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ABSTRACT:Carrier-mediated transport across cell membranes is an important determinant of activity, resistance, and toxicity of chemotherapeutic agents including antiretroviral (ARV) drugs (ARDs). The organic cation transporters (OCTs) 1 and 2 have been implicated in the translocation of different cationic drugs but so far were insufficiently tested for interactions with ARDs. Here, we assessed among cationic drugs commonly used in human immunodeficiency virus (HIV) therapy inhibitors and substrates of OCTs, and analyzed the tissue distribution of OCTs and their expression in lymph nodes (LNs), the primary intracellular target of HIV and ARDs. Inhibitors were identified by measuring the attenuated uptake of the radiolabeled model substrate 1-methyl-4-phenylpyridinium into OCTtransfected human embryonic kidney-293 cells in the presence of ARDs. Substrates were identified by measuring OCT-specific intracellular accumulation using liquid chromatography/tandem mass spectrometry. Inhibitory drugs were (in order of increasing potency): nelfinavir < ritonavir < saquinavir < indinavir < trimethoprim < pentamidine, with consistently lower IC 50 values determined for OCT1. Substrates with highest transport efficacy (V max /K m ) were lamivudine (OCT1, 8 l/mg protein/min; OCT2, 4.4 l/mg protein/min) and zalcitabine (OCT1, 4.1 l/mg protein/min; OCT2, 2.6 l/mg protein/min). Using quantitative real-time polymerase chain reaction, a marked expression level of OCT1 was detected in human samples of liver, ovary, prostate, and testis, and of OCT2 in kidney, colon, heart, skeletal muscle, and testis. Expression of OCTs in LNs was low in HIV-negative control individuals but dramatically increased in HIV-infected persons. These data suggest that drug interactions about the OCTs may be relevant for the ARV therapy, in particular by influencing drug accession to infected tissues and hepatic or renal elimination.

Darunavir AUC and Cmax were substantially decreased in pregnancy for both darunavir/ritonavir regimens. This decrease in exposure did not result in mother-to-child transmission. For antiretroviral-naive patients, who are adherent, take darunavir with food and are not using concomitant medication reducing darunavir concentrations, 800/100 mg of darunavir/ritonavir once daily is adequate in pregnancy. For all other patients 600/100 mg of darunavir/ritonavir twice daily is recommended during pregnancy.

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Summary Hodgkin's disease (HD) is the most common non‐acquired immunodeficiency syndrome (AIDS)‐defining malignancy in human immunodeficiency virus (HIV)‐infected patients. We analysed the outcome of patients with HIV‐associated HD (HIV‐HD) with respect to the use and efficacy of highly active antiretroviral therapy (HAART) and other prognostic factors. To evaluate the effects of several variables on overall survival (OS), Kaplan–Meier statistics and extended Cox regression analysis were performed. Response to HAART was used as a time‐dependent variable and was defined as an increase of >0·1 × 109 CD4 cells/l and/or at least one viral load <500 copies/ml during the first 2 years following diagnosis of HIV‐HD. Fifty‐seven patients with HIV‐HD diagnosed between 1990 and 2002 were included in the study. In the Cox model, the only factors independently associated with OS were HAART response [relative hazard (RH) 0·19; 95% confidence interval (CI) 0·06–0·60], complete remission (RH 0·30, 95% CI 0·13–0·72), and age 45 years (RH 0·23; 95% CI 0·09–0·60). Median survival time in patients without HAART response was 18·6 months, whereas the median survival time in patients with HAART response was not reached (89% OS at 24 months). In this cohort, a significant improvement in survival was found in patients with HIV‐HD who responded to HAART.