Second-line anti-retroviral therapy
in resource-limited settings
Nicholas Paton MD FRCP
Professor of Medicine
National University of Singapore
Disclosures
• Dr Paton has received research grants awarded to his
institution from Janssen, GSK and Merck, has received
speakers fees from AbbVie, Janssen and Merck and serves as
a member of data monitoring committees for Rochesponsored clinical trials.
WHO, 2013 ART guidelines
A pragmatic randomised controlled strategy trial of
three second-line treatment options for use in
public health rollout programme settings:
The Europe-Africa Research Network
for Evaluation of Second-line Therapy
(EARNEST) Trial
The EARNEST question
“moderate quality evidence” for 2nd-line regimen
PI
PI
NNRTI
NRTI
Standardised 1st line
≈ 3% fail/y
?
Standardised 2nd line
The EARNEST question
PI
PI
NNRTI
NRTI
Standardised 1st line
?
Standardised 2nd line
≈ 3% fail/y
PI
RAL
The EARNEST question
PI
PI
NNRTI
NRTI
Standardised 1st line
?
Standardised 2nd line
≈ 3% fail/y
PI
PI
RAL
EARNEST Aims
• EARNEST hypotheses:
1) PI/r + RAL superior efficacy
(↓ toxicity? ↑cost)
2) PI/r mono. non-inferior efficacy (↓toxicity
↓complexity
↓cost )
• EARNEST aim:
– Compare these 3 options for 2nd-line therapy
– A pragmatic trial that replicates typical public health approach settings
(i.e. without all the monitoring)
Trial design (1)
HIV positive adolescents / adults (n=1200)
1st line NNRTI-based regimen >12 months;
Failure by WHO (2010) clinical, CD4 (VL-confirmed) or VL criteria
RANDOMIZE
PI + RAL
(12 wk induction)
PI* + 2-3 NRTIs
(NRTIs according to
local standard of care)
PI + RAL
PI
(monotherapy)
FOLLOW-UP FOR 144 WEEKS
Primary outcome at week 96:
Good HIV disease control – defined as all of:
 Alive and no new WHO4 events from 0–96 weeks AND
 CD4 cell count >250 cells/mm3 at 96 weeks AND
 VL <10,000 c/mL OR >10,000 c/mL without PI res. mutations at 96 weeks
*PI standardized to LPV/r all arms
NRTIs physician-selected without resistance testing
Paton et al, NEJM 2014; 371: 234-47
Trial design (2)
Visits: 1-2 monthly, mainly nurse-led
Adherence: assessed at all visits by structured
questions; intensive counselling
Monitoring:
Clinical + CD4 count: every 12–16 weeks (open)
Viral load: annual visits, done in central lab (seen by
Data Monitoring Committee only)
Resistance: annual visits (all VL >1000 c/mL), done in
central lab (seen by Data Monitoring Committee only)
Sites and recruitment
Sites
14
Uganda
9
Zimbabwe
1
Malawi
2
Kenya
1
Zambia
1
April 2010–April 2011: 1277 patients randomized
Baseline characteristics
(at randomization / switch to second-line)
PI/NRTI
PI/RAL
PI-mono
Total
426
433
418
1277
Female
264 (62%)
263 (61%)
215 (51%)
742 (58%)
Age (years)
37 (31–43)
37 (30–43)
38 (32–44)
37 (31–44)
4.0
(2.8–5.4)
4.0
(2.9–5.5)
3.9
(2.7–5.4)
4.0
(2.8–5.4)
CD4 (cells/mm3)
72 (29–143)
70 (27–142)
70 (33–149)
71 (30–146)
Pre-ART CD4
62 (23–144)
63 (23–135)
63 (22–152)
62 (23–145)
67515
74500
70874
69782
(23065–175800)
(25004–205000)
(21584–210000)
(23183–194690)
168 (40%)
181 (41%)
181 (43%)
530 (42%)
Randomized
Years since started
ART
VL (c/mL)
VL ≥100,000 c/mL
Note: n(%) or median (IQR)
Initial EARNEST NRTIs
Randomized
PI/NRTI
PI/RAL
PI-mono
Total
426
433
418
1277
433 (100%)
418 (100%)
1277 (100%)
NRTIs
TDF + 3TC/FTC (+ZDV*)
