Quantifying the impact of nevirapine-based prophylaxis strategies to prevent mother-to-child transmission of HIV-1: a combined pharmacokinetic, pharmacodynamic, and viral dynamic analysis to predict clinical outcomes.

Single-dose nevirapine (sd-NVP) and extended NVP prophylaxis are widely used in resource-constrained settings to prevent vertical HIV-1 transmission. We assessed the pharmacokinetics of sd-NVP in 62 HIV-1-positive pregnant Ugandan woman and their newborns who were receiving sd-NVP prophylaxis to prevent mother-to-child HIV-1 transmission. Based on these data, we developed a mathematical model system to quantify the impact of different sd-NVP regimens at delivery and of extended infant NVP prophylaxis (6, 14, 21, 26, 52, 78, and 102 weeks) on the 2-year risk of HIV-1 transmission and development of drug resistance in mothers and their breast-fed infants. Pharmacokinetic parameter estimates and model-predicted HIV-1 transmission rates were very consistent with other studies. Predicted 2-year HIV-1 transmission risks were 35.8% without prophylaxis, 31.6% for newborn sd-NVP, 19.1% for maternal sd-NVP, and 19.7% for maternal/newborn sd-NVP. Maternal sd-NVP reduced newborn infection predominately by transplacental exchange, providing protective NVP concentrations to the newborn at delivery, rather than by maternal viral load reduction. Drug resistance was frequently selected in HIV-1-positive mothers after maternal sd-NVP. Extended newborn NVP prophylaxis further decreased HIV-1 transmission risks, but an overall decline in cost-effectiveness for increasing durations of newborn prophylaxis was indicated. The total number of infections with resistant virus in newborns was not increased by extended newborn NVP prophylaxis. The developed mathematical modeling framework successfully predicted the risk of HIV-1 transmission and resistance development and can be adapted to other drugs/drug combinations to a priori assess their potential in reducing vertical HIV-1 transmission and resistance spread.

In silico cytotoxicity assessment on cultured rat intestinal cells deduced from cellular impedance measurements.

Early and reliable identification of chemical toxicity is of utmost importance. At the same time, reduction of animal testing is paramount. Therefore, methods that improve the interpretability and usability of in vitro assays are essential. xCELLigence's real-time cell analyzer (RTCA) provides a novel, fast and cost effective in vitro method to probe compound toxicity. We developed a simple mathematical framework for the qualitative and quantitative assessment of toxicity for RTCA measurements. Compound toxicity, in terms of its 50% inhibitory concentration IC50 on cell growth, and parameters related to cell turnover were estimated on cultured IEC-6 cells exposed to 10 chemicals at varying concentrations. Our method estimated IC50 values of 113.05, 7.16, 28.69 and 725.15 µM for the apparently toxic compounds 2-acetylamino-fluorene, aflatoxin B1, benzo-[a]-pyrene and chloramphenicol in the tested cell line, in agreement with literature knowledge. IC50 values of all apparent in vivo non-toxic compounds were estimated to be non-toxic by our method. Corresponding estimates from RTCA's in-built model gave false positive (toxicity) predictions in 5/10 cases. Taken together, our proposed method reduces false positive predictions and reliably identifies chemical toxicity based on impedance measurements. The source code for the developed method including instructions is available at https://git.zib.de/bzfgupta/toxfit/tree/master.

Multiscale Systems-Pharmacology Pipeline to Assess the Prophylactic Efficacy of NRTIs Against HIV-1.

While HIV-1 continues to spread, the use of antivirals in preexposure prophylaxis (PrEP) has recently been suggested. Here we present a modular systems pharmacology modeling pipeline, predicting PrEP efficacy of nucleotide reverse transcriptase inhibitors (NRTIs) at the scale of reverse transcription, target-cell, and systemic infection and after repeated viral exposures, akin to clinical trials. We use this pipeline to benchmark the prophylactic efficacy of all currently approved NRTIs in wildtype and mutant viruses. By integrating pharmacokinetic models, we find that intracellular tenofovir-diphosphate builds up too slowly to halt infection when taken "on demand" and that lamivudine may substitute emtricitabine in PrEP combinations. Lastly, we delineate factors confounding clinical PrEP efficacy estimates and provide a method to overcome these. The presented framework is useful to screen and optimize PrEP candidates and strategies and to understand their clinical efficacy by integrating the diverse scales which determine PrEP efficacy.

'Time-to-amphotericin B' in cryptococcal meningitis in a European low-prevalence setting: analysis of diagnostic delays.

BACKGROUND: Cryptococcal meningitis is a rare disease in Europe, resulting in delayed recognition and slower initiation of specific treatment. AIM: To analyse the time-to-treatment and the factors that delay the diagnosis and treatment in the low-prevalence setting of a European centre. DESIGN: Retrospective review METHODS: We reviewed full medical records of all adult patients with cryptococcal meningitis referred to an HIV centre in Berlin, Germany in 10-year period between 1st of October 2003 and 31st of September 2013. Multivariant statistics with bootstrap-resampling were performed. RESULTS: We identified 19 patients with a diagnosis of HIV-related cryptococcal meningitis (0.55% of all consecutive HIV-infected patients). In almost half of our patients the diagnosis was not considered initially on admission to the secondary care centre and the first diagnostic clue being an accidental positive blood, cerebrospinal fluid or bronchoalveolar lavage culture growing Cryptococcus neoformans. The median time-to-treatment was 5 days (range: 1-16). Known positive HIV status accelerated the time-to-diagnosis (p < 0.05) by a median of 1.89 days, whereas the CSF cell count ≤ 10/µl delayed diagnosis by a median time of 1.93 days (p < 0.1). CONCLUSIONS: Diagnostic delays could be avoided by encouraging practising physicians (i) to consider cryptococcal meningitis in immunosuppressed HIV-infected patients irrespective of neurological symptoms; (ii) to test for India ink, cryptococcal antigen and fungal cultures in immunosuppressed HIV-infected patients with normal CSF; (iii) to consider a possibility of underlying HIV infection in patients with unknown HIV status presenting with meningitis; and (iv) to consider early targeted HIV testing in persons at risk according to locally validated criteria.