Neuropsychiatric problems related to HIV infection and antiretroviral therapy in Cape Town

Neuropsychiatric problems are common in people living with HIV (PLWH). Cognitive impairment (ie. problems with thinking and memory) can affect around a quarter of PLWH and is often associated with depression and other mental health symptoms. These problems can have a major impact on the person involved, causing difficulties with daily functioning and decision-making, reduced employment and overall poorer quality of life. In addition, people with neuropsychiatric problems are less likely to take their HIV medication regularly, meaning that there is a risk that the treatment could become ineffective. PLWH who do not take their medication regularly (called poor adherence) are more likely to become unwell from HIV, and there is an increased risk they will pass the virus to someone else.

In some PLWH neuropsychiatric problems can be related to damage to the brain, either from the HIV virus itself or from the antiretroviral medication taken to combat HIV. There is little known about the extent of this problem in South Africa, how to test for it and what to do to help those affected. This is an important area of research as these factors are potentially treatable. To investigate this we will perform a brief screening test for cognitive problems in Cape Town clinics. Based on this we will ask 178 people to be involved in our study - half with cognitive problems and half without. These will undergo more detailed neuropsychiatric profiling involving a computer based test of cognitive function and a series of questionnaires related to mental health symptoms. We will assess their adherence to medication by looking at how often they pick up their tablets and how much medication can be measured in their blood. We will then perform a lumbar puncture (LP); this involves putting a needle into the lower spine to take a sample of the fluid that sits around the brain and spinal cord, called cerebrospinal fluid or CSF. We will test the CSF to see if there is HIV virus at greater levels than in blood; this can occur in around 5-10% of patients and may be due to the lower concentrations of antiretroviral drugs found in the brain and CSF. It can cause inflammation to the brain and hence neuropsychiatric problems. We will then change their HIV treatment from efavirenz (current most common treatment in South Africa) to dolutegravir (a newer, more effective treatment). We will repeat testing and LP 6 months later. This will allow us to see to what extent HIV in the brain is causing neuropsychiatric problems, and whether dolutegravir is an effective treatment for this.
Efavirenz can be toxic to the brain potentially leading to cognitive problems and/or depression. Although dolutegravir has fewer side effects it can also be toxic to the brain, causing anxiety and insomnia in some patients. As well as assessing symptoms we will measure drug concentrations in blood and CSF. This will allow us to investigate the toxic effects of these drugs on the brain. We will also test patients DNA to see whether genetic differences play a role in determining which patients are most affected.

ODA compliance:
The reason we are interested in these factors is that both HIV in the brain and drug toxicity can potentially be treated, offering a way to help PLWH with neuropsychiatric problems, and perhaps offer new ways to tackle poor adherence to medication. Such treatments would improve the welfare of PLWH and increase their potential to earn a living, support their family and contribute to society.

Guidelines developed in Europe and North America suggest that PLWH should be routinely tested for cognitive impairment, and a LP performed if other causes have been excluded. We don't know whether this advice is appropriate for South Africa where the challenges are different and resources are more limited. This study will provide useful information to guide public health policy decisions in this area, ensuring funds are allocated most effectively.

Neuropsychiatric problems are a major public health issue in people living with HIV (PLWH) in South Africa. Functional cognitive impairment affects around 25% (a further 25% may have asymptomatic impairment). These have a major impact on daily functioning, employment and quality of life, and are closely linked to poorer antiretroviral therapy (ART) adherence risking virological failure and jeopardising positive heath outcomes, as well as increasing the risk of HIV transmission.
Neuropsychiatric problems may share common underlying biological mechanisms of HIV-related neuroinflammation and/or ART neurotoxicity. In this study we aim to determine the impact of these factors; important as they are potentially modifiable.

We will screen clinic patients for cognitive impairment (in line with European and North American guidelines), recruiting 89 participants with and 89 without cognitive impairment for more detailed testing using computer based cognitive assessment, mental health symptom questionnaires, adherence assessment and lumbar puncture.

HIV can be found at higher levels in cerebrospinal fluid (CSF) than peripherally, potentially a result of low central nervous system (CNS) exposure to ART. This can be associated with neuroinflammation and neuropsychiatric problems. The prevalence has not been investigated in South Africa where the risk factors are more common than in resource rich settings. We will test CSF for biomarkers of neuroinflammation and CNS compartmentalision and correlate with symptoms.

First line ART in South Africa is due to change from efavirenz to dolutegravir, in line with international guidance. Both drugs are associated with neuropsychiatric side effects. We will determine associated CSF pharmacokinetic/genetic parameters associated with symptoms before and 6-months after this switch, and assess the effectiveness of dolutegravir at treating compartmentalised HIV in CSF.

Who will benefit from this research?
This research is primarily designed to benefit people living with HIV (PLWH) in South Africa who are taking antiretroviral therapy (ART); South Africa has the largest ART treatment programme in the world with an estimated 3.4 million people currently receiving treatment. The study also has implications for HIV management more broadly across sub-Saharan Africa, where research findings from South African populations are more applicable than studies from Europe or North America. There are novel clinical aspects to this study that will inform care of PLWH in other HIV populations around the world. Novel scientific aspects that will be of benefit to academics in various fields are described in the 'Academic Beneficiaries' section above.

How will they benefit from this research?
Poor adherence to ART is linked to drug resistance, treatment failure, HIV comorbidity and mortality. Improving adherence is currently a key public health priority in South Africa and globally given the WHO 90-90-90 target. This study will characterise cognitive impairment and mental health symptoms in PLWH across a range of adherence. This will help to understand to what extent neuropsychiatric issues are drivers for poor adherence in this population. This will be of potential direct benefit to PLWH as management of cognitive and/or mental health problems may help improve adherence and, in turn, retention in care. Investigation of biological causes may provide novel treatment strategies for reduced adherence.

Cerebrospinal fluid (CSF) discordance may be more common in South Africa than in resource rich settings due to the prevalence of risk factors in this population. This study will benefit PLWH by identifying who is at risk and should be offered an LP, and conversely which patients can safely avoid undergoing this invasive procedure. It will characterise the implications of CSF discordance, and importantly what degree of CSF discordance should be considered clinically relevant, informing public health policy on investigation and treatment of neuropsychiatric issues in HIV. There are implications for PLWH more widely as findings will help inform definitions of CSF discordance, currently an important issue of debate globally.

Screening for cognitive impairment is recommended by international guidelines and this study informs whether and how this screening should be applied to South African PLWH. Several aspects are examined, including stratification for lumbar puncture and application of low copy assays in CSF. Systematically examining screening in this way is of direct benefit in three ways: firstly it informs the most accurate methods of identifying those that can benefit, secondly it avoids inconvenient and potentially invasive testing in those that will not benefit, and thirdly it informs effectiveness of screening - important in South Africa where limited resources need to be prioritised for maximum impact.

Knowledge of the central nervous system (CNS) side effects associated with the switch from efavirenz to dolutegravir in this population will inform management and help clinicians care for their patients. Those most likely to benefit from early efavirenz to dolutegravir switch can be identified, and the side effects to be aware of on dolutegravir can be identified.
In this study we are looking at host genetics to determine whether common polymorphism in genes known to affect metabolism of these drugs has clinical effects in the CNS. In resource rich areas where clinical genetic testing is available, there may be implications for personalised medicine. Currently such genetic tests are not widely available for clinical use in South Africa, however determining the key drivers of CNS toxicity may help direct treatment in this population.