Day: June 8, 2024

Slow Progress after Decision to Make TB Prevention Pills More Widely Available

Tuberculosis bacteria. Credit: CDC

By Tiyese Jeranji

Besides preventing illness and death, tuberculosis prevention therapy is estimated to be highly cost effective. Yet, uptake of the medication is not what it could be in South Africa. Tiyese Jeranji asks how much has changed since the Department of Health last year decided to make TB prevention therapy much more widely available.

Many people who have the TB bug in their lungs are not ill with TB disease. Having the bug in your body, does mean however that you are at risk of falling ill, should the TB bacteria get the overhand in its battle with your immune system.

Fortunately, we have medications that can kill TB bacteria before one falls ill. A recent World Health Organization (WHO) investment case, suggests such TB prevention therapy, commonly called TPT, reduces the risk of falling ill with TB in those exposed to the bug by 60% to 90% compared to people who do not get the treatment.

In South Africa, TPT has been available in the public sector for years, but until the publication of new government guidelines last year, only kids aged five or younger and people living with HIV could get the medication. Under the new guidelines, everyone who has had close contact with someone with TB should be offered a TB test and if they test negative be offered TPT – if they test positive they should be offered TB treatment. These changes dramatically expanded the number of people in South Africa who are eligible for TPT.

The antibiotics used for TPT has also changed in recent years. For many years, the only option was a medication called isoniazid taken for six or more months. We now also have two three-month options – isoniazid and rifapentine given once weekly and rifampicin and isoniazid given daily. These shorter duration treatment courses should help more people complete the treatment.

Down and up?

Dr Norbert Ndjeka, Chief Director of TB Control and Management at the National Department of Health, tells Spotlight that in recent years, South Africa has seen a steady decline in the number of people initiated on TPT.

The decline has been substantial. In people living with HIV, initiation on TPT dropped from 454 000 in 2018 to around 241 000 in 2023. In children aged five and younger who have had contact with someone with TB, it fell from 25 357 in 2018 to 15 775 in 2023.

TPT enrolments per province for 2023

ProvincePeople living with HIVContacts < 5 YearsContacts > 5 Years
Eastern Cape34 6232 5514 771
Free State14 5355621 027
Gauteng67 3331 3684 241
KwaZulu-Natal62 3623 1688 519
Limpopo15 871391452
Mpumalanga25 6186692 006
Northern Cape3 1788551 595
North West9 4335961 425
Western Cape8 5325 6151 278
South Africa241 48515 77525 314
*Typically, provinces with higher numbers of people diagnosed with TB or those with high numbers of people living with HIV will report higher TPT initiations.

There are two significant reasons for this decline, according to Ndjeka. Firstly, declining TB incidence, and secondly, declining HIV incidence.

“With fewer people diagnosed with TB disease, fewer contacts will need TPT, and with fewer people being diagnosed with HIV, fewer people will initiate TPT regardless of TB exposure,” he says.

WHO figures have shown a significant downward trend in the estimated TB cases per year in South Africa and according to Thembisa, the leading mathematical model of HIV in South Africa, the number of people newly starting HIV treatment has dropped from a peak of over 700 000 in 2011, to well under 300 000 in 2023.

But the recent downward trend in people taking TPT may be coming to an end. “We believe that the implementation of the new guidelines within the current strategic framework will lead to increases in TPT enrolment,” says Ndjeka.

In line with the new guidelines, there are also changes to what TPT data is being collected. “For example, we never used to report on TPT provision to contacts 5 years and older, but now we do and in 2023 at least 25 314 TB contacts 5 years and older were initiated on TPT,” he says.

20% increase expected in 2024

Based on the data reported for January and February of this year, Ndjeka expects that overall TPT initiations will increase by at least 20% in 2024 compared to 2023. Moreover, as documented in the National Strategic Plan for HIV, TB and STIs 2023-2028, there is a plan to have a steady annual increase in TPT enrolments leading up to 2028.

Ndjeka says based on the NSP TPT targets, South Africa is exceeding TPT targets for people living with HIV, but reaching less than 25% of targets for TB contacts. He points out that performance varies by province, but that all provinces have a long way to go in terms of reaching TB contacts.

‘Cost saving over time’

“The aim of offering TPT is to reduce the TB incidence,” Ndjeka says. “So, if everyone eligible is offered TPT there will obviously be increased costs initially but cost saving over time. This looks at cost of treating people with TB, lives saved/ deaths prevented as well as costs to patients.”

For South Africa, he says, it is estimated that we can reduce the number of people with TB by 138 000 by 2050 at an estimated cost of R23 226.90 per TB episode prevented.

