What ARV regimen to start in children ≥ 3 years old living with HIV (NVP versus EFV)

(1)

GRADE tables: What ARV regimen to start with in children older than or equal to three years of age?

What ARV regimen to start in children ≥ 3 years old living with HIV (NVP versus EFV)

Author(s): Anglemyer A, Horvath T, Rutherford G Date: 2012-11-27

Question: Should children ≥3 years old living with HIV initiate ART with NVP- or EFV-based triple antiretroviral therapy?

Settings: South Africa Bibliography: Davies 2011

Quality assessment No. of patients Effect

QualityImportance No. of

studies Design Risk of bias Inconsistency Indirectness Imprecision Other

considerations NVP EFV Relative

(95% CI) Absolute

Viral failure

1 observational studies

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 45/254

(17.7%)¹ 251/3030

(8.3%)¹

RR 1.77 (1.11 to 2.83)

64 more per 1000 (from 9 more to 152 more) ⊕⊕OO

LOW

CRITICAL

1 Numerators estimated from text. Counts not used in relative effect estimates.

What ARV regimen to start in children ≥ 3 years old living with HIV (3 NRTI versus NNRTI)

Author(s): Penazzato M.

Date: 2012-12-06

Question: Should a regimen with three NRTIs be used in children living with HIV as an option to facilitate treatment management in the context of TB coinfection?

Settings:

Bibliography: ARROW team

Quality Importance No. of

studies Design Risk of bias Inconsistency Indirectness Imprecision Other considerations

Three-NRTI

regimen Control Relative

Change in CD4% at 72 weeks (follow-up median 4 years; better indicated by higher values)

(2)

Change in CD4% at 144 weeks (follow-up median 4 years; better indicated by higher values)

1 randomized

trials

serious¹ no serious imprecision

none 379 373 – Mean difference 0.60 lower

(1.84 lower to 0.64 higher)

⊕⊕⊕O MODERATE

CRITICAL

Mortality (follow-up median 4 years)

1 randomized

trials

serious¹ serious³ none – – HR 0.98 (0.53

to 1.82)⁴

– ⊕⊕OO

LOW

CRITICAL

0% –

Mortality or new WHO stage 3 or 4 HIV disease (follow-up median 4 years)

1 randomized

trials

to 1.52)⁴

– ⊕⊕OO

LOW

CRITICAL

0% –

Mortality or new WHO stage 3 or 4 HIV disease or death (follow-up median 4 years) 1 randomized

trials

to 1.17)⁴

– ⊕⊕OO

LOW

CRITICAL

0% –

1 Children in the intervention arm were all started on a 4 drug regimen for 36 weeks therefore some degree of indirectness should be accounted when applying these findings to a population on triple therapy without any induction phase. This is particularly important in light of the benefit being shown during the induction phase by the use of 4 drugs.

2 The induction phase is not relevant to address this question, therefore 36 weeks endpoint was not considered due to the nature of the trial strategy.

3 Small numbers of events in all arms.

4 Over the follow up time there was very weak evidence of a difference in mortality and WHO stage 3/4 between arms (p=0.43)

(3)

What ARV regimen to start in children ≥ 3 years old living with HIV (other regimens)

Question: Should children ≥3 years old living with HIV initiate ART with (1) continuous 3TC + ABC + NVP/EFV or (2) induction with AZT + 3TC + ABC + NVP/EFV and maintenance with 3TC + ABC + NVP/EFV?

