@article{KasangKalluvyaMajingeetal.2011,
  author    = {Kasang, Christa and Kalluvya, Samuel and Majinge, Charles and Stich, August and Bodem, Jochen and Kongola, Gilbert and Jacobs, Graeme B. and Mllewa, Mathias and Mildner, Miriam and Hensel, Irina and Horn, Anne and Preiser, Wolfgang and van Zyl, Gert and Klinker, Hartwig and Koutsilieri, Eleni and Rethwilm, Axel and Scheller, Carsten and Weissbrich, Benedikt},
  title     = {HIV drug resistance (HIVDR) in antiretroviral therapy-naive patients in Tanzania not eligible for WHO threshold HIVDR survey is dramatically high},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-69024},
  year      = {2011},
  abstract  = {Background: The World Health Organization (WHO) has recommended guidelines for a HIV drug resistance (HIVDR) survey for resource-limited countries. Eligibility criteria for patients include age below 25 years in order to focus on the prevalence of transmitted HIVDR (tHIVDR) in newly-infected individuals. Most of the participating sites across Africa have so far reported tHIVDR prevalences of below 5\%. In this study we investigated whether the rate of HIVDR in patients ,25 years is representative for HIVDR in the rest of the therapy-naive population. Methods and Findings: HIVDR was determined in 88 sequentially enrolled ART-naive patients from Mwanza, Tanzania (mean age 35.4 years). Twenty patients were aged, 25 years and 68 patients were aged 25-63 years. The frequency of HIVDR in the study population was 14.8\% (95\%; CI 0.072-0.223) and independent of NVP-resistance induced by prevention of mother-to-child transmission programs. Patients .25 years had a significantly higher HIVDR frequency than younger patients (19.1\%; 95\% CI 0.095-0.28) versus 0\%, P = 0.0344). In 2 out of the 16 patients with HIVDR we found traces of antiretrovirals (ARVs) in plasma. Conclusions: ART-naive patients aged over 25 years exhibited significantly higher HIVDR than younger patients. Detection of traces of ARVs in individuals with HIVDR suggests that besides transmission, undisclosed misuse of ARVs may constitute a significant factor in the generation of the observed high HIVDR rate. The current WHO tHIVDR survey that is solely focused on the transmission of HIVDR and that excludes patients over 25 years of age may therefore result in substantial underestimation of the prevalence of HIVDR in the therapy-naive population. Similar studies should be performed also in other areas to test whether the so far reported optimistic picture of low HIVDR prevalence in young individuals is really representative for the rest of the ART-naive HIV-infected population.},
  subject      = {Tansania},
  language  = {en}
}
@article{KasangKalluvyaMajingeetal.2011,
  author    = {Kasang, Christa and Kalluvya, Samuel and Majinge, Charles and Stich, August and Bodem, Jochen and Kongola, Gilbert and Jacobs, Graeme B. and Mlewa, Mathias and Mildner, Miriam and Hensel, Irina and Horn, Anne and Preiser, Wolfgang and van Zyl, Gert and Klinker, Hartwig and Koutsilieri, Eleni and Rethwilm, Axel and Scheller, Carsten and Weissbrich, Benedikt},
  title     = {HIV Drug Resistance (HIVDR) in Antiretroviral Therapy-Na{\"i}ve Patients in Tanzania Not Eligible for WHO Threshold HIVDR Survey Is Dramatically High},
  series = {PLoS One},
  volume    = {6},
  journal   = {PLoS One},
  number    = {8},
  doi       = {10.1371/journal.pone.0023091},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137988},
  pages     = {e23091},
  year      = {2011},
