Disclosure of Potential Conflicts

Update on HIV

Antiretroviral Therapy (ART): Impact, Limitations and Strategies in Treating CNS HIV Infection

• Honorarium and travel reimbursement:
Abbott Laboratories

• Research support:


Investigator-initiated study support Merck & Co.

Richard W. Price, M.D. Professor Emeritus Department of Neurology, UCSF February 14, 2013; UCSF Neurology Recent Advances

RW Price-SFGH/UCSF

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Treating systemic infection

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Effectiveness & shortcomings treating CNS infection

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Targeting CNS infection

Patient rationale • ART aims to reduce the risk of disease progression through:


Objectives
When to treat?
How to treat?
Objectives
Neurological impact
Virological impact
Objectives
Theoretical rationale
Empirical approach

Recommendations for approach to new CNS disease

February 14, 2013; UCSF Neurology Recent Advances

RW Price-SFGH/UCSF

Systemic ART: Objectives

ART & CNS HIV Infection: Outline

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February 14, 2013; UCSF Neurology Recent Advances

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Suppression of systemic HIV infection
Restoration/preservation of immune competence
Reduction of immune activation and thereby
Prevent OIs and other complications of immunosuppression and HIV (including CNS OIs)
Prevent non-AIDS complications (including CNS diseases)

Community rationale • ART also aims to reduce the risk of sexual transmission of HIV February 14, 2013; UCSF Neurology Recent Advances

RW Price-SFGH/UCSF

Systemic ART: What to Start

Systemic ART: When to Initiate Treatment

Initial drug selection DHHS Guidelines for starting therapy (2012)

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Antiretroviral therapy (ART) is recommended for all HIV-infected individuals. The strength of this recommendation varies on the basis of pretreatment CD4 cell count:

DHHS Guidelines for starting therapy (2012) • Criteria for treatment selection


Efficacy in reducing viral burden and restoring/sustaining immune function: antiviral potency, pharmacokinetics
Factors affecting tolerability and adherence: dosing frequency, pill burden, side effects, toxicities, and drug interactions
Strength of evidence: based on large body of evidence, including particularly randomized clinical trials
Resistance is greatest pitfall to enduring treatment success


CD4 count 500 cells/mm3 (BII)

Antiretroviral therapy (ART) is recommended for all HIV-infected individuals to reduce the risk of:
Disease progression (patient rationale)
Sexual transmission of HIV (community rationale)

Rating of Recommendation Statements: A = Strong; B = Moderate; C = Optional Rating of Evidence: I = data from randomized controlled trials; II = data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = expert opinion

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 Pretreatment drug-resistance testing

Classification of initial regimens
Preferred (AI)
Alternative (BI & BIII)
Other (Acceptable) (CI & CIII)

http://aidsinfo.nih.gov/guidelines February 14, 2013; UCSF Neurology Recent Advances

RW Price-SFGH/UCSF

http://aidsinfo.nih.gov/guidelines

February 14, 2013; UCSF Neurology Recent Advances

RW Price-SFGH/UCSF

Systemic ART: What to Start

Systemic ART: Drug Targets

Initial drug selection Drug classes • Nucleoside/tide reverse transcriptase inhibitors (NRTIs) • Non-nucleoside reverse transcriptase inhibitors (NNRTIs) • Protease inhibitors (PIs) • Integrase strand transfer inhibitors (INSTIs)

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CCR5 antagonists

Fusion inhibitors General principles • 3 active drugs, some with 4th to boost exposure
Most common: 2 NRTIs + NNRTI or PI or INSTI
Boosting drugs: ritonovir (/r), cobicistat

