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

Lawrence Mbuagbaw; Sara Mursleen; James H Irlam; Alicen B Spaulding; George W Rutherford; Nandi Siegfried

doi:10.1002/14651858.CD004246.pub4

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Figure 1

Flow diagram of study screening and selection

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Figure 2

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included trial.

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Figure 3

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.

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Figure 4

Funnel plot of comparison: 1 Efavirenz 600 mg versus Nevirapine all doses, outcome: 1.1 Virological success.

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Analysis 1.1

Comparison 1 Efavirenz 600 mg versus nevirapine all doses, Outcome 1 Virological success.

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Analysis 1.2

Comparison 1 Efavirenz 600 mg versus nevirapine all doses, Outcome 2 Mortality.

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Analysis 1.3

Comparison 1 Efavirenz 600 mg versus nevirapine all doses, Outcome 3 Progression to AIDS.

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Analysis 1.4

Comparison 1 Efavirenz 600 mg versus nevirapine all doses, Outcome 4 All severe adverse events.

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Analysis 1.5

Comparison 1 Efavirenz 600 mg versus nevirapine all doses, Outcome 5 Discontinuation rate.

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Analysis 1.6

Comparison 1 Efavirenz 600 mg versus nevirapine all doses, Outcome 6 Change in CD4 count.

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Analysis 1.7

Comparison 1 Efavirenz 600 mg versus nevirapine all doses, Outcome 7 Treatment failure.

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Analysis 1.8

Comparison 1 Efavirenz 600 mg versus nevirapine all doses, Outcome 8 Development of drug resistance.

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Analysis 2.1

Comparison 2 Efavirenz 600 mg versus nevirapine all doses: adverse events, Outcome 1 Severe adverse events: central nervous system.

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Analysis 2.2

Comparison 2 Efavirenz 600 mg versus nevirapine all doses: adverse events, Outcome 2 Severe adverse events: gastrointestinal tract.

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Analysis 2.3

Comparison 2 Efavirenz 600 mg versus nevirapine all doses: adverse events, Outcome 3 Severe adverse events: pyrexia.

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Analysis 2.4

Comparison 2 Efavirenz 600 mg versus nevirapine all doses: adverse events, Outcome 4 Severe adverse events: elevated transaminases.

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Analysis 2.5

Comparison 2 Efavirenz 600 mg versus nevirapine all doses: adverse events, Outcome 5 Severe adverse events: elevated alkaline phosphatase.

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Analysis 2.6

Comparison 2 Efavirenz 600 mg versus nevirapine all doses: adverse events, Outcome 6 Severe adverse events: elevated amylase.

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Analysis 2.7

Comparison 2 Efavirenz 600 mg versus nevirapine all doses: adverse events, Outcome 7 Severe adverse events: elevated triglycerides.

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Analysis 2.8

Comparison 2 Efavirenz 600 mg versus nevirapine all doses: adverse events, Outcome 8 Severe adverse events: neutropenia.

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Analysis 2.9

Comparison 2 Efavirenz 600 mg versus nevirapine all doses: adverse events, Outcome 9 Severe adverse events: rash.

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Analysis 2.10

Comparison 2 Efavirenz 600 mg versus nevirapine all doses: adverse events, Outcome 10 Severe adverse events: elevated SGOT.

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Analysis 2.11

Comparison 2 Efavirenz 600 mg versus nevirapine all doses: adverse events, Outcome 11 Severe adverse events: elevated SGPT.

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Analysis 2.12

Comparison 2 Efavirenz 600 mg versus nevirapine all doses: adverse events, Outcome 12 Severe adverse events: elevated cholesterol.

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Analysis 3.1

Comparison 3 Efavirenz versus nevirapine: subgroup analyses for concurrent TB treatments, Outcome 1 Virological success.

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Analysis 3.2

Comparison 3 Efavirenz versus nevirapine: subgroup analyses for concurrent TB treatments, Outcome 2 Mortality.

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Analysis 3.3

Comparison 3 Efavirenz versus nevirapine: subgroup analyses for concurrent TB treatments, Outcome 3 Progression to AIDS.

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Analysis 3.4

Comparison 3 Efavirenz versus nevirapine: subgroup analyses for concurrent TB treatments, Outcome 4 Discontinuation rate.

