Neurocognition and HIV

HIV Australia | Vol. 11 No. 2 | July 2013

Rebekah Puls provides an overview of research into the impact of various antiretroviral regimes on cognitive function for people with HIV.

Over the past 20 years, developments in combination antiretroviral therapy (ART) have been associated with great improvements in life expectancy and quality.¹

However, as people living with HIV age, managing other comorbidities has become an increasing priority, and HIV-associated cognitive impairment is one such challenge.²

Cognitive impairment is graded by severity; severe HIV-related dementia (HAD) has been less frequently observed in the past few years³ and milder forms of neurocognitive impairment are increasingly identified.

Mild neurocognitive disorder is associated with some interference with daily living activities and asymptomatic neurocognitive impairment that is only able to be identified on clinical testing of neurocognitive function.⁴

Impairment in neurocognitive function has previously been linked to reduced quality of life,⁵ poor compliance with ART⁶ and increased progression of disease.⁷

There are a number of factors that have been associated with the development of neurocognitive impairment.

The first of these is age; those of more advanced years are more likely to experience some impairment of cognition.⁸

It has also been reported that those with more advanced HIV disease (especially if not on ART) are more likely to experience some degree of impaired cognitive function that has been linked to inflammation due to the virus itself.⁹

Recently, patients with current risk for cardiovascular disease and also those who have experienced past acute cardiovascular events such as congestive heart failure or myocardial infarction have been associated with worsening of neurocognitive function.¹⁰

It was suggested that neurocognitive dysfunction may emerge as a result of earlier inflammatory damage to the brain due to a combination of HIV, cardiovascular disease and age. In addition, co-infection with other chronic viral infections such as hepatitis C can significantly worsen neurocognitive function.¹¹

Although cognition generally improves on commencement of ART, it has also been suggested that different antiretroviral drugs may have differing effects on these changes.

It is thought that antiretroviral therapy with better penetration into the brain and central nervous system may better suppress the virus in these compartments and therefore be associated with lower impairment of neurocognition.

However, as these medications can enter the central nervous system (CNS) readily, they may also readily exert their known toxicities, therefore potentially limiting any expected benefits.

The Altair CNS sub-study

The Altair CNS sub-study was the first prospective study describing changes in cerebral function between different randomised treatment regimens over one year in HIV-infected adults starting combination antiretroviral therapy for the first time.¹²

The study evaluated various common treatment regimens: quadruple NtRTIs (abacavir [ABC] plus zidovudine [ZDV]) compared to efavirenz (EFV) and ritonavir-boosted atazanavir (r/ATV) with Truvada™ (fixed dose tenofovir/ emtricitabine [TDF/FTC]) in a randomised, open-label, clinical trial that recruited treatment-naive adult HIV-positive patients in 15 countries across Australia, Asia, Europe, North and Latin America.¹³

Eligible participants in the main study were ART-naive, with CD4+ T-cell count greater than 50 cells/μL and plasma HIV-1 RNA greater than 2,000 copies/ mL.

Volunteers were excluded if they had laboratory safety values consistent with poor health, were pregnant or were positive to HLA B57*01 (i.e., not able to take ABC), or had any genotypic resistance or significant intercurrent illness.

There were additional exclusions for the CNS substudy that included current or recent use of antidepressant/antipsychotic medication, current or recent alcohol or recreational drug dependence, recent head injury, established dementia, untreated early syphilis, hepatitis C virus, established chronic liver disease, cirrhosis or hepatic encephalopathy.

All of these criteria have been shown to independently cause some degree of cognitive impairment.

Testing for neurocognitive impairment

A wide variety of neuropsychological tests are available to test neurocognitive impairment, most of which were first developed for other neurodegenerative disease states such as Alzheimer’s disease and dementia.

Assessment of cerebral function was conducted using the CogState™ testing platform – a computerised battery of tests based on standard neuropsychological and experimental psychological tests and has been validated for use in HIVpositive people.¹⁴

The CogState™ tests are card games, thereby minimising language and cultural limitations. Brief instructions were translated into the local language.

All participants had one practice test to reduce any learning effect. Three domains were examined: speed domains to test detection, identification, monitoring/matched learning; accuracy domains that investigated associate learning/working memory; and the executive function domain.

Executive functions are higher order cognitive processes that regulate, control, and manage other cognitive processes; planning, anticipating outcomes and adapting to situations. These domains were specifically developed to identify the presence or absence of cognitive change.

