PRELIMINARY RESULTS - WHO · PRELIMINARY RESULTS. Chris Duncombe. HIVNAT, The Netherlands,...

PRELIMINARY RESULTSChris Duncombe

HIVNAT, The Netherlands, Australia, Thailand Research Collaboration

Françoise Renaud-ThéryHIV/AIDS Department, World Health Organization

AIDS Medicine and Diagnostics Service

A systematic review of antiretroviral failure and switching within WHO-recommended first-line regimens

Background

Increased and reliable production of ART is keyuniversal access to care and treatment

Accurate demand forecasting is essential ART programs to be sustainable and efficient

Key factors in ART demand forecastingcohort retention (survival and on ART)substitution within 1st line ART due to adverse events, drug interactions or pregnancyswitching from first-line to second-line ART due to first-line failure

Background

November 2007, WHO and UNAIDS published

Demand Forecast for Antiretroviral Drugs in Low and Middle- Income Countries, 2007–2008

In the absence of concise data

Lack of country-specific survival data

Projection methods made several assumptions

Background

A survival curve was derived based on empirical data from Senegal, Brazil and the USA assumed to apply to all the countries in the model

Loss to follow-up was estimated based on data from Antiretroviral Therapy in Lower Income Countries (ART-LINC) initiative

Background

Probabilitypeople would migrate to second-line treatment after a minimum of six months on first-line treatment

Estimated4% each year for Latin American countries 2% each year for all other countries (1% in first year)

Recent data from large cohort studies suggest the rate may be lower

Definitions

First-line ARTinitial regimen prescribed for a naïve patient

Second-line ARTnext regimen used in sequence immediately after first-line therapy has failed

Definitions

Substitutionchange of ARV, usually within the same classtoxicity, drug-drug interactions (TB) or contraindications (pregnancy)

Switchingchange to second-line ART due to failure of first-line ART

Loss to follow up (LTF)missing at least one scheduled clinic visit

Retention in care and still on ART

In settings where resources permitvirological failure is the gold standard

In resource limited settingsWHO clinical and/or immunologicalmost commonly used

WHO VL cut-off for defining failure in RLS is >10,000We used VL cut reported by the study

<50 <400 or <1,000

WHO definitions of failure in RLS

Methods

A systematic search of English language publications and conference presentations

2003 to 2008

Search focusStudies reporting cohort data in low and middle income countries First line ART regimens recommended by WHO

Separate searches for adult and peadiatric populations

Inclusion criteria

Treatment-naive

Minimum of 100 patients and 6 months follow up

Presented data on survival, loss to follow up and retention

Published in English non-English studies included if English abstract

Search strings

Switching in Adults

resistance OR

failure OR

failure OR

switch* OR

second line OR

salvage

AND

(antiretroviral OR

highly active OR

agent)

…..

AND

(adult OR

adolescent) Switching in Children

……

AND

newborn OR

infant OR

child* OR

pedia* OR

paed*

Cohort retention

surviv* OR

attrition OR

retention OR

mortality OR

lost to follow up

Data extraction

Data extracted into summary tables

Two operators

Working independently

Discrepancies resolved by consensus

Methods

Data abstractedData tabulated into summary tables

First authorReport typeYearCountry(ies) and region(Co) payment or notNumber of individualsFollow up intervalBaseline characteristicsRegimens

Substitutions of individual drugs within first-line for toxicity

Switching from first line to second line drugs due to ART failure

Cohort retention (attrition)

Adherence

Statistical analysis

Estimated switch rates/1000 PYFUSE calculated according to Poisson distributionSwitch rates vs failure ratesData for the effect size (rate/1000 PYFU) were analysed in StataHigh degree of heterogeneity random effects model

Sensitivity analyses modelling of retention rates where switch & retention were reportedvirological vs clinical/immunological failure

Study flow chart for adults

Preliminary

flow chart for children

125,075 patients

Characteristics of 23 adult studies

Region Data Source Study SizeStudy duration

(months)

Africa 16 (70%)

Journal 13

Median 1700

Median 24

Asia 5(22%)

Conference9 Min/Max

100/48,338Min/Max(6 -

60)Sth

America 1

World 1 (MSF)Report

1

Characteristics of 23 adult studies

Baseline Median (IQR)

Females (%)[12 studies]

62 (59-62)

Age (years)[11 studies]

35 (35 – 36)

CD4 cells/mm3

[13 studies]121 (104 – 121)

4,243 patients

Characteristics of 12 paediatric studies (preliminary data)

Region Data Source Study SizeStudy

duration (months)

Median ageYears (IQR)

Africa 6 (50%)

Journal 9

Median 193

Median 12

6(5-7)Asia 4

(33%) Conference3

Min/Max66-1741

Min/Max(12-36)South

America 2

050

100

150

200

250

Sw

ith ra

te/1

000

PY

FU

0 12 24 36 48 60Time (months)

Switch rates (adults) by study size and duration of follow-up

HaitiN=100

MSFN=48,000

NOTE: Weights are from random effects analysis

Overall (I-squared = 99.2%, p = 0.000)

