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HIV-associated neurocognitive disorders (HAND) have long been recognised as the most common clinical disorders affecting people living with HIV & AIDS. Caused by the HI-virus penetrating the central and peripheral nervous system of the brain, HAND impairs individuals' neurocognitive function. This can have a profound impact on the sufferer, limiting their capacity to carry out daily living activities and restricting their participation in society. Consequently, HAND may trickle down and affect the people around the sufferer, ultimately draining the resources of social institutions.
Whereas a wealth of research on HAND has been conducted in the developed world since the early years of the epidemic, the picture of HAND in Africa is incomplete. Progress has been made in recent years as a result of ‘NeuroAIDS in Africa’ conferences,(2,3) but the little literature available echoes that our knowledge of prevalence, characterisation, and treatment responses of HAND remains limited. For this reason, there is a dire need for research investment of HAND in Africa. The myriad of challenges against our understanding slows down treatment and support development for HAND affected individuals. This paper aims to inform what is currently known of HAND in its epidemiology, effects, testing, and treatments in Africa highlighting the particular areas that require further research.
Causes and Effects of HAND
HIV is part of a group of viruses known aslentiviruses that have a tendency to cause neurological diseases such as HAND. HIV penetrates the nervous system from very early on in the disease progression, possibly at initial systemic infection, albeit in the absence of neurological symptoms at that point.(4) The HIV virus infects macrophages and microglia in the blood, causing damage in the peripheral nervous system, and then directly crosses the blood-brain barrier to reside in the central nervous system.(5) HIV-associated neurotoxicity is therefore caused indirectly through the activation of the macrophages and changes in immune and inflammatory activity rather than by infecting the neurons themselves.(6) Within the brain, HIV can be found in any region but seems to affect the sub-cortical areas in particular and has been found in the basal ganglia and central white matter as well as the brainstem and the cerebellum to a lesser extent.(7) As the HIV virus progresses to AIDS and individuals’ immune systems deplete, these infectious pathophysiological pathways cause symptoms to occur.(8)
HIV infection in the brain expresses as unique neurological syndromes affecting 3 clinical processes - motor dysfunction, behavioural abnormalities and neurocognitive impairments.(9) The neurocognitive disorders manifest along a continuum of clinical severity going from Asymptomatic Neurocognitive Impairment (ANI) characterised as abnormality in two or more cognitive abilities, followed by Mild Neurocognitive Disorder (MND) which is cognitive impairment with mild functional impairment to full blown HIV Associated Dementia (HAD) with marked cognitive and functional impairment.(10,11)
The neurocognitive effects of HAND commonly involve deficits in attention, learning, memory and abstraction, in addition to verbal, psychomotor and sensory function. A study conducted in Cameroon(12) found that HIV or AIDS infected participants performed worse compared to HIV negative controls in the cognitive domains of executive function, speed of information processing, working memory and memory recall. Similarly, in Uganda, HIV positive individuals showed deficits in these cognitive areas as well as learning and attention compared to uninfected individuals.(13) While this provides an overview of HAND manifestations, there are important between country differences. In Cameroon for example, no deficit in visual episodic memory was found in HIV infected patients, however studies in Ethiopia have reported impairments in visual episodic memory, as have studies in developed countries.(14) Further investigation is required to find potential symptom differences between countries.
In relation to everyday activity and participation in society, such impairments have shown to result in HAND affected populations suffering from higher unemployment and loss of income, difficulty with complex tasks such as driving, reduced adherence to antiretroviral (ARV) treatment which has been identified as the reason for increased risk of death in HAND patients(15) and a lower quality of life.(16,17,18) This lack of capacity and performance can of course have consequences on families who have very little external support, causing emotional, financial, and social burden in addition to poorer health status. Concerning society, the economy may incur losses due to the lack of productivity and the increased health and social care burden in countries where infrastructures have little capacity to cope; although these wider effects described have yet to be documented in Africa.(19)
Literature indicates that HAND is an ongoing and prevalent problem, although efforts to determine prevalence rates have produced variable results. Prevalence rates of HAND estimated in different studies are found to range from 12% to 56% across the world.(20) A similar variability is found for African prevalence, where the prevalence of HAD is reported from 3% to as high as 54%.(21) The WHO Neuropsychiatric AIDS study in Zaire and Kenya found that in HIV symptomatic individuals, neuropsychological impairment was reported at 19.1% and 15.3% respectively.(22) Likewise, in Northern Tanzania a prevalence rate of 54% HAD in HIV infected populations was observed, while in a Ugandan hospital a prevalence of 16% was found.(23) However, when taking the different types of diagnoses into account, in Uganda Wong et al. found that HAD was present in 31% of HIV infected patients and MND in 47% of the patients.(24) Therefore, a good estimate of HAND should account for the prevalence of all and each type of HAND in HIV populations.