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Analysis 4.1

Comparison 4 Efavirenz 600 mg versus nevirapine: subgroup analyses for dosage, Outcome 1 Virological success.

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Analysis 4.2

Comparison 4 Efavirenz 600 mg versus nevirapine: subgroup analyses for dosage, Outcome 2 Mortality.

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Analysis 4.3

Comparison 4 Efavirenz 600 mg versus nevirapine: subgroup analyses for dosage, Outcome 3 Progression to AIDS.

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Analysis 4.4

Comparison 4 Efavirenz 600 mg versus nevirapine: subgroup analyses for dosage, Outcome 4 Discontinuation rate.

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Summary of findings for the main comparison. 'Summary of findings' table 1

Efavirenz (600 mg) versus nevirapine (all doses) for three‐drug combination therapy with two nucleoside‐reverse transcriptase inhibitors for initial treatment of HIV infection in antiretroviral‐naïveindividuals
Patient or population: antiretroviral‐naïve individuals Setting: all settings Intervention: efavirenz 600 mg Comparison: nevirapine all doses (400 mg once daily and 400 mg twice daily) as part of a three‐drug combination therapy with two NRTIs
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (RCTs)	Quality of the evidence (GRADE)
Outcomes	Risk with nevirapine all doses	Risk with efavirenz 600 mg	Relative effect (95% CI)	Number of participants (RCTs)	Quality of the evidence (GRADE)
Virological success	688 per 1000	715 per 1000 (681 to 750)	RR 1.04 (0.99 to 1.09)	2438 (10 RCTs)	⊕⊕⊕⊕ high^1,2,3
Mortality	64 per 1000	54 per 1000 (38 to 76)	RR 0.84 (0.59 to 1.19)	2317 (8 RCTs)	⊕⊕⊕⊝ moderate^4,5
Progression to AIDS	41 per 1000	50 per 1000 (29 to 86)	RR 1.23 (0.72 to 2.11)	2005 (5 RCTs)	⊕⊕⊕⊝ moderate^5,6
All severe adverse events	192 per 1000	216 per 1000 (162 to 285)	RR 0.91 (0.71 to 1.18)	2329 (8 RCTs)	⊕⊝⊝⊝ very low^5,7,8
Discontinuation rate	176 per 1000	164 per 1000 (122 to 220)	RR 0.93 (0.69 to 1.25)	2384 (9 RCTs)	⊕⊕⊕⊝ moderate⁵
Change in CD4 count	The mean change in CD4 count was 0	MD 3.03 lower (17.41 lower to 11.35 higher)	—	1829 (9 RCTs)	⊕⊕⊕⊝ moderate^5,9,10,11
Treatment failure	249 per 1000	242 per 1000 (189 to 309)	RR 0.97 (0.76 to 1.24)	737 (5 RCTs)	⊕⊕⊝⊝ low^12,13
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: CI: confidence interval; RR: risk ratio; OR: odds ratio; RCT: randomized controlled trial; GRADE: Grading of Recommendations Assessment, Development and Evaluation; MD: mean difference.
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹Three trials used a cut‐off point of 400 copies/mL (Ayala Gaytán 2004; Swaminathan 2011; Sinha 2013), but we did not downgrade for this. ²Nine trials were open‐label (Ayala Gaytán 2004; Bonnet 2013a; Landman 2014; Manosuthi 2009a; Mateelli 2013; Núñez 2002; Sinha 2013; Swaminathan 2011; van Leth 2004), but we did not downgrade for this. ³Two trials were industry‐funded (Landman 2014; van Leth 2004), but we did not downgrade for this. ⁴Seven trials were open‐label but we did not downgrade for this (Ayala Gaytán 2004; Bonnet 2013a; Landman 2014; Manosuthi 2009a; Sinha 2013; Swaminathan 2011; van Leth 2004). ⁵We downgraded by 1 for imprecision due to wide CIs including appreciable harm or benefit. ⁶Four trials were open‐labelled but we did not downgrade for this (Ayala Gaytán 2004; Bonnet 2013a; Manosuthi 2009a; van Leth 2004) ⁷Six trials were open‐label (Ayala Gaytán 2004; Bonnet 2013a; Manosuthi 2009a; Núñez 2002; Swaminathan 2011; van Leth 2004). We downgraded by 1 for this. ⁸Trials did not report the same adverse events and used different severity scales. We downgraded by 1 for this. ⁹Seven of the trials were open‐label but we did not downgrade for this (Ayala Gaytán 2004; Bonnet 2013a; Manosuthi 2009a; Mateelli 2013; Núñez 2002; Swaminathan 2011; van Leth 2004). ¹⁰In one trial, the risk of bias was unclear (Sow 2006). ¹¹One trial had industry funding (van Leth 2004), but we did not downgrade for this. ¹²All trials were open‐labelled but we did not downgrade for this. ¹³Each included trial that reported this outcome defined treatment failure differently. We downgraded by 2.

