Efavirenz or nevirapine in three‐drug combination therapy with two nucleoside‐reverse transcriptase inhibitors for initial treatment of HIV infection in antiretroviral‐naïve individuals

Lawrence CE Mbuagbaw; James H Irlam; Alicen Spaulding; George W Rutherford; Nandi Siegfried

doi:10.1002/14651858.CD004246.pub3

Efavirenz o nevirapina en el tratamiento de combinación de tres fármacos con dos inhibidores nucleósidos de la transcriptasa inversa para el tratamiento inicial de la infección por VIH en individuos que nunca recibieron tratamiento antirretroviral

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Referencias

Referencias de los estudios incluidos en esta revisión

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Referencias de los estudios excluidos de esta revisión

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Lapphra K, Vanprapar N, Chearskul S, Phongsamart W, Chearskul P, Prasitsuebsai W, et al. Efficacy and tolerability of nevirapine‐ versus efavirenz‐containing regimens in HIV‐infected Thai children. International Journal of Infectious Diseases : IJID : official publication of the International Society for Infectious Diseases 2008;12(6):e33‐8. [PUBMED: 18573672]

Manfredi R, Calza L, Chiodo F. Efavirenz versus nevirapine in current clinical practice: a prospective, open‐label observational study. Journal of Acquired Immune Deficiency Syndromes 2004;35:492‐502.

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Manfredi R, Calza L. Nevirapine versus efavirenz in 742 patients: no link of liver toxicity with female sex, and a baseline CD4 cell count greater than 250 cells/microl. AIDS 2006;20:2233‐6.

Manosuthi W, Sungkanuparph S, Vibhagool A, Rattanasiri S, Thakkinstian A. Nevirapine‐ versus efavirenz‐based highly active antiretroviral therapy regimens in antiretroviral‐naive patients with advanced HIV infection. HIV Medicine 2004;5:105‐9.

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Puthanakit T, Aurpibul L, Sirisanthana T, Sirisanthana V. Efficacy of non‐nucleoside reverse transcriptase inhibitor‐based highly active antiretroviral therapy in Thai HIV‐infected children aged two years or less. The Pediatric Infectious Disease Journal 2009;28(3):246‐8. [PUBMED: 19165130]

Puthanakit T, Kerr SJ, Ananworanich J, Bunupuradah T, Boonrak P, Sirisanthana V. Pattern and predictors of immunologic recovery in Human Immunodeficiency Virus‐infected children receiving non‐nucleoside reverse transcriptase inhibitor‐based highly active antiretroviral therapy. Pediatric Infectious Disease Journal 2009;28:488‐92.

Referencias de los estudios en espera de evaluación

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Anonymous. NNRTI data in naive patients. AIDS Patient Care and STDS 2007;21(4):287‐8.

Antela A, Iribarren JA, Mahillo B, Santos I, Ribera E, Gutierrez C, et al. Final analysis of a prospective, randomized, open‐label, multicentre trial in naive, HIV‐1‐infected patients, comparing ZDV/3TC vs d4T/ddI, plus Efavirenz, Nevirapine or Indinavir/Ritonavir (AMADEUS 01 study). International Conference on AIDS. Bangkok,Thailand., 2004 Jul 11‐16; Vol. 15:abstract no. B11920.

Referencias adicionales

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

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Ayala Gaytan 2004

Methods	A prospective, open, randomised trial in the department of infectiology of the Hospital de Especialidades in Moterry, Nuevo Leon, Mexico.
Participants	58 participants. Inclusion criteria: At least 18 years old, of either gender, HIV‐positive, antiretroviral‐naïve. Exclusion criteria: Patients with contraindications to either NVP or EFV, pregnant women, diminished renal or liver functions.
Interventions	AZT 300mg and 3TC 150mg with either NVP 200mg twice daily (N=28) or EFV 600mg at night (N=30)
Outcomes	Viral load, CD4 count, adverse events, AIDS‐defining conditions, death. Follow up was for 48 weeks.
Notes	All patients provided informed consent to participate in the study.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	The author provided this information
Allocation concealment?	High risk	The author provided this information
Blinding? All outcomes	High risk	Open‐label study
Incomplete outcome data addressed? All outcomes	Unclear risk	Unclear, ITT analyses conducted but loss to follow‐up was quite high and reasons for drop‐outs were not reported.
Free of selective reporting?	Low risk	All outcomes of interest were reported upon
Free of other bias?	Low risk	Yes, was funded by the Mexican Ministry of Health (based on author communication).
Baseline data reported?	Low risk	Demographic characteristics, clinical stage, CD4 count, viral load

