Safe sex practices: What to know
Cancer Drug Shows Promise In Killing 'silent' HIV Cells And Delaying The Virus From Re-emerging In Mice
An existing blood cancer drug has shown promise in killing "silent" HIV cells in animal models and human cells from people living with HIV—a significant pre-clinical discovery that could lead to a cure for the disease.
Hidden HIV cells, known as latent infection, are responsible for the virus permanently remaining in the body and cannot be treated by current therapy options. These hibernating, infected cells are the reason why people living with HIV require life-long treatment to suppress the virus.
Led by WEHI and The Peter Doherty Institute for Infection and Immunity (Doherty Institute), the landmark study is being translated into a new clinical trial to assess whether the blood cancer treatment can be repurposed to offer a pathway towards an HIV cure.
An estimated 39 million people worldwide are living with HIV, including more than 29,400 Australians.
Antiretroviral therapy (ART) is the standard of care treatment given to people living with HIV and is highly effective. But the medication cannot target hibernating HIV-infected cells, meaning it can only suppress the virus—not cure it.
ART for people living with HIV is life-long: if a person stops taking this medication, hibernating HIV-infected cells will reactivate within a very short timeframe, leading to a resurgence of the virus. An estimated 98% of Australians living with HIV currently have undetectable levels of the virus, as it is completely suppressed by their ongoing ART treatment.
In the new study, WEHI researchers used the cancer drug venetoclax on enhanced pre-clinical models of HIV and found it delayed the virus from rebounding by two weeks, even without ART.
The article, "Venetoclax, alone and in combination with the BH3-mimetic S63845, depletes HIV-1 latently infected cells and delays rebound in humanized mice," involves collaborations with the University of Melbourne and Royal Melbourne Hospital, and is published in Cell Reports Medicine.
Co-first author, Dr. Philip Arandjelovic from WEHI, said the discovery is an exciting step towards developing treatment options for the tens of millions of people currently living with HIV globally. "In attacking dormant HIV cells and delaying viral rebound, venetoclax has shown promise beyond that of currently approved treatments," he said.
"Every achievement in delaying this virus from returning brings us closer to preventing the disease from re-emerging in people living with HIV. Our findings are hopefully a step towards this goal."
The study marks the first time venetoclax has been used on its own to assess HIV persistence in pre-clinical models. However, researchers also found the cancer treatment can be combined with another drug that acts on the same pathway and is currently in clinical trials, to achieve a longer delay in viral rebound, with a shorter duration of venetoclax treatment.
"It has long been understood that one drug may not be enough to completely eliminate HIV. This finding has supported that theory, while uncovering venetoclax's powerful potential as a weapon against HIV," Dr. Arandjelovic said.
HIV primarily targets CD4+ T cells, a type of white blood cell crucial for the immune system to properly function.
It is within these cells that HIV can lie dormant, ready to reactivate if the virus is not effectively eliminated. Using human CD4+ T cells donated by people living with HIV who are on suppressive ART, scientists at the Doherty Institute found venetoclax was also able to reduce the amount of HIV DNA in these white blood cells.
Co-first author, The University of Melbourne's Dr. Youry Kim and a Postdoctoral researcher at the Doherty Institute, said venetoclax potently reduced the amount of intact viral DNA in patient cells when studied in the laboratory.
"This indicates that venetoclax is selectively killing the infected cells, which rely on key proteins to survive. Venetoclax has the ability to antagonize one of the key survival proteins," said Dr. Kim.
Venetoclax, marketed as VENCLEXTA, is based on a landmark discovery by Professor David Vaux AO in 1988. The drug is the result of a research collaboration between WEHI and companies Roche, Genentech (a member of the Roche Group) and AbbVie. It was developed by Roche, Genentech and AbbVie and co-developed and trialed in Australia.
The Phase I/IIb clinical trial using venetoclax to treat HIV will start at the end of the year in Denmark, with plans to expand the study to Melbourne in 2024. It will be led by Professor Sharon Lewin (Director of the Doherty Institute), Professor Marc Pellegrini (Executive Director at the Centenary Institute) and Dr. Thomas Rasmussen (clinician scientist at Denmark's Aarhus University).
Prof Marc Pellegrini, a joint corresponding author and WEHI Honorary Fellow, said the trial will replicate the pre-clinical study conducted using WEHI's state-of-the-art technology and facilities. "The trial will assess the safety and tolerability of venetoclax in people living with HIV who are on suppressive antiretroviral therapy."
Melbourne Laureate Professor Sharon Lewin, a joint corresponding author, concluded, "It's exciting to see venetoclax, which has already helped thousands of blood cancer patients, now being repurposed as a treatment that could also help change the lives of people living with HIV and put an end to the requirement for life-long medication."
More information: Marc Pellegrini, Venetoclax, alone and in combination with the BH3-mimetic S63845, depletes HIV-1 latently infected cells and delays rebound in humanized mice, Cell Reports Medicine (2023). DOI: 10.1016/j.Xcrm.2023.101178. Www.Cell.Com/cell-reports-medi … 2666-3791(23)00331-2
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Do I Have To Tell Anyone That I Have HIV?
