CHAIN is a large scale integrating project aimed at effectively and durably combating new and existing anti-HIV drug resistance in clinical settings, with a special emphasis on Eastern Europe and heavily affected resource-poor regions in Africa.
A joint project on transmitted drug resistance (TDR) and its impact on treatment response between EuroCoord and the EU funded FP7 CHAIN was instigated due to the large number of patients required to address the scientific question.
The objective was to compare virological, immunological, and clinical outcome up to 12-16 months following initiation of cART, according to markers of virus variability (specific mutations, subtypes), and relevant to the drugs in the regimen (objective 3.4 of CHAIN WP3 entitled ‘Clinical implications of HIV drug resistance’). A project team with epidemiologists, statisticians, virologists, and clinicians was established (project lead: Geneviève Chêne, project coordinator: Linda Wittkop).
The Standardised Operating Procedure (SOP) in HICDEP format used for COHERE data mergers was improved and adapted for this joint project to involve other founding networks of EuroCoord: CASCADE, EUROSIDA, and PENTA.
Data collection started in April 2009 (all HIV-1 infected patients with at least one genotypic resistance test while antiretroviral naive and with minimal core data available as described in the SOP) and the last cohort submitted data in September 2009.
A total of 10,056 patients from 25 cohorts were included in the final analysis which was published in Lancet Infectious Diseases. The study found that TDR was associated with virological failure in patients who received at least one drug to which the virus had lost susceptibility. The group also found that treatment with a drug classified even with low-level resistance is associated with a significantly higher risk for virological, emphasising the need for at least three fully-active drugs in a first-line regimen.
A further finding of the study showed that patients with TDR who started a regimen containing two NRTIs plus one ritonavir-boosted protease inhibitor and received fully-active treatment had a similar risk of virological failure to patients with a virus with no TDR mutations. Therefore, if drug resistance mutations are detected before treatment initiation, a ritonavir-boosted protease inhibitor can be included in the first treatment regimen, which, because of its higher genetic barrier, could better protect from the risk of virological failure than could NNRTI.
Further proposals have been made to use the dataset, and they are currently undergoing review.
Wittkop L, Günthard H, de Wolf F, Dunn D, Cozzi-Lepri A, de Luca A, Kücherer C, Obel N, von Wyl V, Masquelier B, Stephan C, Torti C, Antinori A, García F, Judd A, Porter K, Thiébaut R, Castro H, van Sighem AI, Colin C, Kjaer J, Lundgren JD, Paredes R, Pozniak A, Clotet B, Phillips A, Pillay D, Chêne G, for the EuroCoord-CHAIN study group. Effect of transmitted drug resistance on virological and immunological response to initial combination antiretroviral therapy for HIV (EuroCoord-CHAIN joint project): a European multicohort study. Lancet Infect. Dis. 2011. [Epub ahead of print]