Second-line anti-retroviral therapy in resource-limited settings Nicholas Paton MD FRCP Professor of Medicine National University of Singapore
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 Roche-sponsored 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
PINNRTINRTI
PI
Standardised 1st line Standardised 2nd line≈ 3% fail/y
?“moderate quality evidence” for 2nd-line regimen
The EARNEST question
PINNRTINRTI
PI
Standardised 1st line Standardised 2nd line≈ 3% fail/y
?
PI RAL
The EARNEST question
PINNRTINRTI
PI
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)
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* + 2-3 NRTIs(NRTIs according to
local standard of care)
PI + RAL(12 wk induction)
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 without PI res. mutations at 96 weeks
PI + RAL
Trial design (1)
*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
April 2010–April 2011: 1277 patients randomized
Sites 14
Uganda 9
Zimbabwe 1
Malawi 2
Kenya 1
Zambia 1
Baseline characteristics (at randomization / switch to second-line)
PI/NRTI PI/RAL PI-mono Total
Randomized 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)
Years since started ART
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)
VL (c/mL) 67515(23065–175800)
74500(25004–205000)
70874(21584–210000)
69782 (23183–194690)
VL ≥100,000 c/mL 168 (40%) 181 (41%) 181 (43%) 530 (42%)
Note: n(%) or median (IQR)
Initial EARNEST NRTIs
PI/NRTI PI/RAL PI-mono Total
Randomized 426 433 418 1277
NRTIs
TDF + 3TC/FTC (+ZDV*) 336 (79%)
ABC + ddI/3TC 67 (16%)
ZDV + ddI/3TC 20 (8%)
Other 3(
Adherence to ART and follow-up
PI/NRTI PI/RAL PI-mono Total
Randomized 426 433 418 1277
Regimen compatible with strategy (% time)
99.5% 97.1% 97.4% 98.0%
Visits with completeART adherence*
87% 89% 88% 88%
Protocol-mandated visits attended¶
98% 98% 98% 98%
LTFU/ withdrawn 4(0.9%) 7(1.6%) 7(1.7%) 18 (1.3%)
* 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%
0%
20%
40%
60%
80%
100%
PI/NRTI PI/RAL PImono
Pe
rce
nta
ge
Good disease control
Alive & no new WHO4
CD4>250
VL1000 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)
0%
20%
40%
60%
80%
100%
PI/NRTI PI/RAL PImono
Pe
rce
nta
ge
Good disease control
Alive & no new WHO4
CD4>250
VL1000 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)
0%
20%
40%
60%
80%
100%
PI/NRTI PI/RAL PImono
Pe
rce
nta
ge
Good disease control
Alive & no new WHO4
CD4>250
VL1000 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)
0%
20%
40%
60%
80%
100%
PI/NRTI PI/RAL PImono
Pe
rce
nta
ge
Good disease control
Alive & no new WHO4
CD4>250
VL1000 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)
0%
20%
40%
60%
80%
100%
PI/NRTI PI/RAL PImono
Pe
rce
nta
ge
Good disease control
Alive & no new WHO4
CD4>250
VL1000 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)
0%
20%
40%
60%
80%
100%
PI/NRTI PI/RAL PImono
Pe
rce
nta
ge
Good disease control
Alive & no new WHO4
CD4>250
VL1000 c/ml ) at week 96
P
VL suppression at 96 weeks
91%88% 86%
74%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
VL suppression at 96 weeks
91%88% 86%
74%
93%87% 86%
73%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
VL suppression at 96 weeks
91%88% 86%
74%
93%87% 86%
73%
83%
67%
61%
44%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Note: assuming susceptible if VL1000 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
Resistance at 96 weeks (predicted in whole population)
4
0 0
221
18
0
2
4
6
8
10
12
14
16
18
20
PI/NRTIs PI/RAL PI-mono
% o
f ra
nd
om
ise
d p
atie
nts
wit
h
