Consuming THC (Delta-9-tetrahydrocannabinol) while pregnant could potentially affect development of the foetus and lead to life-long health impacts for offspring, according to a new study published in the journal Clinical Epigenetics.
THC is the main psychoactive ingredient in cannabis, which is growing in popularity and availability. The prevalence of cannabis use in pregnancy is also rapidly increasing, especially during the first trimester, when the foetus is most vulnerable to environmental exposures, to mitigate common symptoms like morning sickness. However, the potential effects of prenatal cannabis use on foetal development remain inconclusive, in part due to a lack of safety data. This study aimed to identify the potential long-term health impacts of THC use during pregnancy.
In a non-human primate model, Oregon Health & Science University researchers found that exposing a pregnant subject to THC altered placental and foetal epigenetics. Researchers also found that that these changes to gene regulation and expression are consistent with those seen with many common neurobehavioural conditions, including autism spectrum disorder.
“Cannabis is one of the most commonly used drugs and is widely available across the country, so there is a common perception that its completely safe to use,” said the study’s lead author Lyndsey Shorey-Kendrick, PhD, a computational biologist in the Division of Neurosciences at OHSU’s Oregon National Primate Research Center, or ONPRC. “The reality is that cannabis still carries many health risks for certain populations, including those who are pregnant. If we’re able to better understand the impacts, we can more effectively communicate the risks to patients and support safer habits during the vulnerable prenatal period.”
In a model using nonhuman primates, researchers administered THC in a daily edible and compared its effects to a group receiving a placebo. Specifically, researchers evaluated the epigenetic changes in several key areas that indicate healthy prenatal development: the placenta and foetal lung, brain and heart.
When looking at these areas, analyses showed that THC exposure altered the epigenome, meaning a process in which the information encoded in a gene is turned into a function or observable trait. Genes are all specifically coded to contribute to different functions of the body and brain, so any impact on epigenetic processes due to drug exposure is concerning, especially during a critical developmental window such as pregnancy.
Researchers found that significant changes involved genes associated with common neurobehavioral disorders, including autism spectrum disorder and attention deficit hyperactivity disorder. These conditions are linked to adverse health outcomes in childhood and adolescence, including poorer memory and verbal reasoning skills, and increased hyperactivity, impulsivity and inattention.
The research team hopes findings from this study will add to the limited existing literature on THC use during pregnancy, and help guide patient counselling and public health polices focused on cannabis in the future.
“It’s not common practice for providers to discuss cannabis use with patients who are pregnant or trying to conceive,” said the study’s corresponding author, Jamie Lo, MD, MCR, associate professor of obstetrics and gynaecology (maternal-foetal medicine) at OHSU. “I hope our work can help open up a broader dialogue about the risks of cannabis use in the preconception and prenatal period, so we can improve children’s health in the long run.”
Most cancer cells are aneuploid, having extra chromosomes, and they depend on those chromosomes for tumour growth, a new study in the journal Science reveals. Eliminating them prevents the cells from forming tumours, which suggests that selectively targeting extra chromosomes may lead to a new form of cancer treatment which could spare healthy tissue which has the typical 23 pairs.
“If you look at normal skin or normal lung tissue, for example, 99.9% of the cells will have the right number of chromosomes,” said senior study author Jason Sheltzer, assistant professor of surgery at Yale School of Medicine. “But we’ve known for over 100 years that nearly all cancers are aneuploid.”
However, it was unclear what role extra chromosomes played in cancer, such as whether they cause cancer or are caused by it.
“For a long time, we could observe aneuploidy but not manipulate it. We just didn’t have the right tools,” said Sheltzer. “But in this study, we used the gene-engineering technique CRISPR to develop a new approach to eliminate entire chromosomes from cancer cells, which is an important technical advance. Being able to manipulate aneuploid chromosomes in this way will lead to a greater understanding of how they function.”
