Transcript Antiepileptic Drug Selection for People with HIV/AIDS

Antiepileptic Drug Selection
for People with HIV/AIDS
Report of the American Academy of
Neurology and the International League
Against Epilepsy
Gretchen L. Birbeck, MD, MPH, DTMH, FAAN; Jacqueline A. French,
MD, FAAN; Emilio Perucca, MD, PhD, FRCP(Edin); David M.
Simpson, MD; Henry Fraimow, MD; Jomy M. George, PharmD,
BCPS; Jason F. Okulicz, MD; David B. Clifford, MD; Houda Hachad,
PharmD; René H. Levy, PhD
© 2012 AMERICAN ACADEMY OF NEUROLOGY
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Presentation Objectives
• To present analysis of the evidence for drug–drug
interactions between antiepileptic drugs (AEDs) and
antiretrovirals (ARVs)
• To present evidence-based recommendations
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Overview
• Background
• Gaps in care
• American Academy of Neurology (AAN) guideline
process
• Analysis of evidence, conclusions, recommendations
• Recommendations for future research
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Background
• No formal AED treatment guidelines currently exist for
individuals with HIV/AIDS.
• Worldwide the concurrent use of AEDs and ARVs is
substantial.
o Seizure disorders are common in individuals infected with HIV,
with a reported incidence as high as 11%.1–3
o HIV/AIDS, especially prevalent in sub-Saharan Africa, is
becoming a chronic condition as ARV therapies become
increasingly available.4
o The indications for AEDs include neurologic and psychiatric
conditions other than epilepsy.
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Background, cont.
• Potential interactions between ARVs and AEDs are
complex and extensive.
o P450 system enzyme induction effects of several oldergeneration AEDs (e.g., phenobarbital, carbamazepine,
phenytoin) are of greatest concern.
o P450 system enzyme inducers might be expected to lower the
effective dose of nonnucleotide reverse transcriptase inhibitors
(NNRTIs) and protease inhibitors (PIs).
• Several potential mechanisms of interaction and the
impact of ARVs on AEDs also warrant consideration.
o Effective HIV care requires lifelong treatment using regimens
typically comprising at least 3 drugs.5
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Background, cont.
• AED-ARV interactions that raise blood levels of drugs in
either class may increase toxicity risk.
• Use of ARVs that reduce AED levels could lead to loss of
therapeutic effects, including seizure control.
• Use of AEDs that decrease ARV levels (e.g., the
enzyme-inducing AEDs [EI-AEDs] phenytoin,
phenobarbital, and carbamazepine) may lead to virologic
failure.
o Because first-line AED availability in most developing countries
is limited to phenobarbital, carbamazepine, and phenytoin, and
ARV regimen options may also be limited, there is substantial
risk for occurrence of clinically important drug interactions.6,7
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Gaps in Care
• No formal AED treatment guidelines currently exist for
individuals with HIV/AIDS; at the same time, seizure
disorders are common in individuals infected with HIV.
• Worldwide the concurrent use of AEDs and ARVs is
substantial, as ARV use expands with the increasingly
chronic nature of HIV/AIDS and the increased use of
AEDs for conditions other than epilepsy (e.g.,
neuropathic pain).
• Potential interactions between ARVs and AEDs are
complex and extensive. This, along with the impact of
ARVs on AEDs, warrants consideration.
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Gaps in Care, cont.
• AED-ARV interactions that raise blood levels of drugs in
either class may increase toxicity risk. Use of ARVs that
reduce AED levels could lead to loss of therapeutic AED
effects, including seizure control. Use of AEDs that
decrease ARV levels (e.g., EI-AEDS phenytoin,
phenobarbital, and carbamazepine) may lead to virologic
failure and ARV resistant HIV strains.
© 2012 AMERICAN ACADEMY OF NEUROLOGY
AAN Guideline Process
Clinical Question
Evidence
Conclusions
Recommendations
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Clinical Questions
• What is the evidence that AED-ARV interactions are
clinically meaningful?
• What is the evidence for an interaction between AEDs
and PI ARVs?
• What is the evidence for interaction between AEDs and
integrase inhibitors?
• What is the evidence for an interaction between AEDs
and nucleoside reverse transcriptase inhibitor and
NNRTI ARVs?
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Literature Search/Review
Rigorous, Comprehensive, Transparent
Complete
Search
Review abstracts
Review full text
Select articles
Relevant
© 2012 AMERICAN ACADEMY OF NEUROLOGY
AAN Classification of
Evidence
• All studies rated Class I, II, III, or IV
• Five different classification systems:
o Therapeutic
− Randomization, control, blinding
o Diagnostic
− Comparison to gold standard
o Prognostic
o Screening
o Causation
© 2012 AMERICAN ACADEMY OF NEUROLOGY
AAN Level of
Recommendations
• A = Established as effective, ineffective or harmful (or
established as useful/predictive or not useful/predictive)
for the given condition in the specified population.
• B = Probably effective, ineffective or harmful (or
probably useful/predictive or not useful/predictive) for the
given condition in the specified population.
• C = Possibly effective, ineffective or harmful (or possibly
useful/predictive or not useful/predictive) for the given
condition in the specified population.
