If someone living with HIV is not on antiretroviral therapy, the virus can cause inflammation in, among other places, the brain. (Photo: Shutterstock)News & Features
3rd March 2026 | Biénne Huisman
Antiretroviral therapy has shifted HIV from a fatal to a chronic condition. But neuropsychiatrists say it is imperative for people living with the virus to start treatment immediately as the “duration of untreated exposure” may cause irreversible brain damage and impact long-term cognitive health.
It has been recognised for decades that cognitive impairment is a potential complication of HIV infection. Questions over how likely and how serious this potential complication is have become more urgent over time as the population of people living with HIV ages — ageing after all also increases the risk of cognitive decline.
There were around 1.75 million people over the age of 50 living with HIV in South Africa in 2024, according to Thembisa, the leading mathematical model of HIV in the country. This is just over 20% of the estimated eight million HIV positive people in the country. A study published in the Lancet medical journal also has the number at around 20% in sub-Saharan Africa.
This is a delicate field of enquiry as researchers walk a tightrope to avoid “the burden of double stigma”, while conceptualising the necessary tools to best diagnose brain problems and suitable interventions.
Within as little as two weeks
At Groote Schuur Hospital’s Neuroscience Institute, Professor John Joska, director of the University of Cape Town’s (UCT’s) HIV Mental Health Research Unit, explains that HIV can enter the brain within as little as two weeks after the initial infection – primarily through infected white blood cells, such as lymphocytes. If a person is not on antiretroviral therapy, the virus can cause inflammation in the brain and possibly also tissue damage.
“The brain is a protected compartment,” says Joska. “A theory as to how the virus, which is a protein particle, gets into the brain is through infected lymphocytes. This doesn’t directly infect nerve cells, what we call neurons. It infects other supporting tissues and cells in the brain, causing an inflammation which damages typically the white matter of the brain. Over time, that inflammation can cause loss of neurons, but indirectly.”
While antiretroviral therapy is crucial for clearing and suppressing HIV in all body compartments, including in the brain, he says that it does not reverse damage that occurred before the treatment was started.
“Today, people with HIV are living near normal lifespans,” he says. “The question is, will the fact that they’ve had HIV, with some duration of untreated exposure and potential loss of brain tissue, cause them to be at higher risk than the average person for developing dementias of old age – which really are mainly Alzheimer’s disease or vascular dementia.” It is these longer-term effects that are the main concern when it comes to the impact of HIV on the brain.
Part of the problem is that South Africa not only has an ageing population of people living with HIV, but many of these people would only have started treatment quite long after they contracted the virus. One key reason for this is the South African government’s reluctance to make antiretroviral treatment available in the early 2000s. It has been estimated that those delays resulted in over 300 000 avoidable deaths – they may also be contributing to brain health issues now and in the future.
From efavirenz to dolutegravir
Apart from HIV itself, some of the medicines used to treat the infection have also had an impact on the brain.
In 2019, the standard HIV treatment in South Africa changed from a three-drug combination containing an antiretroviral drug called efavirenz, to a combination containing the drug dolutegravir. This shift had mental health benefits, as evidenced in research lead by Joska’s fellow UCT Neuro-HIV researcher, Associate Professor Sam Nightingale.
Joska says: “The study looked at the period from 2017 to 2020 and the switch from efavirenz to dolutegravir based treatment. It was well known that efavirenz caused, certainly for the first two months, a bunch of psychotropic or psychological issues like nightmares or anxiety, even psychosis for some people. But our findings showed people who switched to dolutegravir actually do very well. They look more like people without HIV after eight months. So dolutegravir has been a huge advantage, not only because it’s robust, but because it’s neuro-protective.”
New models for HIV and cognitive impairment
A shift is underway in how experts are thinking about cognitive impairment in people with HIV. Some neuropsychiatrists, including Joska, are recommending a shift away from the 2007 HIV-Associated Neurocognitive Disorders model, arguing that its cognitive test scores do not adequately account for variables such as education and socioeconomic background, and that it can overdiagnose impairment. The argument is set out in an article, lead-authored by Nightingale, that was published in the journal Nature Reviews Neurology in 2023.
