Chapter 41
HIV-Associated Dementia
Miquel G. Madariaga and Susan Swindells
Questions
1. Which of the following drug classes are not currently licensed for the treatment of HIV disease?
a. Nucleoside reverse transcriptase inhibitors.
b. Non-nucleoside reverse transcriptase inhibitors
c. Protease inhibitors
d. Inhibitors of viral maturation
2.
A patient with HIV-associated dementia was started on antiretroviral therapy two weeks ago.
complains of dizziness, insomnia and vivid dreams. This reaction is most likely related to the use of:
a. Zidovudine
b. Tenofovir
c. Lamivudine
d. Efavirenz
e. Nevirapine
3.
Which of the following class of drugs is not recommended for first line therapy in patients with HIVassociated dementia?
a. Nucleoside reverse transcriptase inhibitors.
b. Non-nucleoside reverse transcriptase inhibitors
c. Protease inhibitors
d. Entry inhibitors
e. All can be used as first line agents in the treatment of HAD
f.
Contemporary treatment of HIV infection requires the use of two nucleoside reverse transcriptase
inhibitors (NRTI) combined with either a non-nucleoside reverse transcriptase inhibitors or a protease
inhibitor. Which of the following NRTI backbones will you prefer to use in a patient recently diagnosed
with HIV-associated dementia:
a. Zidovudine plus stavudine
b. Zidovudine plus lamivudine
c. Zalcitabine plus didanosine
d. Zalcitabine plus lamivudine
e. Didanosine plus tenofovir
4.
He
5.
Which of the following combinations will not be recommended for first line therapy in a patient with HIV
associated dementia?
a. Zidovudine plus lamivudine plus efavirenz
b. Tenofovir plus emtricitabine plus lopinavir/ritonavir
c. Tenofovir plus emtricitabine plus atazanavir/ritonavir
d. Lamivudine plus abacavir plus fosamprenavir
e. Zidovudine plus lamivudine plus abacavir
6.
Which of the following nucleoside reverse transcriptase inhibitors has the best penetration into CSF?
a. Zidovudine
b. Didanosine
c. Lamivudine
d. Stavudine
e. Abacavir
41. HIV-Associated Dementia
Miquel G. Madariaga and Susan Swindells
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7.
A patient with HIV-associated dementia receiving antiretroviral therapy presents with a burning
sensation in feet and hands, numbness and tingling in the feet, cramps in the legs, and absent ankle
reflexes. What drug will you be the LEAST likely to blame on his/her new symptoms?
a. Zidovudine
b. Stavudine
c. Didanosine
d. Zalcitabine
e. All of the above can cause the patient’s symptoms.
8.
Which of the following protease inhibitors is the most powerful inhibitor of the P450 enzyme?
a. Atazanavir
b. Fosamprenavir
c. Indinavir
d. Nelfinavir
e. Ritonavir
9.
Which of the following drugs has been proven to be effective as adjuvant therapy for HIV associated
dementia?
a. Lexipafant
b. Memantine
c. Minocylcine
d. Nimodipine
e. None of the above
f. All of the above
10. In a busy clinical practice setting, the simplest neuropsychological test to diagnose HIV dementia is?
a. Standard Mini-Mental Status test
b. HIV-dementia scale
c. Memorial Sloan Kettering Scale
d. Halstead-Reitan Neuropsychological Battery
e. San Diego HIV Neurobehavioral Research Center
11. HIV-associated dementia is also referred to as:
a. HIV dementia
b. AIDS Dementia Complex
c. Subacute encephalopathy
d. HIV-1-associated cognitive-motor complex
e. All of the above
12. What is correct about the “Trojan Horse” model of HIV invasion into the CNS?
a. Proposes that monocyte-macrophage carry progeny virions from blood to the brain inside cytoplasmic
vacuoles and across the blood-brain barrier
b. Requires an inflammatory response in the brain, which elicits a chemokine gradient.
c. After infiltrating the brain parenchyma, blood borne monocyte-macrophages also release additional
chemokines and further attract additional inflammatory cells
d. Does not require productive viral replication in brain microvascular endothelial cells.
e. All of the above.
