Nervenheilkunde 2011; 30(05): 341-344
DOI: 10.1055/s-0038-1627815
Originalarbeit
Schattauer GmbH

Die hochaktive antiretrovirale Therapie

Nebenwirkungen auf kognitive Funktionen während der HIV-InfektionHighly active antiretroviral therapySide effects on neurocognitive function during HIV-infection
B. Hudelmaier
1   Klinik und Poliklinik für Neurologie, Universitätsklinikum Münster
,
D. Reichelt
2   Medizinische Klinik und Poliklinik D, Universitätsklinikum Münster
,
U. Oelker-Grueneberg
2   Medizinische Klinik und Poliklinik D, Universitätsklinikum Münster
,
N. Gregor
1   Klinik und Poliklinik für Neurologie, Universitätsklinikum Münster
,
I. W. Husstedt
1   Klinik und Poliklinik für Neurologie, Universitätsklinikum Münster
› Author Affiliations
Further Information

Publication History

Eingegangen am: 23 June 2010

angenommen am: 02 July 2010

Publication Date:
23 January 2018 (online)

Zusammenfassung

Nebenwirkungen der hochaktiven antiretroviralen Therapie (HAART) zur Behandlung der HIV-Infektion werden insbesondere als Polyneuropathie klinisch manifest. Die Substanzen ddI, ddC und d4T gelten als besonders neurotoxisch. Es wurden ereigniskorrelierte Potenziale (EKP) von Patienten, die HAART mit ddI, ddC oder d4T erhielten, analysiert und mit einer Kontrollgruppe gleichen Stadiums ohne diese Substanzen verglichen. In der Gruppe mit ddI, ddC oder d4T waren mehr Patienten, die unter einer HIV-assoziierten neurokognitiven Störung oder distalsymmetrischen Polyneuropathie litten (p ≥ 0,01). Patienten unter der Therapie mit ddI, ddC oder d4T wiesen eine signifikante Verlängerung der Komponente P3 der EKP (p ≥ 0,02) auf. In Übereinstimmung mit der Literatur weisen diese Ergebnisse darauf hin, dass unter der Therapie mit ddI, ddC und d4T zusätzlich kognitive Beeinträchtigungen hervorgerufen werden. Möglicherweise liegt diesen Veränderungen eine Auswirkung von ddI, ddC und d4T auf die Funktion der Mitochondrien im ZNS zugrunde.

Summary

The highly active antiretroviral therapy (HAART) can cause peripheral neuropathy. In this study, the impact of specific substances of HAART on neurocognitive function during HIV infection was measured. Event-related potentials (ERP) from patients receiving (HAART) with ddI, ddC, or d4T were compared to a control group without any of these three substances. More patients suffering from neurocognitive disorders and peripheral neuropathy were found in the patients receiving ddI, ddC, or d4T (p ≥ 0.01). Patients treated with ddI, ddC, or d4T showed a significant increase of the latency of the P3 component (p ≥ 0.02). In accordance to the literature, these results indicate that ddI, ddC, and d4T represent an additional factor in the development of HIV associated neurocognitive disorder besides the HIV infection itself. It is assumed that these alterations are induced by the toxic impact of ddI, ddC and d4T on γ-polymerase of the mitochondrias in the central nervous system.