Summary of findings for the main comparison. 'Summary of findings' table 1

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Summary of findings 2. 'Summary of findings' table 2

Efavirenz (600 mg) versus nevirapine (all doses): adverse events for three‐drug combination therapy with two nucleoside‐reverse transcriptase inhibitors for initial treatment of HIV infection in antiretroviral‐naïveindividuals
Patient or population: antiretroviral‐naïve individuals Setting: all settings Intervention: efavirenz 600 mg Comparison: nevirapine all doses (400 mg once daily and 400 mg twice daily) as part of a three‐drug combination therapy with two NRTIs
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (RCTs)	Quality of the evidence (GRADE)
Outcomes	Risk with nevirapine all doses: adverse events	Risk with efavirenz 600 mg	Relative effect (95% CI)	Number of participants (RCTs)	Quality of the evidence (GRADE)
Severe adverse events: central nervous system	2 per 1000	7 per 1000 (2 to 18)	RR 4.46 (1.65 to 12.03)	2049 (6 RCTs)	⊕⊕⊕⊝ moderate¹
Severe adverse events: gastrointestinal	18 per 1000	14 per 1000 (9 to 22)	RR 0.76 (0.48 to 1.21)	2049 (6 RCTs)	⊕⊕⊝⊝ low^1,2
Severe adverse events: pyrexia	0 per 1000	0 per 1000 (0 to 0)	RR 0.65 (0.15 to 2.73)	1799 (3 RCTs)	⊕⊕⊝⊝ low^2,3
Severe adverse events: raised transaminases	257 per 1000	134 per 1000 (90 to 201)	RR 0.52 (0.35 to 0.78)	1299 (3 RCTs)	⊕⊕⊕⊕ high⁴
Severe adverse events: raised alkaline phosphatase	12 per 1000	7 per 1000 (2 to 29)	RR 0.65 (0.17 to 2.50)	1007 (1 RCT)	⊕⊕⊝⊝ low^2,5
Severe adverse events: raised amylase	14 per 1000	20 per 1000 (10 to 38)	RR 1.40 (0.72 to 2.73)	1071 (2 RCTs)	⊕⊕⊝⊝ low^2,6,7
Severe adverse events: raised triglycerides	7 per 1000	7 per 1000 (3 to 21)	RR 1.10 (0.39 to 3.13)	1071 (2 RCTs)	⊕⊕⊝⊝ low^2,6,7
Severe adverse events: neutropenia	38 per 1000	18 per 1000 (11 to 31)	RR 0.48 (0.28 to 0.82)	1799 (3 RCTs)	⊕⊕⊕⊕ high^3,8
Severe adverse events: rash	229 per 1000	133 per 1000 (78 to 229)	RR 0.58 (0.34 to 1.00)	2277 (7 RCTs)	⊕⊕⊕⊝ moderate^2,9
Severe adverse events: serum glutamic oxaloacetic transaminase (SGOT)	The mean severe adverse events: SGOT was 0	MD 3.3 higher (2.06 lower to 8.66 higher)	—	135 (1 RCT)	⊕⊕⊕⊝ moderate²
Severe adverse events: serum glutamic‐ pyruvic transaminase (SGPT)	The mean severe adverse events: SGPT was 0	MD 5.7 higher (4.23 lower to 15.63 higher)	—	135 (1 RCT)	⊕⊕⊕⊝ moderate²
Raised cholesterol	29 per 1000	172 per 1000 (21 to 1000)	RR 6.03 (0.75 to 48.78)	64 (1 RCT)	⊕⊕⊕⊝ moderate²
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: CI: confidence interval; RR: risk ratio; OR: odds ratio; RCT: randomized controlled trial; GRADE: Grading of Recommendations Assessment, Development and Evaluation; MD: mean difference; SGOT: glutamic oxaloacetic transaminase; SGPT: serum glutamic‐ pyruvic transaminase
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹Five trials (Manosuthi 2009a; Núñez 2002; Swaminathan 2011; van Leth 2004; Wester 2010) were open‐label. One trial did not report blinding (Sow 2006). We downgraded by 1 for this. ²We downgraded by 1 for very wide CIs. ³All trials were open‐label. ⁴Two trials (Núñez 2002; van Leth 2004) were open label. van Leth 2004 was industry‐funded. We did not downgrade for this. ⁵Data from one open‐label industry‐funded study (van Leth 2004). We downgraded by 1 for this. ⁶Both trials were open‐label (Núñez 2002; van Leth 2004), but we did not downgrade for this. ⁷Most data came from one industry‐funded trial (van Leth 2004). We downgraded one point for this. ⁸We upgraded by 1 due to the large effect. ⁹Six studies were open‐label (Manosuthi 2009a; Núñez 2002; Sow 2006; Swaminathan 2011; van Leth 2004; Wester 2010). We did not downgrade for this.

