Variability of the HIV-1 3' polypurine tract (3'PPT) region and implication in integrase inhibitor resistance.

BACKGROUND: Integrase strand-transfer inhibitors (INSTIs) are efficient at impairing retroviral integration, which is a critical step in HIV-1 replication. To date, resistance to these compounds has been explained by mutations in the viral protein integrase, which catalyses the integration step. Recently, it has been shown that selected mutations in the 3' polypurine tract (3'PPT), a sequence involved in the reverse transcription mechanism, result in high-level resistance to these compounds. This observation was reinforced by the description of a patient who failed INSTI treatment by selecting mutations in the 3'PPT sequence. METHODS: Sequences of the 3'PPT region were analysed in 30706 treatment-naive patients from the public Los Alamos database belonging to six different subtypes and, in parallel, in 107 patients failing INSTI treatment. RESULTS: The analysis showed that the sequences of patients failing INSTI treatment, in the same way as those of treatment-naive patients, are very well conserved regardless of the presence or absence of resistance mutations in the integrase gene. CONCLUSIONS: This study confirms that the selection of a mutation in the 3'PPT region conferring high-level resistance to INSTIs is a rare event. It would require a particular in vivo context and especially a long enough time to be selected, this exposure time being generally reduced by the rapid change of treatment in the case of virological failure. Larger-scale studies in patients with INSTI treatment failure are needed to determine whether the 3'PPT region can play an important role in vivo in INSTI resistance.

Plasma cystatin C as a marker for estimated glomerular filtration rate assessment in HIV-1-infected patients treated with dolutegravir-based ART.

Objectives: Inhibition of the organic cation transporter-2 renal tubule transporter by dolutegravir leads to serum creatinine increase. Serum cystatin C is a non-organic cation transporter-2-dependent marker, possibly enabling glomerular filtration rate (GFR) estimation under dolutegravir. Our goal was to evaluate the changes in creatinine- and cystatin C-based estimated GFR values before and after dolutegravir initiation. Methods: Creatinine and cystatin measurements were carried out on frozen plasma samples from HIV-1-infected patients, before and after dolutegravir initiation, between October 2016 and March 2017 at Pitié-Salpêtrière Hospital. CKD-EPI equations were used to estimate mean GFR from creatinine and cystatin C values. Variations were analysed by paired t-test. Results: Forty-four patients were included [median age = 48 years (IQR 36-58) and median CD4 count = 592 cells/mm3 (IQR 388-728)], including 6 ART-naive patients and 38 on switch strategies [72% with viral load <50 copies/mL and median ART duration = 13 years (IQR 5-20)]. Before dolutegravir initiation (median time = 41 days), 19 patients (43%) had creatinine-based estimated GFR <90 mL/min/1.73 m2 and 11 (25%) had cystatin C-based estimated GFR <90 mL/min/1.73 m2. After dolutegravir initiation, serum creatinine values significantly increased (+8.6 µmol/L, 95% CI +5.8; +11.4, P < 0.001) and associated estimated GFR significantly decreased (-7.7 mL/min/1.73 m2, 95% CI -10.4; -5.1, P < 0.001). In contrast, there was no significant change in cystatin C value variation and associated estimated GFR. The same results were observed regardless of renal function at baseline. Conclusions: Creatinine values increased after dolutegravir initiation, whereas no change was observed for cystatin C values. Use of cystatin C may enable better understanding of plasma creatinine fluctuations after dolutegravir initiation, particularly in high-risk renal patients.