Sanjay U. C. Sankatsing

P Glycoprotein in Human Immunodeficiency Virus Type 1 Infection and Therapy

A polymer having a satisfactory balance between in vivo degradability and satisfactory mechanical properties, which is an A BA type polymer comprising a segment A and a segment A each having a modified amino acid and a segment B consisting of polyethylene glycol with a number-average molecular weight of 8000 or higher bonded at one end to the segment A and at the other end to the segment A , and has a number-average molecular weight of 10000 to 600000; an in vivo degradable material which comprises the polymer; and a film for preventing tissue adhesion, an artificial dura mater, a suture, an implant preparation, or a sustained-release drug base each comprising the degradable material.

Analysis of the effect of highly active antiretroviral therapy during acute HIV-1 infection on HIV-specific CD4 T cell functions

Background:It has been reported that antiretroviral therapy (HAART) during acute HIV-1 infection may rescue HIV-1-specific CD4 T cell responses. Objective:To determine the duration of this preserved response by investigating the long-term effects of HAART during acute infection on HIV-specific CD4 T cell function related to possible immune control during subsequent therapy interruption. Methods:A longitudinal analysis followed HIV-specific CD4 T cell reactivity in 17 individuals with well-documented acute HIV-1 infection where five out of 11 HAART-treated patients stopped therapy and six were untreated. Peripheral blood mononuclear cells were stimulated with overlapping peptide pools derived from Gag and Nef. Production of interferon-γ (IFN-γ) and interleukin-2 (IL-2) by CD4 T cells was analysed together with proliferative responses. Results:Absolute numbers, but not percentages, of Gag-specific IFN-γ-, IL-2- or IFN-γ/IL-2-producing CD4 T cells were increased in treated compared with untreated individuals up to 2 years after seroconversion. HAART during acute HIV-1 infection was associated with lower viral load but did not result in increased proliferation of HIV-specific CD4 T cells. One out of five individuals who discontinued therapy showed evidence for immune control. However, patients who failed to control viraemia also had measurable proliferative HIV-specific CD4 T cell responses and preserved numbers of cytokine-producing CD4 T cells. Conclusions:Early HAART during acute HIV-1 infection resulted in higher numbers of HIV-specific IFN-γ- and IL-2-producing CD4 T cells, but this preservation in four out of five patients was not associated with control of viraemia upon treatment interruption.

Highly active antiretroviral therapy with or without mycophenolate mofetil in treatment-naive HIV-1 patients

Objective: To study the effect of mycophenolate mofetil (MMF) on the decay rate of plasma HIV-1 RNA and the latently infected cellular reservoir in treatment-naive patients starting antiretroviral therapy. Design: Randomized trial. Methods: A group of 19 HIV-1 infected patients (9 with a chronic and 10 with a primary infection) starting a triple antiretroviral drug regimen were randomized to a group with or without MMF. Plasma samples for HIV-1 RNA were taken and HLA-DR−CD4+ T cells were co-cultured for HIV-1 isolation. Slopes of plasma HIV-1 RNA and cellular viral load decay were calculated for the first 14 days and the first 24 weeks of treatment, respectively. Results: The median plasma HIV-1 RNA daily decay rate in chronically infected patients was 0.25 log10 copies/ml [interquartile range (IQR), 0.18–0.30] with MMF and 0.28 log10 copies/ml (IQR, 0.22–0.32) without MMF (P = 0.56); in primary infected patients, it was 0.31 log10 copies/ml (IQR, 0.31–0.32) with MMF and 0.32 log10 copies/ml (IQR, 0.26–0.34) without MMF (P = 0.75). The median daily decay rate of latently infected cells was 0.017 and 0.004 infected cells/106 cells in patients with and without MMF, respectively (P = 0.89). The increase in CD4 T cells was comparable between patients with and without MMF. After stopping MMF, there was an increase in the cellular reservoir in six of eight patients. Conclusion: The addition of MMF to a triple class antiretroviral regimen in treatment-naive patients does not significantly increase the plasma HIV-1 RNA decay rate or the decay rate of the latently infected cellular reservoir.

Effect of mycophenolate mofetil on the pharmacokinetics of antiretroviral drugs and on intracellular nucleoside triphosphate pools.

ObjectiveTo study the effect of mycophenolate mofetil therapy on the pharmacokinetic parameters of a number of antiretroviral drugs, on intracellular pools of deoxycytidine triphosphate (dCTP) and deoxyguanosine triphosphate (dGTP), and on intracellular concentrations of the triphosphate of lamivudine (3TCTP).DesignRandomised pharmacokinetic study.ParticipantsNineteen HIV-1-infected patients.MethodsAntiretroviral-naive men starting treatment with didanosine 400mg once daily, lamivudine 150mg twice daily, abacavir 300mg twice daily, indinavir 800mg twice daily, ritonavir 100mg twice daily and nevirapine 200mg twice daily were randomised to a group with or without mycophenolate mofetil 500mg twice daily. After 8 weeks of therapy, the plasma pharmacokinetic profiles of mycophenolic acid (the active metabolite of mycophenolate mofetil), abacavir, indinavir and nevirapine, and triphosphate concentrations (dCTP, dGTP and 3TCTP) in peripheral blood mononuclear cells, were determined.ResultsNine of the 19 patients received mycophenolate mofetil. There was no difference in plasma clearance of indinavir or abacavir between the two groups. The clearance of nevirapine was higher in patients using mycophenolate mofetil (p = 0.04). In 12 patients, of whom five also received mycophenolate mofetil, intracellular triphosphates were measured. There was no significant difference in intracellular dCTP, dGTP or 3TCTP concentrations between the two groups. Conclusion: In this small cohort of patients, mycophenolate mofetil therapy reduced the plasma concentration of nevirapine but had no effect on plasma concentrations of indinavir and abacavir. There were no consistent effects of mycophenolic acid on the intracellular concentrations of dCTP, dGTP or 3TCTP.