  abstract  = {Background The World Health Organization (WHO) has recommended guidelines for a HIV drug resistance (HIVDR) survey for resource-limited countries. Eligibility criteria for patients include age below 25 years in order to focus on the prevalence of transmitted HIVDR (tHIVDR) in newly-infected individuals. Most of the participating sites across Africa have so far reported tHIVDR prevalences of below 5\%. In this study we investigated whether the rate of HIVDR in patients <25 years is representative for HIVDR in the rest of the therapy-na{\"i}ve population. Methods and Findings HIVDR was determined in 88 sequentially enrolled ART-na{\"i}ve patients from Mwanza, Tanzania (mean age 35.4 years). Twenty patients were aged <25 years and 68 patients were aged 25-63 years. The frequency of HIVDR in the study population was 14.8\% (95\%; CI 0.072-0.223) and independent of NVP-resistance induced by prevention of mother-to-child transmission programs. Patients >25 years had a significantly higher HIVDR frequency than younger patients (19.1\%; 95\% CI 0.095-0.28) versus 0\%, P = 0.0344). In 2 out of the 16 patients with HIVDR we found traces of antiretrovirals (ARVs) in plasma. Conclusions ART-na{\"i}ve patients aged over 25 years exhibited significantly higher HIVDR than younger patients. Detection of traces of ARVs in individuals with HIVDR suggests that besides transmission, undisclosed misuse of ARVs may constitute a significant factor in the generation of the observed high HIVDR rate. The current WHO tHIVDR survey that is solely focused on the transmission of HIVDR and that excludes patients over 25 years of age may therefore result in substantial underestimation of the prevalence of HIVDR in the therapy-na{\"i}ve population. Similar studies should be performed also in other areas to test whether the so far reported optimistic picture of low HIVDR prevalence in young individuals is really representative for the rest of the ART-na{\"i}ve HIV-infected population.},
  language  = {en}
}
@article{KasangKalluvyaMajingeetal.2016,
  author    = {Kasang, Christa and Kalluvya, Samuel and Majinge, Charles and Kongola, Gilbert and Mlewa, Mathias and Massawe, Irene and Kabyemera, Rogatus and Magambo, Kinanga and Ulmer, Albrecht and Klinker, Hartwig and Gschmack, Eva and Horn, Anne and Koutsilieri, Eleni and Preiser, Wolfgang and Hofmann, Daniela and Hain, Johannes and M{\"u}ller, Andreas and D{\"o}lken, Lars and Weissbrich, Benedikt and Rethwilm, Axel and Stich, August and Scheller, Carsten},
  title     = {Effects of Prednisolone on Disease Progression in Antiretroviral-Untreated HIV Infection: A 2-Year Randomized, Double-Blind Placebo-Controlled Clinical Trial},
  series = {PLoS One},
  volume    = {11},
  journal   = {PLoS One},
  number    = {1},
  doi       = {10.1371/journal.pone.0146678},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146479},
  pages     = {e0146678},
  year      = {2016},
  abstract  = {Background HIV-disease progression correlates with immune activation. Here we investigated whether corticosteroid treatment can attenuate HIV disease progression in antiretroviral-untreated patients. Methods Double-blind, placebo-controlled randomized clinical trial including 326 HIV-patients in a resource-limited setting in Tanzania (clinicaltrials.gov NCT01299948). Inclusion criteria were a CD4 count above 300 cells/μl, the absence of AIDS-defining symptoms and an ART-na{\"i}ve therapy status. Study participants received 5 mg prednisolone per day or placebo for 2 years. Primary endpoint was time to progression to an AIDS-defining condition or to a CD4-count below 200 cells/μl. Results No significant change in progression towards the primary endpoint was observed in the intent-to-treat (ITT) analysis (19 cases with prednisolone versus 28 cases with placebo, p = 0.1407). In a per-protocol (PP)-analysis, 13 versus 24 study participants progressed to the primary study endpoint (p = 0.0741). Secondary endpoints: Prednisolone-treatment decreased immune activation (sCD14, suPAR, CD38/HLA-DR/CD8+) and increased CD4-counts (+77.42 ± 5.70 cells/μl compared to -37.42 ± 10.77 cells/μl under placebo, p < 0.0001). Treatment with prednisolone was associated with a 3.2-fold increase in HIV viral load (p < 0.0001). In a post-hoc analysis stratifying for sex, females treated with prednisolone progressed significantly slower to the primary study endpoint than females treated with placebo (ITT-analysis: 11 versus 21 cases, p = 0.0567; PP-analysis: 5 versus 18 cases, p = 0.0051): No changes in disease progression were observed in men. Conclusions This study could not detect any significant effects of prednisolone on disease progression in antiretroviral-untreated HIV infection within the intent-to-treat population. However, significant effects were observed on CD4 counts, immune activation and HIV viral load. This study contributes to a better understanding of the role of immune activation in the pathogenesis of HIV infection.},