Summary of findings 2. 'Summary of findings' table 2

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Table 1. Additional characteristics of included studies

Trial ID	Location	NVP dosage	NRTI combination drugs	Co‐infection with tuberculosis	Virological success cut‐off point
Ayala Gaytán 2004	Mexico	200 mg twice daily	AZT 300 mg and 3TC 150 mg	No	< 400 copies/mL
Bonnet 2013a	Mozambique	200 mg twice daily	3TC and d4T/AZT¹	No	< 50 copies/mL
Landman 2014	Cameroon and Senegal	200 mg twice daily	TDF 300 mg and FTC 200 mg	No	< 50 copies/mL
Manosuthi 2009a	Thailand	400 mg once daily	3TC 150 mg and D4T 30 or 40 mg	Yes	< 50 copies/mL
Mateelli 2013	Burkina Faso	200 mg twice daily	D4T and 3TC¹	Yes	Not reported
Núñez 2002	Spain	400 mg once daily	D4T 40 mg and DDI 400 mg	No	< 50 copies/mL
Sinha 2013	India	200 mg twice daily	AZT, d4T, 3TC¹	Yes	< 400 copies/mL
Sow 2006	Senegal	200 mg twice daily	AZT 300 mg and 3TC 150 mg	No	Not reported
Swaminathan 2011	India	400 mg once daily	DDI 250 mg or 400 mg and 3TC 300 mg	Yes	Not reported
van den Berg‐Wolf 2008	USA	200 mg twice daily	ABC/3TC, DDI/d4T, AZT/3TC, d4T/3TC¹	No	< 50 copies/mL
van Leth 2004	North/South America, Australia, Europe, South Africa, and Thailand	200 mg twice daily and 400 mg twice daily	D4T 40 mg and 3TC 150 mg	No	< 50 copies/mL
Wester 2010	Botswana	Not reported	AZT or d4T/3TC or DDI¹	No	Not reported
¹Dosage not specified. Abbreviations: NRTI: Nucleoside Reverse Transcriptase Inhibitor; ART: antiretroviral therapy; AZT: zidovudine; d4T: stavudine; 3TC: lamivudine; NVP: nevirapine; DDI: didanosine; ABC: abacavir; FTC: Emtricitabine; TDF: Tenofovir.