Using their newly developed approach, which they dubbed Restoring Disomy in Aneuploid cells using CRISPR Targeting (ReDACT), the researchers targeted aneuploidy in melanoma, gastric cancer, and ovarian cell lines. Specifically, they removed an aberrant third copy of the long portion, or ‘q arm’, of chromosome 1, which is found in several types of cancer, is linked to disease progression, and occurs early in cancer development.
“When we eliminated aneuploidy from the genomes of these cancer cells, it compromised the malignant potential of those cells and they lost their ability to form tumours,” said Sheltzer.
Based on this finding, the researchers proposed cancer cells may have an ‘aneuploidy addiction’ – a discovery that eliminating oncogenes, which can turn a cell into a cancer cell, disrupts cancers’ tumour-forming abilities. This finding led to a model of cancer growth called ‘oncogene addiction’.
When investigating how an extra copy of chromosome 1q might promote cancer, the researchers found that multiple genes stimulated cancer cell growth when they were overrepresented – because they were encoded on three chromosomes instead of the typical two.
This overexpression of certain genes also pointed the researchers to a vulnerability that might be exploited to target cancers with aneuploidy.
Previous research has shown that a gene encoded on chromosome 1, known as UCK2, is required to activate certain drugs. In the new study, Sheltzer and his colleagues found that cells with an extra copy of chromosome 1 were more sensitive to those drugs than were cells with just two copies, because of the overexpression of UCK2.
Further, they observed that this sensitivity meant that the drugs could redirect cellular evolution away from aneuploidy, allowing for a cell population with normal chromosome numbers and, therefore, less potential to become cancerous. When researchers created a mixture with 20% aneuploid cells and 80% normal cells, aneuploid cells took over: after 9 days, they made up 75% of the mixture. But when the researchers exposed the 20% aneuploid mixture to one of the UCK2-dependent drugs, the aneuploid cells comprised just 4% of the mix nine days later.
“This told us that aneuploidy can potentially function as a therapeutic target for cancer,” said Sheltzer. “Almost all cancers are aneuploid, so if you have some way of selectively targeting those aneuploid cells, that could, theoretically, be a good way to target cancer while having minimal effect on normal, non-cancerous tissue.”
More research needs to be done before this approach can be tested in a clinical trial. But Sheltzer aims to move this work into animal models, evaluate additional drugs and other aneuploidies, and team up with pharmaceutical companies to advance toward clinical trials.
“We’re very interested in clinical translation,” said Sheltzer. “So we’re thinking about how to expand our discoveries in a therapeutic direction.”
Older people who have fluctuating levels of total cholesterol and triglycerides may have a higher risk of Alzheimer’s disease and related dementias compared to people who have steady levels, according to new research published online in Neurology. Since the study is observational, it cannot establish a causative link.
“Prevention strategies for Alzheimer’s and related dementias are urgently needed,” said study author Suzette J. Bielinski, PhD, of the Mayo Clinic in Rochester, Minnesota. “Routine screenings for cholesterol and triglyceride levels are commonly done as part of standard medical care. Fluctuations in these results over time could potentially help us identify who is at greater risk for dementia, help us understand mechanisms for the development of dementia and ultimately determine whether levelling out these fluctuations could play a role in reducing dementia risk.”
Researchers used health care data to identify 11 571 people age 60 or older without a prior diagnosis of Alzheimer’s disease or dementia. They assessed total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) for the participants on at least three different days in the five years before the start of the study. Then participants were assigned into five equal groups based on the degree of measurement fluctuation, from lowest to highest.
Participants were followed for an average of 13 years. During that time, 2473 of them developed Alzheimer’s disease or another form of dementia. After adjusting for confounding variables, researchers found for total cholesterol, participants in the highest fluctuation group had a 19% increased risk of dementia compared to those in the lowest group. Of the 2311 people in the highest group, 515 developed dementia compared to 483 of the 2311 people in the lowest group. For triglycerides, those in highest group had a 23% increased risk.