Settings: Uganda, Zimbabwe Bibliography: ARROW, 2012

studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations

3TC + ABC + NVP/EFV + AZT

(36 weeks) 3TC + ABC + NVP/EFV Relative (95%

CI)

Absolute Switch to second-line therapy

1 randomized trials

very serious²

none 17/404

(4.2%)

26/397 (6.5%)

RR 0.64 (0.35 to 1.17)

24 fewer per 1000 (from 43 fewer to 11 more)

⊕⊕OO

LOW CRITICAL Mortality

1 randomized trials

very serious²

none 14/404

(3.5%)

20/397 (5%)

RR 0.69 (0.35 to 1.34)

⊕⊕OO

LOW CRITICAL New WHO stage 4 disease or mortality

1 randomized trials

very serious²

none 31/404

(7.7%)

40/397 (10.1%)

RR 0.76 (0.49 to 1.19)

⊕⊕OO LOW

CRITICAL

New WHO stage 3 or 4 disease or mortality 1 randomized

trials

serious¹ none 60/404

(14.9%)

73/397 (18.4%)

RR 0.81 (0.59 to 1.10)

⊕⊕⊕O

MODERATE CRITICAL

1 Few events.

2 Very few events.

(4)

Question: Should children ≥3 years old living with HIV initiate ART with (1) continuous 3TC + ABC + NVP/EFV or (2) induction with AZT + 3TC + ABC + NVP/EFV and maintenance with AZT + 3TC + ABC?

Settings: Uganda, Zimbabwe Bibliography: ARROW

bias Inconsistency Indirectness Imprecision Other considerations

3TC + ABC + AZT + NVP/EFV (36

weeks)

3TC + ABC + NVP/EFV

Relative

(95% CI) Absolute Switch to second-line therapy

1 randomized

trials

very serious² none 20/405

(4.9%)

26/397 (6.5%)

RR 0.75 (0.43 to 1.33)

16 fewer per 1000 (from 37 fewer to 22

more)

⊕⊕OO

LOW CRITICAL

Mortality

1 randomized

trials no serious risk of bias

no serious

inconsistency no serious

indirectness very serious² none 20/405

(4.9%) 20/397

(5%) RR 0.98

(0.54 to 1.79)

⊕⊕OO

LOW CRITICAL

New WHO stage 4 disease or mortality

1 randomized

no serious

(7.9%) 40/397

(10.1%) RR 0.78 (0.50 to 1.22)

more)

⊕⊕OO LOW

CRITICAL

trials

(13.3%)

73/397 (18.4%)

RR 0.73 (0.52 to 1.00)

more)

⊕⊕⊕O MODERATE

CRITICAL

1 Few events.

2 Very few events.

(5)

Question: Should children ≥3 years old living with HIV initiate ART with (1) continuous 3TC + ABC + NVP/EFV or (2) induction with AZT + 3TC + ABC + NVP/EFV and maintenance with 3TC + ABC + NVP/EFV?

Settings: Uganda, Zimbabwe Bibliography: ARROW, 2012

bias Inconsistency IndirectnessImprecision Other considerations

3TC + ABC + NVP/EFV + AZT

(36 weeks) 3TC + ABC + NVP/EFV Relative

(95%

CI)

Absolute Switch to second-line therapy

1 randomized trials

very serious²

none 17/404

(4.2%)

26/397 (6.5%)

RR 0.64 (0.35 to 1.17)

⊕⊕OO

LOW CRITICAL Mortality

1 randomized trials

very serious²

none 14/404

(3.5%)

20/397 (5%)

RR 0.69 (0.35 to 1.34)

⊕⊕OO LOW

CRITICAL

New WHO stage 4 disease or mortality 1 randomized

trials

very serious²

none 31/404

(7.7%)

40/397 (10.1%)

RR 0.76 (0.49 to 1.19)

⊕⊕OO LOW

CRITICAL

trials

(14.9%)

73/397 (18.4%)

RR 0.81 (0.59 to 1.10)

⊕⊕⊕O

MODERATE CRITICAL

1 Few events.

2 Very few events.

(6)

Question: Should children ≥3 years old living with HIV initiate ART with (1) continuous 3TC + ABC + NVP/EFV or (2) induction with AZT + 3TC + ABC + NVP/EFV and maintenance with AZT + 3TC + ABC?