Ndjeka says it costs the health department an estimated at R1 498.51 to treat one person with drug-susceptible TB for 6 months and R16 612.82 to treat one person with the standard drug-resistant TB treatment for 6 months. “These costs are for medications alone, which can also go beyond R70 000 depending on the patient and the type of resistant TB. Moreover, when factoring in clinical consultations, hospitalisations, and costs to patients the costs go up considerably,” he says.

The cost of providing TPT also depends on the regimen. One person on TPT can cost as little as R608.77 for a course of three months of isoniazid and rifapentine given once weekly, and up to R1 358.02 for 12 months of isoniazid. “TPT also has much lower associated costs for example there is no hospitalisation, fewer clinic visits and consultations,” Ndjeka says.

“By preventing TB, the cost of TB treatment is avoided along with the costs of treating some of the acute and chronic conditions that someone with TB may experience even after being cured of TB. These include chronic obstructive pulmonary disease, bronchiectasis and pneumonia,” says Alison Best, communication manager at Cape Town-based NGO TB HIV Care.

“For children under five in particular, who are at increased risk of disseminated TB like TB meningitis, the cost of not preventing TB could be death or severe lifelong disability,” she says, adding that preventing TB in a single individual also prevents the costs associated with any onwards transmission of TB from that individual to others.

Questions over implementation

Expanded TPT eligibility has been widely welcomed, but questions have been raised over how well the new guidelines are being implemented.

Best says government austerity measures have made implementing new initiatives in the healthcare setting challenging.

“There is not much political will to implement the guidelines (to expand eligibility for TPT) at provincial and district levels and this has translated into the slow release of circulars, delays in training health workers, poor knowledge of the policy and its low prioritisation,” she says.

Ingrid Schoeman, Director of Advocacy and Strategy at TB Proof (a local advocacy group), says often when a national policy is released, there are delays at provincial-level in releasing circulars to enable health worker training.

“This results in these services not being available at district-level. In the Western Cape, civil society organisations, the [provincial] Department of Health, City of Cape Town and implementing partners are now all working together to support health worker training, and implementing community-led awareness campaigns so that all close TB contacts know they are eligible for TPT,” she says.

Best adds that tracking the data to show how many people are starting and completing TPT tends to be difficult. She notes there are many gaps in capturing the information. This includes, at times, the limited recording of information in patient folders by clinicians and suboptimal inputting of data by data capturers.

Ndjeka says the national department of health has been conducting training on the new guidelines with provincial and district TB and HIV programme managers, district support partners and other trainers.

“They are then responsible for training health care workers. The antiretroviral therapy guideline training also includes TPT. Webinars on the knowledge hub (an online training platform) have also conducted,” he says.

However, Ndjeka conceded that there is a lack of awareness about the value of TPT. “Additionally,” he says, “there is reluctance from clinicians to provide TPT. This result in poor demand for TPT. Treatment adherence is another problem especially for people on the long regimen (12 months)”.

Plans to address these challenges, among other things, include marketing TPT as treatment for TB infection rather than prevention, targeted communication strategies, community mobilisation, and ongoing training and mentoring of healthcare workers, says Ndjeka.

Republished from Spotlight under a Creative Commons licence.

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Less of a Specific Amino Acid Extends Lifespan and Health in Mice

Photo by Jose Ignacio Pompe on Unsplash

New research in mice has demonstrated that not having too much of a certain amino acid – present in many foods commonly eaten by overweight or obese individuals – extends their lifespan and reduces the incidence of diseases such as cancers.

“We like to say a calorie is not just a calorie,” says Dudley Lamming, a professor and metabolism researcher at the University of Wisconsin School of Medicine and Public Health. “Different components of your diet have value and impact beyond their function as a calorie, and we’ve been digging in on one component that many people may be eating too much of.”

Lamming is the lead author of a new study in mice, published recently in the journal Cell Metabolism showing that cutting down the amount of a single amino acid called isoleucine can, among other benefits, extend their lifespan, make them leaner and less frail as they age and reduce cancer and prostate problems, all while the mice ate more calories.

Amino acids are the molecular building blocks of proteins, and Lamming and his colleagues are interested in their connection to healthy aging.

In earlier research, data from UW–Madison’s Survey of the Health of Wisconsin showed the scientists that Wisconsinites with higher body mass index measurements tend to consume more isoleucine, an essential amino acid. Isoleucine is plentiful in foods including eggs, dairy, soy protein and many kinds of meat.