DHHS Rating NRTI1 Preferred

Drug Class NRTI2

NNRT

TDF TDF TDF TDF

FTC FTC FTC FTC

EFV

ABC ABC ABC ABC ABC ABC TDF TDF ABC TDF TDF

3TC 3TC 3TC 3TC 3TC 3TC FTC FTC 3TC FTC FTC

EFV

Alternative

PI DRV/r ATV/r

RPV RPV

DRV/r FPV/r LPV/r ATV/r FPV/r LPV/r

INSTI

RAL

RAL

EVG/COBI

CCR5

DHHS Rating NRTI1 Other ZDV ZDV ZDV ZDV ZDV ZDV ZDV ABC ABC TDF TDF ZDV ZDV ZDV ABC TDF

Drug Class NRTI2 3TC 3TC 3TC 3TC 3TC 3TC 3TC 3TC 3TC FTC FTC 3TC 3TC 3TC 3TC FTC

NNRT

NVP EFV

PI

RAL

NVP

CCR5

MVC MVC

NVP

RPV

INSTI

DRV/r FPV/r LPV/r

ATV/r SQV/r

MVC

SQV/r SQV/r

http://aidsinfo.nih.gov/guidelines February 14, 2013; UCSF Neurology Recent Advances

RW Price-SFGH/UCSF

February 14, 2013; UCSF Neurology Recent Advances

RW Price-SFGH/UCSF

CNS ART: Objectives

Neurological Effects of ART

• Treatment:

• Impact on HAD


Suppress CNS HIV infection
Stop progression of and reverse CNS dysfunction


Treatment: reversal of dysfunction (variable but often substantial)
Prevention: marked reduction in incidence

• Prevention:


Prevent late effects: HIV-associated dementia (HAD)
Prevent milder CNS dysfunction
Eliminate viral reservoir (barrier to viral eradication)

February 14, 2013; UCSF Neurology Recent Advances

 Similar to impact on CNS OIs

• Shortcomings


Persistence of milder CNS impairment in treated patients
Symptomatic CNS escape

RW Price-SFGH/UCSF

CSF HIV

5

Plasma HIV

50

6

100

6

50

6

40

5

80

5

40

5

80

30

4

60

4

30

4

60

20

3

40

3

20

3

40

10

2

20

2

10

2

20

0

1

5002

4013

4034

100

4

CSF WBCs

3 2 1 0

50

100 150 200 250 300 350 400

0 0

50

14000

QNPZ-4

0

1

100 150 200 250 300 350 400

14000

0 0 25 50 75100

1

1

500

1

1000

0

0 0

2

2400

50

100 150 200 250 300 350 400

1

2400

1

0

12000

-1

2000

0

2000

-1

-2

10000

-2

1600

-1

1600

-2

8000

-3

8000

-3

-4

6000

CSF NFL

4000 2000 0

-5 -6

0

50

100 150 200 250 300 350 400

6000 4000

-3

1200

-4

-5

800

-4

800

-5

-6

-7

-7

-8

0

-8 50

100 150 200 250 300 350 400

-3

1200

2000 0

-2

-4

-5

400

-6

0

-7 0 25 50 75100

500

1000

QNPZ-4

-1

10000

12000

NFL (ng/L)

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CSF WBCs (/µL)

HIV-1 RNA (log 10 copies/ml)

4033

6

-6

400

-7

0

-8 0

50

100 150 200 250 300 350 400

QNPZ-4 = quantitative neurological performance on 4 tests NFL = light chain of neurofilament protein, marker of axonal degeneration February 14, 2013; UCSF Neurology Recent Advances

RW Price-SFGH/UCSF

Prevention of HAD: Example

Treatment of HAD: Four Examples

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February 14, 2013; UCSF Neurology Recent Advances

RW Price-SFGH/UCSF

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Study design:
Nationwide, population-based cohort study using Danish registries of severe neurocognitive disorders (SNCD)

Findings:
32 cases per 4,452 HIV+
120 cases per 62,328 controls
Relative risk 10.1 when CD4 2 of 5-7 domains

Major functional impairment: usually cognitive and motor dysfunction

Minor Neurocognitive Disorder (MND)

Mild sympoms and/or functional impairment

Below 1 SD in >2 of 5-7 domains

Mild but distinct functional impairment varified by examination

Asymptomatic No symptoms or Neurocognitive functional impairment Impairment (ANI)

