NNRTI resistance found in 12% of people stopping treatment with undetectable viral load: implications for stock-outs

Although stopping ART is not recommended, this still occurs due to drug stock-outs in some countries and retrospective data from the UK HIV Drug Resistance Database (HDRD) highlighted the risk this has for developing drug resistance.

Valentina Cambiano from University College London and colleagues analysed drug resistance mutations in rebound viraemia in people who interrupted NNRTI-based treatment when their viral load was consistently undetectable <200 copies/mL for at least six months and who had no prior evidence of NNRTI resistance.

Of 208 eligible patients with a resistance test after stopping treatment, 39% were on efavirenz and 61% on nevirapine. Background therapy was most commonly with 3TC (85%) and/or AZT (63%) and treatment was stopped after a median of 12 months on ART (IQR: 5-32 months).

At the first resistance test after stopping treatment, 25/208 patients (12%, 95% CI: 8-17) had one or more major NNRTI mutations, with no indication of a reduced rate in the 20/208 people who staggered the interruption, though small numbers meant that there were wide confidence intervals around these estimates. In these patients, the resistance test was taken after a median of 12 months (IQR: 3-20).

The most common mutations were K103N (64%) and G190A (12%), with K101E, V108I, Y181C, L100I, V106A, Y188L and P225H found in 8% (n=2) or less. In multivariate analysis, the only independent predictor of NNRTI resistant mutations was a lower CD4 count nadir (RR per 100 cells higher = 0.67; 95% CI: 0.53-0.85; p=0.001).

The authors concluded that in this largest study to date, NNRTI resistance was common occurring in 12% of patients tested. Although this was a retrospective analysis, this may underestimate the risk given the time taken between stopping treatment and testing for drug resistance.

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These results are important in countries where the drug supply is less secure, and when using NNRTI-based ART with AZT and/or 3TC. Further research is needed to determine whether the longer half-life of tenofovir has a protective impact on NNRTI resistance in this context.

This also highlights the lack of research into the clinical outcomes of people who do not have access to an assured and continuous supply of ARVs. While stock-outs are commonly reported, research into the outcomes is not.

A recent paper in HIV Medicine reported resistance data after stopping atazanavir/r-based combinations (largely related to poor adherence), and suggested a benefit of PI/r-based combinations when stock-outs are common. This was a retrospective analysis of 110 patients in Ireland and although minor PI mutations were common, viral load was resuppressed after restarting atazanavir/r. [2]

1. Cambiano V et al. Detection of NNRTI resistance mutations after interrupting NNRTI-based regimens. 21st CROI, 3–6 March 2014, Boston. Poster abstract 593.
http://croiconference.org/sites/all/abstracts/593.pdf (PDF)

2. Tinago W et al. Characterisation of associations and development of atazanavir resistance after unplanned treatment interruptions. HIV Medecine (2014), 15 (4) 224-232. DOI: 10.1111/hiv.12107.
http://www.ncbi.nlm.nih.gov/pubmed/24215370