13. The clinical and laboratory features of HIV-associated dementia include all “except” which of the
following?
a. Psychomotor slowing,
b. History of HIV related disease,
c. Extrapyramidal symptoms,
d. Depression
e. Reduced viral loads and serum beta 2 microglobulin
41. HIV-Associated Dementia
Miquel G. Madariaga and Susan Swindells
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14. What is not correct in regards to a diagnosis of HIV-associated dementia?
a. HAD is a diagnosis of exclusion
b. HIV does elicit an inflammatory response. This can be detected by mild lymphocytic pleocytosis, elevation
of total protein, increase of total IgG, and/or the presence of oligoclonal bands.
c. HAD is always associated with a concurrent diagnosis of progressive multifocal leukoencephalopathy
d. HAD almost always is associated with CD4+ T cell counts of less than 600
e. The clinical manifestations of HAD include behavioral, cognitive, and/or motor abnormalities.
15. What aspects of clinical care have impacted the natural history of cognitive impairments in HIV infected
individuals?
a. The introduction of potent, combination anti-retroviral therapy.
b. The use of prophylactic medications against opportunistic infections
c. Improved biomarkers for disease diagnosis
d. One and two
e. None of the above
16. Antiretroviral agents currently in use include inhibitors of reverse transcriptase, HIV protease, and
fusion inhibitors.
True/False
17. Currently there are six classes of antiretroviral agents available in the United States for clinical use:
- Nucleoside analogue reverse transcriptase inhibitors
- Nonnucleoside analogue reverse transcriptase inhibitors
- Protease inhibitors
- Entry inhibitors
- Tat inhibitors
- Nef inhibitors
True/False
18. Nucleoside analogue reverse transcriptase inhibitors are drugs of diverse chemical structure that act by
non-competitive inhibition of HIV-1 reverse transcriptase.
True/False
19. Recent guidelines for starting anti-retroviral therapy recommend that patients with advanced disease, as
manifested by the development of an AIDS-defining illness including HAD, or presence of severe
symptoms such as unexplained fever, persistent diarrhea, or unexplained weight loss, should be started
on ART if their CD4+ T cell count is < 100.
True/False
20. Abacavir plus lamivudine plus zidovudine, which is commercially available as a fixed combination in a
single tablet, has inferior rates of viral suppression and should only be used when an NNRTI or a PIbased regimen cannot or should not be used as first line of therapy.
True/False
41. HIV-Associated Dementia
Miquel G. Madariaga and Susan Swindells
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Answers
1.
Which of the following drug classes are not currently licensed for the treatment of HIV disease?
e. Inhibitors of viral maturation
Current guidelines recommend that antiretroviral therapy should include a combination of two nucleoside
reverse transcriptase inhibitors plus one non-nucleoside reverse transcriptase inhibitor or a protease inhibitor.
Enfuvirtide, the only entry inhibitor used in current clinical practice is not a first line drug choice, but reserved
for patients with previous extensive antiretroviral experience and viral resistance. HIV maturation inhibitors are
investigational compounds and none of them has been approved for use in humans yet.
2.
A patient with HIV-associated dementia was started on antiretroviral therapy two weeks ago.
complains of dizziness, insomnia and vivid dreams. This reaction is most likely related to the use of:
d. Efavirenz
He
Efavirenz is commonly associated with central nervous system (CNS) adverse effects. In fact, up to 2.6% of
patients may discontinue this drug due to CNS effects. The most common reactions include confusion, poor
concentration, insomnia, abnormal vivid dreams, dizziness, and headache. Serious psychiatric reactions are les
common but can happen including hallucinations, delusions, paranoia, anxiety, agitation, aggressive behavior,
mania, emotional liability and suicidal ideation. Patients with psychiatric illness or substance abuse disorders
may be more susceptible to these adverse effects.