336 (79%)
ABC + ddI/3TC
67 (16%)
ZDV + ddI/3TC
20 (8%)
Other
3(<1%)
PI
LPV
426 (100%)
*Malawi national guidelines suggested 3 NRTIs
This changed to 2 in August 2011
Adherence to ART and follow-up
PI/NRTI
PI/RAL
PI-mono
Total
426
433
418
1277
99.5%
97.1%
97.4%
98.0%
Visits with complete
ART adherence*
87%
89%
88%
88%
Protocol-mandated
visits attended¶
98%
98%
98%
98%
4(0.9%)
7(1.6%)
7(1.7%)
18 (1.3%)
Randomized
Regimen compatible
with strategy (% time)
LTFU/ withdrawn
* Complete adherence defined as report of no pills missed in the last month
¶ 19,448 mandated protocol visits
Primary endpoint at 96 weeks
• Good disease control: PI/NRTI: 60%
Percentage
100%
80%
Good disease control
60%
Alive & no new WHO4
40%
CD4>250
20%
VL<10,000 or no PI
resistant mutations
0%
PI/NRTI
PI/RAL
PImono
Note: using multiple imputation for missing CD4 (10%), VL (10%) and resistance (11% with VL >1000 c/ml ) at week 96
Primary endpoint at 96 weeks
• Good disease control: PI/NRTI: 60% PI/RAL: 64%
• Risk diff (95% CI): PI/RAL – PI/NRTI: +4.2% (-2.4%,+10.8%; P=0.21)
Percentage
100%
80%
Good disease control
60%
Alive & no new WHO4
40%
CD4>250
20%
VL<10,000 or no PI
resistant mutations
0%
PI/NRTI
PI/RAL
PImono
Note: using multiple imputation for missing CD4 (10%), VL (10%) and resistance (11% with VL >1000 c/ml ) at week 96
Primary endpoint at 96 weeks
• Good disease control: PI/NRTI: 60% PI/RAL: 64% PI mono: 56%
• Risk diff (95% CI): PI/RAL – PI/NRTI: +4.2% (-2.4%,+10.8%; P=0.21)
• Risk diff (95% CI): PImono – PI/NRTI: -4.1% (-10.8%, +2.6%; P=0.23)
Percentage
100%
80%
Good disease control
60%
Alive & no new WHO4
40%
CD4>250
20%
VL<10,000 or no PI
resistant mutations
0%
PI/NRTI
PI/RAL
PImono
Note: using multiple imputation for missing CD4 (10%), VL (10%) and resistance (11% with VL >1000 c/ml ) at week 96
Primary endpoint at 96 weeks
• Good disease control: PI/NRTI: 60% PI/RAL: 64% PI mono: 56%
• Risk diff (95% CI): PI/RAL – PI/NRTI: +4.2% (-2.4%,+10.8%; P=0.21)
• Risk diff (95% CI): PImono – PI/NRTI: -4.1% (-10.8%, +2.6%; P=0.23)
Percentage
100%
80%
Good disease control
60%
Alive & no new WHO4
40%
CD4>250
20%
VL<10,000 or no PI
resistant mutations
0%
PI/NRTI
PI/RAL
PImono
Note: using multiple imputation for missing CD4 (10%), VL (10%) and resistance (11% with VL >1000 c/ml ) at week 96
Primary endpoint at 96 weeks
• Good disease control: PI/NRTI: 60% PI/RAL: 64% PI mono: 56%
• Risk diff (95% CI): PI/RAL – PI/NRTI: +4.2% (-2.4%,+10.8%; P=0.21)
• Risk diff (95% CI): PImono – PI/NRTI: -4.1% (-10.8%, +2.6%; P=0.23)
Percentage
100%
80%
Good disease control
60%
Alive & no new WHO4
40%
CD4>250
20%
VL<10,000 or no PI
resistant mutations
0%
PI/NRTI
PI/RAL
PImono
Note: using multiple imputation for missing CD4 (10%), VL (10%) and resistance (11% with VL >1000 c/ml ) at week 96
Primary endpoint at 96 weeks
• Good disease control: PI/NRTI: 60% PI/RAL: 64% PI mono: 56%
• Risk diff (95% CI): PI/RAL – PI/NRTI: +4.2% (-2.4%,+10.8%; P=0.21)
• Risk diff (95% CI): PImono – PI/NRTI: -4.1% (-10.8%, +2.6%; P=0.23)
P<0.0001
Percentage
100%
80%
Good disease control
60%
Alive & no new WHO4
40%
CD4>250
20%
VL<10,000 or no PI
resistant mutations
0%
PI/NRTI
PI/RAL
PImono
Note: using multiple imputation for missing CD4 (10%), VL (10%) and resistance (11% with VL >1000 c/ml ) at week 96