inte
rme
dia
te/h
igh
leve
l re
sist
ance
TDF/ZDV/ABC/ddI RAL LPV
X X*
HR (PI/RAL: PI/NRTI)=1.08 (0.81, 1.43)
HR (PI-mono: PI/NRTI)=1.09 (0.82, 1.45)
Global P=0.54
Grade 3/4 adverse events
PI/NRTI PI/RAL PI-mono Total
Total participants 426 433 418 1277
Gr3/4 AEs (participants) 94 (22%) 100 (23%) 100 (24%) 294 (23%)
Rate per 100 PY 14.4 15.1 13.8 14.5
Pro
bab
ility
of
rem
ain
ing
grad
e 3
/4 a
dve
rse
even
t-fr
ee
0.00
0.25
0.50
0.75
1.00
0 24 48 72 96Weeks from randomization
PI-mono
PI/RALPI/NRTI
Mean eGFR through 96 weeks
27
-15
-10
-5
0
Mean c
hange e
GF
Rm
l/m
in/1
.73m
2(9
5%
CI)
0 12 48 96Weeks from randomisation
PI/NRTI PI/RAL PImono
PI/RAL vs PI/NRTI w96 P=0.02 Global P=0.03PImono vs PI/NRTI w96 P=0.06 Global P=0.14
EARNEST Conclusions (1)
PI (LPV/r)/NRTI • Excellent clinical outcome:
– 90% WHO4 event-free survival– 86% VL suppression
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
32Kityo et al, Poster 595, CROI 2015
0
20
40
60
80
100
Perc
en
tage
3TC FTC ABC TDF ZDV DDI D4T
Susceptible Potential low Low Intermediate High
Baseline sequences obtained in 92% of those randomized to PI/NRTI armFigure shows resistance data from 792 randomized patients
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:0 114 (29%)
0.25-0.75 177 (45%)
1-1.75 73 (19%)
≥2 27 (7%)
33Paton N, Abstract 119, CROI 2015
PI + RAL (N>280)
PI Monotherapy (N>374)
Perc
ent
wit
h V
L<4
00
co
pie
s/m
l
Weeks from switch to second-line
81%
61%
VL response by number of active NRTIs in the regimen
0
20
40
60
80
100
0 4 12 24 36 48 64 80 96 144128112
VL response by number of active NRTIs in the regimen
PI/NRTI(0) (N>149)
PI + RAL (N>280)PI Monotherapy (N>374)
Global p
PI/NRTI(0) (N>149)
PI/NRTI(1) (N>86)
PI + RAL (N>280)
PI Monotherapy (N>374)
81%
88%85%
61%
VL response by number of active NRTIs in the regimen
Perc
ent
wit
h V
L<4
00
co
pie
s/m
l
Weeks from switch to second-line
0
20
40
60
80
100
0 4 12 24 36 48 64 80 96 144128112
Global p
VL response by number of active NRTIs in the regimen
PI/NRTI(0) (N>149)PI/NRTI(1) (N>86)PI/NRTI(2-3) (N>17)PI + RAL (N>280)PI Monotherapy (N>374)
Within PI+NRTIs global p=0.02
88%
77%
85%81%
61%
Perc
ent
wit
h V
L<4
00
co
pie
s/m
l
Weeks from switch to second-line
0
20
40
60
80
100
0 4 12 24 36 48 64 80 96 144128112
Global p
PI + 0 GSS (N>86) PI + 0.25-0.75 GSS (N>140)PI + 1-1.75 GSS (N>59) PI + 2+ GSS (N>21)PI + RAL (N>280) PI Monotherapy (N>374)Global p
Factors Associated with VL < 400c/ml in PI/NRTI
39
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.
Unadjusted
Odds ratio (95% CI)
p value Adjusted
Odds ratio (95% CI)P value
GSS of second line regimen
0 1 0.19 1 0.12
0.25-0.75 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) 0.23 (0.06, 0.88)
Viral load at baseline (per doubling) 0.70 (0.60, 0.83)
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 2nd-line 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, MPhiri, 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-KaloustianZambia: 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 NamfukweThe 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 YoungMonitors: C Kapuya, F Kyomuhendo, D Kyakundi, N Mkandawire, S Mulambo, S SenyonjoClinical Expert Review Committee: B Angus, A Arenas-Pinto, A Palfreeman, F Post, D IsholaEuropean Collaborators: J Arribas, B Colebunders, M Floridia, M Giuliano, P Mallon, P Walsh, M De Rosa, E RinaldiTrial 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 MatengaPharmaceutical 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)