No link was found between dementia and variations in LDL and HDL, however.
“It remains unclear why and how fluctuating levels of cholesterol and triglycerides are related to the risk of Alzheimer’s disease,” said Bielinski. “Further studies looking at the changes over time for this relationship are needed in order to confirm our results and potentially consider preventative strategies.”
One study limitation was that researchers looked at Alzheimer’s disease and related dementias as a whole and did not differentiate between the types of dementia.
Children prescribed a stimulant to manage symptoms of attention deficit hyperactivity disorder (ADHD) do not have more substance use or substance use disorder (SUD) as adolescents or young adults, according to a new study appearing in JAMA Psychiatry.
The study’s findings may provide some reassurance to parents and clinicians who may be hesitant to prescribe ADHD stimulant medications out of fear that this may result in future substance abuse.
“Stimulants are the first-line treatment recommended for most individuals with ADHD – the drug class is an evidence-based treatment with few side effects,” said Brooke Molina, PhD, professor of psychiatry, psychology and paediatrics at University of Pittsburgh. “Because stimulant medications are classified by the Drug Enforcement Administration as schedule two substances with the potential for misuse, many people fear that harmful substance use could result.”
Marked by chronic patterns of inattention, hyperactivity or impulsivity, ADHD is a chronic condition that must be monitored throughout an individual’s life.
Molina and her colleagues assessed patients with ADHD over a 16-year period from childhood through adolescence to early adulthood to see if there was any association between stimulant treatment and subsequent substance use. The study accounting for dozens of demographic, clinical and psychosocial factors that may predispose an individual to treatment and substance use to address the relationship between childhood use of prescription stimulants and later SUD.
“Our study not only accounted for age, but also used a statistical method that adjusted over time for the many characteristics that may distinguish treated from non-treated individuals,” said study co-author Traci Kennedy, PhD, assistant professor of psychiatry at Pitt. “Considering these factors allowed us to more accurately test the relationship between stimulants and substance use.”
While other studies have sought to uncover and define a possible connection between prescription stimulant use for ADHD and SUD, the association between the two has remained controversial. Some studies suggested a protective effect of prescription stimulant use on the risk of having SUD later in life, while others failed to find an association.
After accounting for a number of factors, the researchers found no evidence that prescription stimulant treatment in childhood provided protection against developing a SUD for adolescents or young adults with ADHD. Nor did they find an association between stimulant use during childhood and increased substance misuse in the future
While some study participants self-reported an increase over time in heavy drinking, marijuana use, daily cigarette smoking and using other substances, an association with age was also found for stimulant treatment, with older participants being less likely to continue taking medication. When these trends were paired with rigorous statistical analysis, results provided no evidence that prolonged stimulant use is associated with reduced or increased risk for SUD.
“We hope the results of this study will help educate providers and patients,” Molina said. “By understanding that stimulant medication initially prescribed in childhood is not linked to harmful levels of substance use, I anticipate that parents’ and patients’ fears will be alleviated.”
Pitt researchers plan to study individuals who were first diagnosed with ADHD and treated with stimulants in adulthood. The study aims to learn if there are differences in the characteristics and outcomes of these adults compared to people who were diagnosed and first treated with stimulants in childhood.
A small South African study published in the open-access journal PLOS ONE suggests that programmes promoting interaction between retirement home residents and children may provide quality of life improvements and could help manage residents’ anxiety and depression.
Among retirement home residents, previous research has shown that common mental health conditions often go undetected and untreated. These conditions, which include anxiety and depression, are typically treated with a combination of drugs and non-pharmacological interventions.
One intervention is the Eden Alternative, which identifies loneliness, helplessness and boredom as key challenges to overcome provide a higher quality of life. Evidence suggests that programmes that enable older adults to regularly interact with children may improve mental health, but these have mostly been done outside of retirement homes and few have looked at such programmes in South Africa.
