second-line anti-retroviral therapy in resource-limited...

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


PINNRTINRTI

PI


?

PI RAL


PINNRTINRTI

PI


?

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


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


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


• 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%


Pe

rce

nta

ge


Alive & no new WHO4

CD4>250



• Good disease control: PI/NRTI: 60% PI/RAL: 64% PI mono: 56%


• Risk diff (95% CI): PImono – PI/NRTI: -4.1% (-10.8%, +2.6%; P=0.23)

0%

20%

40%

60%

80%

100%


Pe

rce

nta

ge


Alive & no new WHO4

CD4>250



• Good disease control: PI/NRTI: 60% PI/RAL: 64% PI mono: 56%


• Risk diff (95% CI): PImono – PI/NRTI: -4.1% (-10.8%, +2.6%; P=0.23)

0%

20%

40%

60%

80%

100%


Pe

rce

nta

ge


Alive & no new WHO4

CD4>250


P

VL suppression at 96 weeks

91%88% 86%

74%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%


91%88% 86%

74%

93%87% 86%

73%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%


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


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/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


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%


Perc

ent

wit

h V

L<4

00

co

pie

s/m

l


0

20

40

60

80

100

0 4 12 24 36 48 64 80 96 144128112

Global p


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


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)

second-line anti-retroviral therapy in resource-limited...

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