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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.
