1. X. Anglaret, S. Eholié, R. Landman ANRS research site in Côte d’Ivoire
MOAB0104
Reinforcement of adherence and switch to third-line in HIV-infected adults who fail second-line ART Thilao study (ANRS 12269), West Africa
Raoul Moh, A. Benalycherif, D. Gabillard, ML. Chaix, C. Danel, L.Slama, C. Michon, PM. Girard, C. Toure-Kane, T. Toni, E. Bissagnéné, J. Drabo, M. Seydi, D. Minta, A. Sawadogo,
X. Anglaret, S. Eholié, R. Landman 1
ANRS research site in Côte d’Ivoire

2. Conflict of Interest
“No conflicts of interest to declare”. 2

3. Background In sub-Saharan Africa:
ART regimen sequencing is based on WHO guidelines:
NNRTI-based (1st line), PI (LPVr or ATVr)-based (2nd line), DRVr + INSTI-based (3rd line).
Increasing access to:
Second-line antiretroviral drugs
Viral load testing
Very low access to:
Third-line antiretroviral drugs
Genotypic resistance testing
 Need for strategies that help physicians to decide when to stwich to third-line ART
« Not too early » (unjustified switch, patients with high GSS)
« Not too late » (risk of resistance accumulation) 3

4. Thilao ANRS : Methods
Design: Pilot study. First inclusion: March Last visit: Aug 2016
Settings: Burkina-Faso, Côte d’Ivoire, Mali, Senegal
Inclusion criteria:
Adults >18 years
History of:
1st-line NNRTI-based regimen
Switch to 2nd-line PI-based ART for virological failure
More than 6 months on 2nd-line PI-based ART (LPV/r or ATV/r)
Confirmed plasma HIV-RNA >1000 copies/ml
Signed informed consent 4

5. Thilao ANRS 12269 : Design Month-4 Decision Month-16 Outcomes Day-0
Inclusion
Continue 2nd-line
Continue 2nd-line
Adherence reinforcement
Switch to 3rd-line (2NRTI+darunavir 600 BID/r+raltegravir 400 BID)
Inclusion criteria:
VL >1000 copies/ml
Month-4 Decision criteria:
VL <400 copies/ml or
>2 log decrease : Continue
VL ≥ 400 copies/ml or
< 2 log decrease : Switch
Month-16 Outcomes:
1ary: Virol. success: <50 copies/ml
2ary: - Mortality
Resistance
Tolerance 5

6. Thilao ANRS 12269 : Design Day-0 Month-4 Month-16 Inclusion Decision
Outcomes
Continue 2nd-line
Continue 2nd-line
Adherence reinforcement
Switch to 3rd-line (2NRTI+darunavir 600 BID/r+raltegravir 400 BID)
Adherence reinforcement =
Therapeutic education sessions (all patients)
+ measures chosen by each patient among the following ones :
Involvement of a relative, pill organizer, weekly phone calls, alarm reminders, SMS, home visits, extra visits to the study center, support group, adjustment of ART drug doses, adjustment of non-ART drugs 6

7. Viral load and genotypic testing
Viral load monitoring :
Every 3-months
PROSPECTIVE, RESULTS PROVIDED IN REAL-TIME TO CLINICIANS
Month-3 result used to inform Month-4 decision
Month-7, 10, 13 results : switch to 3rd-line at any time during follow-up if confirmed VL >1000 copies/ml
Genotypic resistance testing:
Plasma sample frozen at Day-0 and Month-16
Genotypic testing for all D-0 and M-16 samples with VL > 400 copies/ml
RETROSPECTIVE, RESULTS NOT AVAILABLE IN REAL-TIME TO CLINICIANS
Genotypic testing for all samples with VL > 400 copies/ml 7

8. Definitions - Genotypic Sensitivity Score (GSS)
Number of drugs in ongoing regimen to which the patient’s virus has genotypic sensitivity
- Month-4 decision appropriateness  
Decision taken at Month-4 retrospectively judged on the basis of genotypes at Day-0 :
- Inappropriate absence of switch: resistance to PI or GSS<2
- Inappropriate switch: sensitivity to PI and GSS=3
- Resistance accumulations
New resistance mutations occuring between Day-0 and Month- 16 in patients with viral load >400 copies at Day-0 and Month-16 8

9. Baseline characteristics, N=198
Age, years, median (IQR) 41
(36-48)
Women, n (%)
136
(69)
WHO Stage 3 or 4, n (%)
157
(79)
Baseline CD4 count, /mm3, median (IQR)
238
( )
CD4 nadir, /mm3, median (IQR)
149
(66-277)
Ongoing ART regimen, n (%)
2 NRTI* + lopinavir/ritonavir
171
(86)
2 NRTI* + atazanavir/ritonavir 27
(14)
Previous time on ART, years, median (IQR) 8
(6-10)
Time on 1st-line 3
(2-5)
Time on 2nd-line
(2-6)
Plasma HIV-1 RNA, log10 copies/ml
4.5
( )
* The NRTIs were TDF-XTC in 52% of patients 9