  language  = {en}
}
@article{HornSchellerduPlessisetal.2013,
  author    = {Horn, Anne and Scheller, Carsten and du Plessis, Stefan and Arendt, Gabriele and Nolting, Thorsten and Joska, John and Sopper, Sieghart and Maschke, Matthias and Obermann, Mark and Husstedt, Ingo W. and Hain, Johannes and Maponga, Tongai and Riederer, Peter and Koutsilieri, Eleni},
  title     = {Increases in CSF dopamine in HIV patients are due to the dopamine transporter 10/10-repeat allele which is more frequent in HIV-infected individuals},
  series = {Journal of Neural Transmission},
  volume    = {120},
  journal   = {Journal of Neural Transmission},
  doi       = {10.1007/s00702-013-1086-x},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132385},
  pages     = {1411-1419},
  year      = {2013},
  abstract  = {Dysfunction of dopaminergic neurotransmission has been implicated in HIV infection. We showed previously increased dopamine (DA) levels in CSF of therapy-na{\"i}ve HIV patients and an inverse correlation between CSF DA and CD4 counts in the periphery, suggesting adverse effects of high levels of DA on HIV infection. In the current study including a total of 167 HIV-positive and negative donors from Germany and South Africa (SA), we investigated the mechanistic background for the increase of CSF DA in HIV individuals. Interestingly, we found that the DAT 10/10-repeat allele is present more frequently within HIV individuals than in uninfected subjects. Logistic regression analysis adjusted for gender and ethnicity showed an odds ratio for HIV infection in DAT 10/10 allele carriers of 3.93 (95 \% CI 1.72-8.96; p = 0.001, Fishers exact test). 42.6 \% HIV-infected patients harbored the DAT 10/10 allele compared to only 10.5 \% uninfected DAT 10/10 carriers in SA (odds ratio 6.31), whereas 68.1 versus 40.9 \%, respectively, in Germany (odds ratio 3.08). Subjects homozygous for the 10-repeat allele had higher amounts of CSF DA and reduced DAT mRNA expression but similar disease severity compared with those carrying other DAT genotypes. These intriguing and novel findings show the mutual interaction between DA and HIV, suggesting caution in the interpretation of CNS DA alterations in HIV infection solely as a secondary phenomenon to the virus and open the door for larger studies investigating consequences of the DAT functional polymorphism on HIV epidemiology and progression of disease.},
  language  = {en}
}
@phdthesis{Horn2014,
  author    = {Horn, Anne},
  title     = {Die Wirkung von Dopamin und Faktoren der dopaminergen Neurotransmission auf HIV-Infektion und Immunaktivierung: Fokus auf Dopamin-assoziierte Gene},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-107639},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {HIV verursacht eine progressive Zerst{\"o}rung des Immunsystems und f{\"u}hrt zus{\"a}tzlich durch Ver{\"a}nderungen im ZNS zu neurokognitiven St{\"o}rungen (HIV-associated neurocognitive disorders, HAND). Die HIV-Infektion geht mit einer Dysfunktion von dopaminergen Signalwegen einher, die sich unter anderem in einer erh{\"o}hten Dopamin-Verf{\"u}gbarkeit im Liquor von Therapie-naiven HIV-Patienten {\"a}ußert. Der Grund f{\"u}r die Dysregulation der dopaminergen Signalwege in HIV-Patienten ist nicht gekl{\"a}rt. Aufgrund dessen war das Hauptziel dieser Arbeit die Identifizierung des pathogenetischen Mechanismus, der zu einer erh{\"o}hten Dopamin-Konzentration im Liquor von HIV-Patienten f{\"u}hrt. Die prim{\"a}re Hypothese