VL suppression at 96 weeks
100%
Percentage suppressed
90%
91%
88%
86%
80%
74%
70%
60%
50%
40%
30%
20%
10%
0%
<10000 c/ml
<1000 c/ml
PI/NRTI
<400 c/ml
<50 c/ml
21
VL suppression at 96 weeks
PI/RAL vs PI/NRTI
100%
Percentage suppressed
90%
P=0.36
91% 93%
P=0.87
88% 87%
P=0.97
P=0.88
86% 86%
80%
74% 73%
70%
60%
50%
40%
30%
20%
10%
0%
<10000 c/ml
<1000 c/ml
PI/NRTI
<400 c/ml
PI/RAL
<50 c/ml
22
VL suppression at 96 weeks
PI/RAL vs PI/NRTI
P=0.36
PImono+ vs PI/NRTI P=0.002
100%
93%
Percentage suppressed
90%
91%
83%
P=0.87
P<0.0001
88% 87%
P=0.97
P<0.0001
P=0.88
P<0.0001
86% 86%
80%
74% 73%
67%
70%
61%
60%
50%
44%
40%
30%
20%
10%
0%
<10000 c/ml
<1000 c/ml
PI/NRTI
PI/RAL
<400 c/ml
PImono+
<50 c/ml
23
Resistance at 96 weeks
(predicted in whole population)
TDF/ZDV/ABC/ddI
RAL
LPV
% of randomised patients with
intermediate/high level resistance
20
18
18
16
14
12
10
8
6
4
2
0
4
2
X
PI/NRTIs
2
0*
PI/RAL
1
0
X
PI-mono
Note: assuming susceptible if VL<1000 c/mL at week 96; and using inverse probability weighting for VL>1000 c/mL with
missing genotype at week 96 based on those with observed genotypes
*One patient in RAL/PI with intermediate/high level resistance to TDF had moved to 3TC TDF LPV/r at week 4 due to rash
Grade 3/4 adverse events
Total participants
Gr3/4 AEs (participants)
Probability of remaining
grade 3/4 adverse event-free
Rate per 100 PY
PI/NRTI
PI/RAL
PI-mono
Total
426
433
418
1277
94 (22%)
100 (23%)
100 (24%)
294 (23%)
14.4
15.1
13.8
14.5
1.00
HR (PI/RAL: PI/NRTI)=1.08 (0.81, 1.43)
0.75
HR (PI-mono: PI/NRTI)=1.09 (0.82, 1.45)
PI-mono
0.50
PI/RAL
PI/NRTI
0.25
Global P=0.54
0.00
0
24
48
72
Weeks from randomization
96
PI/RAL vs PI/NRTI
PImono vs PI/NRTI
w96 P=0.02
w96 P=0.06
Global P=0.03
Global P=0.14
0
2
Mean change eGFR ml/min/1.73m (95% CI)
Mean eGFR through 96 weeks
-5
-10
-15
0
12
48
Weeks from randomisation
PI/NRTI
PI/RAL
96
PImono
27
EARNEST Conclusions (1)
PI (LPV/r)/NRTI
• Excellent clinical outcome:
– 90% WHO4 event-free survival
– 86% VL suppression <400 c/mL at 96 weeks, even in advanced 1st-line
failure
• Well-tolerated and safe
• Given with laboratory monitoring approach widely attainable in
this setting:
–
–
–
–
Clinical and CD4 monitoring
VL testing prior to switch to second line
No resistance testing - NRTIs selected by clinical algorithm
Modest safety monitoring
• PI/NRTI merits its place as standardised regimen in 2nd line
therapy in public health approach
EARNEST conclusions (2)
• PI/RAL was not superior to PI/NRTI (“good disease
control” and VL suppression)
• With cost differential, PI/RAL not suited for a
standardized 2nd-line regimen for large-scale use in
WHO public health approach
• But PI/RAL non-inferior across range of outcomes and
safe/well-tolerated
• May represent an alternative regimen for some patients
in resource-rich settings where individualized therapy is
possible
EARNEST conclusions (3)
PI-mono
• Inferior to PI/NRTI: lower VL suppression, more resistance
• Unsuitable for public health approach
EARNEST conclusions (4) –
the marvel of “recycled” NRTIs
• NRTIs retain substantial virological activity in 2nd-line
• Even in patient population with advanced 1st-line failure
expected to have extensive cross-resistance
• Further exploration of these data…..
