Low lopinavir plasma or hair concentrations explain second-line protease inhibitor failures in a resource-limited setting

Abstract

Background: In resource-limited settings, many patients, with no prior protease inhibitor (PI) treatment on a second-line, high genetic barrier, ritonavir-boosted PI-containing regimen have virologic failure.

Methods: We conducted a cross-sectional survey to investigate the aetiology of virologic failure in 2 public health antiretroviral clinics in South Africa documenting the prevalence of virologic failure (HIV RNA load >500 copies/mL) and genotypic antiretroviral resistance; and lopinavir hair and plasma concentrations in a nested case-control study.

Results: Ninety-three patients treated with a second-line regimen including lopinavir boosted with ritonavir were included, of whom 50 (25 cases, with virologic failure and 25 controls) were included in a nested case control study. Of 93 patients, 37 (40%) had virological failure, only 2 of them had had major PI mutations. The negative predictive values: probability of failure with lopinavir plasma concentration >1 µg/mL or hair concentrations >3.63 ng/mg for virologic failure were 86% and 89%, and positive predictive values of low concentrations 73% and 79%, respectively, whereas all virologic failures with HIV RNA loads above 1000 copies per milliliter, of patients without PI resistance, could be explained by either having a low lopinavir concentration in plasma or hair.

Conclusions: Most patients who fail a lopinavir/ritonavir regimen, in our setting, have poor lopinavir exposure. A threshold plasma lopinavir concentration (indicating recent lopinavir/ritonavir use) and/or hair concentration (indicating longer term lopinavir exposure) are valuable in determining the aetiology of virologic failure and identifying patients in need of adherence counselling or resistance testing.

Figures

Figure 1

Scatterplot of Lopinavir hair (ng/mg) and plasma concentrations ((μg/mL) in patients with virologic failure (triangles) and non-failure patients (open circles). The dashed lines indicate the respective concentration cut-offs: LPV plasma concentration of 1 μg/mL and LPV hair concentration of 3.63 ng/mg.

Figure 2

Proposed algorithm to investigate the cause of virologic failure of a Lopinavir boosted with low dose ritonavir (LPV/r) containing second-line regimen in resource-limited settings. LPV concentrations in plasma and hair will only be analysed when the viral load is >1000. This would allow the differentiation of patients who are failing due to poor adherence versus probable genotypic resistance. *: Asterisk indicating the tests that are done at the ‘viral load’ visit.