Manosuthi 2009

Methods	Prospective open‐label randomised, comparative trial in Nonthaburi, Thailand from December 2006 to October 2007
Participants	Inclusion criteria: HIV‐1 infection in individuals aged 18‐60 years, active TB diagnosed by clinical features plus acid‐fast stain and/or culture positive for Mycobacterium tuberculosis, receipt of treatment with a rifampicin‐ containing anti‐TB regimen 4‐16 weeks before enrolment,naïve to ART, and CD4+ cell count, <350 cells/ mm3. Exclusion criteria: aspartate aminotransferase and alanine aminotransferase levels >5 times the upper limit of normal range;serum creatinine level >12 mg/ dL; receipt of a medication that has drug‐drug interactions with nevirapine or efavirenz;receipt of immunosuppressive drugs; and pregnancy or lactation
Interventions	Efavirenz 600mg or Nevirapine 200mg twice daily with 3TC 150mg/D4T 30 or 40mg BID. Follow up was for 48 weeks. 142 patients with 71 in each arm.
Outcomes	Primary outcome: Proportion of patients achieving a plasma HIV‐RNA level<50 copies/mL after 48 weeks of ART. Secondary outcomes: Proportion of patients with concentrations of NNRTI at 12 hours after dosing, lower than the recommended minimal level, CD4 cell count at week 48 of ART, incidence of NNRTI‐associated adverse reactions
Notes	Written consent was obtained from participants aka N2R study.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	"Patients were randomised"
Allocation concealment?	Unclear risk	"Patients were randomised"
Blinding? All outcomes	High risk	Open‐label study
Incomplete outcome data addressed? All outcomes	Low risk	No missing outcome data
Free of selective reporting?	High risk	Primary, but not all secondary outcomes are reported.
Free of other bias?	Low risk	Yes, this study was funded by the Thailand Ministry of Public Health, Thailand Research Fund, and Bamrasnaradura Infectious Diseases Institute.
Baseline data reported?	Low risk	Age, sex, body weight, body mass index, site of tuberculosis, time from tuberculosis diagnosis to initiation of ART, CD4 cell count, plasma HIV‐1 RNA level, Hemoglobin concentration, serum alkaline phosphatase, alanine aminotransferase, albumin, creatinine, hepatitis B virus antigen, hepatitis C antibody, cholesterol, triglycerides

Nunez 2002

Methods	A randomised, open‐label, pilot study in Hospital Carlos III in Madrid Span from March 1999 to January 2002
Participants	Eligibility criteria: HIV‐infected antiretroviral‐naïve adults, aged above 18 years old with CD4 counts >100 cells/mm3 and detectable plasma HIV RNA below 100,000 copies/mL, no major organ failure, use of standard of care prophylaxis for opportunistic infections, negative pregnancy test in women of child‐bearing age, and no current high alcohol intake or substance abuse. N= 67 (NVP=36/ EFV=31).
Interventions	d4T and ddI with either NVP or EFV at the following doses: NVP 400 mg once a day, d4T 40 mg twice a day, ddI 400 mg once a day, and EFV 600 mg once a day. Follow up was for 48 weeks.
Outcomes	Primary: the proportion of individuals achieving plasma HIV RNA <50 copies/ mL and the proportion developing drug‐related toxicities, which caused cessation of the NNRTI. Secondary: mean changes in CD4+ lymphocyte counts, overall safety, degree of adherence, and adverse events.
Notes	All patients provided informed consent to participate in the study. aka SENC trial.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	"Participants were randomised"
Allocation concealment?	Unclear risk	"Participants were randomised"
Blinding? All outcomes	High risk	Open‐label study.
Incomplete outcome data addressed? All outcomes	Low risk	No missing outcome data. 3 patients lost to follow up right after enrolment
Free of selective reporting?	Low risk	Primary and secondary outcomes are reported.
Free of other bias?	Low risk	Yes, not funded by industry. Funded by the Asociacíon Investigacíon y Educación en SIDA (AIES) and Comunidad Autónoma de Madrid.
Baseline data reported?	Low risk	Age, gender, HIV transmission, plasma HIV RNA, absolute CD4 count, number with AIDS, positive antiHCV antibody, positive HBsAg

Sow 2006

Methods	A randomised controlled trial to compare AZT+3TC+NVP vs. AZT+3TC+EFV among 70 HIV‐infected patients in Senegal Age limits not given.
Participants	70 ART treatment‐naïve patients from Senegal
Interventions	AZT 300 mg,3TC 150 mg and NVP 200 mg (N=35) on one hand versus AZT 300 mg,3TC 150 mg and EFV 600 mg (N=35)
Outcomes	Decrease in viral burden, side‐effects and change in CD4 count. Follow up was for 76 weeks.
Notes	This study was reported in abstract form only, so information and data for abstraction was limited.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Not reported
Allocation concealment?	Unclear risk	Not reported
Blinding? All outcomes	Unclear risk	Not reported
Incomplete outcome data addressed? All outcomes	Unclear risk	Not reported
Free of selective reporting?	Unclear risk	Not reported
Free of other bias?	Unclear risk	Not reported
Baseline data reported?	Unclear risk	Not reported