To deepen the understanding of potential benefits of intergenerational interactions, Elizabeth Jane Earl and Debbie Marais of Stellenbosch University, South Africa, conducted a study at a retirement home in South Africa. Residents were able to regularly interact with children who attend an onsite preschool. Activities include playing games, doing puzzles, reading, or singing with the children.
Ten female residents were recruited and invited to complete a questionnaire evaluating their anxiety and depression levels, as well as asking them to describe their experiences with the children. Four of the participants were screened as possible having anxiety, depression, or both. The participants all took part in the same interactions, though to varying degrees of participation.
Generally, the participants reported positive experiences with the children. Analysing their responses, the researchers found that the interactions fostered a sense of purpose and belonging, fond reminiscences of their own childhood and a positive influence on mood and emotions. Recollections of childhood also sparked a sense of playfulness and positive self-evaluation. They noted that the participants differed in their preconceptions of children, which might have affected their experiences.
The authors wrote that, “Interactions with children promote a sense of belonging and purpose, evoke reminiscence, and positively influence the mental well-being of older persons.”
Based on their findings, Earl and Marais concluded that intergenerational interaction programmes may help manage the mental health conditions that are common for retirement home residents. They suggest that trained staff facilitate the interaction, preparing the children and residents, and should be voluntary, which helps preserve the residents’ agency. Running the interaction as a regular programme should help build bonds and give the residents something to look forward to. Additionally, there should be an educational aspect for the children, giving the residents a sense of purpose.
Looking to the future, they wrote that larger studies would be able to better outline the benefits of such programmes.
Photo by Towfiqu barbhuiya: https://www.pexels.com/photo/person-feeling-pain-in-the-knee-11349880/
Although osteoarthritis has been extensively studied through a medical perspective, the molecular changes associated with osteoarthritis remain unclear. New research published in Biointerphases suggests that there may be an optimum concentration and size of molecules in the synovial fluid needed to form the protective film in joints.
Osteoarthritis is the most common degenerative joint disease, affecting 22% of adults over 40 globally. The cartilage in the joints, in concert with the synovial fluid, provides a smooth surface to support weight-bearing movements. The fluid contains several molecules, including hyaluronan (HA) and phospholipids. Since the cartilage environment cannot be quickly healed or repaired, researchers have tried to diagnose the early stages of joint disease by monitoring the molecular weight and concentration of HA.
“Although we know that in healthy joints there is very low friction, it is unclear which other molecules are involved and how they change during osteoarthritis,” said Rosa Espinosa-Marzal (EIRH), professor of environmental engineering & science, and materials science & engineering. “During the early stages of osteoarthritis, cartilage starts degrading, and previous research has shown that the molecular composition of the synovial fluid changes. We wanted to see if the two changes are related to each other.”
In a healthy joint, the molecular weight of HA varies between 2–20 MDa with a concentration ranging from 1–4 mg/mL. Studies have shown that in diseased joints, HA is broken down resulting in a lower molecular weight and its concentration is also reduced by 10x. Based on these observations, made by other researchers, the study looked at how the concentration and molecular weight of HA influences the structure of healthy and diseased joints.
To do so, the researchers combined vesicles with high and low molecular weight HA. Using neutron scattering and light scattering, they discovered that the molecular weight of HA can vastly change the structure of the vesicles. Lower molecular weight HA, which mimics osteoarthritis-diseased joints, results in larger vesicle size. Changes in HA’s molecular weight also changed the thickness of the phospholipid layers in the joints.
The researchers also studied how these differences can influence the formation of a protective film; in joints this film is responsible for the very low friction we need for unhindered motion. Once again, they used a combination of techniques, quartz crystal microbalance and atomic force microscopy, to examine how these molecules assemble on gold surfaces.
“The formation of a film is possible only when there is an optimal concentration of HA and phospholipids. Even though the gold surfaces have very little in common with cartilage, our studies indicate that there could also be an optimum concentration under biological conditions,” Espinosa-Marzal said. “This is an important observation because we can use the concentration changes as a diagnostic tool.”
