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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)
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
0 100 200 300
Overall effect size 39/1000 PYFUAdult studies (n = 23)
3.9% (95CI 3.3-4.4%)
NOTE: Weights are from random effects analysis
Overall (I-squared = 98.5%, p = 0.000)
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)
Rate/1000PYFU (95% CI)
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)
Rate/1000PYFU (95% CI)
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%)
NOTE: Weights are from random effects analysis
Overall (I-squared = 99.1%, p = 0.000)
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)
Rate/1000PYFU (95% CI)
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)
Rate/1000PYFU (95% CI)
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%)
NOTE: Weights are from random effects analysis
Overall (I-squared = 99.3%, p = 0.000)
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)
Rate/1000PYFU (95% CI)
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)
Rate/1000PYFU (95% CI)
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%)
NOTE: Weights are from random effects analysis
Overall (I-squared = 96.1%, p = 0.000)
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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