Swaminathan 2009

Methods	Open‐label, randomised trial of 127 HIV patients co‐infected with TB in the Tuberculosis Research Centre, Chennai, India, between May 2006 and June 2008.
Participants	HIV positive patients, co‐infected with pulmonary or extra pulmonary tuberculosis receiving treatment including rifampicin. EFV 600mg arm N= 59, NVP 400mg arm, N= 57. Age limits not given.
Interventions	Two arms: EFV 600 mg or NVP 400 mg (after a 14‐day phase with 200 mg) with a DDI 250/400 mg and 3TC 300 mg backbone, all given once‐daily in the morning. Follow up was for 24 weeks.
Outcomes	Sputum smear and mycobacterial, CD4 cell count, viral load (> 400 copies/mL), liver function and death.
Notes	This study was reported in abstract form only, so information and data for abstraction was limited.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Not reported
Allocation concealment?	Unclear risk	Not reported
Blinding? All outcomes	High risk	" Open‐label clinical trial"
Incomplete outcome data addressed? All outcomes	Unclear risk	Not reported
Free of selective reporting?	Unclear risk	Not reported
Free of other bias?	Unclear risk	Not reported
Baseline data reported?	Unclear risk	Not reported

van den Berg‐Wolf 2008

Methods	The FIRST study randomised patients into three strategy arms, one of which was NNRTI+NRTI. NNRTI was determined by optional randomisation (NVP or EFV) or by choice.
Participants	228 antiretroviral‐naïve, HIV‐positive patients, aged at least 13 years.
Interventions	There were 111 participants in the EFV arm (EFV 600mg once daily) and 117 in the NVP arm (NVP 200mg twice daily). Dosing was obtained from the authors. Four different NRTI backbones were used (ABC/3TC, ddI/d4T, AZT/3TC, d4T/3TC)
Outcomes	HIV RNA >50 copies /ml, change in CD4 count or death. Follow up was for 32 weeks.
Notes	All patients provided informed consent to participate in the study. aka FIRST or CPCRA study
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	1:1 allocation
Allocation concealment?	Low risk	Participants called a hotline to be assigned a treatment
Blinding? All outcomes	Low risk	Yes, in the FIRST paper (2001) the study team was blinded to interm results so for this sub‐study we assumed they were blinded to treatment as well.
Incomplete outcome data addressed? All outcomes	Low risk	ITT analyses were used
Free of selective reporting?	Low risk	Yes, all outcomes of interest were reported.
Free of other bias?	Low risk	Yes, this study was sponsored by non‐industry funding (NIH).
Baseline data reported?	Low risk	Socio‐demographic data, CD4 count, viral load, prior AIDS event, hepatitis B or C and history of injection drug use

van Leth 2004a

Methods	Multicentre, open‐label, randomised trial of 1216 ARV naïve patients in North/South America, Australia, Europe, South Africa and Thailand
Participants	Inclusion criteria: ARV naïve patients of both sexes, aged at least 16 years, with plasma RNA > 5000 copies per ml Exclusion criteria: Pregnancy, lactation, HB<6.3mmol/L in males and 5.7mmol/L in females, neutrophils <1 x 10^9, platelets<75 x 109, serum amylases > 2·0 times the upper limit of normal in combination with serum lipase < 1·5 times the upper limit of normal; aspartate aminotransferase < 5·0 times the upper limit of normal; or bilirubin< 2·5 times the upper limit of normal; history of clinical pancreatitis or neuropathy within the previous 6 months; renal failure necessitating dialysis; radiotherapy, cytotoxic, or immunomodulating treatment within the month preceding the start of study or the expected need for it; infection with HIV‐2; or likely non adherence as judged by the investigator. NVP once daily N=220, NVP twice daily N= 387, EFV N=400.
Interventions	Four arms; only three of interest: d4T 40mg BID and 3TC 150mg BID with either NVP 400mg once daily, NVP 200mg twice daily or EFV 600mg once daily. Follow up for 48 weeks.
Outcomes	Primary: Proportion of patients with treatment failure Secondary: proportion of patients with virological failure (never having a plasma HIV‐1 RNA concentration <50 copies per mL, or two consecutive measurements 50 copies per mL after having had a concentration below the cut‐off), the proportion of patients with plasma HIV‐1 RNA concentrations below 50 copies/mL at each study week; the change in CD4‐positive cells between the start of treatment and week 48; and the frequencies of clinical and laboratory adverse events.
Notes	Ethics: approved by the ethics review bodies in the participating countries, and all patients gave written informed consent. aka 2NN study.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	"A treatment allocation sequence was generated by use of the minimisation variables CD4‐positive T‐cell count (350 vs >350 cells per μL) and study region. Treatment allocation was stratified by baseline plasma HIV‐1 RNA concentration (30 000 copies per mL vs >30 000 copies per mL)".
Allocation concealment?	Low risk	"Allocation was done at the central study coordination centre, concealed from the investigator before enrolment"
Blinding? All outcomes	High risk	"There was no masking after treatment allocation"
Incomplete outcome data addressed? All outcomes	Low risk	"All analyses were done for the intention‐to‐treat population, including all randomised patients (n=1216)."
Free of selective reporting?	Low risk	All outcome measurements were analysed and reported
Free of other bias?	High risk	Some of the authors had received travel grants and honoraria from the sponsors. This study was industry funded (Boehringer‐Ingelheim).
Baseline data reported?	Low risk	Gender,age, body mass index, geographical region, HIV risk behaviour, CDC class C, CD4 cell count, HIV RNA, co‐infection(hepatitis B, hepatitis C viruses)

