Maraviroc in treatment-experienced patients with HIV-1 infection - experience from routine clinical practice

<p>Abstract</p> <p>Objective</p> <p>Few data are available about the efficacy of maraviroc (MVC) during routine use. We characterized indications for MVC use and the efficacy of MVC in clinical practice.</p> <p>Methods</p> <p>Thirty-two patients treated with MVC at our institution between 2006 and 2009 were included. Genotypic (n = 31) and phenotypic (n = 13) tropism analysis was performed. We determined indications for MVC use, characteristics of antiretroviral combination partners and treatment outcome.</p> <p>Results</p> <p>Complete suppression of viral replication was achieved in 78% after 6 months. A median increase of 124 CD4⁺cells/μl after 6 months was observed. Concordance between phenotypic and genotypic tropism was found in 75%. Indications for MVC treatment included treatment failure (n = 15), intolerance to previous antiretrovirals (n = 6) and add-on MVC for intensification without changing the current regimen (n = 11). The add-on strategy was used in patients with a relatively low viremia in order to achieve complete viral load suppression or in situations with suppressed viral load but judged as unstable due to an extensive resistance pattern. Salvage drugs most frequently combined with MVC were darunavir (n = 14) and raltegravir (n = 14).</p> <p>The genotypic assay had predicted CXCR4 tropism in 5 patients, using a false positive rate (FPR) of 20%. Lowering the FPR to 5% predicted CCR5 tropism in 4 cases, still resulting in sustained complete viral response under MVC use.</p> <p>Conclusions</p> <p>MVC containing salvage regimens achieve relevant CD4 cell increases and high viral response rates. In patients with few remaining treatment options it may be justified to lower the FPR-cutoff to 5% when predicting the coreceptor usage. Hereby, MVC could still be applied in selected patients with otherwise limited treatment options.</p

A Mesoarchean Large Igneous Province on the Eastern Kaapvaal Craton (Southern Africa) Confirmed by Metavolcanic Rocks from Kubuta, Eswatini

Mesoarchean magmatism is widespread on the eastern margin of the Kaapvaal Craton, but its origin is still poorly understood, mainly because geochemical data is rare. To shed some light on the source of this Mesoarchean magmatism and to relate different Mesoarchean volcanic sequences to each other, we provide major and trace element data as well as Hf-Nd isotope compositions of amphibolites sampled close to the Kubuta Ranch in south-central Eswatini. These amphibolites, so far, were of unknown correlation to any volcanic sequence in Eswatini or South Africa. Hence, the aim of our study is to characterize the mantle source composition of these volcanic rocks and, furthermore, to constrain their genetic relation to other volcanic sequences in Eswatini and South Africa. Our findings reveal that, based on coherent trace element patterns and similar Nd isotope characteristics, the Kubuta volcanic rocks can be genetically linked to the ca. 3.0 Ga Usushwana Igneous Complex in West-Central Eswatini and the ca. 2.9 Ga Hlagothi Complex located in the KwaZulu-Natal province. In contrast, the coeval ca. 3.0 Ga Nsuze and ca. 2.9 Ga Mozaan Groups (Pongola Supergroup) of south-central Eswatini and northern KwaZulu-Natal province have slightly enriched compositions compared to the newly sampled Kubuta volcanic rocks. Our results suggest that the Nsuze and Mozaan Groups were sourced from a primitive mantle reservoir, whereas the Usushwana, Hlagothi, and Kubuta mafic rocks were derived by melting of a more depleted mantle source comparable to that of modern depleted MORB. Furthermore, our assimilation-fractional crystallization (AFC) calculations and Nd isotope constraints reveal that some samples were contaminated by the crust and that the crustal contaminants possibly represent felsic rocks related to the ca. 3.5 Ga crust-forming event in the Ancient Gneiss Complex. Alternatively, melting of a metasomatized mantle or plume-lithospheric mantle interaction may also produce the trace element and isotopic compositions observed in the samples. From a synthesis of our geochemical observations and age data from the literature, we propose a refined petrogenetic model, for a continental flood basalt setting in a Mesoarchean large igneous province on the eastern Kaapvaal Craton. Our petrogenetic model envisages two magma pulses sourced from a primitive mantle reservoir that led to the formation of the Nsuze (first) and Mozaan (second) lavas. Conductive heating of ambient depleted mantle by the mantle plumes caused partial melting that led to the formation of the Usushwana Igneous Complex associated with the first magmatic event (Nsuze) and the Hlagothi Igneous Complex associated with the second magmatic event (Mozaan). However, due to lacking age data of sufficient resolution, it is not possible to affiliate the Kubuta lavas to either the first or the second magmatic event