• U = Data inadequate or conflicting; given current
knowledge, treatment (test, predictor) is unproven.
Note that recommendations can be positive or negative.
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Translating Class to Recommendations
• A = Requires at least two consistent Class I
studies.*
• B = Requires at least one Class I study or two
consistent Class II studies.
• C = Requires at least one Class II study or two
consistent Class III studies.
• U = Studies not meeting criteria for Class I
through Class III.
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Translating Class to Recommendations,
cont.
*In exceptional cases, one convincing Class I study
may suffice for an “A” recommendation if 1) all
criteria are met, 2) the magnitude of effect is large
(relative rate improved outcome >5 and the lower
limit of the confidence interval is >2).
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Applying This Process
to the Issue
We will now turn our attention to the guidelines.
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Methods
• MEDLINE
o 1950 to April 2008 (updated in 2010)
o Relevant, fully published, peer-reviewed articles
o For the original and updated search strategies, see
appendices e-1 and e-2 of the published guideline
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Methods, cont.
• At least two authors reviewed each article for inclusion.
• Risk of bias was determined using the classification of
evidence for each study (Classes I–IV).
• Strength of practice recommendations were linked directly
to levels of evidence (Levels A, B, C, and U).
• Conflicts of interest were disclosed.
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Literature Review
4,480 abstracts
Inclusion criteria:
- Articles on co-usage of
AEDs and ARVs
- Articles on AED-ARV
drug–drug interactions
- Articles reporting human
in vivo data and 1
outcome measure(s)
Exclusion criteria:
15 articles
© 2012 AMERICAN ACADEMY OF NEUROLOGY
- Case reports, review
articles
AAN Classification of Evidence
for Therapeutic Intervention
• Class I: A randomized, controlled clinical trial of the intervention of
interest with masked or objective outcome assessment, in a
representative population. Relevant baseline characteristics are
presented and substantially equivalent among treatment groups or
there is appropriate statistical adjustment for differences. The following
are also required:
o Concealed allocation
o Primary outcome(s) clearly defined
o Exclusion/inclusion criteria clearly defined
© 2012 AMERICAN ACADEMY OF NEUROLOGY
AAN Classification of Evidence
for Therapeutic Intervention, cont.
o Adequate accounting for dropouts (with at least 80% of enrolled subjects
completing the study) and crossovers with numbers sufficiently low to have
minimal potential for bias.
o For noninferiority or equivalence trials claiming to prove efficacy for one or
both drugs, the following are also required*:
– The authors explicitly state the clinically meaningful difference to be excluded by
defining the threshold for equivalence or noninferiority.
– The standard treatment used in the study is substantially similar to that used in
previous studies establishing efficacy of the standard treatment (e.g., for a drug,
the mode of administration, dose and dosage adjustments are similar to those
previously shown to be effective).
– The inclusion and exclusion criteria for patient selection and the outcomes of
patients on the standard treatment are comparable to those of previous studies
establishing efficacy of the standard treatment.
– The interpretation of the results of the study is based upon a per protocol analysis
that takes into account dropouts or crossovers.
© 2012 AMERICAN ACADEMY OF NEUROLOGY
AAN Classification of Evidence
for Therapeutic Intervention, cont.
• Class II: A randomized controlled clinical trial of the intervention of
interest in a representative population with masked or objective
outcome assessment that lacks one criteria ae above or a
prospective matched cohort study with masked or objective outcome
assessment in a representative population that meets be above.
Relevant baseline characteristics are presented and substantially
equivalent among treatment groups or there is appropriate statistical
adjustment for differences.
• Class III: All other controlled trials (including well-defined natural
history controls or patients serving as own controls) in a representative
population, where outcome is independently assessed, or
independently derived by objective outcome measurement.**
© 2012 AMERICAN ACADEMY OF NEUROLOGY
AAN Classification of Evidence
for Therapeutic Intervention, cont.
• Class IV: Studies not meeting Class I, II or III criteria including
consensus or expert opinion.
*Note that numbers 13 in Class I, item 5 are required for Class II in equivalence trials. If
any one of the three is missing, the class is automatically downgraded to Class III.
**Objective outcome measurement: an outcome measure that is unlikely to be affected by
an observer’s (patient, treating physician, investigator) expectation or bias (e.g., blood
tests, administrative outcome data).
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Clinical Question 1
Question 1: What is the evidence that
AED-ARV interactions are clinically
meaningful?
© 2012 AMERICAN ACADEMY OF NEUROLOGY
ARVs and EI-AEDs
Conclusion:
• Coadministration of highly active ARV therapy containing a PI or
NNRTI and an EI-AED possibly results in higher virologic failure
rates (1 Class II study).
Recommendation:
• It may be important to avoid EI-AEDs in people on ARV regimens
that include PIs or NNRTIs, as pharmacokinetic interactions may
result in virologic failure, which has clinical implications for disease
progression and development of ARV resistance. If such regimens
are required for seizure control, patients may be monitored through
pharmacokinetic assessments to ensure efficacy of the ARV
regimen (Level C).
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Clinical Question 2
Question 2: What is the evidence for an
interaction between AEDs and PI ARVs?