Characteristics of excluded studies [ordered by study ID]

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estudios incluidos
estudios a la espera de clasificación

Study	Reason for exclusion
Bannister 2008	Not a randomised clinical trial, a retrospective cohort study from the EUROSIDA data base.
Bruck 2008	Not a randomised clinical trial
de Beaudrap 2008	Not a randomised clinical trial, a retrospective cohort study from 'Initiative Senegalaise d'Acces aux Medicaments Antiretroviraux' (ISAARV) prospective cohort of which the EFV arm was a clinical trial.
Han 2005	Not a randomised clinical trial
Hartmann 2005a	Not a randomised clinical trial, a prospective cohort study.
Hartmann 2005b	Not a randomised clinical trial,a prospective cohort study.
Hartmann 2005c	Not a randomised clinical trial,a prospective cohort study.
Lapphra 2008	Not a randomised clinical trial, a retrospective cohort study from medical records.
Manfredi 2004	Not a randomised clinical trial, an observational study.
Manfredi 2005	Not a randomised clinical trial, an observational study.
Manfredi 2006	Not a randomised clinical trial, an observational study.
Manosuthi 2004	Not a randomised clinical trial, a retrospective cohort study from medical records.
Nachega 2008	Not a randomised clinical trial, a retrospective cohort study from the Aid for AIDS prospective data base in southern Africa.
Negredo 2004	Not a randomised clinical trial
Puthanakit 2009a	Not a randomised clinical trial, a prospective cohort study.
Puthanakit 2009b	Not a randomised clinical trial, a prospective cohort study. Data collected from 2 treatment cohorts.

Characteristics of studies awaiting assessment [ordered by study ID]

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estudios incluidos
estudios excluidos

Anonymous 2007

Methods
Participants
Interventions
Outcomes
Notes

Antela 2004

Methods	A prospective, randomised, open‐label, multi centre comparative trial by the AMADEUS study group in Madrid, Spain.
Participants	69 HIV positive treatment‐naïve patients were included.
Interventions	ZDV/3TC versus D4T/ddI plus EFV, NVP or Indinavir/Ritonavir.
Outcomes	Viral load < 200 copies/ml, median increase in CD4 count.
Notes	aka AMADEUS 01 Study. Full text not available.