17

20

22

3

19

21

7

16

ID

1

4

14

23

5

Study

13

15

6

11

89

18

12

2

10

38.62 (32.93, 44.32)

30.02 (27.56, 32.47)

58.86 (36.23, 81.48)

39.66 (34.70, 44.63)

66.68 (61.91, 71.46)

20.99 (15.29, 26.70)

190.65 (166.38, 214.92)

14.97 (12.76, 17.18)

100.16 (75.03, 125.30)

Rate/1000PYFU (95% CI)

4.80 (4.33, 5.28)

140.68 (108.63, 172.74)

240.00 (143.98, 336.02)

66.67 (60.90, 72.44)

39.61 (34.15, 45.07)

80.58 (73.17, 87.99)

29.85 (15.66, 44.04)

24.60 (20.25, 28.95)

6.91 (0.85, 12.96)

3.15 (2.20, 4.11)2.40 (1.49, 3.31)

9.98 (6.81, 13.16)

57.80 (39.89, 75.72)

14.51 (10.60, 18.41)

16.76 (9.42, 24.11)

100.00

5.25

2.89

5.10

5.11

5.04

2.70

5.26

2.61

Weight

5.30

1.98

0.33

5.03

5.06

%

4.87

3.99

5.14

5.00

5.305.30

5.22

3.48

5.17

4.87

38.62 (32.93, 44.32)

30.02 (27.56, 32.47)

58.86 (36.23, 81.48)

39.66 (34.70, 44.63)

66.68 (61.91, 71.46)

20.99 (15.29, 26.70)

190.65 (166.38, 214.92)

14.97 (12.76, 17.18)

100.16 (75.03, 125.30)


4.80 (4.33, 5.28)

140.68 (108.63, 172.74)

240.00 (143.98, 336.02)

66.67 (60.90, 72.44)

39.61 (34.15, 45.07)

80.58 (73.17, 87.99)

29.85 (15.66, 44.04)

24.60 (20.25, 28.95)

6.91 (0.85, 12.96)

3.15 (2.20, 4.11)2.40 (1.49, 3.31)

9.98 (6.81, 13.16)

57.80 (39.89, 75.72)

14.51 (10.60, 18.41)

16.76 (9.42, 24.11)

100.00

5.25

2.89

5.10

5.11

5.04

2.70

5.26

2.61

Weight

5.30

1.98

0.33

5.03

5.06

%

4.87

3.99

5.14

5.00

5.305.30

5.22

3.48

5.17

4.87

0 100 200 300

Overall effect size 39/1000 PYFUAdult studies (n = 23)

3.9% (95CI 3.3-4.4%)



19

14

16

13

15

6

7

23

3

10

12

5

4

ID

20

Study

56.07 (41.46, 70.68)

20.99 (15.29, 26.70)

240.00 (143.98, 336.02)

100.16 (75.03, 125.30)

80.58 (73.17, 87.99)

29.85 (15.66, 44.04)

24.60 (20.25, 28.95)

14.97 (12.76, 17.18)

66.67 (60.90, 72.44)

66.68 (61.91, 71.46)

16.76 (9.42, 24.11)

57.80 (39.89, 75.72)

39.61 (34.15, 45.07)

140.68 (108.63, 172.74)


58.86 (36.23, 81.48)

100.00

8.02

1.80

6.55

7.96

7.55

8.07

8.11

8.02

8.05

7.96

7.24

8.03

5.84

Weight

6.80

%

56.07 (41.46, 70.68)

20.99 (15.29, 26.70)

240.00 (143.98, 336.02)

100.16 (75.03, 125.30)

80.58 (73.17, 87.99)

29.85 (15.66, 44.04)

24.60 (20.25, 28.95)

14.97 (12.76, 17.18)

66.67 (60.90, 72.44)

66.68 (61.91, 71.46)

16.76 (9.42, 24.11)

57.80 (39.89, 75.72)

39.61 (34.15, 45.07)

140.68 (108.63, 172.74)


58.86 (36.23, 81.48)

100.00

8.02

1.80

6.55

7.96

7.55

8.07

8.11

8.02

8.05

7.96

7.24

8.03

5.84

Weight

6.80

%

0 100 200 300

Overall effect size 56/1000 PYFUAdult studies using virological criteria for switch (n = 14)

5.6% (95CI 4.2-7.1%)



21

8

ID

22

1

17

9

2

Study

11

18

19.79 (14.51, 25.07)

190.65 (166.38, 214.92)

3.15 (2.20, 4.11)


39.66 (34.70, 44.63)

4.80 (4.33, 5.28)

30.02 (27.56, 32.47)

2.40 (1.49, 3.31)

14.51 (10.60, 18.41)

6.91 (0.85, 12.96)

9.98 (6.81, 13.16)

100.00

3.45

12.63

Weight

11.40

12.67

12.35

12.64

11.86

%

10.87

12.13

19.79 (14.51, 25.07)