To better understand its health effects, Lamming and collaborators from across disciplines at UW–Madison fed genetically diverse mice either a balanced control diet, a version of the balanced diet that was low in a group of about 20 amino acids, or a diet formulated to cut out two-thirds of the diet’s isoleucine. The mice, which began the study at about six months of age (equivalent to a 30-year-old person) got to eat as much as they wanted.

“Very quickly, we saw the mice on the reduced isoleucine diet lose adiposity – their bodies got leaner, they lost fat,” says Lamming, while the bodies of the mice on the low-amino-acid diet also got leaner to start, but eventually regained weight and fat.

Mice on the low-isoleucine diet lived longer – on average 33% longer for males and 7% longer for females. And, based on 26 measures of health, including assessments ranging from muscle strength and endurance to tail use and even hair loss, the low-isoleucine mice were in much better shape during their extended lives.

“Previous research has shown lifespan increase with low-calorie and low-protein or low-amino-acid diets starting in very young mice,” says Lamming, whose work is supported by the National Institutes of Health. “We started with mice that were already getting older. It’s interesting and encouraging to think a dietary change could still make such a big difference in lifespan and what we call ‘healthspan,’ even when it started closer to mid-life.”

The mice on the low-isoleucine diets chowed down, eating significantly more calories than their study counterparts – probably to try to make up for getting less isoleucine, according to Lamming. But they also burned far more calories, losing and then maintaining leaner body weights simply through adjustments in metabolism, not by getting more exercise.

At the same time, Lamming says, they maintained steadier blood sugar levels and male mice experienced less age-related prostate enlargement. And while cancer is the leading cause of death for the diverse strain of mice in the study, the low-isoleucine males were less likely to develop a tumour.

Dietary amino acids are linked to a gene called mTOR that appears to be a lever on the aging process in mice and other animals as well as to a hormone that manages the body’s response to cold and has been considered a potential diabetes drug candidate for human patients. But the mechanism behind the stark benefits of low-isoleucine intake is not well understood. Lamming thinks the new study’s results may help future research pick apart causes.

“That we see less benefit for female mice than male mice is something we may be able to use to get to that mechanism,” he says.

While the results are promising, humans do need isoleucine to live, and reducing isoleucine from a diet that hasn’t been preformulated by a mouse chow company is not an easy task.

“We can’t just switch everyone to a low-isoleucine diet,” Lamming says. “But narrowing these benefits down to a single amino acid gets us closer to understanding the biological processes and maybe potential interventions for humans, like an isoleucine-blocking drug.”

The Survey of the Health of Wisconsin showed that people vary in isoleucine intake, with leaner participants tending to eat a diet lower in isoleucine. Other data from Lamming’s lab suggest that overweight and obese Americans may be eating significantly more isoleucine than they need.

“It could be that by choosing healthier foods and healthier eating in general, we might be able to lower isoleucine enough to make a difference,” Lamming says.

Source: University of Wisconsin-Madison

Researchers Develop Nanoparticle Therapeutic for Fibrosis

Credit: Scientific Animations CC4.0

Researchers at The University of Texas at El Paso are developing a new therapeutic approach that uses nanoparticles for the treatment of skin and lung fibrosis, conditions that can result in severe damage to the body’s tissues.

Md Nurunnabi, PhD, is an associate professor in UTEP’s School of Pharmacy and the lead researcher on two studies published this June in the Journal of Controlled Release; one study focuses on skin fibrosis and the other on lung fibrosis.

“We are closer than ever to developing a safe, effective and reliable approach to treating fibrosis,” Nurunnabi said.

Fibrosis is a condition in which the tissues in an organ become thicker and stiffer, Nurunnabi says. This can have multiple damaging effects, such as the lungs not being able to hold enough oxygen or blood vessels becoming narrower, leading to high blood pressure.

“I studied fibrosis during my postdoctoral training but became interested in focusing on it in my lab during the COVID-19 pandemic,” Nurunnabi said. “I observed that many people were passing away not because of COVID itself, but because of the inflammation and fibrosis caused by the viral infection in the lungs. Our lab focuses on developing nanotechnology that can target specific cells.”

Fibrosis can occur as a side effect of chemotherapy or the result of a viral infection or autoimmune disease, a condition in which the body’s immune system attacks its own cells. For example, with an autoimmune condition, the body kills fibroblasts, the cells that help form connective tissue. The body then produces more collagen than it needs, which leads to fibrosis.