Data and analyses

Open in table viewer

Comparison 1. Efavirenz 600mg versus Nevirapine 200mg twice daily

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Virological success Show forest plot	4	1200	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.95, 1.10]
Open in figure viewer Analysis 1.1 Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 1 Virological success.
2 Change in CD4 count Show forest plot	5	1285	Mean Difference (IV, Random, 95% CI)	0.00 [‐23.17, 19.18]
Open in figure viewer Analysis 1.2 Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 2 Change in CD4 count.
3 Mortality Show forest plot	4	1215	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.50, 1.57]
Open in figure viewer Analysis 1.3 Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 3 Mortality.
4 Progression to AIDS Show forest plot	4	1215	Risk Ratio (M‐H, Random, 95% CI)	1.32 [0.53, 3.30]
Open in figure viewer Analysis 1.4 Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 4 Progression to AIDS.
5 Discontinuation rate Show forest plot	4	1215	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.72, 1.22]
Open in figure viewer Analysis 1.5 Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 5 Discontinuation rate.
6 Severe adverse events:Rash Show forest plot	4	1227	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.41, 1.03]
Open in figure viewer Analysis 1.6 Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 6 Severe adverse events:Rash.
7 Severe adverse events:CNS Show forest plot	3	999	Risk Ratio (M‐H, Random, 95% CI)	2.87 [0.64, 12.79]
Open in figure viewer Analysis 1.7 Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 7 Severe adverse events:CNS.
8 Severe adverse events: GIT Show forest plot	3	999	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.33, 1.38]
Open in figure viewer Analysis 1.8 Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 8 Severe adverse events: GIT.
9 Severe adverse events: Pyrexia Show forest plot	2	929	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.10, 1.36]
Open in figure viewer Analysis 1.9 Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 9 Severe adverse events: Pyrexia.
10 Severe adverse events: Raised transaminases Show forest plot	2	1015	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.37, 0.95]
Open in figure viewer Analysis 1.10 Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 10 Severe adverse events: Raised transaminases.
11 Severe adverse events: Raised alkaline phosphatase Show forest plot	1	787	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.14, 2.41]
Open in figure viewer Analysis 1.11 Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 11 Severe adverse events: Raised alkaline phosphatase.
12 Severe adverse events: Raised Amylase Show forest plot	1	787	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.54, 2.32]
Open in figure viewer Analysis 1.12 Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 12 Severe adverse events: Raised Amylase.
13 Severe adverse events: Raised Triglycerides Show forest plot	1	787	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.28, 3.32]
Open in figure viewer Analysis 1.13 Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 13 Severe adverse events: Raised Triglycerides.
14 Severe adverse events: Neutropenia Show forest plot	2	929	Risk Ratio (M‐H, Random, 95% CI)	0.28 [0.11, 0.76]
Open in figure viewer Analysis 1.14 Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 14 Severe adverse events: Neutropenia.
15 All severe adverse events Show forest plot	4	1054	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.60, 1.70]
Open in figure viewer Analysis 1.15 Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 15 All severe adverse events.

Open in table viewer

Comparison 2. Efavirenz 600mg versus Nevirapine 400mg once daily

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Virological success Show forest plot	3	803	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.94, 1.31]
Open in figure viewer Analysis 2.1 Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 1 Virological success.
2 Change in CD4 count Show forest plot	2	687	Mean Difference (IV, Random, 95% CI)	8.74 [‐7.60, 25.08]
Open in figure viewer Analysis 2.2 Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 2 Change in CD4 count.
3 Mortality Show forest plot	3	878	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.18, 0.94]
Open in figure viewer Analysis 2.3 Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 3 Mortality.
4 Progression to AIDS Show forest plot	1	620	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.30, 2.04]
Open in figure viewer Analysis 2.4 Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 4 Progression to AIDS.
5 Discontinuation rate Show forest plot	2	674	Risk Ratio (M‐H, Random, 95% CI)	1.48 [1.15, 1.90]
Open in figure viewer Analysis 2.5 Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 5 Discontinuation rate.
6 Severe adverse events: Rash Show forest plot	2	684	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.45, 3.07]
Open in figure viewer Analysis 2.6 Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 6 Severe adverse events: Rash.
7 Severe adverse events:CNS Show forest plot	2	684	Risk Ratio (M‐H, Random, 95% CI)	7.52 [1.14, 49.80]
Open in figure viewer Analysis 2.7 Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 7 Severe adverse events:CNS.
8 Severe adverse events: GIT Show forest plot	2	684	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.49, 3.44]
Open in figure viewer Analysis 2.8 Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 8 Severe adverse events: GIT.
9 Severe adverse events: Pyrexia Show forest plot	1	620	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.14, 4.90]
Open in figure viewer Analysis 2.9 Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 9 Severe adverse events: Pyrexia.
10 Severe adverse events: Raised transaminases Show forest plot	2	684	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.22, 0.81]
Open in figure viewer Analysis 2.10 Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 10 Severe adverse events: Raised transaminases.
11 Severe adverse events: Raised alkaline phosphatase Show forest plot	1	620	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.14, 4.90]
Open in figure viewer Analysis 2.11 Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 11 Severe adverse events: Raised alkaline phosphatase.
12 Severe adverse events: Raised Amylase Show forest plot	2	684	Risk Ratio (M‐H, Random, 95% CI)	2.19 [0.78, 6.14]
Open in figure viewer Analysis 2.12 Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 12 Severe adverse events: Raised Amylase.
13 Severe adverse events: Raised Triglycerides Show forest plot	2	684	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.32, 4.22]
Open in figure viewer Analysis 2.13 Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 13 Severe adverse events: Raised Triglycerides.
14 Severe adverse events: Raised cholesterol Show forest plot	1	64	Risk Ratio (M‐H, Random, 95% CI)	6.03 [0.75, 48.78]
Open in figure viewer Analysis 2.14 Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 14 Severe adverse events: Raised cholesterol.
15 Severe adverse events: Neutropenia Show forest plot	1	620	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.30, 2.29]
Open in figure viewer Analysis 2.15 Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 15 Severe adverse events: Neutropenia.
16 All severe adverse events Show forest plot	3	803	Risk Ratio (M‐H, Random, 95% CI)	1.34 [0.93, 1.91]
Open in figure viewer Analysis 2.16 Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 16 All severe adverse events.