The authors argue that a label of cognitive impairment might cause a “double burden of stigma” for people living with HIV – affecting self-esteem, inciting fear and prompting further discrimination against persons already subject to stigma as it stands. To illustrate the point, they point out how, up until recently, people with HIV in the United Kingdom could not become airline pilots due to concerns over cognitive impairment. However, following a campaign by a pilot living with HIV, the United Kingdom’s Civil Aviation Authority removed the ban in 2022.
Nightingale and his colleagues argue that traditional test scores be used in conjunction with real-life symptoms and medical evidence of brain problems. It introduces the conceptual model of HIV-Associated Brain Injury, which refers specifically to damage caused by the virus. This distinguishes it from other causes of cognitive impairment such as depression, substance abuse, diabetes and cardiovascular disease. As Spotlight previously reported, HIV is also associated with an increased risk of depression, though this is at least partially driven by social factors.
Lower cognitive function associated with late diagnosis
At the 2026 Conference on Retroviruses and Opportunistic Infections hosted in Denver in the United States in late February, these issues were tabled at a discussion titled “When I’m 64: Neurodegeneration, Epigenetic Aging, and Cognition in Older People With HIV.”
In his presentation, Professor Alan Winston of Imperial College London, also a member of the International HIV-Cognition Working Group, and a frequent co-author alongside Joska and Nightingale, relayed existing research findings that on average, people living with HIV have lower cognitive function – including memory, attention span and executive function like planning – compared to people who don’t have HIV of the same age. He said that this manifests as an increased risk of lower grade early dementia.
Like Joska, Winston stressed that the most deteriorated cognitive function in people living with HIV is associated with untreated HIV and late HIV diagnosis. He reiterated that starting HIV treatment soon after diagnosis is protective, and that viral suppression is associated with better cognition. In groups of patients with HIV well controlled on dolutegravir-based HIV treatment, cognition appears similar to HIV negative groups, he said.
HIV clinicians need to pay better attention to the brain
In an impassioned presentation, Dr Shibani Mukerji, Associate Professor of Neurology at Harvard Medical School, argued that protecting the brain is an overlooked frontier in effective HIV treatment, and that clinicians need to pay more attention to it.
“By the time patients and clinicians notice cognitive decline – generally and in HIV – the damage to the brain is done and lives are affected negatively. People don’t raise cognitive concerns early enough due to stigma, fear, [and] lack of recognition of the issues. It is seen as ‘just getting old’,” she said.
Mukerji emphasised the need to prioritise brain health. “HIV doctors and treatment programmes are focused, almost exclusively, on viral load as the marker of successful treatment. They may be thinking laterally and consider TB and other infections, maybe cardiovascular disease – but they are definitely not paying enough attention to brain health. HIV doctors aren’t aware enough of brain health issues in people living with HIV, and even when they are, they often don’t feel comfortable diagnosing or managing it, so it is under recognised and under diagnosed.”
The perception that there is no way to manage or treat cognitive decline –generally and in people living with HIV – is wrong, she said, adding that optimising physical, mental and social health is critical for brain health.
“Almost half of dementia risk [in people in general] is linked to preventable causes,” she told conference delegates, along with a slide listing preventable causes including loss of hearing, social isolation, cardiovascular disease and depression.
She explained: “If someone has cognitive decline and for example you improve their hearing – if they have hearing issues – and you work on their social isolation, and treat their vascular disease, and treat their depression, you can see a marked improvement in their cognition.”
Ending her presentation with a twist of humour, Mukerji’s last slide referred to the session’s title, a reference to the Beatles song on aging “When I am 64”. She printed the song’s lyrics: “When I get older, losing my hair, many years from now…”, closing her talk by saying: “It’s okay to stand up and sing, in fact your doctor might prescribe it.”
