December 01, 2019| By Dr. Chris Ball
People
living with HIV (PLWH) may experience problems in thinking, remembering,
concentrating and language. This is not solely the result of HIV infection of
the brain but also the result of many associated problems: alcohol or drug use,
depression and anxiety, and vascular disease. Difficulties caused by viral
infection directly are known as HIV-associated Neurocognitive
Disorder (HAND).
In
general, significant improvement has been made in neurological problems in
PLWH, largely due to early treatment reducing the number of immune compromised
individuals. However, HAND remains an important problem across the world,
particularly when the diagnosis is made late and sophisticated treatment
regimens are not available. The problems of measuring cognitive function across
cultures and social boundaries is well-recognized and this makes generalizing
the findings of studies difficult.
Frascati
Criteria, the most commonly used classification of HAND, requires impairment in
two areas of neuropsychological functioning and impairment of day-to-day
functioning and is used to define three categories (see Graphic 1).
However, this has proved difficult to apply in practice and may produce a high
false positive rate.
The prevalence of cognitive impairment in PLWH is a source of
considerable debate. When the infection is well-controlled, a rate of 17% has
been diagnosed against a control population of 5%. In this cohort, impairment
was associated with non-HIV factors, such as cannabis use, depressive symptoms,
cardiovascular and metabolic factors. In the CHARTER study, the rate was 52%,
but the cohort contained many patients with unsuppressed viral loads,
AIDs-defining illnesses and other comorbidities.1
In
highly-selected groups with long-term, effective ART (antiretroviral therapy)
and no co-morbidity, similar rates to uninfected cohorts have been reported.
Women, particularly black women, may be most at risk for HIV-associated
neurocognitive impairment but much of the difference may be explained by
non-medical factors such as educational attainmen. For the majority, the
impairment remains stable; some improve but a slightly larger minority decline.
The associations with non-HIV comorbidities are important in identifying those
who will potentially decline.
Making a
diagnosis is difficult. Not all those who complain of problems will have
objective evidence of decline on testing, particularly on short screening
tests, and some with no subjective problems will have underlying changes. A
unique pattern of impairment on more detailed testing has not been identified
although prospective memory – remembering to remember – might be a
useful marker.
HIV
enters the brain early in the infection establishing itself in the perivascular
macrophages and microglia. Direct neurotoxicity also occurs with sustained
inflammation present even during ART. Although ART stops replication of the
virus, sensitive analysis of cell-associated HIV DNA identified persistence of
the virus in the brains of half of patients after a nearly a decade of “strict”
HIV treatment. Those with evidence of viral DNA were almost three times more
likely to meet the criteria for cognitive impairment than those who did not
have the DNA, raising hopes that this might be a useful marker in
the future.
No
imaging biomarker of HAND has been established to reliably identify those who
experience cognitive impairment. MRI imaging often shows non-specific white
matter changes of uncertain significance, whilst functional imaging holds
greater promise with the ability to identify neuronal loss
and inflammation.
The
introduction of HIV therapy transformed a rapidly fatal disease into a chronic
illness and made HIV dementia a vanishing or rare problem in those receiving
effective ART. Dementia occurs in less than 2% of individuals and is usually
associated with treatment failure or advanced, undiagnosed disease.
The idea
that smoldering infection is the underlying cause of HAND has led to attempts
to improve ART penetration into the brain, but these have yet to enter routine
clinical practice. The concept that ART might itself may be neurotoxic remains
unproven. Beyond maintaining good compliance, and ensuring that lifestyle risks
for cognitive impairment are reduced, no specific treatments
are available.
Since the
development of ART, the incidence and severity of neurocognitive problems have
declined significantly. For a small minority, a possibility remains for
impairment that will have an impact upon their abilities to maintain their
employment. This is most likely for older workers, with comorbid risk factors,
who undertake roles that require highly-developed cognitive skills. Small
decrements, that have little effect on day-to-day functioning, may impair their
performance in very complex tasks. Risk factors for cognitive decline – such as
previous neurological problems, poor control of HIV infection, drug abuse and
cardiovascular risks – should be taken into account at underwriting.
Endnote
1.
Heaton, R.K. et al. Neurocognitive change in the era of
HIV combination antiretroviral therapy: the longitudinal CHARTER study. Clin
Infect Dis. 2015 Feb 1; 60(3):473-80. https://www.ncbi.nlm.nih.gov/pubmed/25362201
Sources
·
Nightingale, S. & Winston, A. Measuring and managing
cognitive impairment in HIV AIDS 2017, 31 (Suppl 2):S165-S172
·
Clifford, DB. HIV Associated Neurocognitive Disorder Curr
Opin Infect Dis. 2017 February; 30(1): 117–122.
·
Sundermann, E.E. et al., Sex differences in
HIV-associated cognitive impairment AIDS: November 28, 2018 -
Volume 32 - Issue 18 - p 2719-2726
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