Key pointsTelling people that you are living with HIV can be a difficult decision to make. Stigma surrounding HIV means that people may be quick to make judgements about you or your behaviour and may act differently towards you once you've shared that you're living with HIV. However, there is also the possibility that sharing your status can unburden you and provide important forms of support that you may need.
This page outlines some general considerations regarding sharing your status or deciding to keep it private.
Many people have outdated ideas of what it means to have HIV. They may have had little education about treatment advances or ways of preventing HIV beyond condoms. Other common misconceptions include that HIV is accompanied by frequent illness, that it inevitably leads to AIDS, or that it is always passed on to babies. Unfortunately, many still have a visceral negative reaction to any mention of HIV; this is rooted in stigma and misinformation.
The weight of choosing to tell someone you have HIV is likely to be impacted by the persistent stigma that surrounds it. Because of this stigma, it means that you need to decide if sharing your status is in your best interests, and if it is necessary. You should carefully consider possible pros and cons of disclosing your status, prior to doing so.
In most instances, it simply isn't relevant and there's no need to share that you are living with HIV, unless you choose to. Many people living with HIV decide that the majority of people they come into contact with have no need to know about their health status. Here, your relationship with the person you are disclosing to takes on central importance.
There are specific considerations for sharing your status with sexual partners, your employer and healthcare providers. There may be important legal considerations in some cases; this will differ depending on where you live.
While some people living with HIV have reported negative reactions to disclosure, there are also those who have been met with incredibly supportive and empathic responses. A third outcome that many report is a feeling of anticlimax: instead of an overly positive or negative response, they find that the build-up to the moment of disclosure is more nerve-wracking than the event itself. This 'shoulder shrug' type response is often very helpful for a person living with HIV, as it helps to normalise the virus with little fanfare or excessive emotion.
Importantly, you can neither predict nor control how someone responds to your disclosure. You also cannot control what they do with the information after you tell them. In instances where you are financially or otherwise dependent on someone, and a negative response can have material consequences, such as a loss of income or shelter, the decision requires more careful consideration.
Sharing that you are living with HIVLiving with HIV has changed a great deal, but not everyone knows or understands this. It might be helpful to share some current information about HIV when you choose to share your status.
Most people living with HIV can expect to live healthy lives, with a normal life expectancy. The vast majority will not go on to develop AIDS and will have good outcomes if they start treatment as soon as possible after their diagnosis and remain adherent to treatment. Treatment has been simplified, is highly effective and has few or negligible side effects in most cases.
Glossary undetectable viral loadA level of viral load that is too low to be picked up by the particular viral load test being used or below an agreed threshold (such as 50 copies/ml or 200 copies/ml). An undetectable viral load is the first goal of antiretroviral therapy.
stigmaSocial attitudes that suggest that having a particular illness or being in a particular situation is something to be ashamed of. Stigma can be questioned and challenged.
disclosureIn HIV, refers to the act of telling another person that you have HIV. Many people find this term stigmatising as it suggests information which is normally kept secret. The terms 'telling' or 'sharing' are more neutral.
diagnosisThe determination that a patient has a particular disease or condition, through evaluation of their medical history, clinical symptoms and/or laboratory test results.
Undetectable = Untransmittable (U=U)U=U stands for Undetectable = Untransmittable. It means that when a person living with HIV is on regular treatment that lowers the amount of virus in their body to undetectable levels, there is zero risk of passing on HIV to their partners. The low level of virus is described as an undetectable viral load.
One important finding – that people living with HIV with an undetectable viral load cannot transmit it to their sexual partners – has been described as life-changing by many people living with HIV. This is known as 'Undetectable = Untransmittable', or simply U=U.
Regardless of whether you're sharing your status with a sexual partner or someone else, it usually helps to frame it in a way that highlights some of the medical advances that have been made both in terms of treating HIV and preventing transmission. Not only does this help to educate people you choose to share your status with, but it also works to destigmatise and normalise speaking about HIV.
It is not your responsibility to educate others about HIV, but this framing may be a helpful way of approaching disclosure. It could also be a way of starting a general discussion about HIV, gauging the reaction, and then deciding if it is the right time to share your status or not.
"So much has changed when it comes to HIV. I take only one pill a day, with no side effects. I can expect to live as long as someone without HIV, and because I'm undetectable, I don't worry about passing it on to my sexual partners."
"I'm working with my doctor to find the right medication to control my HIV. There are so many treatment options these days. If one medication doesn't work well for me – either to control my HIV or because of unpleasant side effects – it's easy to find one that will work. Treatment has come such a long way."
"U=U is an amazing scientific finding! If someone living with HIV is on successful treatment, the virus drops to very low levels. This is called undetectable because it is no longer detected on a lab test. When a person is undetectable, they can't pass HIV on when having sex – even if a condom is not used. It's made a huge difference for me."