3.
Which of the following class of drugs is not recommended for first line therapy in patients with HIVassociated dementia?
d. Entry inhibitors
HIV associated dementia (HAD) is an indication for starting antiretroviral therapy. Early studies have shown
that drugs that penetrate the blood-brain barrier, particularly zidovudine, lead to improvement and at least
partial return of functioning in patients diagnosed with HAD. However, other agents that may have not good
penetration in the CNS may also be effective by virtue of peripheral viral suppression. Hence, either a nonnucleoside reverse transcriptase inhibitor or a protease inhibitor-based regimen is warranted in the presence of
HAD. Entry inhibitors are only used in patients with extensive use of other antiretroviral drugs and cannot be
considered as first line therapy.
4.
Contemporary treatment of HIV infection requires the use of two nucleoside reverse transcriptase
inhibitors (NRTI) combined with either a non-nucleoside reverse transcriptase inhibitors or a protease
inhibitor. Which of the following NRTI backbones will you prefer to use in a patient recently diagnosed
with HIV-associated dementia:
b. Zidovudine plus lamivudine
Not all the combinations of two NRTI are satisfactory for therapy of HAD and HIV in general. The
combination of zidovudine with stavudine is antagonistic and should never be used. Zalcitabine with
didanosine increases the risk of mitochondrial damage and peripheral neuropathy. Zalcitabine and lamivudine
may competitively inhibit intracellular phosphorylation. Didanosine and tenofovir are associated with higher
rate of early virological failure. The best choice in a patient with HAD is be zidovudine and lamivudine. These
drugs are available in a fixed-dose combination as Combivir; they have been widely studied, and achieve good
penetration into CSF.
5.
Which of the following combinations will not be recommended for first line therapy in a patient with HIV
associated dementia?
e. Zidovudine plus lamivudine plus abacavir
The standard of care for initial therapy of HIV includes the use of two nucleoside reverse transcriptase
inhibitors (NRTI) combined with either a non-nucleoside reverse transcriptase inhibitors or a protease inhibitor.
A triple-NRTI combination may have advantages such as low pill burden (in fact, the combination of
41. HIV-Associated Dementia
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zidovudine plus lamivudine plus abacavir is available as a single pill, Trizivir), fewer drug-drug interactions,
and sparing patients from potential side effects seen with other antiretrovirals. However, several clinical trials
have shown inferior virologic activity and significantly higher chance of virologic failure as compared to two
nucleoside reverse transcriptase inhibitors and a non-nucleoside reverse transcriptase inhibitor.
6.
Which of the following nucleoside reverse transcriptase inhibitors has the best penetration into CSF?
e. Abacavir
The ratio of CSF concentrations to IC50 may provide a better estimate of CNS efficacy than CSF concentration
alone. The ratio for abacavir is above 4.0 (whereas the ratio for other nucleoside reverse transcriptase inhibitors
is less than one). However, better CSF penetration does not necessarily correlate with improved clinical
efficacy. A trial of 105 patients with mild to moderate HIV-associated dementia on antiretroviral therapy for at
least 8 weeks randomly assigned participants to receive abacavir (600 mg twice a day) or matched placebo for
12 weeks. Patients were assessed using several neuropsychological tests. No evidence of clinical improvement
was found at the end of the study, despite a decrease of CSF HIV-1 RNA and a mean abacavir concentration of
0.741 ug/ml 3-4 h post-dosing (exceeding a representative abacavir IC50 for HIV-1).
7.
A patient with HIV-associated dementia receiving antiretroviral therapy presents with a burning
sensation in feet and hands, numbness and tingling in the feet, cramps in the legs, and absent ankle
reflexes. What drug will you be the LEAST likely to blame on his/her new symptoms?
a. Zidovudine
Distal sensory peripheral neuropathy (DSPN) has been associated with the use of ddC, ddI and stavudine, alone
or in combination. The symptoms of this condition include a burning sensation in feet and hands, numbness
and tingling in the feet, cramps in the legs, and absent ankle reflexes. The patient may also exhibit decreased
sensation to temperature, pinprick, vibration, and proprioception. The symptoms are similar to HIV-associated
axonal neuropathy. This condition may become irreversible, so it is important to diagnose it earlier. The
treatment of choice is symptomatic therapy and discontinuation of the toxic agent when possible.