Data were analysed using the methodology supplied and recommended by CogState™.

The Altair CNS sub-study was the first study to prospectively describe different changes in cerebral function testing parameters between participants randomised to different initial therapies for HIV.

Greater improvements in neuronal recovery were observed for recipients of TDF/FTC plus EFV and greater improvements in neurocognitive function testing were observed for recipients of TDF/FTC plus ZDV/ ABC.

However, the dynamics of such improvements are poorly understood, so we conducted research which aimed to assess the dynamics of the changes in neurocognitive function over 48 weeks.

A total of 28 participants consented to participate at four study sites in Bangkok (Thailand), Alberta (Canada), London (UK) and Hong Kong (China).

Study participants were randomised to one of three first line antiretroviral treatment combinations: nine participants were randomised to EFV/ TDF/FTC, eight to r/ATV/TDF/ FTC and 11 to ABC/ZDV/TDF/ FTC.¹⁵ CogState™ was conducted at baseline, weeks 24 and 48 to assess changes in neurocognitive function.

Participants were on average 35 years, with 230 CD4+ T-cells and plasma HIV-RNA virus load of 4.6 log 10 copies/mL; 17 (60%) were Asian.

Global composite scores

Cognitive improvement among the study cohort was expressed as an overall ‘global composite score’.

Study results reflected improvement in study participants by week 24, which was maintained at week 48.

These findings were consistent across all the randomised treatment combinations used in the study and a similar pattern of improvement had been seen in other neurocognitive research conducted by Cysique and colleagues.¹⁶

These improvements may be due in part to control of HIV viremia in the brain after commencing ART and/or partial recovery from cerebral injury in chronic HIV inflammation.

Composite speed scores

For the speed score, a reduction in score represents an increase in speed (a faster reaction time). and therefore an improved response. For the overall group, the composite speed z-scores (a system of standardised scoring) were reduced at week 24, continuing to week 48.

Participants randomised to the combination of EFV/TDF/FTC showed significantly less improvement of their speed score over 48 weeks, compared to participants on the other two arms. EFV has common CNS side effects including depression, anxiety.¹⁷

A recent cohort study found increased risk of neurocognitive impairment with EFV use.¹⁸ This finding may indicate that sub-clinical neuropsychiatric effects of the ART were blunting the expected recovery from HIV-associated neurological damage when ART was commenced.

Executive function

‘Executive function’ describes highlevel cognitive abilities that regulate other abilities and behaviours, including the ability to monitor and change behaviour, and to anticipate and plan for future events.

In our study, improvements in executive function became apparent only by week 48.

Executive function may take time to recover, as it is thought that these complex processes are impaired during chronic HIV infection (resulting from widespread structural and chemical changes – known as synaptodendritic injury – to areas of the frontal cortex). There was no difference for each of the study arms.

Conclusion

The study found there were overall improvements in neurocognitive function in neurologically asymptomatic, HIV-positive patients commencing combination antiretroviral therapy for the first time.

This improvement occurred predominately within the first 24 weeks and either continued to improve or stabilised to 48 weeks on study therapy.

Improvements were less marked in those randomised to EFV, although the difference was only statistically meaningful in the speed domains.

Therefore, the choice of initial combination antiretroviral therapy regimen may lead to temporal different effects on neurocognitive function over a 48 week period.

As people living with HIV continue to age, and quality of life for those living long and prosperous lives becomes more important, there has been a surge in attention to neurocognitive health.

The observations described may assist in the design and development of future treatment and research programs assessing and monitoring changes in cerebral function over time in people living with HIV.

Further work to continue to monitor neurocognitive function over longer periods of therapy is needed.

Antiretroviral drugs glossary
TDF tenofovir
FTC emtricitabine
ABC abacavir
ZDV zidovudine
r/ATV ritonavir-boosted atazanavir
TDF/FTC fixed dose tenofovir/emtricitabine

References

1 Antiretroviral Therapy Cohort Collaboration. (2008). Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet, 372, 293–9.

2 Brew, B., Crowe, S., Landay, A., Cysique, L., Guillemin, G. (2009). Neurodegeneration and ageing in the HAART era. J Neuroimmune Pharmacol, 4(2), 163–174. DOI:10.1007/s11481-008-9143-1

3 Dore G., Correll P., Li, Y., Kaldor, J., Cooper, D., Brew, B. (1999). Changes to AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS 13(10),1249–1253.