Limited penetration of lopinavir into seminal plasma of HIV-1-infected men.

Joep M.A. Lange a,b,c and Jan M. Prins a , a Department of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS, b International Antiviral Therapy Evaluation Center (IATEC), and c Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, the Netherlands; and Department of Clinical Pharmacy, University Medical Center, Nijmegen, the Netherlands.

Mycophenolate mofetil inhibits T-cell proliferation in kidney transplant recipients without lowering intracellular dGTP and GTP.

To study if mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), indeed inhibits T‐cell proliferation in kidney transplant recipients by lowering intracellular deoxyguanosine triphosphate (dGTP) and guanosine triphosphate (GTP) levels. Blood was drawn from 11 kidney transplant recipients. Ex vivo T‐cell proliferation was measured by stimulation with phytohemagglutin (PHA) and anti‐CD3 monoclonal antibody (mAb). Plasma MPA levels and intracellular dGTP and GTP in peripheral blood mononuclear cells were measured. MMF induces a significant decrease in T‐lymphocyte proliferation at all time points (i.e. 24 h, 10 days and 8 weeks) after stimulation with both PHA (P = 0.001, 0.002 and 0.013 respectively) and anti‐CD3 mAb (P = 0.004, 0.004 and 0.005 respectively). There was no significant change in intracellular dGTP (P = 0.31, 0.16 and 0.35) or GTP levels (P = 0.99, 0.32 and 0.49) between baseline and day 1, day 10 or week 8. All MPA levels were above the minimal required concentration for the inhibition of lymphocyte proliferation. MMF inhibits T‐lymphocyte proliferation in kidney transplant recipients without lowering intracellular dGTP or GTP levels. This suggests another mechanism underlying its immunosuppressive capacity.

Prolonged decrease of CD4+ T lymphocytes in HIV-1-infected patients after radiotherapy for a solid tumor

Background:In HIV-negative patients, radiotherapy (RT) decreases CD4+ T-cell counts. We studied the effects of RT in HIV-1 positive patients. Methods:HIV-1 positive patients with a subsequent diagnosis of a solid tumor were selected from the Dutch national observational HIV cohort, Aids Therapy Evaluation in the Netherlands (ATHENA). The patients were grouped according to whether they had received RT or not. Primary endpoint of the study was the time from baseline to reaching CD4 cell counts higher than those at baseline. Kaplan–Meier estimates of the percentage of patients reaching the endpoint were calculated. Results:Ninety patients were included of whom 36 received RT and 54 did not. Median duration of RT was 46 [interquartile range (IQR) 30–63] days. Median first CD4 cell count after stopping RT was 150 (IQR 30–270) × 106/L lower compared with baseline. In 13 of the 36 patients receiving RT, CD4 cell counts recovered to baseline, after a median of 469 (IQR 345–595) days. In 35 of the 54 patients without RT, the CD4 cell count recovered to baseline or higher, after a median of 112 (IQR 42–182) days. After 3 years, in 39% of patients who had RT compared with 71% of patients without RT, CD4 cell counts recovered to baseline or higher (P < 0.0001). In a Cox regression adjusted for potential confounders, RT was associated with a longer (hazard ratio 0.29; 95% confidence interval 0.13 to 0.63) and combination antiretroviral therapy use with a shorter time to return to baseline [hazard ratio 2.46 (95% confidence interval 1.11 to 5.48)]. Conclusions:RT resulted in a significant and prolonged decrease in CD4 cell counts.

The Skin Microbiota in Patients Hospitalized for Cellulitis and Association With Outcome

BACKGROUND The skin microbiota plays a key role in the pathogenesis of several skin diseases, but its role in cellulitis remains unknown. We investigated the skin microbiota in patients with cellulitis, studied whether its analysis could help determine the causative pathogen, and explored whether skin microbiota composition was associated with clinical outcomes. METHODS We prospectively included 58 patients hospitalized for cellulitis. Skin swabs obtained from the lesion sites were compared with swabs from identical sites on the contralateral unaffected limbs and with swabs obtained from 19 age- and sex-matched control subjects without cellulitis. Bacterial profiling of the skin microbiota was performed by interspacer profiling (IS-pro). RESULTS A large interpersonal variation in the skin microbiota composition of patients hospitalized with cellulitis was observed. Firmicutes were the dominant phylum, and Staphylococcus and Streptococcus the dominant genera. In most patients, a strong correlation between the microbiota of the affected lesion and the microbiota of the unaffected, contralateral limb was seen. Overall, the composition of the cellulitis microbiota could not be distinguished from the skin microbiota of controls. No consistent association could be found between traditional culture results and skin microbiota signatures in patients with cellulitis. Lastly, we found that neither microbiota composition nor diversity were associated with clinical parameters and outcomes in patients with cellulitis. CONCLUSIONS In this exploratory study on the skin microbiota in patients hospitalized with cellulitis, we were unable to identify a typical cellulitis microbiota. The diagnostic and prognostic information that could be derived from skin microbiota profiling in this patient cohort was limited. CLINICAL TRIALS REGISTRATION NCT02032654.