Between-country variability of HAND prevalence could be a result of how prevalent risk factors of HAND are in respective countries. In particular, the type of HIV clade/subtype that is predominant in each country could account for the prevalence found. There is a growing concern that the existing 10 HIV subtypes may differ in their biological properties and disease progression, determining whether individuals develop HAND.(25) In Uganda where HIV subtype A and D are dominant, compared with subtype A, subtype D is found to be associated with an increased risk of dementia.(26) Eighty nine percent of individuals with HIV subtype D were categorised as having dementia compared to only 24% of subtype A. Conversely, in Ugandan HIV positive non-ART children, it appears that subtype A is associated with poorer neuropsychological performance than subtype D,(27) indicating that Ugandan children and adults may be at different risk of dementia. Regarding subtype C, a study in Ethiopia where subtype C is most prevalent showed no neuropsychological difference between HIV positive and negative individuals therefore concluding that subtype C was less neurotropic.(28) However, in South Africa where subtype C is also prevalent, a pilot study suggested that subtype C is associated with neurocognitive impairment.(29) Mixed results could be for a variety of reasons including that the Ethiopia study was carried out in a community and not a clinical group but also the possibility that environmental interactions with subtype C influence whether it is a risk factor in countries or not. Unfortunately, the neurovirulence of each HIV subtype and their relation to each other is unknown territory and requires further work. It may also be important to investigate the reasons for HIV subtypes developing HAND including environmental interactions in order to identify the differences found between age and cultural populations.
In addition to HIV subtypes, older age is commonly found as a correlate associated with HAND.(30,31,32,33) It has been illustrated that for each additional 10 years of age, a greater than 2 times risk of HAD can be observed.(34) Lower CD 4 counts are also risk factors indicating that the further the disease progression of HIV & AIDS, the higher the chance is of developing HAND.(35) Similarly, drug abuse has been identified as a risk factor and studies implicate the use of methamphetamine,(36) injection drug use,(37) and alcohol abuse,(38) although causality of the relationship between substance abuse and HAND is difficult to establish.(39) The final, most frequent HAND risk factor identified by researchers, is low education.(40) However, it should be mentioned that educational level can influence neuropsychological test performance and therefore studies may confound the true effect of education on HAND. Adding to these common risk factors, studies have reported anaemia, low body mass index,(41) co-infections(42) and the female sex as associated with HAND. Mixed results are reported for risk factors, thus studies need to be replicated as well as their effect sizes established.
Screening and Neuropsychological Testing of HAND in Africa
The confounding effect that education has on neuropsychological testing highlights the importance of standardised and validated outcome measures (OMs) solely measuring neurocognitive changes. OMs for diagnosing and screening HAND in clinical practice and trials need to demonstrate validity (the extent to which a measure actually evaluates the underlying construct it intends to measure) and reliability (the consistency and repeatability within and between administrations) in the populations they are administered in. In Africa, standardised examination is largely lacking and less well studied, making the transfer and validation of Western neuropsychological tests to African settings a difficult but imperative task.(43) There are clear cultural, way of life, and language differences(44) between African and developed country settings, which make assumptions in the development of OMs in the West inapplicable to African populations. For example, the level of education and the presence of a written language can affect test understanding and administration, such that those with a higher as opposed to lower education perform better at the tests irrelevant of neurocognition.(45) Likewise, way of life differences can affect the interpretation of items in functional OMs where the difficulty of organising housework or daily chores for example would have different implications in a European city than in a rural village in Africa.
A recent study in Zambia(46) analysed the results of how adult controls performed on the adapted Western neuropsychological tests compared to Western norms. It was found that Zambian scores on the International HIV Dementia Scale (IHDS), Colour trails 2, Timed Gait, and Grooved Pegboard fell below that of Western norms, indicating that culture and education can have an influence on neuropsychological performance. The IHDS is an adaption of the original HIV Dementia scale so it can be “easily performed across different cultures”.(47) Although results in Ugandan populations showed the IHDS to be valid,(48) it does not show universal applicability and researchers should very cautiously assess the suitability of the measure for intended populations. Recently, researchers put together the HIV International Neuropsychological Battery to assess HAND in Africa, which has showed promising results.(49) Nevertheless, the problems indicate that tests may be inappropriate and of little use for application in Africa in their original form. If tests are redesigned and validated to ensure that they are appropriate to use in African settings, they can prove useful.(50) Otherwise, confounding factors can make interpretation of tests qualitatively and clinically difficult and potentially not meaningful. This not only wastes resources but also stunts our understanding of HAND.