4 Antinori, A., Arendt, G., Becker, J., Brew, B., Byrd, D., Cherner, M., et al. (2007). Updated research nosology for HIVassociated neurocognitive disorders. Neurology 69(18), 1789–99.

5 T ozzi, V., Balestra, P., Galgani, S., Murri, R., Bellagamba, R., Narciso, P., et al. (2003). Neurocognitive performance and quality of life in patients with HIV infection. AIDS Res Hum Retroviruses 19(8), 643–652.

6 Ettenhofer M., Hinkin, C., Castellon, S., Durvasula, R., , Ullman, J., Lam, M., et al. (2009). Aging, neurocognition and medication adherence in HIV infection. Am J Geriatr Psychiatry 17(4), 281–290.

7 Tozzi, V., Balestra, P., Serraino, D., Bellagamba, R., Corpolongo, A., Piselli, P., et al. (2005). Neurocognitive impairment and survival in a cohort of HIV-infected patients treated with HAART. AIDS Res Hum Retroviruses 21(8), 706–13.

8 Jevtovi, D., Vanovac, V., Veselinovi, M., Salemovi, D., Ranin, J., Stefanova, E. (2009). The incidence of and risk factors for HIV-associated cognitive-motor complex among patients on HAART. Biomed Pharmacotherapy, 63(8), 561–565. DOI:10.1016/j.biopha.2008.09.015

9 Robertson, K., 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(14), 1915–1921.

10 Cysique L., Moffat K., Moore, D., Lane, T., Davies, N., Carr, A., et al. (2013). HIV, vascular and aging injuries in the brain of clinically stable HIV-infected adults: A 1H MRS Study. PLoS One, 8(4), e61738. DOI:10.1371/journal.pone.0061738

11 Parsons, T., Tucker, K., Hall, C., Robertson, W., Eron, J., Fried M., et al. (2006). Neurocognitive functioning and HAART in HIV and hepatitis C virus coinfection. AIDS, 20(12), 1591–1595.

12 Winston, A., Duncombe, C., Li, P.C.K., Gill, J., Kerr, S., Puls, R., et al. (2010). Does choice of combination antiretroviral therapy (cART) alter changes in cerebral function testing after 48 weeks in treatment-naive, HIV-1-infected individuals commencing cART? A randomized, controlled study. Clin Infect Dis, 50:920–9.

13 Puls, R., Srasuebkul, P., Petoumenos, K., Boesecke, C., Duncombe, C., Belloso, W., et al. (2010). Efavirenz versus boosted atazanavir or zidovudine and abacavir in antiretroviral treatment-naive, HIV-infected subjects: week 48 data from the Altair study. Clin Infect Dis, 51(7), 855–64. DOI:10.1086/656363

14 Cysique, L., Maruff, P., Darby, D., Brew, B. (2006). The assessment of cognitive function in advanced HIV-1 infection and AIDS dementia complex using a new computerised cognitive test battery. Arch Clin Neuropsychol 21(2), 185–94.

15 Winston, A., Puls, R., Kerr, S.J., Duncombe, C., Li, P.C.K., Gill, J.M, Taylor-Robinson, S.D., Emery, S. and Cooper, D.A. for the Altair Study Group (2012). Dynamics of cognitive change in HIV-infected individuals commencing three different initial antiretroviral regimens: a randomized, controlled study. HIV Medicine, 13, 245–251.

16 Cysique, L., Vaida, F., Lestendre, S., et al. (2009). Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy. Neurology, 4, 73(5):342–8.

17 Bristol-Myers Squibb Sustiva Product information. Retrieved from: http://packageinserts.bms.com/pi/pi_sustiva.pdf

18 Ciccarelli, N., Fabbiani, M., Di Giambenedetto, S., Fanti, I., Baldonero, E., Bracciale, L., et al. (2011). Efavirenz associated with cognitive disorders in otherwise asymptomatic HIV-infected patients. Neurology, 76(16), 1403–9. DOI:10.1212/WNL.0b013e31821670fb

---

Dr Rebekah Puls is Senior Lecturer, Therapeutic and Vaccine Research Program at The Kirby Institute, The University of New South Wales, responsible for conduct of international clinical studies of therapy optimisation in HIV.