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Central nervous system antiretroviral penetration and cognitive functioning in largely pretreated HIV-infected patients

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Abstract

Prolonged time on effective antiretroviral therapy (ART) should be associated with a low incidence of neurocognitive impairment (NCI). We investigated the rate of NCI in 162 largely pretreated patients with HIV RNA suppression according to CNS antiretroviral drug penetration in comparison with 67 patients on their first ART line. Cognitive performance (Trailmaking A, B, Digit Symbol, Grooved Pegboard; demographically adjusted and converted to Z scores, NPZ4) was evaluated, and CNS penetration effectiveness (CPE) ranks of 1 to 4 were assigned and summed per regimen. After a median of 173.2 months on therapy (1,909.3 patients-year), the rate of NCI was similar in both groups (mean NPZ4, −0.24 vs −0.2). Pretreated patients received regimens with a CPE <7 in a large proportion (30 vs 9 %; p < 0.01). Patients in monotherapy had worse NPZ4 score than patients receiving triple therapy (−0.78 vs −0.18; p = 0.02; effect sizes 1.38), and a lower CPE score was observed in patients with a CD4+ count nadir <200 cells/ml with NCI (6.5 vs 7.3, p = 0.04). In the multivariate model, only the lowest CD4+ count and hepatitis C virus coinfection were associated with NPZ4, whereas CPE <7 showed a trend to association (p = 0.06) probably due to patients on monotherapy (estimate −0.33, p < 0.01). In conclusion, the rate of NCI in largely pretreated patients was similar to that observed in patients on their first regimen, and nadir CD4+ count continue to be critical. CNS drug penetration should be considered in cases of high risk for NCI.

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References

  • Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M et al (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69:1789–1799

    Article  CAS  PubMed  Google Scholar 

  • Antinori A, Giancola ML, Grisetti S, Soldani F, Alba L, Liuzzi G et al (2002) Factors influencing virological response to antiretroviral drugs in cerebrospinal fluid of advanced HIV-1-infected patients. AIDS 16:1867–1876

    Article  CAS  PubMed  Google Scholar 

  • Bhaskaran K, Mussini C, Antinori A, Walker AS, Dorrucci M, Sabin C et al (2008) Changes in the incidence and predictors of human immunodeficiency virus-associated dementia in the era of highly active antiretroviral therapy. Ann Neurol 63:213–221

    Article  PubMed  Google Scholar 

  • Canestri A, Lescure FX, Jaureguiberry S, Moulignier A, Amiel C, Marcelin AG et al (2010) Discordances between cerebrospinal fluid and plasma replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy. Clin Infect Dis 50:773–8. doi:10.1086/650538

    Article  PubMed  Google Scholar 

  • Cysique L, Maruff P, Brew B (2004) Prevalence and pattern of neuropsychological impairment in human immunodeficiency virus infected/acquired immunodeficiency syndrome (HIV/AIDS) patients across pre- and post-highly active antiretroviral therapy eras: a combined study of two cohorts. J Neurovirol 10:350–357

    Article  PubMed  Google Scholar 

  • Cysique LA, Vaida F, Letendre S, Gibson S, Cherner M, Woods SP et al (2009) Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy. Neurology 73:342–348. doi:10.1212/WNL.0b013e3181ab2b3b

    Article  CAS  PubMed  Google Scholar 

  • d’Arminio Monforte A, Cinque P, Mocroft A, Goebel FD, Antunes F, Katlama C et al (2004) Changing incidence of central nervous system diseases in the EuroSIDA cohort. Ann Neurol 55:320–328

    Article  PubMed  Google Scholar 

  • Eggers C, Hertogs K, Sturenburg HJ, van Lunzen J, Stellbrink HJ (2003) Delayed central nervous system virus suppression during highly active antiretroviral therapy is associated with HIV encephalopathy, but not with viral drug resistance or poor central nervous system drug penetration. AIDS 17:1897–1906

    Article  PubMed  Google Scholar 

  • Ellis RJ, Evans SR, Clifford DB, Moo LR, McArthur JC, Collier AC et al (2005) Clinical validation of the NeuroScreen. J Neurovirol 11(6):503–511

    Article  PubMed  Google Scholar 

  • Ellis RJ, Gamst AC, Capparelli E, Spector SA, Hsia K, Wolfson T et al (2000) Cerebrospinal fluid HIV RNA originates from both local CNS and systemic sources. Neurology 54:927–936

    Article  CAS  PubMed  Google Scholar 

  • Ellis RJ, Moore DJ, Childers ME, Letendre S, McCutchan JA, Wolfson T et al (2002) Progression to neuropsychological impairment in human immunodeficiency virus infection predicted by elevated cerebrospinal fluid levels of human immunodeficiency virus RNA. Arch Neurol 59:923–928

    Article  PubMed  Google Scholar 

  • Giancola ML, Lorenzini P, Balestra P, Larussa D, Baldini F, Corpolongo A et al (2006) Neuroactive antiretroviral drugs do not influence neurocognitive performance in less advanced HIV-infected patients responding to highly active antiretroviral therapy. J Acquir Immune Defic Syndr 41:332–337

    Article  PubMed  Google Scholar 

  • Heaton RK, Franklin DR, Ellis RJ, McCutchan JA, Letendre SL, Leblanc S et al (2011) HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol 17:3–16

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Heaton RK, Marcotte TD, Mindt MR, Sadek J, Moore DJ, Bentley H et al (2004) The impact of HIV-associated neuropsychological impairment on everyday functioning. J Int Neuropsychol Soc 10:317–331

    Article  PubMed  Google Scholar 

  • Letendre S (2011) Central nervous system complications in HIV disease: HIV-associated neurocognitive disorder. Top Antivir Med 19:137–42

    PubMed  Google Scholar 

  • Letendre S, McClernon D, Ellis R, et al. (2009). Persistent HIV in the central nervous system during treatment is associated with worse ART penetration and cognitive impairment. [Abstract 484b.] 16th Conference on Retroviruses and Opportunistic Infections (CROI). February 8-11; Montreal, Canada.