10. Month-4 decision Inclusion Month-4 decision Continue 2nd-line:
Death, 5 (2.5%)
Switch to 3rd-line:
N=63 (32%) 10

11. Month-16 outcomes Inclusion Month-4 decision Month-16 outcomes
Continue 2nd-line:
N=130 (66%)
Overall, n (%)
Death: 15 (8%)
LTFU: 4 (2%)
VL <50 cp/ml: 101 (51%)
cp/ml: (23%)
>400 cp/ml: 31 (17%)
2nd-line
Switch to 3rd-line:
N=63 (32%) 11

12. Month-16 outcomes, by Month-4 decision
Inclusion
Month-4 decision
Month-16 outcomes
Continue 2nd-line:
N=130
Death: 6 (5%)
LTFU: 4 (3%)
VL <50 cp/ml: 64 (49%)
cp/ml: 39 (30%)
>400 cp/ml: 17 (13%)
2nd-line
Death, 5 (2.5%)
Death: 4 (6%)
LTFU: 0 (0%)
VL <50 cp/ml: 37 (59%)
cp/ml: 7 (11%)
>400 cp/ml: (22%)
Switch to 3rd-line:
N=63 12

13. Probability of first VL<50 over time, by Month-4 decision
82%
77% 13

14. Other secondary endpoints, by Month-4 decision
Continue 2nd line
Switch to 3rd line
Severe adverse events (Grade 4), n (%)
10 (8%)
> 1 resistance mutation to at least 1 ART in patients with VL >400 copies/ml at Month-16
14/17 (82%) *
10/14 (71%) **
Appropriateness of month-4 decision
Appropriate maintenance of 2nd line: N=105 (81%)
Inappropriate maintenance of 2nd line: N=25 (19%)
Appropriate switch to 3rd line: N=46 (73%)
Inappropriate switch to 3rd line: N=17 (27%)
Accumulation of resistance mutations between inclusion and Month-16
6 (5%)
2 (3%)
* 11 NRTI, 12 NNRTI, 8 PI
** 3 NRTI, 8 NNRTI, 5 PI, 0 RAL 14

15. Discussion
In settings where viral load is routinely used for monitoring but routine genotypic testing is not available for real time use :
An intense adherence reinforcement phase, used as a tool to distinguish between patients who can still benefit from their current regimen and those who truly need third-line ART allowed to take appropriate decision of switching/ not switching in most patients
Resistance accumulation was rare
Third-line ART was well tolerated
Accessibility to viral load monitoring, to adherence reinforcement measures, and to third-line drugs should be reinforced 15

16. ANRS research site in Côte d’Ivoire
Acknowlegments
ANRS research site in Côte d’Ivoire
All patients who accepted to participate in the study
Coordinating Investigators: R. Landman, Paris, France; SP. Eholié, Abidjan, Cote d’ivoire
ANRS: JF . Delfraissy, B. Bazin, G. Colin, P. Garcia
IMEA: PM. Girard, A. Benalycherif, B. Gadaleta
INSERM 1219/PACCI: X. Anglaret, J. Lecarrou, D. Gabillard, S. Karcher, L. N’Guessan, C. Nchot, E. Amani, A. Kouakou, R. Konan
GIP ESTHER: G. Raguin, C. Michon, A. Laurent, JM. Masumboko, A. Beugny
Trainer Forma Santé : C. Pinosa, N. Bernard, AM. Ane
Adherence group: C. Danel, C. Michon, L. Slama, A. Sawadago, R. Tubiana
SMIT Abidjan: E. Bissagnéné, F. Ello, F. Eboumou, Z. Diallo, Y. Siloué, F. Kouakou, J. Dano , M. Abanou
CePreF Abidjan: E. Messou, A. Anzian, P. Gouessé, J. Goli, A. Tchéhy, MC. Kassi
Day care Unit Bobo-Dioulasso: A. Sawadogo, L. Slama , J. Zoungrana, I. Soré, J.R. Traoré, G. Bado
CRCF Dakar and SMIT Dakar: M. Seydi, G. Laborde, M. Maynart, N. Gaye, M. Diallo, M. Basty
Cedres Abidjan: H. Menan, A. Emieme
Virology Unit (Necker et St Louis, Paris, Dakar): ML. Chaix, C. Rouzioux, C. Toure-Cane
Mali team: D. Minta, L. Tubiana, M. Fomba, A. Maiga, O. Dogoni, K. Kassogué, M. Cissé
Ouagadougou team: J. Drabo, I. Diallo, M. Congo
Scientific Advisory Board: PM. Girard (Chairman), E. Bissagnéné, B. Bazin, X. Anglaret, A. Desclaux, G. Raguin, C. Michon, C. Katlama, Y. Yazdapanah, E. Bissagnéné, R. Tubiana, E. Ouattara, ML. Chaix, AG. Marcellin, C. Touré-Kane, D. Minta, M. Seydi, AM. Maiga, G. Peytavin, Y. Coulibaly, A. Kambou-Sawadogo, I. Ba, A. Sangho, L. Slama . 16