Treatment and Care
Treatment for HAND focuses largely on fighting HIV through highly active antiretroviral therapy (HAART), although adjuvant therapies are becoming popular. HAART aims to restrain the effect of HIV on the nervous system through a combination drug treatment. Since its introduction in 1996-97, anecdotal and epidemiological evidence has demonstrated the success of HAART in reducing the incidence of HAD and improving cognitive impairment.(51) Incidence rates of HAD have shown a drop of 15 to 50% reaching a rate as low as 10.5%.(52) In some cases cognition is stated to improve for at least 3 months after beginning therapy with one study showing improvement maintained for up to 2 years. How HAART has this effect has yet to be determined, but it is possible that it suppresses initial HIV infection progressing in the CNS and/or controls the replication of infection in the peripheral nervous system, lessening the risk of viral re-infection in the brain.
Unfortunately, it is increasingly shown that HAART does not provide complete protection from HAND. There is evidence illustrating that patients on HAART continue to display cognitive decline albeit at a lower intensity than before HAART.(53) Furthermore, while the incidence of HAD has decreased, the pathological manifestation has not reduced. In fact, the frequency of MCD has increased.(54) Therefore, HAART may reduce HAND from the high intensity of HAD to a less severe form of HAND, although not completing stopping it. The theoretical reasons speculated for neurocognitive decline despite HAART are based on ARV drug regimens having different effects on the nervous system. This means that HAND treatment may depend on the choice of the drug combination used.(55) Some regimens have poor penetration into the CNS and lower concentration of them in the cerebrospinal fluid (CSF).(56) Studies have indeed suggested that the brain may harbour ARV resistant strains and that certain ARV regimens are not suitable for combating HAND. On the other hand, ARV drugs that optimise penetration across the CNS, known as ‘neuroactive’ ARVs are able to exceed the concentration required to suppress HIV replication to improve HAND treatment.(57) The use of 3 or more neuroactive ARVs has been recommended by one study(58) where HIV infected patients who did so showed better neuropsychological improvements than individuals receiving fewer neuroactive ARVs. However, not all studies have observed this result and controversy remains on the relationship between highly penetrating ARV drugs and HAND. The situation is clearly complex and definitive conclusions concerning ARV regimens and penetration of the CNS and CSF are required.
Also complicating HAART is the associated ARV-induced neurotoxicity of higher CNS drug concentrations. NRTIs such as didanosine, zalvitabine, and stavudine and new PIs such as amprenavir and lopinavir have shown to be risk factors for peripheral neuropathy. CNS side effects are also reported, with efravirenz and psychiatric symptoms that begin soon after treatment and decline with ongoing treatment. These side effects include confusion, impaired concentration, psychotic symptoms and sleep disturbances.(59) Intriguingly, studies show neurological pathology to shift post-HAART, from the sub-cortical pattern to the hippocampus and surrounding entorhinal and temporal cortex during HAART treatment. Symptoms may express this pathological fluctuation. For example, in one study HIV-infected individuals on HAART expressed improvement in attention, verbal fluency, and visuoconstruction areas compared with individuals on monotherapy, although greater deficits were exhibited in learning efficiency and complex attention for patients on HAART.(60) Therefore, while HAART can yield positive effects on certain areas, it may exert negative effects in other areas of the brain and neurocognitive function. Increased understanding of ARVs may help to reveal the most effective regimens for reducing the prevalence and incidence of HAND.
This broad overview suggests that the picture of HAND in Africa is incomplete due to gaps in knowledge and information surrounding the issue. Research is needed to further our understanding of the pathology and subtypes of HAND, as well as the benefits and adverse effects of specific ARV regimens - with explanatory reasons to support the results. Despite the importance of these needs, emphasis must be placed on creating and validating the screening tools used for detecting neurocognitive functional status and change. Validated tools are imperative - not only for diagnosing HAND but also for improving the quality of HAND studies and the speed of therapeutic development. Taking into account the resource constraints that African countries face individually, developing a network for HAND, like the experts holding conferences in Africa are aiming for, could be very beneficial. Collaboration and sharing resources such as neurocognitive OMs, participant pools, and research projects on treatment options could lead to a better understanding of HAND, standardise OMs, aid therapeutic development, and guide standards of care for HAND across Africa where many providers may have little awareness of it. Given the many years of research neglect, it is time for us to reflect, invest, and lend a hand for HAND.
(1) Contact Farah Seedat through Consultancy Africa Intelligence’s HIV & AIDS Unit (email@example.com).
(2) Robertson, K. et al., 2008. Second assessment of NeuroAIDS in Africa. Journal of Neurovirology, 14, pp.89-101.
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Written by Farah Seedat (1)