The aim of the study was to explore how viral resistance and antiretroviral central nervous system (CNS) penetration could impact on cognitive performance of HIV-infected patients.
Methods
We performed a multicentre cross-sectional study enrolling HIV-infected patients undergoing neuropsychological testing, with a previous genotypic resistance test on plasma samples. CNS penetration-effectiveness (CPE) scores and genotypic susceptibility scores (GSS) were calculated for each regimen. A composite score (CPE-GSS) was then constructed. Factors associated with cognitive impairment were investigated by logistic regression analysis.
Results
A total of 215 patients were included. Mean CPE was 7.1 (95% CI 6.9, 7.3) with 206 (95.8%) patients showing a CPE≥6. GSS correction decreased the CPE value in 21.4% (mean 6.5, 95% CI 6.3, 6.7), 26.5% (mean 6.4, 95% CI 6.1, 6.6) and 24.2% (mean 6.4, 95% CI 6.2, 6.6) of subjects using ANRS, HIVDB and REGA rules, respectively. Overall, 66 (30.7%) patients were considered cognitively impaired. No significant association could be demonstrated between CPE and cognitive impairment. However, higher GSS-CPE was associated with a lower risk of cognitive impairment (CPE-GSSANRS odds ratio 0.75, P=0.022; CPE-GSSHIVDB odds ratio 0.77, P=0.038; CPE-GSSREGA odds ratio 0.78, P=0.038). Overall, a cutoff of CPE-GSS≥5 seemed the most discriminatory according to each different interpretation system.
Conclusions
GSS-corrected CPE score showed a better correlation with neurocognitive performance than the standard CPE score. These results suggest that antiretroviral drug susceptibility, besides drug CNS penetration, can play a role in the control of HIV-associated neurocognitive disorders.
References
1.
d'Arminio MonforteA., CinqueP., MocroftA.Changing incidence of central nervous system diseases in the EuroSIDA cohort.Ann Neurol2004; 55: 320–328.
2.
RobertsonK.R., SmurzynskiM., ParsonsT.D.The prevalence and incidence of neurocognitive impairment in the HAART era.AIDS2007; 21: 1915–1921.
3.
SimioniS., CavassiniM., AnnoniJ.M.Cognitive dysfunction in HIV patients despite long-standing suppression of viremia.AIDS2010; 24: 1243–1250.
4.
HeatonR.K., FranklinD.R., EllisR.J.HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors.J Neurovirol2011; 17: 3–16.
5.
Antiretroviral Therapy Cohort Collaboration.Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies.Lancet2008; 372: 293–299.
6.
Ciccarelli N, Fabbiani M, Grima P, et al.Comparison of cognitive performance in HIV or HCV mono-infected and HIV-HCV co-infected patients.Infection2013; 41: 1103–1109.
7.
FabbianiM., CiccarelliN., TanaM.Cardiovascular risk factors and carotid intima-media thickness are associated with lower cognitive performance in HIV-infected patients.HIV Med2013; 14: 136–144.
8.
GrimaP., FabbianiM., CiccarelliN.Increased ophthalmic artery resistance index is associated with cognitive impairment in HIV-infected patients.J Infect2012; 65: 439–446.
9.
LovejoyT.I., SuhrJ.A.The relationship between neuropsychological functioning and HAART adherence in HIV-positive adults: a systematic review.J Behav Med2009; 32: 389–405.
10.
CiccarelliN., FabbianiM., Di GiambenedettoS.Efavirenz associated with cognitive disorders in otherwise asymptomatic HIV-infected patients.Neurology2011; 76: 1403–1409.
11.
LetendreS., Marquie-BeckJ., CapparelliE.Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system.Arch Neurol2008; 65: 65–70.
12.
LetendreS.Central nervous system complications in HIV disease: HIV-associated neurocognitive disorder.Top Antivir Med2011; 19: 137–142.
13.
CysiqueL.A., VaidaF., LetendreS.Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy.Neurology2009; 73: 342–348.
14.
TozziV., BalestraP., SalvatoriM.F.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 Syndr2009; 52: 56–63.
15.
SmurzynskiM., WuK., LetendreS.Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort.AIDS2011; 25: 357–365.
16.
CiccarelliN., FabbianiM., ColafigliM.Revised central nervous system neuropenetration-effectiveness score is associated with cognitive disorders in HIV-infected patients with controlled plasma viraemia.Antivir Ther2013; 18: 153–160.
17.
MarraC.M., ZhaoY., CliffordD.B.Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance.AIDS2009; 23: 1359–1366.
18.
KahouadjiY., DumurgierJ., SellierP.Cognitive function after several years of antiretroviral therapy with stable central nervous system penetration score.HIV Med2013; 14: 311–315.
19.
CanigliaE.C., CainL.E., JusticeA.Antiretroviral penetration into the CNS and incidence of AIDS-defining neurologic conditions.Neurology2014; 83: 134–141.
20.
GarveyL., SurendrakumarV., WinstonA.Low rates of neurocognitive impairment are observed in neuro-asymptomatic HIV-infected subjects on effective antiretroviral therapy.HIV Clin Trials2011; 12: 333–338.
21.
CiccarelliN., FabbianiM., BaldoneroE.Effect of aging and human immunodeficiency virus infection on cognitive abilities.J Am Geriatr Soc2012; 60: 2048–2055.
22.
BartelsC., WegrzynM., WiedlA., AckermannV., EhrenreichH.Practice effects in healthy adults: a longitudinal study on frequent repetitive cognitive testing.BMC Neurosci2010; 11: 118.
23.
AntinoriA., ArendtG., BeckerJ.T.Updated research nosology for HIV-associated neurocognitive disorders.Neurology2007; 69: 1789–1799.
De LucaA., CingolaniA., Di GiambenedettoS.Variable prediction of antiretroviral treatment outcome by different systems for interpreting genotypic human immunodeficiency virus type 1 drug resistance.J Infect Dis2003; 187: 1934–1943.
26.
CysiqueL.A., MaruffP., BrewB.J.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 Neurovirol2004; 10: 350–357.
27.
CysiqueL.A., MaruffP., BrewB.J.Antiretroviral therapy in HIV infection: are neurologically active drugs important?Arch Neurol2004; 61: 1699–1704.
28.
CysiqueL.A., BrewB.J.Prevalence of non-confounded HIV-associated neurocognitive impairment in the context of plasma HIV RNA suppression.J Neurovirol2011; 17: 176–183.
29.
HeatonR.K., CliffordD.B., FranklinD.R.Jr.HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study.Neurology2010; 75: 2087–2096.
30.
BergrothT., EkiciH., GisslénM., HagbergL., SönnerborgA.Difference in drug resistance patterns between minor HIV-1 populations in cerebrospinal fluid and plasma.HIV Med2009; 10: 111–115.
31.
BierhoffM., BoucherC.A., FibrianiA., Ten KateR.W.Ongoing HIV replication in cerebrospinal fluid under successful monotherapy.Antivir Ther2013; 18: 641–643.