Below 1 SD in >2 of 5-7 domains

Not applicable to bedside clinical diagnosis

Antinori, A., G. Arendt, et al. (2007). "Updated research nosology for HIV-associated neurocognitive disorders." Neurology 69(18): 1789-1799. February 14, 2013; UCSF Neurology Recent Advances

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Study of 200 subjects with treatmentinduced plasma viral suppression

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50 with neurological complaints (84% impairment)

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27% Cognitive complaints


24% asymptomatic neurocognitive impairment (ANI)
52% mild neurocognitive disorder (MND)
8% HAD

50 without neurological complaints (64% impairment)
60% ANI
4% MND
0% HAD

Simioni et al. Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS 2010, 24:1243–1250. RW Price-SFGH/UCSF

February 14, 2013; UCSF Neurology Recent Advances

CNS Shortcomings of ART: Milder CNS Impairment

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RW Price-SFGH/UCSF

Causes of Mild Impairment (ANI/MND) in Treated Patients

Heaton et al. Charter Study Cohort
Cross-sectional study of 1,555 subjects, 6 centers, extensive NP testing

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Confounding conditions Amenable to CNS-directed ART Past (static) HIV-related injury
With residual damage
Reduced reserve, additive with other conditions (e.g., aging)

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Active immune activation-related injury without CNS infection
Related to systemic immune activation
Sustained local CNS immune activation? Active CNS HIV-related injury
With detectable CSF virus
With level or type or infection below detection?

 CD4 420 (IQR 49-300); 71% on cART; 59% with detectable plasma HIV (44% on cART); 34% detectable in CSF (16% on cART)


52% neuropsych (NP) test impairment in those cases ‘not severely confounded’:  33% asymptomatic (ANI)  12% mild NP impairment (MND)  2% severe (HAD)

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Low CD4 nadir strong predictor of impairment

Heaton et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy. Charter Study. Neurology, 75: 2087-2096, 2010. February 14, 2013; UCSF Neurology Recent Advances

RW Price-SFGH/UCSF

February 14, 2013; UCSF Neurology Recent Advances

RW Price-SFGH/UCSF

CNS Virological Effects of ART

Favorable CSF HIV RNA Suppression in Most Patients

• CNS (CSF) infection is nearly ubiquitous facet of •

systemic HIV infection In most patients who achieve plasma virus suppression, CSF HIV is also suppressed
In most of these CSF HIV RNA levels 50 cpm) with suppressed ( controlled (median 5.1, p=0.03)
Resistance mutations not done
No relation to cpe score
Only ZDV-treated without CSF escape

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Preliminary data suggest most do not evolve to symptomatic disease HIV-1 Viral Escape in Cerebrospinal Fluid of Subjects on Suppressive Antiretroviral Treatment. Edén A et al. J Infect Dis. 2010;202:1819-1825

February 14, 2013; UCSF Neurology Recent Advances

RW Price-SFGH/UCSF

RW Price-SFGH/UCSF

Retrospective case series patients with neurological symptoms and HIV in CSF with suppressed plasma
CSF > 200 cpm, plasma 10x plasma in treated patients

11 patients






Acute or subacute neurological disease 10/11 CSF pleocytosis Median CSF HIV 880 cpm (588 – 12,885) Resistance mutations in 7/8 All improved after optimization of treatment with respect to:  Resistance  CNS drug entry

Relative incidence
2 centers, 6000 patients/year
Review over 5 year period

February 14, 2013; UCSF Neurology Recent Advances

Canestri, A., F. X. Lescure, et al. (2010). "Discordance between cerebral spinal fluid and plasma HIV replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy." Clinical infectious diseases 50(5): 773-778. RW Price-SFGH/UCSF

Symptomatic CSF Escape

Symptomatic CSF Escape: Peluso et al • Retrospective case series patients with neurological symptoms and HIV in CSF with suppressed plasma

• 10 patients









Acute or subacute neurological disease 10/10 CSF pleocytosis Median plasma HIV 62 cpm (