Author: Christopher Hoffmann - 2013-08-23

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Current guidelines for the management of virological failure recommend excluding drug interactions and inter-current infections, intensifying adherence support and switching to second-line ART if a patient remains viraemic. The aim being to ensure that non-adherent patients receive appropriate adherence support and those with resistance switch regimens.

Figure 2: First-line antiretroviral therapy drug concentrations in stored plasma samples taken prior to switching to second-line antiretroviral therapy

This study highlights that ongoing non-adherence remains a major contributor to first-line virological failure when switching regimens with 55% of patients in this study having sub-therapeutic first-line drug concentrations pre-switch. Perhaps unsurprisingly, these patients were less likely to achieve viral suppression once switched to second-line ART. Furthermore, resistance to NRTIs did not increase risk of first-line failure. In fact, overall patients with resistance did better, perhaps because it reflected a higher degree of adherence. These findings suggest that efforts to intensify adherence support when switching regimens are often unsuccessful and lead to sub-optimal second-line outcomes.

Sub-therapeutic drug concentrations also influenced the patterns of resistance mutations observed at switch; NRTI mutations were detected in 97% of patients on 'therapeutic' first-line ART, compared to 31% on a 'sub-therapeutic' regimen. In particular 47% versus 18% had >1 TAM detected and 26% versus 13% NRTI cross-resistance mutations.

The findings from this study indicate that it is unresolved non-adherence at time of switch, not NRTI resistance, which drives early second-line failure. These findings underline the need to develop simple point-of-care tools for reliably identifying patients in whom non-adherence continues to contribute to viraemia, including options such as simple bio-assays for therapeutic drug levels or other robust measures of adherence. Drug resistance assays at the time of first-line failure appear to be mostly useful to assess adherence, but not for guiding ART management.

Open Access publication:

Johnston V, Cohen K, Wiesner L, Morris L, Ledwaba J, Fielding KL, Charalambous S, Churchyard G, Phillips A, Grant AD. Viral suppression following switch to second-line antiretroviral therapy: associations with NRTI resistance and sub-therapeutic drug concentrations prior to switch. J Infect Dis. 2013 Aug 13. [Epub ahead of print]

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