 
  • Literatur

  • 1 Antinori A. et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007; 69: 1789-1799.
  • 2 Arendt G. et al. Intrathecal virus replication and cerebral deficits in different stages of of human immunodeficiency virus disease. J Neurovirol 2007; 13: 225-232.
  • 3 Aquaro S. et al. HIV-1-associated dementia during HAART therapy. Recent Path CNS Drug Discov 2008; 03: 23-33.
  • 4 Arezzo JC. Dideoxycytidine and other nucleoside analogs. In: Spencer PS, Schaumburg HH, Ludolph AC. (eds). Experimental and clinical neurotoxicology. 2nd ed.. Oxford: University Press Oxford; 2000
  • 5 Cohen RA. et al. Neurocognitive performance enhanced by highly active antiretroviral therapy in HIV infected women. AIDS 2001; 15: 341-345.
  • 6 Cote H. et al. Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. N Engl J Med 2002; 346: 811-820.
  • 7 Deutsch R. et al. Aids associated mild cognitive impairment is delayed in the era of highly active antiretroviral therapy. AIDS 2001; 15: 1898-1899.
  • 8 Dore GJ. et al. Changes to AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS 1999; 13: 1249-1253.
  • 9 Dore G. et al. National HIV Surveillance Committee. Marked improvement in survival following AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS 2003; 17: 1539-1545.
  • 10 Evers S. et al. Prevention of AIDS dementia by HAART does not depend on cerebrospinal fluid drug penetrance. AIDS Res Hum Retroviruses 2004; 05: 483-491.
  • 11 Evers S. et al. Impact of antiretroviral treatment on AIDS dementia: A long prospective event-related potential study. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 17: 143-148.
  • 12 Fein G, Biggins CA, MacKay S. Delayed latency of the event-related brain potentials P3a component in HIV disease. Arch Neurol 1995; 52: 1109-1118.
  • 13 Goodwin GM, Chiswick A, Egan V, St Clair D. The Brittle Prather Edinburgh cohort of HIV positive drug users. Auditory event related potentials show progressive slowing in patients with CDC stage IV disease. AIDS 1990; 04: 1243-1250.
  • 14 Grant S, Sacktor N, McArthur J. HIV neurocognitive disorders. In: Grant S, Everall IP, Lipton SA, Swindells S. (eds). The neurology of Aids. 2nd ed.. Oxford: University Press Oxford; 2005
  • 15 Grotemeyer KH. et al. Event-related potentials in HIV infected outpatients. AIDS Res Hum Retroviruses 1991; 07: 629-635.
  • 16 Hahn K, Husstedt IW. Arendt G für die Deutsche Neuro-AIDS-Arbeitsgemeinschaft (DNAA). HIVassoziierte Neuropathien. Nervenarzt 2010; 81: 409-417.
  • 17 Hofstede HJM, Burger DM, Koopmans PP. Antiretroviral therapy in HIV patients: Aspects of metabolic complications and mitochondria toxicity. Neth J Med 2003; 61: 393-403.
  • 18 Husstedt IW. et al. Impact of highly active antiretroviral therapy on cognitive processing in HIV infection: Cross- sectional and longitudinal studies on event-related potentials. AIDS Res Hum Retroviruses 2002; 18: 485-490.
  • 19 Husstedt IW. et al. Neurotoxicity and side-effects of highly active antiretroviral therapy [HAART] on the central and peripheral nerve system. Anti-Inflam Anti-Allergy Agents Med Chem 2009; 08: 192-201.
  • 20 Jellinger KA. et al. Neuropathology and general autopsy findings in AIDS during the last 15 years. Acta Neuropathol 2000; 100: 213-220.
  • 21 Johnson AA. et al. Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase. J Biol Chem 2001; 276: 40847-40857.
  • 22 Keilbaugh SA, Prusoff WH, Simpson MV. The PC12 cell as a model for studies of the mechanism of induction of peripheral neuropathy by anti-HIV-1 dideoxynucleoside analogs. Biochem Pharmacol 1991; 42: 5-8.
  • 23 Keswani SC, Leitz GJ, Hoke A. Erythropoietin is neuroprotective in models of HIV sensory neuropathy. Neurosci Lett 2004; 371: 102-105.
  • 24 Keswani SC. et al. HIV associated sensory neuropathies. AIDS 2002; 16: 2105-2117.
  • 25 Lee H, Hanes J, Johnson KA. Toxicity of antiviral nucleoside analogues used to treat AIDS and the selectivity of the mitochondrial DNA polymerase. Biochemistry 2003; 42: 14711-14719.
  • 26 Lewis W. et al. Antiretroviral nucleosides, deoxynucleoside carrier and mitochondrial DNA: evidence supporting the DNA pol g hypothesis. AIDS 2006; 20: 675-684.
  • 27 Luciano CA, Pardo CA, McArthur JC. Recent developments in the HIV neuropathies. Cur Opinion in Neurol 2003; 16: 403-409.
  • 28 McArthur JC, Brew JB, Nath A. Neurological complications of HIV infection. Lancet Neurol 2005; 04: 543-555.
  • 29 McArthur JC. et al. Human immunodeficiency virus-associated dementia: an evolving disease. J Neurovirol 2003; 09: 205-221.
  • 30 Medina DJ, Tsai CH, Hsiung GD. Comparison of mitochondrial morphology, mitochondrial DNA content and cell viability in cultured cells treated with three anti-human immunodeficiency virus dideoxynucleosides. Antimicro Agents Chemother 1994; 18: 1824-1828.
  • 31 Moore RD, Wong WM, Keruly JC, McArthur JC. Incidence of neuropathy in HIV-infected patients on monotherapy versus those on combination therapy with didanosine, stavudine and hydroxyurea. AIDS 2000; 14: 273-278.
  • 32 Poirier M. et al. Long-term mitochondrial toxicity in HIV-uninfected infants born to HIV-infected mothers. J AIDS 2003; 33: 175-183.
  • 33 Ribera E. et al. Improvements in subcutaneous fat, lipid profile, and parameters of mitochondrial toxicity in patients with peripheral lipoatrophy when stavuduine is switched to tenofovir (lipotest study). HIV Clin Trials 2008; 09: 407-417.
  • 34 Sacktor N. The epidemiology of human immunodeficiency virus associated disease in the era of highly active antiretroviral therapy. J Neurovirol 2002; 08 (Suppl. 02) 115-121.
  • 35 Schweinsburg BC, Taylor MJ, Alhassoon OM. Brain mitochondrial injury in human immunodeficiency virus-seropositive (HIV+) individuals taking nucleoside reverse transcriptase inhibitors. J Neurovirol 2005; 11: 356-364.
  • 36 Stankoff B, Tourbah A, Suarez S. Clinical and spectroscopic improvement in HIV- associated cognitive impairment. Neurology 2001; 56: 112-115.