Table 1. Additional characteristics of included studies

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Comparison 1. Efavirenz 600 mg versus nevirapine all doses

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Virological success Show forest plot	10	2438	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.99, 1.09]

2 Mortality Show forest plot	8	2317	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.59, 1.19]

3 Progression to AIDS Show forest plot	5	2005	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.72, 2.11]

4 All severe adverse events Show forest plot	8	2329	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.71, 1.18]

5 Discontinuation rate Show forest plot	9	2384	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.69, 1.25]

6 Change in CD4 count Show forest plot	9	1829	Mean Difference (IV, Random, 95% CI)	‐3.03 [‐17.41, 11.35]

7 Treatment failure Show forest plot	5	737	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.76, 1.24]

8 Development of drug resistance Show forest plot	4	988	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.60, 0.95]

Comparison 1. Efavirenz 600 mg versus nevirapine all doses

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Comparison 2. Efavirenz 600 mg versus nevirapine all doses: adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Severe adverse events: central nervous system Show forest plot	6	2049	Risk Ratio (M‐H, Random, 95% CI)	4.46 [1.65, 12.03]

2 Severe adverse events: gastrointestinal tract Show forest plot	6	2049	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.48, 1.21]

3 Severe adverse events: pyrexia Show forest plot	3	1799	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.15, 2.73]

4 Severe adverse events: elevated transaminases Show forest plot	3	1299	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.35, 0.78]

5 Severe adverse events: elevated alkaline phosphatase Show forest plot	1	1007	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.17, 2.50]

6 Severe adverse events: elevated amylase Show forest plot	2	1071	Risk Ratio (M‐H, Random, 95% CI)	1.40 [0.72, 2.73]

7 Severe adverse events: elevated triglycerides Show forest plot	2	1071	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.39, 3.13]

8 Severe adverse events: neutropenia Show forest plot	3	1799	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.28, 0.82]

9 Severe adverse events: rash Show forest plot	7	2277	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.34, 1.00]

10 Severe adverse events: elevated SGOT Show forest plot	1	135	Mean Difference (IV, Random, 95% CI)	3.30 [‐2.06, 8.66]

11 Severe adverse events: elevated SGPT Show forest plot	1	135	Mean Difference (IV, Random, 95% CI)	5.70 [‐4.23, 15.63]

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

Comparison 2. Efavirenz 600 mg versus nevirapine all doses: adverse events

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Comparison 3. Efavirenz versus nevirapine: subgroup analyses for concurrent TB treatments

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Virological success Show forest plot	9	2369	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.99, 1.10]

1.1 Concurrent treatment for TB	4	963	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.99, 1.18]
1.2 No treatment for TB	5	1406	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.95, 1.08]
2 Mortality Show forest plot	8	2317	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.59, 1.19]

2.1 Concurrent treatment for TB	4	963	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.40, 1.19]
2.2 No treatment for TB	4	1354	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.62, 1.64]
3 Progression to AIDS Show forest plot	5	2005	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.72, 2.11]

3.1 Concurrent treatment for TB	2	712	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.62, 1.92]
3.2 No treatment for TB	3	1293	Risk Ratio (M‐H, Random, 95% CI)	1.51 [0.44, 5.16]
4 Discontinuation rate Show forest plot	9	2384	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.69, 1.25]

4.1 Concurrent treatment for TB	4	963	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.59, 1.42]
4.2 No treatment for TB	5	1421	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.63, 1.55]

Comparison 3. Efavirenz versus nevirapine: subgroup analyses for concurrent TB treatments

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Comparison 4. Efavirenz 600 mg versus nevirapine: subgroup analyses for dosage

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Virological success Show forest plot	9	2369	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.99, 1.09]

1.1 Nevirapine 200 mg twice daily	7	1766	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.97, 1.09]
1.2 Nevirapine 400 mg once daily	3	603	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.94, 1.35]
2 Mortality Show forest plot	8	2459	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.57, 1.12]

2.1 Nevirapine 200 mg twice daily	7	1781	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.64, 1.28]
2.2 Nevirapine 400 mg once daily	3	678	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.13, 0.90]
3 Progression to AIDS Show forest plot	5	2005	Risk Ratio (M‐H, Random, 95% CI)	1.20 [0.76, 1.89]

3.1 Nevirapine 200 mg twice daily	5	1585	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.75, 2.23]
3.2 Nevirapine 400 mg once daily	1	420	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.25, 2.44]
4 Discontinuation rate Show forest plot	9	2384	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.66, 1.14]

4.1 Nevirapine 200 mg twice daily	7	1781	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.71, 1.21]
4.2 Nevirapine 400 mg once daily	3	603	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.40, 1.57]

Comparison 4. Efavirenz 600 mg versus nevirapine: subgroup analyses for dosage

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