Recently, many people living with HIV share their status by simply stating, "I am undetectable." Like the word AIDS, the term 'HIV positive' has become stigmatised and may cause discomfort. While it may be important to explain what undetectable means, there may be a sense of empowerment and a newfound identity by disclosing in this way.
For many people living with HIV, talking about it in an empowering manner, where they have been able to take control of the situation and manage their diagnosis confidently, has made it much easier to share their story with others. Speaking about HIV in this way communicates hope and resilience, instead of shame.
However, this also means that you may need to take some time to process and understand your diagnosis and its implications before you feel ready to tell anyone about it. For some, this needs to be done privately, while others find it easiest to navigate this initial period with the help of their partner, close friends or family. It's important to find what works best for you.
After careful consideration, you may decide that you will choose to share your status with some people, but not others, or in some instances and not others. The process of deciding to share this information can feel burdensome and it may cause you significant anxiety or worry trying to anticipate someone's reaction. It may be most helpful to first share your status with a very trusted friend or confidante, or even a trained professional, such as a psychologist. It is highly beneficial for your first sharing experience to be supportive and non-threatening.
Ultimately, it is your choice to tell someone else that you are living with HIV. It is also up to you to decide how and when to do this, or if you need additional support when doing so. Disclosure should not be a traumatising event, and your wellbeing – mental, emotional and physical – should be the top priority.
HIV Patient With Movement Disorder Has Different Symptoms On Left And Right Sides
A 59-year-old woman with a background of HIV living with an uncontrollable movement disorder presented to Eoghan Donlon, MB, BCh BAO, MRCPI, of the Mater Misericordiae University Hospital in Dublin, Ireland, and colleagues.
Of note, the symptoms occurring on the left side of her body were very different than those on her right side, the team reported in JAMA Neurology.
They learned that the patient had been diagnosed with cerebral toxoplasmosis 18 months previously, shortly after the movement disorder first developed. At that time, she received antimicrobial treatment, but that had been largely ineffective.
On examination, Donlon and team observed cogwheel rigidity affecting her right upper limb, which moved very slowly, with tremor at rest. When clinicians assessed her gait, they noted reduced swing of her right arm. "In contrast, there were prominent hyperkinetic movements of the left side of her body with dystonic posturing of the left upper and lower limb and choreiform movements," they wrote.
The patient underwent a brain MRI with contrast that revealed several ring-enhancing lesions located in the right thalamus, left lentiform nucleus, right frontal lobe, and right posterior-temporal lobe.
Cerebrospinal fluid (CSF) analysis returned normal findings, with no evidence of HIV-1 and HIV-2. On blood tests, HIV viral load was undetectable; she had a CD4 count of 174. Neither serum nor CSF tests detected Toxoplasma DNA.
Donlon and colleagues performed a CT scan of the patient's brain and compared the findings to a scan from 18 months before. Evidence of increased calcification of all lesions suggested the diagnosis of chronic toxoplasmosis. The team considered that the hemiparkinsonism affecting the patient's right side was due to the lesion in the left lentiform nucleus, and the hemidystonia of her left limbs was caused by the lesion in the right thalamus.
They recommended a short trial of risperidone 0.5 mg daily; however, the patient experienced adverse effects of flattened mood and orobuccal dyskinesia, and declined to continue with treatment.
Discussion
Opportunistic infection with cerebral toxoplasmosis is not uncommon in patients with HIV, and as this case demonstrates, may be associated with movement disorders.
During the HIV epidemic, data suggested that 2% to 3% of patients with HIV were affected by movement disorders, particularly parkinsonism and tremor, Donlon and team said. However, they cautioned that use of neuroleptic medications to manage neuropsychiatric complications may have a confounding effect.
Of hyperkinetic movement disorders that may be associated with HIV infection, hemiballismus and hemichorea are reported most commonly, especially in the setting of toxoplasmosis, since it frequently involves the basal ganglia structures, the group noted.
"The presence of hemichorea-hemiballism in patients with AIDS is felt to be pathognomonic of cerebral toxoplasmosis," they wrote.
A series of 64 cases found that the rates of the various manifestations of movement disorders associated with toxoplasmosis were:
There is scarce evidence regarding response to treatment of toxoplasmosis, Donlon and team said. As in this patient's case, treatment may improve symptoms but not necessarily resolve them.
In three of the 64 cases that reported treatment outcomes, "response to levodopa was mild to absent." And while treating the infection tends to improve chorea, "there are few reports of response to symptomatic treatment (apart from 1 report of partial response to tetrabenazine)," the authors wrote.
Kate Kneisel is a freelance medical journalist based in Belleville, Ontario.
Disclosures
The authors reported no conflicts of interest.
Primary Source
JAMA Neurology
Source Reference: Donlon E, et al "Alternate hemibody hyperkinetic and hypokinetic movement disorders due to strategic lesions in cerebral toxoplasmosis" JAMA Neurol 2023; DOI: 10.1001/jamaneurol.2023.2709.
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