Evolution of protease inhibitor resistance in HIV-1-infected patients failing protease inhibitor monotherapy as second-line therapy in low-income countries: an observational analysis within the EARNEST randomised trial

Journal article

Background

Limited viral load (VL) testing in HIV-infected individuals on treatment in low-income countries often results in late detection of treatment failure. The impact of remaining on failing second-line, protease inhibitor (PI) containing regimens is unclear.

Methods

We retrospectively tested VL from 2,164 stored plasma samples from 386 patients randomised to receive PI-monotherapy (ritonavir-boosted lopinavir, after initial PI+raltegravir induction) in the EARNEST trial. Protease genotypic resistance testing was performed in samples with VL>1000 copies/ml. We assessed evolution of drug resistance mutations from virological failure (confirmed VL>1000 copies/ml) until discontinuation of PI-monotherapy and examined associations using Poisson and linear mixed-effects models.

Results

118 patients had a median 68(IQR 48-88) weeks on PI-monotherapy post-failure. At failure, 21/107(20%) had intermediate/high resistance to lopinavir. 40-48 weeks post-failure, 49/72(68%) and 36/71(51%) had intermediate/high-level resistance to lopinavir and atazanavir. Most remained susceptible to darunavir (12/72[17%] intermediate, no high resistance). Common PI mutations were M46I, I54V, and V82A. On average, 1.7(95% CI 1.5,2.0) PI mutations developed per year; this increased after the first mutation developed, but decreased with subsequent mutations (p≺0.0001). Modest VL changes were mainly driven by non-adherence (p=0.006) and PI-mutation development. I47A was associated with a larger increase in log10 VL(+0.53[+0.18,+0.87], p=0.003) than other PI mutations (+0.15[+0.07,+0.23] p≺0.001; heterogeneity p=0.05).

Conclusion

Most develop intermediate/high-level lopinavir resistance within one year when lopinavir/ritonavir is exposed to sustained VL replication without protection from other drugs. Even in this extreme situation, annual VL testing (current WHO recommendation) would identify failure when most would still benefit from switching to darunavir.

Authors: Thompson, J; Kityo, C; Dunn, D; Hoppe, A; Ndashimye, E

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Oxford University Press
• Journal: Clinical Infectious Diseases
• Volume: 68
• Issue: 7
• Pages: 1184-1192
• Publication date: 2018-07-28
• Acceptance date: 2018-07-17
• DOI: 10.1093/cid/ciy589
• EISSN: 1537-6591
• ISSN: 1058-4838
• Keywords: sub-Saharan Africa; HIV-1; protease inhibitor; drug resistance; second-line antiretroviral therapy