NRTI resistance at baseline
Percentage
100
80
60
40
20
0
3TC
FTC
Susceptible
ABC
Potential low
TDF
ZDV
Low
DDI
D4T
Intermediate
High
Baseline sequences obtained in 92% of those randomized to PI/NRTI arm
Figure shows resistance data from 792 randomized patients
Kityo et al, Poster 595, CROI 2015
32
Predicted activity of NRTIs in regimens
• Number of predicted “active” NRTIs in prescribed
second-line Rx*:
0
230 (59%)
1
128 (33%)
≥2
33 (8%)
*NRTI predicted “active” if no int./high level resistance by Stanford
• GSS for NRTIs in prescribed second-line Rx:
0
0.25-0.75
1-1.75
≥2
114 (29%)
177 (45%)
73 (19%)
27 (7%)
Paton N, Abstract 119, CROI 2015
33
VL response by number of active NRTIs
in the regimen
Percent with VL<400 copies/ml
100
81%
80
60
61%
40
20
0
0 4 12
24
36
48
64
80
96
112
128
144
Weeks from switch to second-line
PI + RAL (N>280)
PI Monotherapy (N>374)
VL response by number of active NRTIs
in the regimen
Percent with VL<400 copies/ml
100
88%
81%
80
60
61%
40
20
0
0 4 12
24
36
48
64
80
96
112
128
144
Weeks from switch to second-line
Global p<0.0001
NRTI() = number or active(susceptible-low resistance) NRTIs
PI/NRTI(0) (N>149)
PI + RAL (N>280)
PI Monotherapy (N>374)
VL response by number of active NRTIs
in the regimen
Percent with VL<400 copies/ml
100
88%
80
85%
81%
60
61%
40
20
0
0 4 12
24
36
48
64
80
96
112
128
144
Weeks from switch to second-line
Global p<0.0001
NRTI() = number or active(susceptible-low resistance) NRTIs
PI/NRTI(0) (N>149)
PI/NRTI(1) (N>86)
PI + RAL (N>280)
PI Monotherapy (N>374)
VL response by number of active NRTIs
in the regimen
Percent with VL<400 copies/ml
100
88%
85%
81%
80
77%
60
61%
40
20
0
0 4 12
24
36
48
64
80
96
112
Weeks from switch to second-line
Global p<0.0001
Within PI+NRTIs global p=0.02
NRTI() = number or active(susceptible-low resistance) NRTIs
128
144
PI/NRTI(0) (N>149)
PI/NRTI(1) (N>86)
PI/NRTI(2-3) (N>17)
PI + RAL (N>280)
PI Monotherapy (N>374)
VL response by GSS of NRTIs in the
regimen
Percent with VL<400 copies/ml
100
89%, 89%
83%
81%
73%
80
60
61%
40
20
0
0 4 12
24
36
48
64
80
96
144
Weeks from switch to second-line
Global p<0.0001
Within PI+NRTIs global p=0.007
PI + 0 GSS (N>86)
PI + 1-1.75 GSS (N>59)
PI + RAL (N>280)
PI + 0.25-0.75 GSS (N>140)
PI + 2+ GSS (N>21)
PI Monotherapy (N>374)
Factors Associated with VL < 400c/ml in PI/NRTI
Unadjusted
Odds ratio (95% CI)
p value
1
0.25-0.75
Adjusted
Odds ratio (95% CI)
P value
0.19
1
0.12
0.59 (0.26, 1.33)
(trend
0.46 (0.19, 1.09)
(trend
1-1.75
0.60 (0.23, 1.61)
0.08)
0.39 (0.13, 1.19)
0.03)
2-3
0.28 (0.09, 0.89)
GSS of second line regimen
0
0.23 (0.06, 0.88)
Viral load at baseline (per doubling)
0.70 (0.60, 0.83)
<0.001