Settings: Uganda, Zimbabwe Bibliography: ARROW

bias Inconsistency Indirectness Imprecision Other considerations

3TC + ABC + AZT + NVP/EFV (36

weeks)

3TC + ABC + NVP/EFV

Relative

(95% CI) Absolute Switch to second-line therapy

1 randomized

trials

(4.9%)

26/397 (6.5%)

RR 0.75 (0.43 to 1.33)

more)

⊕⊕OO

LOW CRITICAL

Mortality

1 randomized

no serious

(4.9%) 20/397

(5%) RR 0.98

(0.54 to 1.79)

⊕⊕OO

LOW CRITICAL

New WHO stage 4 disease or mortality

1 randomized

no serious

(7.9%) 40/397

(10.1%) RR 0.78 (0.50 to 1.22)

more)

⊕⊕OO LOW

CRITICAL

trials

(13.3%)

73/397 (18.4%)

RR 0.73 (0.52 to 1.00)

more)

⊕⊕⊕O MODERATE

CRITICAL

1 Few events.

2 Very few events.

(7)

Question: Should children ≥3 years old living with HIV initiate ART with LPV/r- or NVP-based triple antiretroviral therapy?

Settings: Central African Republic, South Africa, Uganda Bibliography: Davies 2011, Charpentier 2012, PROMOTE 2012

considerations LPV/r NVP Relative

Viral failure

2⁶ observational studies

serious⁶ serious¹ no serious indirectness

serious⁴ none 147/1834

(8%)²

105/404 (26%)²

RR 0.83 (0.47 to 1.19)

44 fewer per 1000 (from 138

fewer to 49 more) ⊕OOO VERY LOW

CRITICAL

Mortality

1 randomized

trials

very serious³

none 3/35

(8.6%) 1/10 (10%)

RR 0.86 (0.1 to 7.37)

fewer to 637 more) ⊕⊕OO LOW

CRITICAL

Change in mean CD4% (better indicated by higher values)

1 randomized

trials no serious

risk of bias no serious

indirectness very serious³

none 29 34 – Mean difference 3.30% lower

(6.88% lower to 0.28% higher) ⊕⊕OO LOW

CRITICAL

Rate of resistant viruses 1 observational

studies

serious⁵ no serious inconsistency

very serious³

none 9/10

(90%) 50/59 (84.7%)

RR 1.06 (0.84 to 1.34)

51 more per 1000 (from 136

fewer to 288 more) ⊕OOO VERY LOW

CRITICAL

1 1/2 point estimates reflect contradictory results.

3 Very few events.

4 Few events.

5 Not all subjects had plasma tested.

6 One of two studies did not provide adjusted estimates.

(8)

Question: Should children ≥3 years old living with HIV initiate ART with LPV/r- or EFV-based triple antiretroviral therapy?

Settings: Italy, South Africa

Bibliography: Davies 2011, Vigano 2005

QualityImportance No. of

LPV

(PI/r) EFV Relative

Viral failure

1³ observational studies

no serious imprecision

none 140/1819

(7.7%)¹

251/3030 (8.3%)¹

HR 1.07 (0.76 to 1.51)

6 more per 1000 (from 19 fewer to 40 more) ⊕⊕OO

LOW

CRITICAL

Cholesterol >95th percentile for age, sex and race at 12 weeks 1⁴ randomized

trials

(53.8%) 1/14 (7.1%)

RR 7.54 (1.07 to 53.23)

467 more per 1000 (from 5 more to 1000 more) ⊕⊕OO

LOW

CRITICAL

2 Very few events.

3 Davies (2011).

4 Vigano (2005).

Question: Should children ≥3 years old living with HIV initiate ART with LPV/r- or NNRTI-based (NVP or EFV) triple antiretroviral therapy?