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Phenytoin: Impact on Lopinavir/ritonavir
Conclusion:
• Phenytoin possibly reduces lopinavir and ritonavir levels by about
30% (1 Class II study).
Recommendation:
• Patients receiving phenytoin may require a lopinavir/ritonavir
dosage increase of about 50% to maintain unchanged serum
concentrations (Level C).
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Atazanavir and Atazanavir/ritonavir:
Impact on Lamotrigine
Conclusion:
• Ritonavir/atazanavir possibly reduces lamotrigine exposure by
about 30% (1 Class II study).
Recommendation:
• Coadministration of atazanavir and lamotrigine may not require
lamotrigine dosage adjustment (Level C).
• Patients receiving ritonavir/atazanavir may require a lamotrigine
dosage increase of about 50% to maintain unchanged lamotrigine
serum concentrations (Level C).
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Clinical Question 3
Question 3: What is the evidence for
interaction between AEDs and integrase
inhibitors?
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Raltegravir: Impact on Lamotrigine
Conclusion:
• Raltegravir and atazanavir possibly have no effect on lamotrigine
exposure (1 Class II study).
Recommendation:
• Coadministration of raltegravir and lamotrigine may not require
lamotrigine dosage adjustment (Level C).
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Raltegravir: Impact on Midazolam
Conclusion:
• Raltegravir possibly has no effect on midazolam exposure (1 Class
II study).
Recommendation:
• Coadministration of raltegravir and midazolam may not require
midazolam dosage adjustment (Level C).
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Clinical Question 4
Question 4: What is the evidence for an
interaction between AEDs and nucleoside
reverse transcriptase inhibitor and NNRTI
ARVs?
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Valproic Acid: Impact on Efavirenz /
Efavirenz: Impact on Valproic Acid
Conclusion:
• Valproic acid possibly has no effect on efavirenz exposure (Class II
study).
Recommendation:
• Coadministration of valproic acid and efavirenz may not require
efavirenz dosage adjustment (Level C).
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Valproic Acid: Impact on Zidovudine
Conclusion:
• Valproic acid possibly increases zidovudine exposure (1 Class II
study).
Recommendation:
• Patients receiving valproic acid may require a zidovudine dosage
reduction to maintain unchanged serum zidovudine concentrations
(Level C).
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Effects of Combining Other
AEDs and ARVs
Conclusion:
• The evidence is insufficient to support or refute other
pharmacokinetic AED-ARV interactions (single Class III/multiple
Class IV studies).
Recommendation:
• Patients may be counseled that it is unclear whether dosage
adjustment is necessary when other AEDs and ARVs are combined
(Level U).
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Clinical Context
• A retrospective cohort study and numerous
pharmacokinetic studies indicate that EI-AEDs interact with
ARVs.
• The optimal choice of epilepsy treatment in patients with
HIV should reflect an accounting for the metabolic and
inhibitory/inducing profiles of coadministered drugs.
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Clinical Context, cont.
• Clinicians who prescribe ARVs and AEDs are encouraged
to refer to the Department of Health and Human Services
treatment guidelines for HIV/AIDS, which provide specific
recommendations for the management of possible drug–
drug interactions with AED-ARV combinations (available at
http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.
pdf).
• For newer ARV agents, minimal data exist on drug
interactions with AEDs.
© 2012 AMERICAN ACADEMY OF NEUROLOGY
Future Research
• Future research regarding AED-ARV interactions is
needed.
• Special priority should be given to the study of first-line
AED-ARV combinations used in low- and middle-income
countries where second-line agents may not be available.
© 2012 AMERICAN ACADEMY OF NEUROLOGY
References
1.
2.
3.
4.
5.
6.
7.
Holmberg SD, Buchbinder SP, Conley LJ, et al. The spectrum of medical conditions
and symptoms before acquired immunodeficiency syndrome in homosexual and
bisexual men infected with the human immunodeficiency virus. Am J Epidemiol
1995;141:395– 404; discussion 405–396.
Kellinghaus C, Engbring C, Kovac S, et al. Frequency of seizures and epilepsy in
neurological HIV-infected patients. Seizure 2008;17:27–33.
Wong MC, Suite ND, Labar DR. Seizures in human immunodeficiency virus infection.
Arch Neurol 1990;47: 640–642.
Bradshaw D, Groenewald P, Laubscher R, et al. Initial burden of disease estimates
for South Africa, 2000. S Afr Med J 2003;93:682–688.
World Health Organization. Patient Monitoring Guidelines for HIV Care and
Antiretroviral Therapy. Geneva: WHO Press; 2006.
Epilepsy and HIV: a dangerous combination. Lancet Neurol 2007;6:747.
Birbeck G, Chomba E, Ddumba E, Kauye F, Mielke J. Lack of appropriate treatment
for people with comorbid HIV/AIDS and epilepsy in sub-Saharan Africa. Epilepsia
2007;48:1424–1425.
© 2012 AMERICAN ACADEMY OF NEUROLOGY
References, cont.
For a complete list of references, please access the full
guideline at www.aan.com/guidelines
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Questions/Comments
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Thank you for your participation!
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