Reappearance of Minority K103N HIV-1 Variants after Interruption of ART Initiated during Primary HIV-1 Infection

BACKGROUND: In the Zurich Primary HIV infection study (ZPHI), minority drug-resistant HIV-1 variants were detected in some acutely HIV-1-infected patients prior to initiation of early antiretroviral therapy (ART). Here, we investigated the reappearance of minority K103N and M184V HIV-1 variants in these patients who interrupted efficient early ART after 8-27 months according to the study protocol. These mutations are key mutations conferring drug resistance to reverse transcriptase inhibitors and they belong to the most commonly transmitted drug resistance mutations. METHODOLOGY/PRINCIPAL FINDINGS: Early ART was offered to acutely HIV-1-infected patients enrolled in the longitudinal prospective ZPHI study. Six patients harboring and eleven patients not harboring drug-resistant viruses at low frequencies prior to ART were included in this substudy. Minority K103N and M184V HIV-1 variants were quantified in longitudinal plasma samples after treatment interruption by allele-specific real-time PCR. All 17 patients were infected with HIV-1 subtype B between 04/2003 and 09/2005 and received LPV/r+AZT+3TC during primary HIV-1 infection (PHI). Minority K103N HIV-1 variants reappeared after cessation of ART in two of four patients harboring this variant during PHI and even persisted in one of those patients at frequencies similar to the frequency observed prior to ART (<1%). The K103N mutation did not appear during treatment interruption in any other patient. Minority M184V HIV-1 variants were detected in two patients after ART interruption, one harboring and one not harboring these variants prior to ART. CONCLUSION: Minority K103N HIV-1 variants, present in acutely HIV-1 infected patients prior to early ART, can reappear and persist after interruption of suppressive ART containing two nucleoside/nucleotide analogue reverse transcriptase inhibitors and a ritonavir-boosted protease inhibitor. TRIAL REGISTRATION: Clinicaltrials.gov NCT00537966

Well-being and side effects in a tDCS-supported verbal recognition task. The older, the better tolerated?

Balduin LS, Weiss S, Müller HM. Well-being and side effects in a tDCS-supported verbal recognition task. The older, the better tolerated? Presented at the IMPRS Conference 2018, Nijmegen

Speeding up recognition: Effects of tDCS on the dominant hand in a verbal memory task

Balduin LS, Weiss S, Müller HM. Speeding up recognition: Effects of tDCS on the dominant hand in a verbal memory task. 7th IMPRS NeuroCom Summer School, London. 2017;7:40-41

tDCS and semantic processing: speeding up word recognition in older adults with verbal memory difficulties

Balduin LS, Weiss S, Müller HM. tDCS and semantic processing: speeding up word recognition in older adults with verbal memory difficulties. Presented at the The 13th CME International Conference on Complex Medical Engineering, Dortmund

Individual transcranial alternating current stimulation (tACS) within the beta range during verbal working memory

Weiss S, Balduin LS, Müller HM. Individual transcranial alternating current stimulation (tACS) within the beta range during verbal working memory. Clinical Neurophysiology. 2016;128(3):e106

tDCS in a verbal recognition task. Boosting older participants’ word recognition time

Balduin LS, Weiss S, Müller HM. tDCS in a verbal recognition task. Boosting older participants’ word recognition time. Presented at the Neuroscience 2018. SfN's 48th annual meeting, San Diego