Figure 1

Results of search

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Figure 2

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

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Figure 3

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

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Analysis 1.1

Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 1 Virological success.

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Analysis 1.2

Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 2 Change in CD4 count.

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Analysis 1.3

Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 3 Mortality.

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Analysis 1.4

Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 4 Progression to AIDS.

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Analysis 1.5

Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 5 Discontinuation rate.

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Analysis 1.6

Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 6 Severe adverse events:Rash.

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Analysis 1.7

Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 7 Severe adverse events:CNS.

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Analysis 1.8

Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 8 Severe adverse events: GIT.

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Analysis 1.9

Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 9 Severe adverse events: Pyrexia.

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Analysis 1.10

Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 10 Severe adverse events: Raised transaminases.

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Analysis 1.11

Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 11 Severe adverse events: Raised alkaline phosphatase.

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Analysis 1.12

Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 12 Severe adverse events: Raised Amylase.

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Analysis 1.13

Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 13 Severe adverse events: Raised Triglycerides.

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Analysis 1.14

Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 14 Severe adverse events: Neutropenia.

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Analysis 1.15

Comparison 1 Efavirenz 600mg versus Nevirapine 200mg twice daily, Outcome 15 All severe adverse events.

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Analysis 2.1

Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 1 Virological success.

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Analysis 2.2

Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 2 Change in CD4 count.

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Analysis 2.3

Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 3 Mortality.

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Analysis 2.4

Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 4 Progression to AIDS.

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Analysis 2.5

Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 5 Discontinuation rate.

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Analysis 2.6

Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 6 Severe adverse events: Rash.

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Analysis 2.7

Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 7 Severe adverse events:CNS.

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Analysis 2.8

Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 8 Severe adverse events: GIT.

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Analysis 2.9

Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 9 Severe adverse events: Pyrexia.

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Analysis 2.10

Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 10 Severe adverse events: Raised transaminases.

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Analysis 2.11

Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 11 Severe adverse events: Raised alkaline phosphatase.

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Analysis 2.12

Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 12 Severe adverse events: Raised Amylase.

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Analysis 2.13

Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 13 Severe adverse events: Raised Triglycerides.

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Analysis 2.14

Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 14 Severe adverse events: Raised cholesterol.

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Analysis 2.15

Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 15 Severe adverse events: Neutropenia.

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Analysis 2.16

Comparison 2 Efavirenz 600mg versus Nevirapine 400mg once daily, Outcome 16 All severe adverse events.

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Summary of findings for the main comparison. Efavirenz 600mg versus Nevirapine 200mg twice daily for initial treatment of HIV infection in antiretroviral‐naive individuals

Efavirenz 600mg versus Nevirapine 200mg twice daily for initial treatment of HIV infection in antiretroviral‐naive individuals
Patient or population: patients with initial treatment of HIV infection in antiretroviral‐naive individuals Settings: Multiple locations Intervention: Efavirenz 600mg versus Nevirapine 200mg twice daily
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Efavirenz 600mg versus Nevirapine 200mg twice daily
Virological success Follow‐up: median 48 weeks	699 per 1000	713 per 1000 (664 to 769)	RR 1.02 (0.95 to 1.1)	1200 (4 studies)	⊕⊕⊕⊕ high^1,2,3,4,5
Change in CD4 count Follow‐up: median 48 weeks		The mean Change in CD4 count in the intervention groups was 2 lower (23.17 lower to 19.18 higher)		1285 (5 studies)	⊕⊕⊕⊕ high^1,3,4,5
Mortality Follow‐up: median 48 weeks	55 per 1000	49 per 1000 (28 to 86)	RR 0.89 (0.5 to 1.57)	1215 (4 studies)	⊕⊕⊕⊝ moderate^1,3,4,5,6
Progression to AIDS Follow‐up: median 48 weeks	32 per 1000	42 per 1000 (17 to 106)	RR 1.32 (0.53 to 3.3)	1215 (4 studies)	⊕⊕⊕⊝ moderate^1,3,4,5,6
Discontinuation rate Follow‐up: median 48 weeks	164 per 1000	154 per 1000 (118 to 200)	RR 0.94 (0.72 to 1.22)	1215 (4 studies)	⊕⊕⊕⊝ moderate^1,3,4,5,6
All severe adverse events Follow‐up: median 48 weeks	201 per 1000	203 per 1000 (121 to 342)	RR 1.01 (0.6 to 1.7)	1054 (4 studies)	⊕⊕⊕⊝ moderate^1,3,4,5,6
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ 3 of the 7 RCT studies were open‐label (Ayala, Manosuthi, Swaminathan), but studies were not downgraded based on this fact. ² 2 of the 7 RCT studies did not use the <50 copies/mL level for defining virological success (Ayala used <400 copies/mL and Sow did not report the level used). ³ 1 RCT study (van den Berg) looked at multiple indirect comparisons. Also, only 2 out of 7 RCT studies were conducted in developed country settings (Sow, Swaminathan). ⁴ 2 of the 7 RCT studies looked at treatment in patients with tuberculosis (Manosuthi, Swaminathan). ⁵ 1 out of the 7 RCT studies were industry funded (van Leth), while 2 out of the 7 studies had funding sources that were unclear. ⁶ Number of events <300 and/or confidence intervals include potential harm and benefit.