The researchers are now testing this theory using cartilage. They are also interested in studying the other molecular components that are found in joints to build a more comprehensive model of the changes that are associated with osteoarthritis.
New drugs are often used not only for one disease (first approved indication) but also for other diseases (supplemental indications). But a study published by The BMJ finds that less than half of approved first indications for new drugs in the US and Europe between 2011 and 2020 add substantial therapeutic value over existing treatments. Only about a third of supplemental approvals add substantial therapeutic value compared with first approvals.
The researchers argue that when first or supplemental indications do not offer added benefit over existing treatments, this information should be clearly communicated to patients and reflected in the price of the drugs.
Previous study findings on the value of new drugs were unclear. To address this, researchers examined all new drugs approved for more than one indication in the US and Europe between 2011 and 2020, and assessed the therapeutic value of supplemental indications compared with first indications.
Using publicly available data, they identified 124 first and 335 supplemental indications approved by the US Food and Drug Administration (FDA) and 88 first and 215 supplemental indications approved by the European Medicines Agency (EMA).
In the US, 48% of drugs had one supplemental indication, 20% had two, 14% had three, and 18% had four or more. In Europe, 48% of drugs had one supplemental indication, 23% had two, 13% had three, and 17% had four or more. Most (58%) of indications approved by the FDA and EMA were for treatment of cancer.
Therapeutic ratings from French and German health technology assessment (HTA) bodies were available for 107 (86%) first and 179 (53%) supplemental indications in the US and for 87 (99%) first and 184 (86%) supplemental indications in Europe.
Among FDA-approved indications with available ratings, 41% (44 of 107) had high therapeutic value ratings for first, compared with 34% (61 of 179) for supplemental indications. In Europe, 47% (41 of 87) of first and 36% (67 of 184) of supplemental indications had high therapeutic value ratings.
Among FDA approvals, when the sample was restricted to the first three approved indications, second indication approvals were 36% less likely to have a high value rating and third indication approvals were 45% less likely when compared to the first indication approval. Similar findings were observed for Europe.
These are observational findings and the researchers acknowledge that therapeutic value ratings were not available for all indications, particularly indications approved in the US but not in Europe. Furthermore, the methods and value assessment system can be influenced by country specific factors and assumptions.
However, they point out that they focused on the highest rating provided by one of the two HTA bodies and did sensitivity analyses with the value scores of each authority separately, which confirmed the initial results.
As such, they conclude: “Fewer than half of approved first indications in the US and Europe were rated as having high therapeutic value, and the proportion of approved supplemental indications rated as having high therapeutic value was substantially lower than for approved first indications.”
“When indications do not offer added therapeutic benefit over other available treatments, that information should be clearly communicated to patients and reflected in the price of the drugs.”
The fact that new does not necessarily mean better needs to be clearly communicated to both patients and clinicians, agrees Beate Wieseler at the German Institute for Quality and Efficiency in Health Care, in a linked editorial.
“The system’s current performance does not meet the expectations of patients and the public, clinicians, or policy makers,” she writes. “Having experienced the potential of a coordinated drug development effort during the covid-19 pandemic, we should seek to align current legislation on drug development more closely with defined public health goals.”
A new joint health supplement has been launched in South Africa by iNOVA Pharmaceuticals which supports healthy joints and helps reduce the symptoms of osteoarthritis such as joint pain and stiffness1. Unlike other osteoarthritis supplements on the market, POSTEON™ has been shown to start working in as little as five days1.
According to scientifically based research, the ingredients in Posteon™ may help reduce the symptoms of osteoarthritis such as joint pain and stiffness, as well as improving range of motion and mobility1.
