Ernesto Martínez B., MDInternal Medicine, Infectious Diseases

Disclosure – C.O.I.

1. Honorary as speakers from MSD, ViiV, GSK, Gilead, Stendhal, Janssen and Abbvie

2. Honorary in Advisory Boards from MSD, ViiV/GSK, Gilead and Stendhal

3. Research Grants from ViiV/GSK.

4. Financial Support for medical Education foundations and networking fromGSK, MSD, Stendhal, Abbvie and Janssen

• Cognitive complaints common in HIV:

o Acute delirium secondary to metabolic and infectious complications

o Other chronic cognitive impairments not directly related to HIV (alcohol and/or other drugs, Hep C, vascular, seizures)

o Cognitive symptoms associated psychiatric illness

o HAND: HIV-associated neurocognitive disorders is the virus

• Casos: 2854; Controles: 8562• Co-morbilidades evaluadas: Hipertensión, DM, ECV y osteoporosis.• La prevalencia de comorbilidades fué MAYOR en los VIH+ que en VIH neg. en todas las edades

(todos p <0.001)• La prevalencia de poli-Patología en HIV+ fue similar a la observada en la población general pero

10 años más tarde!Guaraldi G et al. Clin Infect Dis 2011; 53: 1120-1126

Direct relation between clinical stage and presence of HAND,but more asymptomatic patients have ANI in CART era

(1). Heaton RK., et al. J. Neurovirol. (2011) 17:3–16(2). Bhaskaran K., et al. Ann Neurol 2008;63:213–221

***p=0.001

(1)

(2)

HIV infection without cognitive

impairment

HIV Asymptomatic Neurocognitive

Impairment

Mild Neurocognitive

Disorder

HIV-associated Dementia

Consensus Working Group, Neurology 2007

Neuropsychological Testing

Function

Asymptomatic Neurocognitive Impairment (ANI)

Any degree of impairmentin at least two cognitive domains

No identifiedimpairment

Mild Neurocognitive Disorder (MND)

Mild-moderately impaired in at least two cognitive domains

Typically mild to moderate impairment

HIV-associated Dementia (HAD)

More severely impaired in at least two cognitive domains

Typically more severeimpairment

Antinori A., et al. Neurology. 2007 30; 69(18): 1789–1799

All “HIV encephalopathy”

(1). Grant I. International Review of Psychiatry 2008;20(1):33-47.(2). Clifford DB. Top HIV Med 2008 Jun-Jul;16(2):94-8

(3). McArthur, J. C. et al. Ann. Neurol. 67, 699–714 (2010)

(1)(2)

(3)

• 15–55% of HIV+ individuals are estimated to have HAND

• Conclusion: Prevalence is the same,• Distribution of diagnosis and severity

have changed with HAART

• Grant Pre-HAART (≈ 50%)• CHARTER (CNS HIV Antiretroviral Therapy

Effects Research) HAART era (≈ 55%)

Neurocognitive impairment rate is higher in older compared to youngerindividuals.

CROI, Seattle, February 13-16, 2017. Abstract 343.

• Nearly 100% adherent – can’t compare to younger cohorts• More symptomatic impairment• Survival tendencies

From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.

• Older than 50 yo.• Female gender• More advanced HIV disease (including CD4 count of <100

cells/µL, wasting)• Time living with HIV• High plasma HIV RNA (viral load)• Comorbid conditions (anemia, metabolic dis., infection with

cytomegalovirus, human herpesvirus 6, HCV, and JC virus)• History of injection drug use (especially with cocaine)• History of delirium• Host genetic factors: Polymorphisms (Apo E4, CCR2, MCP-1)

Modified from https://aidsetc.org/guide/hiv-associated-neurocognitive-disorders

Williams, D. W. et al. Curr. HIV Res. 12, 85–96 (2014)

• MMSE (not very sensitive, Crum et al., 1993)• HIV Dementia Scale (Power et al., 1995)• International HIV Dementia Scale (Sacktor et al.,

2005)• Montreal Cognitive Assessment (MoCA, Overton et

al. CROI 2011)• MOS-IV

Antinori A., et al. Neurology. 2007 30; 69(18): 1789–1799

• Of 37 patients who at baseline were neurocognitively normal, at 1 year 30% had progressed to some stage of impairment.

• Of 53 patients initially diagnosed with asymptomatic NP, 17.7% were classified as normal 1 year later, while 44.1% had progressed to more severe categories of impairment.

Diagnostic transitions from baseline to year 1

Cysique LA., et al. Neurology. 2009 Aug 4;73(5):342-8.

Clinically meaningful neuropsychological improvement seemed to peak around24–36 weeks after cART initiation and was prolonged over the 1-year study period.

37 HIV+ individuals with mild to moderate NP impairmentwho initiated CART

The Mind Exchange Working Group. Clinical Infectious Diseases 2013;56(7):1004–1

Letendre S.Top Antivir Med. 2011 Nov;19(4):137-42.