0.66 (0.55, 0.80)
<0.001
Proportion non-adherent visits (per 5% higher)*
0.89 (0.82, 0.96)
0.003
0.89 (0.81, 0.98)
0.01
Unemployed at baseline
0.51 (0.28, 0.94)
0.03
0.48 (0.24, 0.98)
0.04
Age (per 10 years older)
1.45 (1.10,1.92)
0.008
1.60 (1.15,2.22)
0.005
Note: Multivariable regression modelling for VL suppression at week 96. N=346, excluding those with missing week 96 VL, baseline genotype or
baseline employment status. Factors with p>0.1 sex, centre, baseline CD4, diabetes, cardiovascular disease, prior tuberculosis, smoking, alcohol
consumption, hours worked per week, household income, food availability, presence of M184V in the baseline genotype, years on first-line, eGFR,
haemoglobin, and glucose, previous CNS disease; viral subtype
*Non-adherent visit defined as missed, more than 7 days late, or reported any missing ART in the last month.
39
Conclusions
• Paradoxical relationship between resistance and VL
suppression
– Confounding by adherence (although persists after
adjustment)
– Also consistent with fitness / fidelity effect
– Maybe be better to base NRTI choice on tolerability/
convenience than predicted activity?
• Algorithmic NRTI drug selection + attention to
adherence can achieve excellent outcomes from 2ndline therapy in public health approach
– Resistance testing to select NRTIs is of little added value.
Acknowledgments
Uganda: JCRC Kampala (African trial co-ordinating centre; 231) E Agweng, P Awio, G Bakeinyaga, C Isabirye, U Kabuga, S Kasuswa, M Katuramu, C Kityo, F Kiweewa, H
Kyomugisha, E Lutalo, P Mugyenyi, D Mulima, H Musana, G Musitwa, V Musiime, M Ndigendawan, H Namata, J Nkalubo, P Ocitti Labejja, P Okello, P Olal, G Pimundu, P
Segonga, F Ssali, Z Tamale, D Tumukunde, W Namala, R Byaruhanga, J Kayiwa, J Tukamushaba. IDI, Kampala (216): G Bihabwa, E Buluma, P Easterbrook, A Elbireer, A Kambugu,
D Kamya, M Katwere, R Kiggundu, C Komujuni, E Laker, E Lubwama, I Mambule, J Matovu, A Nakajubi, J Nakku, R Nalumenya, L Namuyimbwa, F Semitala, B Wandera, J
Wanyama; JCRC, Mbarara (97): H Mugerwa, A Lugemwa, E Ninsiima, T Ssenkindu, S Mwebe, L Atwine, H William, C Katemba, S Abunyang, M Acaku, P Ssebutinde, H Kitizo, J
Kukundakwe, M Naluguza, K Ssegawa, Namayanja, F Nsibuka, P Tuhirirwe, M Fortunate; JCRC Fort Portal (66): J Acen, J Achidri, A Amone, M. Chamai, J Ditai, M Kemigisa, M
Kiconco, C Matama, D Mbanza, F Nambaziira, M Owor Odoi, A Rweyora, G. Tumwebaze. San Raphael of St Francis Hospital, Nsambya (48): H Kalanzi, J Katabaazi , A Kiyingi, M
Mbidde, M. Mugenyi, R Mwebaze, P Okong, I Senoga. JCRC Mbale (47): M Abwola, D Baliruno, J Bwomezi, A Kasede, M Mudoola, R Namisi, F Ssennono, S Tuhirwe.