Boswellia serrata gum resin extract has traditionally been used to relieve symptoms of osteoarthritis. Taken once a day, Posteon™ contains 100mg of 3-O-Acetyl-11-keto-beta- boswellic acid (AKBA), the most active compound of Boswellia extract which is an inhibitor of 5-lipoxygenase (5-LOX). This is a key enzyme in the biosynthesis of leukotrienes from arachidonic acid in the cellular inflammatory cascade1.
It also contains 300mg of Avocado soy unsaponifiables (ASU), a dietary supplement consisting of one-third avocado oil and two-thirds soybean oil. Studies have found that ASU can reduce the production/action of various joint inflammatory substances which can prevent the destruction of joint cartilage and also help in its repair1.
Osteoarthritis is the most common form of arthritis2 and affects between 55.1% and as many as 82.7% of adults aged over 65 years in South Africa3. Globally, the prevalence of osteoarthritis is increasing, and is expected to continue to escalate4.
POSTEON™, which is now available at leading pharmacies, may reduce these symptoms1 which can significantly impact day-to-day functioning2.
Usenbo, A et al. Prevalence of Arthritis in Africa: A Systematic Review and Meta-Analysis. A Systematic Review of Arthritis Prevalence in Africa (2015) at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4524637/ (website accessed on 4 May 2023).
Osteoarthritis Research Society International (OARSI) Osteoarthritis: A Serious Disease, Submitted to the U.S. Food and Drug Administration (2016) at https://oarsi.org/oarsi-white-paper-oa-serious-disease (website accessed on 4 May 2023).
DISCLAIMER: This editorial has been commissioned and brought to you by iNova Pharmaceuticals.
Content in this editorial is for general information only and is not intended to provide medical or other professional advice. For more information on your medical condition and treatment options, speak to your healthcare professional.
A new study shows the sugar sialic acid, which makes up part of the protective intestinal mucus layer, fuels disease-causing bacteria in the gut. The findings, published in PNAS, suggest a potential treatment target for intestinal bacterial infections and a range of chronic diseases linked to gut bacteria, including inflammatory bowel disease (IBD), celiac disease, irritable bowel syndrome and short bowel syndrome.
The research by researchers at the University of British Columbia (UBC) and BC Children’s Hospital, used a mouse model of gut infections.
“Bacteria need to find a place in our intestines to take hold, establish and expand, and then they need to overcome all the different defences that normally protect our gut,” says Dr Bruce Vallance, a professor in the department of paediatrics at UBC and investigator at BC Children’s Hospital. “In the future, we can potentially target this sugar, or how pathogens sense it, to prevent clinically important disease.”
Inflammatory diseases such as IBD are on the rise in children, who are more susceptible to gut infections because of their immature immune systems. Dr Vallance and his team sought to understand what enables these bacterial pathogens to survive and expand inside our intestines.
For the study, the researchers examined Citrobacter rodentium, an intestinal bacterial pathogen of mice that’s used to model infections with human E. coli. The team discovered that the bacteria have genes involved in sialic acid consumption, and when these genes are removed, the bacteria’s growth is impaired.
Further investigation revealed that upon consuming the sugars, the bacteria produced two special virulence proteins that help the bacteria cross the colonic mucus layer and stick to the underlying epithelial cells. The findings reveal how the bacteria can change over time and actually worsen disease.
“You start off with IBD, your microbes change, they start digging their way into the cells lining your gut, causing more inflammation, and that may be one reason why IBD becomes chronic,” says Dr Vallance. “Specific nutrients such as sialic acid or other sugars might be the Achilles heels for them in terms of things you could target to remove dangerous bacteria from the intestine.”
Dr Vallance and his team are now examining the role other sugars in the gut may play in feeding pathogenic bacteria. They’re also looking for probiotics that could outcompete the dangerous bacteria, stealing the sugars away from them.
They also plan to explore potential interactions between resident and pathogenic bacteria. Pathogenic bacteria can’t access the sugars on their own and thus, some of the normally harmless resident bacteria must serve as accomplices.