Summary of findings for the main comparison. Efavirenz 600mg versus Nevirapine 200mg twice daily for initial treatment of HIV infection in antiretroviral‐naive individuals

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Summary of findings 2. Efavirenz 600mg versus Nevirapine 400mg once daily for initial treatment of HIV infection in antiretroviral‐naive individuals

Efavirenz 600mg versus Nevirapine 400mg once daily for initial treatment of HIV infection in antiretroviral‐naive individuals
Patient or population: patients with initial treatment of HIV infection in antiretroviral‐naive individuals Settings: Multiple locations Intervention: Efavirenz 600mg versus Nevirapine 400mg once daily
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Efavirenz 600mg versus Nevirapine 400mg once daily
Virological success Follow‐up: mean 48 weeks	687 per 1000	763 per 1000 (646 to 900)	RR 1.11 (0.94 to 1.31)	803 (3 studies)	⊕⊕⊕⊕ high^1,2,3,4,5
Change in CD4 count Follow‐up: median 48 weeks		The mean Change in CD4 count in the intervention groups was 8.74 higher (7.6 lower to 25.08 higher)		687 (2 studies)	⊕⊕⊕⊕ high^1,3,4,5
Mortality Follow‐up: median 48 weeks	52 per 1000	21 per 1000 (9 to 49)	RR 0.41 (0.18 to 0.94)	878 (3 studies)	⊕⊕⊕⊝ moderate^1,3,4,5,6
Progression to AIDS Follow‐up: 48 weeks	32 per 1000	25 per 1000 (10 to 65)	RR 0.79 (0.3 to 2.04)	620 (1 study)	⊕⊕⊕⊝ moderate^1,3,4,5,6
Discontinuation rate Follow‐up: median 48 weeks	222 per 1000	329 per 1000 (255 to 422)	RR 1.48 (1.15 to 1.9)	674 (2 studies)	⊕⊕⊕⊝ moderate^1,3,4,5,6
All severe adverse events Follow‐up: median 48 weeks	163 per 1000	218 per 1000 (152 to 311)	RR 1.34 (0.93 to 1.91)	803 (3 studies)	⊕⊕⊕⊝ moderate^1,3,4,5,6
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ 3 of the 7 RCT studies were open‐label (Ayala, Manosuthi, Swaminathan), but studies were not downgraded based on this fact. ² 2 of the 7 RCT studies did not use the <50 copies/mL level for defining virological success (Ayala used <400 copies/mL and Sow did not report the level used). ³ 1 RCT study (van den Berg) looked at multiple indirect comparisons. Also, only 2 out of 7 RCT studies were conducted in developed country settings (Sow, Swaminathan). ⁴ 2 of the 7 RCT studies looked at treatment in patients with tuberculosis (Manosuthi, Swaminathan). ⁵ 1 out of the 7 RCT studies were industry funded (van Leth), while 2 out of the 7 studies had funding sources that were unclear. ⁶ Number of events <300 and/or confidence intervals include potential harm and benefit.

Summary of findings 2. Efavirenz 600mg versus Nevirapine 400mg once daily for initial treatment of HIV infection in antiretroviral‐naive individuals

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Comparison 1. Efavirenz 600mg versus Nevirapine 200mg twice daily

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Virological success Show forest plot	4	1200	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.95, 1.10]

2 Change in CD4 count Show forest plot	5	1285	Mean Difference (IV, Random, 95% CI)	0.00 [‐23.17, 19.18]

3 Mortality Show forest plot	4	1215	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.50, 1.57]

4 Progression to AIDS Show forest plot	4	1215	Risk Ratio (M‐H, Random, 95% CI)	1.32 [0.53, 3.30]

5 Discontinuation rate Show forest plot	4	1215	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.72, 1.22]

6 Severe adverse events:Rash Show forest plot	4	1227	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.41, 1.03]

7 Severe adverse events:CNS Show forest plot	3	999	Risk Ratio (M‐H, Random, 95% CI)	2.87 [0.64, 12.79]

8 Severe adverse events: GIT Show forest plot	3	999	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.33, 1.38]

9 Severe adverse events: Pyrexia Show forest plot	2	929	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.10, 1.36]

10 Severe adverse events: Raised transaminases Show forest plot	2	1015	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.37, 0.95]