190.65 (166.38, 214.92)

3.15 (2.20, 4.11)


39.66 (34.70, 44.63)

4.80 (4.33, 5.28)

30.02 (27.56, 32.47)

2.40 (1.49, 3.31)

14.51 (10.60, 18.41)

6.91 (0.85, 12.96)

9.98 (6.81, 13.16)

100.00

3.45

12.63

Weight

11.40

12.67

12.35

12.64

11.86

%

10.87

12.13

0 100 200 300

Overall effect size 20/1000 PYFUAdult studies using clin/immunol criteria for switch (n = 9)

2.0% (95CI 1.5-2.5%)



14

1

10

19

ID

16

Study

3

12

22

56.12 (31.37, 80.88)

256.68 (153.99, 359.38)

5.14 (4.63, 5.65)

18.73 (10.52, 26.94)

22.10 (16.09, 28.10)


119.96 (89.85, 150.06)

70.94 (65.86, 76.02)

62.15 (42.89, 81.42)

46.66 (40.82, 52.51)

100.00

4.13

14.29

14.07

14.17

Weight

11.80

%

14.21

13.15

14.18

56.12 (31.37, 80.88)

256.68 (153.99, 359.38)

5.14 (4.63, 5.65)

18.73 (10.52, 26.94)

22.10 (16.09, 28.10)


119.96 (89.85, 150.06)

70.94 (65.86, 76.02)

62.15 (42.89, 81.42)

46.66 (40.82, 52.51)

100.00

4.13

14.29

14.07

14.17

Weight

11.80

%

14.21

13.15

14.18

0 100 200 300

Overall effect size 56/1000 PYFUAdult studies adjusting for attrition (n = 8)

5.6% (95CI 3.1-8.1%)



12

Study

7

5

10

11

2

ID

8

3

6

1

4

210.70 (150.86, 270.55)

440.00 (355.31, 524.69)

114.67 (73.54, 155.80)

190.00 (131.53, 248.47)

290.00 (160.56, 419.44)

302.72 (236.32, 369.12)

197.00 (125.91, 268.09)

Rate/1000 PYFU (95% CI)

160.00 (97.73, 222.27)

230.00 (170.29, 289.71)

270.00 (245.59, 294.41)

96.67 (84.13, 109.20)

86.67 (54.36, 118.98)

100.00

8.40

%

9.64

9.21

6.86

8.98

8.84

Weight

9.10

9.18

9.93

10.05

9.81

210.70 (150.86, 270.55)

440.00 (355.31, 524.69)

114.67 (73.54, 155.80)

190.00 (131.53, 248.47)

290.00 (160.56, 419.44)

302.72 (236.32, 369.12)

197.00 (125.91, 268.09)

Rate/1000 PYFU (95% CI)

160.00 (97.73, 222.27)

230.00 (170.29, 289.71)

270.00 (245.59, 294.41)

96.67 (84.13, 109.20)

86.67 (54.36, 118.98)

100.00

8.40

%

9.64

9.21

6.86

8.98

8.84

Weight

9.10

9.18

9.93

10.05

9.81

0-525 0 525

Overall effect size 211/1000 PYFUPaediatric studies using virological criteria for switch (n = 11)

21% (95CI 15-27%)

Conclusions

125,075 adults Median follow up 24 months (6-60 months)

Overall switch rate

VL definition of failure

Clin/imm

definition of failure

Overall adjusted for attrition

8 studies6/8 VL failure

N=94,901

39/1000 PYFU 56/1000 PYFU 20/1000 PYFU 56/1000 PYFU

3.9% per year (95% CI 3.3 -

4.45.6% per year

(95% CI 4.2 –

7.1)2% per year

(95% CI 1.5 –

2.5)5.6% per year

(95% CI 3.1-8.1)

Conclusions

4,243 children Median age 6 years (5-7)Median follow up 12 months (12-36 months)

Overall switch rate (11 studies reporting VL failure )

21% per year (95% CI 15 -27% )

One study (72 Thai children) used clin/imm criteria1.5% per year

Study limitations

Studies reporting on 1st line failure and ART switching

Highly heterogenic (different)Definitions of failure and length follow up

Clinical setting and maturity of ART program

Heterogeneity complicates meta-analysis

Study limitations

Baseline characteristics similarFemales/male : 62/48 and age 35 (IQR 35 – 36)CD4 121 (IQR 104 – 121)

Two sensitivity analyses Support the robustness of the data

Paediatric analysis is a work in progress

First meta-analysis of 1st line ART failure rates in RLS

Important new insights into ART needs and forecasting

Acknowledgements

AIDS Medicines and Diagnostics Service, Department of HIV/AIDS, World Health Organization, Geneva

Dr. Joss PerriënsFrançoise Renaud-Théry

Clinical Research AssistantDr Sigrid Thierry

HIVNATDr. Stephen Kerr

National Centre in HIV epidemiology and Clinical Research, SydneyProf .Matthew LawDr. Janaki Amin

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