“Basically, these accomplices cut the sugar off the mucus, and then either they hand it to the dangerous bacteria or the dangerous bacteria have come up with a way of stealing it from them,” he explains.
A better understanding of these interactions could provide new ways to block pathogenic bacteria, something Dr. Vallance says is urgently needed.
“In the past, our ancestors were constantly assaulted by dangerous bacteria,” says Dr. Vallance. “With the advent of more and more antibiotic resistance in bacteria, these bacterial infections are going to become a growing problem again. Without new antibiotics, we need to come up with novel ways to fight these bacteria, like starving them.”
Several sessions at the 11th SA AIDS conference, recently held in Durban, highlighted the worrying fact that key HIV numbers such as treatment coverage are much lower in children than in adults. There is hope, however, that new treatments and new treatment guidelines might help close the gap.
In a plenary session, Dr Sandile Buthelezi, Director General of the National Department of Health, told delegates that on UNAIDS’ 95-95-95 targets, children in South Africa are at 81-65-68. This means that 81% of children living with HIV have been diagnosed, 65% of those diagnosed are on antiretroviral treatment, and 68% of those on treatment are virally suppressed. For the South African population as a whole, the numbers are at 94-76-92.
Throughout the conference, various speakers highlighted the fact that only 65% of children who have been diagnosed are on treatment as a particular concern. To close the gap and reach UNAIDS’ target of 95%, just over an additional 88 000 children would need to be initiated on treatment.
Professor Lee Fairlie, Director of Maternal and Child Health at Wits RHI, said in a presentation that only 52% of children younger than 14 living with HIV are on treatment. Fairlie also pointed out that children lagged behind substantially when it comes to viral suppression, and this is particularly challenging in the youngest age groups.
Not all bad news
But it was not all bad news at this year’s conference. One piece of good news is that new and better child-friendly antiretroviral formulations are being rolled out in South Africa. These new treatments should make it easier for children to start and stay on treatment – children often find it difficult to take medicines formulated for adults, due to factors like incorrect dosing, large pills, and bad taste.
The National Department of Health recently updated the country’s antiretroviral treatment guidelines to allow for the use of several of these new formulations and better HIV treatment regimens for children. Most notable is the introduction of a new regimen consisting of the medicines abacavir, lamivudine and dolutegravir (ALD for short).
Speaking at the conference, Dr Leon Levin, a paediatrician who has been treating infants, children, and adolescents living with HIV for almost three decades, pointed out that the availability of new paediatric formulations had a major impact on the new treatment guidelines. (Spotlight previously reported on the registration of some of these new formulations here.) Levin is also the Senior Technical Advisor in Paediatrics at the NGO Right to Care.
One such child-friendly formulation is a 120/60mg scored, dispersible tablet of abacavir and lamivudine that can be taken in patients who weigh between 3 and 25kg. It is given once daily and two generics are registered with the South African Regulatory Authority (SAHPRA). “It’s going to literally replace all the other paediatric Abacavir+3TC formulations. You can swallow it, chew it, crush it, or dissolve it in water. So [it’s] very versatile,” he said.
Also important is a paediatric formulation of the antiretroviral dolutegravir – a medicine that forms the backbone of HIV treatment in adults. According to Levin, the child-friendly version of dolutegravir is not available to everyone yet, and many clinicians still need to undergo training on how to use it. It is a 10mg dispersible, scored tablet given once daily that can be used at 3kg and higher and from four weeks of age onward. There are two generic versions of this product registered with SAHPRA.
The introduction of paediatric dolutegravir is likely to overshadow the introduction of a four-in-one formulation of abacavir, lamivudine, lopinavir/ritonavir. The four-in-one combination has to be taken twice daily, is strawberry flavoured and comes in a powder form. “Unfortunately, this product to nobody’s fault was launched at the same time as paediatric dolutegravir. Which means paediatric dolutegravir is going to take centre stage and this product unfortunately is not going to be used much,” Levin said.