war, dass die erh{\"o}hte Dopamin-Verf{\"u}gbarkeit nicht durch das Virus selbst, sondern vielmehr durch die genetische Konstitution der HIV-Patienten hervorgerufen wird. Deshalb wurden Polymorphismen untersucht, die die dopaminerge Neurotransmission beeinflussen. Es wurde vermutet, dass a) verschiedene Genotypen dieser Polymorphismen in nicht-infizierten und HIV-infizierten Personen mit anderen H{\"a}ufigkeiten auftreten, b) verschiedene Genotypen mit ver{\"a}nderten Dopamin-Verf{\"u}gbarkeiten assoziiert sind, c) unterschiedliche Genotypen Auswirkungen auf Marker der Progression der HIV-Infektion haben und d) verschiedene Genotypen die Immunaktivierung beeinflussen. Dazu wurden in 190 HIV-infizierten und nicht-infizierten Teilnehmern unterschiedlicher Ethnien die Polymorphismen BDNF Val66Met, COMT Val108/158Met, DAT 3'-UTR VNTR, DRD2 TaqIα, DRD3 Ser9Gly und DRD4 VNRT mit PCR, ggf. Restriktionsverdau und Agarose-Gelelektrophorese analysiert und die Expression des Dopamin-Transporters mit real time PCR bestimmt. Dar{\"u}ber hinaus wurden zur weiteren klinischen Charakterisierung die Immunmarker MCP-1, sCD14, suPAR und RANTES mit ELISA analysiert, da eine Erh{\"o}hung dieser Parameter mit einer beschleunigten HIV-Progression assoziiert ist. Die Bestimmung der T-Zell-Aktivierung (CD3/CD8/CD38/HLA-DR) wurde mit einer durchflusszytometrischen Analyse durchgef{\"u}hrt. In dieser Arbeit haben wir gezeigt, dass HIV-Patienten hochsignifikant h{\"a}ufiger homozygot f{\"u}r das 10-repeat Allel des Dopamin-Transporter-Polymorphismus sind als nicht-infizierte Personen (57,1 \% bzw. 26,8 \%, p = 0,001, OR = 3,93, 95 \% CI 1,72 - 8,96, direkte logistische Regression). HIV-Patienten und nicht-infizierte Personen mit diesem Genotyp weisen eine signifikant h{\"o}here Dopamin-Verf{\"u}gbarkeit im Liquor auf als Personen mit dem 9/10-Genotyp (p = 0,03) und eine signifikant geringere Expression des Dopamin-Transporters auf PBMCs (p = 0,05). Der DAT 10/10-Genotyp ist im Gegensatz zu anderen Genotypen in HIV-Patienten jedoch weder mit unterschiedlichen CD4+-Zellzahlen und Viruslasten noch mit einer ver{\"a}nderten H{\"a}ufigkeit von HAND verbunden. Zus{\"a}tzlich weisen deutsche und s{\"u}dafrikanische nicht-infizierte und HIV-infizierte Personen mit dem DAT 10/10-Genotyp eine signifikant h{\"o}here MCP-1-Konzentration im Plasma auf als Personen mit anderen DAT-Genotypen (p = 0,0076). Keiner der Immunmarker ist mit der Dopamin-Verf{\"u}gbarkeit assoziiert. Dennoch ist die Immunaktivierung in s{\"u}dafrikanischen HIV-Patienten im Vergleich zu nicht-infizierten S{\"u}dafrikanern signifikant erh{\"o}ht: HIV-Patienten zeigen im Vergleich zu nicht-infizierten Personen eine st{\"a}rkere T-Zell-Aktivierung (p = 0,0001), eine erh{\"o}hte Plasma-Konzentration von MCP-1 (p = 0,0014), eine gesteigerte sCD14-Konzentration (p = 0,0004) und eine vermehrte suPAR-Konzentration im Plasma (p = 0,006). In der vorliegenden Arbeit konnte kein Nachweis erbracht werden, dass die erh{\"o}hte Immunaktivierung in den s{\"u}dafrikanischen HIV-Patienten durch die Koinfektion mit Echinoccocus oder durch genetische Polymorphismen bei Chemokinen hervorgerufen wird. Eine chronisch erh{\"o}hte Immunaktivierung stellt eine treibende Kraft f{\"u}r die Virusreplikation dar und kann letztendlich zu einer Ersch{\"o}pfung des Immunsystems f{\"u}hren. Der 10/10-Genotyp des DAT VNTR k{\"o}nnte einen Risiko-Faktor f{\"u}r die HIV-Infektion darstellen, da dieser eine erh{\"o}hte Dopamin-Verf{\"u}gbarkeit nach sich zieht. Dopamin aktiviert HIV in chronisch infizierten T-Lymphoblasten und f{\"u}hrt zudem zu einer erh{\"o}hten Expression und Sezernierung von TNF-α, das wiederum die Expression von HIV induziert. Diese Ergebnisse untermauern den Zusammenhang von Dopamin und HIV. Es ist jedoch nicht v{\"o}llig gekl{\"a}rt, ob die erh{\"o}hte Dopamin-Konzentration ausschließlich durch den Genotyp hervorgerufen oder auch durch die HIV-Infektion beg{\"u}nstigt wird.},
  subject      = {Dopamin},
  language  = {de}
}