decrease in the risk of adverse events, and several had non-overlapping confidence intervals. 4 7 of 23 reported odds ratios in the opposite direction to the estimate; however, of these were statistically significant. A further 3 reported odds ratios with confidence intervals consistent with either an increase or a decrease in the risk of adverse events. 5 4 of 16 reported odds ratios in the other direction to the estimate; however, of these were statistically significant. 6 1 study (138 patients) reported increased skin toxicity associated with EFV use; however, 8 reported odds ratios with confidence intervals consistent with either an increase or a decrease in the risk of adverse events. 7 3 reported odds ratios in the other direction to the estimate; only one of these was statistically significant. However, a further 6 included odds ratios for which the confidence intervals were consistent with either an increase or a decrease in the risk of adverse events. 8 1 study suggested a greater tendency towards HSR with EFV, but this was based on a single event. All other indicated either a statistically significant association or a strong tendency towards a statistically significant association between NVP use and a greater likelihood of severe hypersensitivity reaction. 9 Rated down because lower bound is consistent with a 44% reduction in neurological complications. 10 n-overlapping confidence intervals for several. 11 Different markers of lipid abnormalities were used by different. 12 Result consistent with a 41% decrease or a 23% increase in risk of adverse events. Supplementary Table S4: GRADE review - Children Quality assessment of patients Effect Quality Importance of Hepatotoxicity (assessed with: Laboratory) 3 observational Skin toxicity 2 observational CNS 1 observational Design Risk of bias Inconsistency Indirectness Imprecision Lipid abnormalities 1 observational Discontinuation 1 observational very serious 1 very serious 2 very serious 2 Other considerations Nevirapine Efavirenz Relative (95% CI) 12/393 (3.1%) 24/262 (9.2%) 13/171 (7.6%) very serious 2 11/171 (6.4%) 10/259 (3.9%) 4/260 (1.5%) 10/234 (4.2%) 25/177 (14.1%) 0/177 () 17/3031 (0.6%) Absolute

Chemistry Reference Ranges and Critical Values

Chemistry Reference Ranges and Critical Values Alanine Aminotransferase (ALT, SGPT) 3-9 years 9-18 years 1-9 years 9-18 years 10-30 U/L 10-30 U/L 10-20 U/L Albumin 0-6 days 6 days - 37 months 37 months - 7 years 7-20 years 2.6-3.6 g/dl 3.4-4.2 g/dl