11 Severe adverse events: Raised alkaline phosphatase Show forest plot	1	787	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.14, 2.41]

12 Severe adverse events: Raised Amylase Show forest plot	1	787	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.54, 2.32]

13 Severe adverse events: Raised Triglycerides Show forest plot	1	787	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.28, 3.32]

14 Severe adverse events: Neutropenia Show forest plot	2	929	Risk Ratio (M‐H, Random, 95% CI)	0.28 [0.11, 0.76]

15 All severe adverse events Show forest plot	4	1054	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.60, 1.70]

Comparison 1. Efavirenz 600mg versus Nevirapine 200mg twice daily

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Comparison 2. Efavirenz 600mg versus Nevirapine 400mg once daily

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Virological success Show forest plot	3	803	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.94, 1.31]

2 Change in CD4 count Show forest plot	2	687	Mean Difference (IV, Random, 95% CI)	8.74 [‐7.60, 25.08]

3 Mortality Show forest plot	3	878	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.18, 0.94]

4 Progression to AIDS Show forest plot	1	620	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.30, 2.04]

5 Discontinuation rate Show forest plot	2	674	Risk Ratio (M‐H, Random, 95% CI)	1.48 [1.15, 1.90]

6 Severe adverse events: Rash Show forest plot	2	684	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.45, 3.07]

7 Severe adverse events:CNS Show forest plot	2	684	Risk Ratio (M‐H, Random, 95% CI)	7.52 [1.14, 49.80]

8 Severe adverse events: GIT Show forest plot	2	684	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.49, 3.44]

9 Severe adverse events: Pyrexia Show forest plot	1	620	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.14, 4.90]

10 Severe adverse events: Raised transaminases Show forest plot	2	684	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.22, 0.81]

11 Severe adverse events: Raised alkaline phosphatase Show forest plot	1	620	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.14, 4.90]

12 Severe adverse events: Raised Amylase Show forest plot	2	684	Risk Ratio (M‐H, Random, 95% CI)	2.19 [0.78, 6.14]

13 Severe adverse events: Raised Triglycerides Show forest plot	2	684	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.32, 4.22]

14 Severe adverse events: Raised cholesterol Show forest plot	1	64	Risk Ratio (M‐H, Random, 95% CI)	6.03 [0.75, 48.78]

15 Severe adverse events: Neutropenia Show forest plot	1	620	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.30, 2.29]

16 All severe adverse events Show forest plot	3	803	Risk Ratio (M‐H, Random, 95% CI)	1.34 [0.93, 1.91]

Comparison 2. Efavirenz 600mg versus Nevirapine 400mg once daily

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Referencias

Referencias de los estudios incluidos en esta revisión

Ayala Gaytan 2004 {published data only}

Manosuthi 2009 {published data only}

Nunez 2002 {published data only}

Sow 2006 {published data only}

Swaminathan 2009 {published data only}

van den Berg‐Wolf 2008 {published data only}

van Leth 2004a {published data only}

Referencias de los estudios excluidos de esta revisión

Bannister 2008 {published data only}

Bruck 2008 {published data only}

de Beaudrap 2008 {published data only}

Han 2005 {published data only}

Hartmann 2005a {published data only}

Hartmann 2005b {published data only}

Hartmann 2005c {published data only}

Lapphra 2008 {published data only}

Manfredi 2004 {published data only}

Manfredi 2005 {published data only}

Manfredi 2006 {published data only}

Manosuthi 2004 {published data only}

Nachega 2008 {published data only}

Negredo 2004 {published data only}

Puthanakit 2009a {published data only}

Puthanakit 2009b {published data only}

Referencias de los estudios en espera de evaluación

Anonymous 2007 {published data only}

Antela 2004 {published data only}

Referencias adicionales

Ananworanich 2005

Annan 2009

Aranzabal 2005

Aurpibul 2007

Beck 2008

Bendavid 2009

Berenguer 2008

BHIVA 2001

Boulle 2007

Boulle 2008

Braithwaite 2007

CDC 2002

Cooper 2007

Deeks 2001

DHHS 2001

Division of AIDS 2004

Ena 2003

Furukawa 2006

George 2009

Gilks 2006

GradePro 2008 [Computer program]

Guyatt 2008

Hammer 2008

Higgins 2008

Hogg 1997

Ioannidis 2006

Kappelhoff 2005a

Kappelhoff 2005b

Keiser 2002

Lau 2007

MacArthur 2001

Manosuthi 2008

Martin‐Carbonero 2003

Matthews 2002

Mellors 2007

Mocroft 1998

Moyle 2000

Neuwelt 2003

Palella 1998

Palmon 2002

Patel 2006

Sanne 2005

Shipton 2009

Siegfried 2006

UNAIDS 2008

UNAIDS 2009

van den Berg‐Wolf 2006

van Leth 2004b