* Agents included in recommended regimens for initial therapy.¶ Agents that are not used in regimens for initial therapy.Δ Agents included in alternative regimens for initial therapy.◊ Agents included in other regimens for initial therapy.

Adapted from: Letendre S. Top Antivir Med 2011; 19:137.

Letendre S.Top Antivir Med. 2011 Nov;19(4):137-42.

Higher CPE scores correlated with greater improvements in NPZ-4 (P = 0.0283), NPZ-8 (P = 0.0071), concentration and speed of mental processing (P = 0.0046), and mental flexibility (P = 0.0262) summary z scores. The correlation was stronger among NP-impaired patients.

Tozzi V., et al. J Acquir Immune Defic Syndr 2009;52:56–63

Rates of new CNS event (A) stratified by initial and most recent central nervous penetration effectiveness (CPE) scores (B)

Garvey L., et al. Neurology 2011;76:693–700

• CNS diseases (HIVenc, PML, Toxo, Crypto) occurred more frequently using cARTwith CPE scores ≤4, and less frequently with scores ≥10; the differences were nonsignificant.

• Initial and most recent cART CPE scores ≤4 were independently associated with increased risk of death

Heaton RK., ET AL. Neurology. 2010;75:2087–2096

54.2%

15.4%

30.4%N = 1555 HIV+ indiv.

Observational, cross-sectional

71% on cART

Prevalence:33% ANI

12% MND2% HAD

Caniglia EC., et al. Neurology. 2014;83:134–141

Estimated log hazard ratios and 95% confidence intervals

Caniglia EC., et al. Neurology. 2014;83:134–141

Number initiating treatment by CPE score

Most frequently used cART regimens with a low, medium, and high CPEscore, HIV-CAUSAL Collaboration, 1998–2013

* Agents included in recommended regimens for initial therapy.¶ Agents that are not used in regimens for initial therapy.Δ Agents included in alternative regimens for initial therapy.◊ Agents included in other regimens for initial therapy.

Adapted from: Letendre S. Top Antivir Med 2011; 19:137.

• Prospective, double observer-blinded, open-label pilot randomized-controlled trial. Participants were randomized to remain on their existing cART régimen (control arm; n = 8) or receive maraviroc-intensification (maraviroc arm; n = 9).

Letendre S.Top Antivir Med. 2011 Nov;19(4):137-42.Gates TM., et al. AIDS 2016, 30:591–600

Robertson KR., et al. AIDS 2016, 30:2315–2321

• 262 ART-naive, chemokine coreceptor 5 tropic HIV, and HIV RNA greater than 1000 copies/ml participants were randomized.

• N= 119 DRV/r + ETV + MVC• N= 111 DRV/r + ETV + TDF

Improvement in both arms,But NO difference between them.

Yilmaz A, et al. (2009) PLoS ONE 4(9): e6877

Despite the favorable characteristics of raltegravir for CNS treatment, no evidence was found that intensification reduced either intrathecal immunoactivation or CSF HIV-1 RNA in study subjects

Dahl V., et al. The Journal of Infectious Diseases 2011;204:1936–45

• DTG concentrations in CSF were similar to unbound plasma concentrations and exceeded the in vitro 50% inhibitory concentration for wild-type HIV (0.2 ng/mL), suggesting that DTG achieves therapeutic concentrations in the central nervous system.

• HIV-1 RNA reductions were similar in CSF and plasma

Letendre S., et al. Clinical Infectious Diseases 2014;59(7):1032–7

Change in neuropsychological testing performance (NPZ-4) over 24 weeks by randomized arm.Participants demonstrate improvement with no differences noted by arm.

Valcour VG., et al. PLoS ONE 2015; 10(11): e0142600

• N=167, median nadir CD4 of 436 cells/mm3 ; 4.5 median years on ART, before interruption.

Robertson KR., et al. Neurology 2010;74:1260 –1266

• Significant improvements in mean neuropsychological scores of 0.22, 0.39, 0.53, and 0.74 were found at weeks 24, 48, 72, and 96 (p< 0.001).

Condition First line choice Not recommended

HIV associatedNeurocognitive and psychiatric disorders

Insufficient evidence. Integrase INSTI, MVC, DRV/r, ABC/3TC mightbe more effective

- EFV, - RPV?- NVP?

CROI, Seattle, February 13-16, 2017. Abstract 352LB.

• HIV+ had abnormalities in measures of brain structure and function at baseline.

• There was no difference in the dynamics of these measures over time between PLWHIV and HIV-negative controls.

• Cognitive performance did not decline over two years.

• No evidence for accelerated brain ageing during continued suppressed viraemia on cART

• HAND remains frequent despite cART• More prevalent and severe in aging individuals.• Periodic screening with basic tools is mandatory• Asymptomatic impairment may not be that

asymptomatic• Comorbid illnesses are important contributors to

impairment, particularly in older age• cART improves but does not revert HAND• Best practice for cART High CPE score, low CNS

toxicity, however, evidence is lacking.

G r a c i a s p o r s u a t e n c i ó n . . .