JCRC Gulu (43): G Abongomera, G Amone, J Abach, I Aciro, B Arach, P Kidega, J Omongin, E Ocung, W Odong, A Philliam. JCRC Kabale (33): H Alima, B Ahimbisibwe, E Atuhaire,
F Atukunda, G Bekusike, A Bulegyeya, D. Kahatano, S Kamukama, J Kyoshabire, A Nassali, A Mbonye, T M Naturinda, Ndukukire, A Nshabohurira, H. Ntawiha, A Rogers, M
Tibyasa; JCRC Kakira (31): S. Kiirya, D. Atwongeire, A. Nankya, C. Draleku, D. Nakiboneka, D. Odoch, L. Lakidi, R. Ruganda, R. Abiriga, M. Mulindwa, F. Balmoi, S. Kafuma, E.
Moriku
Zimbabwe: University of Zimbabwe Clinical Research Centre, Harare (265): J Hakim, A Reid, E Chidziva, G Musoro, C Warambwa, G Tinago, S Mutsai, M
Phiri, S Mudzingwa, T Bafana, V Masore, C Moyo, R Nhema, S Chitongo
Malawi: College of Medicine, University of Malawi, Blanytre (92): Rob Heyderman, Lucky Kabanga, Symon Kaunda, Aubrey Kudzala, Linly Lifa, Jane Mallewa, Mike Moore,
Chrissie Mtali, George Musowa, Grace Mwimaniwa, Rosemary Sikwese, Joep van Oosterhout, Milton Ziwoya. Mzuzu Central Hospital, Mzuzu (19): H Chimbaka. B Chitete, S
Kamanga, T Kayinga E Makwakwa, R Mbiya, M Mlenga, T Mphande, C Mtika, G Mushani, O Ndhlovu, M Ngonga, I Nkhana, R Nyirenda
Kenya: Moi Teaching and Referral Hospital (52): P Cheruiyot, C Kwobah, W Lokitala Ekiru, M Mokaya, A Mudogo, A Nzioka, A Siika, M Tanui, S Wachira, K Wools-Kaloustian
Zambia: University Teaching Hospital (37): P Alipalli, E Chikatula, J Kipaila, I Kunda, S Lakhi, J Malama, W Mufwambi, L Mulenga, P Mwaba, E Mwamba, A Mweemba, M
Namfukwe
The Aids Support Organisation (TASO), Uganda: E Kerukadho, B Ngwatu, J Birungi
MRC Clinical Trials Unit: N Paton, J Boles, A Burke, L Castle, S Ghuman, L Kendall, A Hoppe, S Tebbs, M Thomason, J Thompson, S Walker, J Whittle, H Wilkes, N Young
Monitors: C Kapuya, F Kyomuhendo, D Kyakundi, N Mkandawire, S Mulambo, S Senyonjo
Clinical Expert Review Committee: B Angus, A Arenas-Pinto, A Palfreeman, F Post, D Ishola
European Collaborators: J Arribas, B Colebunders, M Floridia, M Giuliano, P Mallon, P Walsh, M De Rosa, E Rinaldi
Trial Steering Committee: I Weller (Chair), C Gilks, J Hakim, A Kangewende, S Lakhi, E Luyirika, F Miiro, P Mwamba, P Mugyenyi, S Ojoo, N Paton, S Phiri, J van Oosterhout, A
Siika, S Walker, A Wapakabulo,
Data Monitoring Committee: T Peto (Chair), N French, J Matenga
Pharmaceutical companies : J van Wyk, M Norton, S Lehrman, P Lamba, K Malik, J Rooney, W Snowden, J Villacian, G Cloherty
Funding and in-kind support: Funded by the European and Developing Countries Clinical Trials Partnership (EDCTP) with contributions from the Medical Research Council, UK,
Institito de Salud Carlos III, Spain, Irish Aid, Ireland, Swedish International Development Cooperation Agency (SIDA), Sweden, Instituto Superiore di Sanita (ISS), Italy and Merck,
USA. Substantive in-kind contributions were made by the Medical Research Council Clinical Trials Unit, UK, CINECA, Bologna, Italy, Janssen Diagnostics, Mechelen, Belgium;
GSK, UK; Abbott Laboratories, USA. Trial medication was donated by AbbVie, Merck, Pfizer, GSK and Gilead
Summary
• Good evidence for LPV/r + 2NRTIs providing excellent
outcomes in second-line using public health approach
• Good evidence for LPV/r + RAL being non-inferior to SOC in
second line – may be attractive in some settings for
individualizing therapy
• Choice of NRTIs in second-line may not matter (and probably
don’t need resistance testing)