Point-of-Care Detection of Nonadherence to Antiretroviral Treatment for HIV-1 in Resource-Limited Settings Using Drug Level Testing for Efavirenz, Lopinavir, and Dolutegravir: A Validation and Pharmacokinetic Simulation Study.

BACKGROUND: Virological failure during antiretroviral treatment (ART) may indicate the presence of drug resistance, but may also originate from nonadherence. Qualitative detection of ART components using drug level testing may be used to differentiate between these scenarios. We aimed to validate and implement qualitative point-of-care drug level tests for efavirenz (EFV), lopinavir (LPV), and dolutegravir (DTG) in rural South Africa. METHODS: Qualitative performance of immunoassays for EFV, LPV, and DTG was assessed by calculating limit of detection (LoD), region of uncertainty, and qualitative agreement with a reference test. Minimum duration of nonadherence resulting in a negative drug level test was assessed by simulation of treatment cessation using validated population pharmacokinetic models. RESULTS: LoD was 0.05 mg/L for EFV, 0.06 mg/L for LPV, and 0.02 mg/L for DTG. Region of uncertainty was 0.01-0.06 mg/L for EFV, 0.01-0.07 mg/L for LPV, and 0.01-0.02 mg/L for DTG. Qualitative agreement with reference testing at the LoD in patient samples was 95.2% (79/83) for EFV, 99.3% (140/141) for LPV, and 100% (118/118) for DTG. After simulated treatment cessation, median time to undetectability below LoD was 7 days [interquartile range (IQR) 4-13] for EFV, 30 hours (IQR 24-36) for LPV, and 6 days (IQR 4-7) for DTG. CONCLUSIONS: We demonstrate that qualitative ART drug level testing using immunoassays is feasible in a rural resource-limited setting. Implementation of this technology enables reliable detection of recent nonadherence and may allow for rapid and cost-effective differentiation between patients in need for adherence counseling and patients who require drug resistance testing or alternative treatment.

Assessment of efficacy and safety of FK778 in comparison with standard care in renal transplant recipients with untreated BK nephropathy.

BACKGROUND: BK polyomavirus infection has been reported in 10% to 60% of renal transplant recipients with progression to BK nephropathy (BKN) occurring in 1% to 5% of patients. Graft loss occurs in up to 60% of renal transplant recipients with BKN. Because BK polyomavirus infection is believed, in part, to be a manifestation of overimmunosuppression, the current standard of care involves the reduction of immunosuppressants. This strategy has been associated with clearance of viral load, preservation of renal function, and improvement in graft survival; however, this may come at a risk of rejection. A safe and effective immunosuppressive agent that does not predispose to viral infection is needed in transplantation. METHODS: In a phase 2, proof-of-concept, randomized, open-label, parallel-group, 6-month study in renal transplant patients, FK778 (an investigational immunosuppressant from the malononitrilamides class) was compared with the current standard of care (reduction of immunosuppression) for treatment of newly diagnosed or untreated BKN, which was confirmed by renal biopsy. RESULTS: Demographic characteristics were similar between the two groups, except there were numerically more females in the FK778 group than in the standard care group. Although the treatment with FK778 decreased BK viral load in this study, it was associated with a less favorable rejection profile and renal function and a higher incidence of serious adverse events compared with reduction of immunosuppression. CONCLUSIONS: Data from this study are consistent with the findings of previous studies that found no benefit of drug therapy in the treatment of BKN in kidney transplant recipients.