Updated guidelines
Levin explained that the changes to South Africa’s treatment guidelines focused on doing two main things when it comes to children living with HIV, the first is to implement an optimised regimen – the ALD regimen and the second is to create an “enabling environment to support engagement in care and adherence”. He said that with the new guidelines, we can expect “much improved [viral] suppression, optimised regimens, improved synchronisation of clinic visits, happier patients and their families and clinicians as well”.
A big change to the guidelines is that now children who weigh 3kg and are four weeks of age should be started on the ALD regimen, instead of the abacavir, lamivudine, and lopinavir/ritonavir regimen that was previously recommended. “This is a major change. It’s a fantastic, well-tolerated regimen. It’s potent and you’re going to get around a lot of the issues you had with these younger children,” Levin said.
Once the children on this regimen get to 30kg, they will be switched to a regimen containing tenofovir, dolutegravir, and lamivudine (TLD for short). TLD is also the regimen adults living with HIV in South Africa are offered when starting treatment for the first time.
For children who are already on treatment, the new guidelines recommend that all children who are four weeks of age and older and weigh 3kg or more should be transitioned to a dolutegravir-containing regimen. For children with suppressed viral loads, the switch to ALD or TLD is straightforward, while for children without viral suppression, it can get more complicated.
Another important change is that children over five years of age are now eligible for Repeat Prescription Collection Strategies (RPCs) if they are virally suppressed and had an age-appropriate disclosure, which means that their HIV status has been explained to them in a way that is appropriate for their age, as outlined in the guidelines. For children under five, they can be given a three months supply at a time, providing they are at least six months old. Levin pointed out that whenever RCPs or a three months supply is considered for children, it is essential to look at where and how the parents may be receiving their own antiretroviral treatment so that it can be co-ordinated, and parents don’t have to go to two different places to collect the medications.
New options in the pipeline
While the paediatric formulations included in the new guidelines are a step forward, there are experimental treatments in the pipeline that may make treatment yet more convenient for children.
“There’s a rich pipeline of new combinations and drug delivery developments. Hopefully, this will further improve access, clinical and virological outcomes,” Fairlie said in a conference presentation. “Obviously, the paediatric market is extremely small and then one has to maintain enthusiasm for manufacturers to actually continue to look at the paediatric population. And so, merging of treatments and prophylaxis regimens is really what would work going forwards.”
In her presentation, she specifically referred to long-acting formulations of cabotegravir (CAB-LA) and rilpivirine (RPV). CAB-LA has already been approved by SAHPRA for HIV prevention in adults and, as Spotlight reported last week, pilot projects evaluating how to best provide the CAB-LA injection in South Africa are set to start soon. The combination of CAB-LA and rilpivirine injections has been approved for the treatment of HIV in adults by the United States Food and Drug Administration, but not yet by SAHPRA. The injections are administered every two months.
Fairlie says that currently there are several studies either ongoing or set to start soon for the use of these agents in the paediatric and adolescent age groups. In addition, there are also trials planned to test another long-acting medication called lenacapavir in adolescents and broadly neutralising antibodies (bNAbs) in children.
She also highlighted several improved delivery methods that are in the pipeline for paediatrics. These include a mechanism that doesn’t require water, like oro-dispersible tablets, also known as fast melts, which disintegrate in the mouth as well as oral films that stick to the mouth, disintegrate there, and dissolve. There are also various tablet options that are small enough for children to swallow easily. Like multi-particulates, which are small and solid, multiple-unit dosages that can take the form of granules, pellets, or beads. Mini-tablets are also a prospect – these are compressed tablets no larger than 4ml. Finally, there are novel mechanisms like long-acting oral drug delivery systems and micro-array patches. Fairlie explained that long-acting oral drugs are where a drug is stored in the centre of a capsule that has a number of “arms”, which are able to keep the capsule in the stomach and slowly dissolve and release the drug into the stomach. This allows for slow-release dosing. The “arms” tend to break down after about seven days.