  • Perez-Valero I, Arribas JR (2011) Protease inhibitor monotherapy. Curr Op Infect Dis 24:7–11. doi:10.1097/QCO.0b013e3283422cdf

    Article  CAS  Google Scholar 

  • Price RW, Deeks SG (2004) Antiretroviral drug treatment interruption in human immunodeficiency virus infected adults: clinical and pathogenetic implications for the central nervous system. J Neurovirol 10(Suppl 1):44–51

    CAS  PubMed  Google Scholar 

  • Robertson KR, Smurzynski M, Parsons T, Wu K, Bosch R, Wu J et al (2007) The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS 21:1915–1921

    Article  PubMed  Google Scholar 

  • Sacktor N, McDermott M, Marder K, Schifitto G, Selnes OA, McArthur JC et al (2002) HIV-associated cognitive impairment before and after the advent of combination therapy. J Neurovirol 8:136–142

    Article  PubMed  Google Scholar 

  • Simioni S, Cavassini M, Annoni JM, Rimbault Abraham A, Bourquin I, Schiffer V et al (2010) Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS 24:1243–1250. doi:10.1097/QAD.0b013e3283354a7b

    PubMed  Google Scholar 

  • Smurzynski M, Wu K, Letendre S, Robertson K, Bosch RJ, Clifford DB et al (2011) Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort. AIDS 25:357–365. doi:10.1097/QAD.0b013e32834171f8

    Article  PubMed Central  PubMed  Google Scholar 

  • Tamarit MDP, Quereda C, Gonzalez-Rozas M, Corral I, Casado JL (2012) HIV-1 viral encephalitis after development of viral resistance to plasma suppressive antiretroviral therapy. AIDS Res Hum Retroviruses 28:83–86. doi:10.1089/AID.2011.0020

    Article  Google Scholar 

  • Tozzi V, Balestra P, Bellagamba R, Corpolongo A, Salvatori MF, Visco-Comandini U et al (2007) Persistence of neuropsychological deficits despite long-term HAART in patients with HIV-related neurocognitive impairment. Prevalence and risk factors. J Acquir Immune Defic Syndr 45:174–182

    Article  PubMed  Google Scholar 

  • Tozzi V, Balestra P, Murri R, Galgani S, Bellagamba R, Narciso P et al (2004) Neurocognitive impairment influences quality of life in HIV-infected patients receiving HAART. Int J STD AIDS 15:254–259

    Article  CAS  PubMed  Google Scholar 

  • Tozzi V, Balestra P, Salvatori MF, Vlassi C, Liuzzi G, Giancola ML et al (2009) Changes in cognition during antiretroviral therapy: comparison of 2 different ranking systems to measure antiretroviral drug efficacy on HIV-associated neurocognitive disorders. J Acquir Immune Defic Syndr 52:56–63

    Article  CAS  PubMed  Google Scholar 

  • Varatharajan L, Thomas SA (2009) The transport of anti-HIV drugs across blood-CNS interfaces: summary of current knowledge and recommendations for further research. Antiviral Res 82:99–109. doi:10.1016/j.antiviral.2008.12.013

    Article  Google Scholar 

  • Yilmaz A, Svennerholm B, Hagberg L, Gisslen M (2006) Cerebrospinal fluid viral loads reach less than 2 copies/ml in HIV-1-infected patients with effective antiretroviral therapy. Antivir Ther 11:833–837

    CAS  PubMed  Google Scholar 

  • Zigmond AS, Snaith RP (1984) The hospital anxiety and depression scale. Acta Psychiatr Scand 67:361–370

    Article  Google Scholar 

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Acknowledgments

The study was partly supported by an unrestricted and unconditional grant from Janssen Laboratories.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Infectious Diseases, Ramon y Cajal Hospital, Cra. Colmenar km 9.1, 28034, Madrid, Spain

    José L. Casado, Ana Marín, Ana Moreno, Verónica Iglesias, María J. Perez-Elías & Santiago Moreno

  2. Department of Neurology, Ramon y Cajal Hospital, Madrid, Spain

    Iñigo Corral

Authors
  1. José L. Casado
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  2. Ana Marín
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  3. Ana Moreno
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  4. Verónica Iglesias
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  5. María J. Perez-Elías
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  6. Santiago Moreno
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  7. Iñigo Corral
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Correspondence to José L. Casado.

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Casado, J.L., Marín, A., Moreno, A. et al. Central nervous system antiretroviral penetration and cognitive functioning in largely pretreated HIV-infected patients. J. Neurovirol. 20, 54–61 (2014). https://doi.org/10.1007/s13365-013-0228-0

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  • DOI: https://doi.org/10.1007/s13365-013-0228-0

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