Settings: Europe, Uganda

Bibliography: Castro 2011 (Plato), PROMOTE 2012, Patel 2008 (no analysable data)

LPV (PI/r)

NNRTI + 2 NRTIs (NVP or

EFV)

Relative (95%

CI)

Absolute

Triple class viral failure

1⁴ observational no serious risk of no serious no serious serious¹ none 10/126 90/467 HR 0.40 111 fewer per ⊕OOO CRITICAL

(9)

1⁵ randomized trials no serious risk of bias

very serious³

none 7/36

(19.4%)² 8/39 (20.5%)²

RR 0.95 (0.38 to 2.35)

fewer to 70 more)

⊕OOO VERY LOW

CRITICAL

Mean CD4%

very serious³

none 29 34 - Mean

difference 3.30 lower (6.88 lower to 0.28

higher)

⊕OOO VERY LOW

CRITICAL

Mortality

very serious³

none 3/35

(8.6%) 2/39 (5.1%)

RR 1.67 (0.30 to 9.43)

fewer to 432 fewer)

⊕OOO VERY LOW

CRITICAL

1 Few cases (<150).

2 Numerators estimated from text. Counts not used for relative effect estimates.

3 Very few cases (<50).

4 Castro (PLATO) (2011).

5 PROMOTE (2012).

Question: Should children ≥3 years old living with HIV initiate ART with LPV/r- or nelfinavir-based or with EFV- or NVP-based triple antiretroviral therapy?

Settings: Europe, North America, South America Bibliography: PENPACT-1 (2011)

LPV/r or nelfinavir

EFV or NVP

Relative

Major NNRTI mutation

1 randomized

trials

very serious¹

None 9/121

(7.4%)

33/125 (26.4%)

RR 0.28 (0.14 to 0.56)

190 fewer per 1000 (from

116 fewer to 227 fewer) ⊕⊕OO

LOW CRITICAL Major PI mutation

1 randomized

trials

very serious¹

none 13/121

(10.7%)

3/125 (2.4%)

RR 4.48 (1.31 to 15.32)

more to 344 more) ⊕⊕OO LOW

CRITICAL

(10)

1 randomized trials

very serious¹

none 10/131

(7.6%)

8/132 (6.1%)

RR 1.26 (0.51 to 3.09)

fewer to 127 more) ⊕⊕OO LOW

CRITICAL

At week 24, VL lower than 400 copies per ml

1 randomized

trials

serious² none 96/131

(73.3%)

106/132 (80.3%)

RR 0.91 (0.8 to 1.04)

72 fewer per 1000 (from

161 fewer to 32 more) ⊕⊕⊕O MODERATE

CRITICAL

At 4 years, VL lower than 400 copies per ml

1 randomized

trials

serious² none 107/131

(81.7%)

108/132 (81.8%)

RR 1 (0.89 to 1.12)

fewer to 98 more) ⊕⊕⊕O MODERATE

CRITICAL

Mean reduction in VL (better indicated by higher values)

1 randomized

trials

serious³ none 121 125 - Mean difference 0.15

lower (0.41 lower to 0.11 higher)

⊕⊕⊕O MODERATE

CRITICAL

Mean increase in CD4% (better indicated by higher values)

1 randomized

trials

serious³ none 121 125 - Mean difference 1.5 higher

(0.7 lower to 3.7 higher) ⊕⊕⊕O MODERATE

CRITICAL

1 Very few events.

2 Few events.

3 Small sample size.

Question: Should children ≥3 years old living with HIV initiate ART with AZT- or d4T-based triple antiretroviral therapy?

Settings: Zambia

Bibliography: Bolton-Moore 2007

considerations AZT d4T Relative

Mortality

1 observational studies

serious² None 90/1389

(6.5%)¹

100/1009 (9.9%)¹

RR 0.90 (0.64 to 1.27)

6 fewer per 1000 (from 23 fewer to 17 more) ⊕OOO

VERY LOW

CRITICAL

1 Numerators estimated from text. Data not used in relative effect estimates.

2 Few events.