8.
Which of the following protease inhibitors is the most powerful inhibitor of the P450 enzyme?
e. Ritonavir
Ritonavir is a potent inhibitor of cytochrome P450 3A (CYP3A) and CYP2D6, as well as an inducer of other
hepatic enzyme systems. Coadministration of other protease inhibitors (PI) with ritonavir is used in clinical
practice to “boost” the levels of other PI. Caution should be used with several drugs that are metabolized by the
liver and may have a significant alteration in serum levels. These drugs include: cardiovascular medications
(antiarrhythmics, cholesterol-lowering agents and calcium channel blockers), sedatives and anti-depressants,
oral contraceptives, recreational substances, and others.
Other PIs may also inhibit the P450 enzymatic system, but are not as potent as ritonavir.
9.
Which of the following drugs has been proven to be effective as adjuvant therapy for HIV associated
dementia?
e. None of the above
No adjuvant therapy has proven efficacy in HIV-associated dementia. In clinical trials, lexipafant, memantine
and nimodipine have not been better that placebo in regards to clinical outcomes. Minocycline may have
neuroprotective effects in a SIV model, but its benefits in humans are yet to be tested.
10. In a busy clinical practice setting, the simplest neuropsychological test to diagnose HIV dementia is?
b. HIV-dementia scale
Neuropsychological testing in HIV-associated dementia (HAD) is a useful tool for the differential diagnosis and to
delineate disease extension and progression. The standard Mini-Mental Status is not particularly sensitive for
detection of early HAD. The HIV Dementia Scale is a useful tool and only takes five minutes to administer and
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score. Other several neuropsychological “batteries” may be useful but they are time–consuming and impractical in
busy clinical settings.
HIV dementia scale
Maximum
score
4
6
4
2
16
11. e
12. e
13. e
14. d
15. d
16. True
17. False
Score
Memory-Registration
Give four words to recall (dog, hat, green, peach) - 1 second to say each. Then
ask the patient all 4 after you have said them.)
Attention1
Anti-saccadic eye movements: 20 (twenty) commands. ____ errors of 20
trials.
Less than or equal to 3 errors = 4; 4 errors = 3; 5 errors = 2; 6 errors = 1; > 6
errors = 0)
1
Attention: Hold both hands up at patient's shoulder width and eye height,
and ask patient to look at your nose. Move the index finger of one hand, and
instruct patient to look at the finger that moves, then look back to your nose.
Practice until patient is familiar with task. Then, instruct patient to look at the
finger, which is NOT moving. Practice until patient understands task. Perform
20 trials. An error is recorded when the patient looks towards the finger that is
moving.
Psychomotor Speed
Ask patient to write the alphabet in upper case letters horizontally across the
page (use back of this form) and record time: ____ seconds.
Less than or equal to 21 sec = 6; 21.1 - 24 sec = 5; 24.1 - 27 sec = 4; 27.1 - 30
sec = 3; 30.1 - 33 sec = 2; 33.1 - 36 sec = 1; > 36 sec = 0)
Memory - Recall
Ask for 4 words from Registration above. Give 1 point for each correct. For
words not recalled, prompt with a "semantic" clue, as follows: animal (dog);
piece of clothing (hat), color (green), fruit (peach). Give 1/2 point for each
correct after prompting.
Construction
Copy the cube below; record time: ____ seconds.
(< 25 sec = 2; 25 - 35 sec = 1; > 35 sec = 0)
A score below 10 is suggestive of HIV dementia
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Miquel G. Madariaga and Susan Swindells
18. True
19. False
20. True
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