WELBB02 - Oral Abstract Session
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
Presented by Nicholas Paton (United Kingdom).
N. Paton1,2, C. Kityo3, A. Hoppe1, J. Hakim4, J. van Oosterhout5, A. Siika6, P. Mwaba7, A. Kambugu8, P. Easterbrook8, J. Boles1, S. Walker1, P. Mugyenyi3, EARNEST Trial Group
1MRC Clinical Trials Unit, London, United Kingdom, 2National University of Singapore, Singapore, Singapore, 3Joint Clinical Research Centre, Kampala, Uganda, 4University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe, 5College of Medicine, University of Malawi, Blantyre, Malawi, 6Moi University School of Medicine, Eldoret, Kenya, 7University Teaching Hospital, Lusaka, Zambia, 8Infectious Diseases Institute, Kampala, Uganda
Background: The incremental benefits of new/recycled NRTIs or raltegravir (RAL) on a boosted PI (bPI) backbone for second-line therapy are uncertain, particularly in typical rollout programme settings where individualised therapy with resistance testing, regular viral load (VL) monitoring, and early treatment switches are infeasible.
Methods: 1277 patients aged ≥12y who met WHO-defined treatment failure criteria (confirmed by VL >400 copies/ml) after >12 months on NNRTI-based first-line treatment were randomised in an open-label trial in 14 sub-Saharan African sites. The superiority of (B) bPI plus RAL (400 mg b.d.) and the non-inferiority (10% margin) of (C) bPI monotherapy (+RAL induction for first 12 weeks) were compared to (A) bPI+2/3 physician-selected NRTIs. bPI was standardised to lopinavir/ritonavir,400mg/100mg b.d. Treatment was monitored clinically and by open CD4 count; VL and resistance testing were done annually blinded, reviewed by a data monitoring committee. The primary (composite) endpoint, good disease control, was defined as no new WHO stage 4 events (or death) after randomisation, and CD4 count >250 cells/mm3 and VL < 10,000 copies/ml (or >10,000 copies/ml without major/minor PI resistance mutations) at week 96.
Results: Patients were 58% female, median baseline CD4=71 cells/mm3, VL=69,782 copies/ml; 1% were withdrawn/lost to follow-up by week 96. Proportions with good disease control were (A) 60%, (B) 65% (absolute risk difference vs A: +5.7% (-0.9%,+12.3%; P=0.09)) and (C) 57% (difference vs A: -2.2% (-9.0%,+4.5%; P=0.52)). There was no difference in grade 3/4 adverse events between groups (P=0.39). However, 61% (C) had VL< 400 copies/ml at 96 weeks vs 86% (A) (difference -25% (-31%,-19%; P< 0.0001)) and 86% (B) (difference vs A -0.2% (-5%,+ 4%; P=0.94). Based on samples analysed to date we estimate 3% (A), 1% (B) and 17% (C) (p=0.002) have intermediate/high level lopinavir resistance (Stanford).
Conclusion: bPI+RAL did not show clear superiority to bPI+2NRTI at week 96; further follow up will determine whether it is advantageous over the longer term. bPI monotherapy was non-inferior on the primary endpoint, but markedly lower rates of VL suppression and more resistance indicate that this approach is unsuitable for typical rollout programme settings that lack regular/reliable VL monitoring. New/recycled NRTIs retain substantial virological activity.
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