Nurunnabi’s team focused on designing a nanoparticle that could target the cells that are responsible for fibrosis development and progression without disturbing the “good” cells necessary for the body’s healthy functioning. Rather than killing the ”bad” cells, the team was successful in modifying them so that they no longer produced excess collagen, in effect rehabilitating the cells. The studies were conducted in the test tube and in mice.  

“Dr Nurunnabi’s research into skin and lung fibrosis sheds light on the devastating impact of these conditions, whether acute or chronic,” said José Rivera, PharmD, founding dean of the School of Pharmacy. “His findings offer hope for improved treatments that could significantly increase life expectancy and enhance the quality of life for affected individuals.” 

Source: University of Texas at El Paso

For Healthy Adults, New Guideline Recommends only Daily Allowance of Vitamin D

Guideline recommends vitamin D higher than the recommended daily allowance for children, pregnant people, adults over 75 and adults with prediabetes

Photo by Michele Blackwell on Unsplash

Healthy adults under the age of 75 are unlikely to benefit from taking more than the daily intake of vitamin D recommended by the Institutes of Medicine (IOM) and do not require testing for vitamin D levels, according to a new Clinical Practice Guideline issued today by the Endocrine Society. For children, pregnant people, adults older than 75 years and adults with high-risk prediabetes, the guideline recommends vitamin D higher than the IOM recommended daily allowance.

Vitamin D use and blood vitamin D levels have been associated with many common diseases. However, whether vitamin D supplementation lowers the risk of these diseases and what vitamin D blood levels are needed for better health have been debated for years.

In this new guideline, the panel of experts established guidelines for vitamin D use and testing for vitamin D levels in healthy persons without established indications for vitamin D treatment or testing. The guideline relied on clinical trials to develop the recommendations.

The guideline, titled “Vitamin D for the Prevention of Disease: An Endocrine Society Clinical Practice Guideline,” was published online and will appear in the August 2024 print issue of The Journal of Clinical Endocrinology & Metabolism (JCEM), a publication of the Endocrine Society.

“The goal of this guideline was to address the vitamin D requirements for disease prevention in a generally healthy population with no underlying conditions that would put them at risk of impaired vitamin D absorption or action,” said Marie Demay, M.D., of Harvard Medical School and Massachusetts General Hospital in Boston, Mass. Demay is the chair of the panel that developed the guideline. “Healthy populations who may benefit from higher dose vitamin D supplements are those 75 and older, pregnant people, adults with prediabetes, and children and adolescents 18 and younger, but we do not recommend routine testing for vitamin D levels in any of these groups.”

Key recommendations from the guideline include:

  • We suggest against vitamin D supplements at doses beyond the reference dietary intakes recommended by the IOM in healthy adults under 75 years old.
  • We identified the following populations that may benefit from supplementation above the intakes recommended by the IOM because of the potential to reduce specific health risks:
    • Children and adolescents 18 and younger—potential to prevent nutritional rickets and to reduce the chance of respiratory infections.
    • Individuals 75 and older—potential to lower mortality risk.
    • Pregnant people—potential to reduce risk of pre-eclampsia, intra-uterine mortality, preterm birth, small-for-gestational age birth and neonatal mortality.
    • People with prediabetes—potential to reduce progression to diabetes.
  • In adults ages 50 years and older who have indications for vitamin D supplementation or treatment, we suggest daily, lower-dose vitamin D instead of non-daily, higher-dose vitamin D.
  •  We suggest against routine testing for 25-hydroxyvitamin D levels in any of the populations studied, since outcome-specific benefits based on these levels have not been identified. This includes 25-hydroxyvitamin D screening in people with dark complexion or obesity.

Even though the evidence on the role of vitamin D in health and disease has increased over the last decade, the panel noted many limitations in the available evidence. For example, many of the large clinical trials were not designed for several of the outcomes that they reported, and the studied populations had vitamin D blood levels that most would consider adequate to begin with. Based on insufficient evidence, the panel could not determine specific blood-level thresholds for 25-hydroxyvitamin D for adequacy or for target levels for disease prevention.

Source: The Endocrine Society

Researchers Offer New Understanding of Antidepressant Mechanism

Evidence suggests serotonin-boosting actions relieve depression by restoring normal communication and connections in the brain

Photo by Sydney Sims on Unsplash

Researchers at the University of Colorado Anschutz Medical Campus have established a new framework for understanding how classic antidepressants work in treating major depressive disorder (MDD), reemphasising their importance and aiming to reframe clinical conversation around their role in treatment.

The nature of the dysfunction at the root of MDD has been under investigation for decades. Classic antidepressants, such as SSRIs (selective serotonin reuptake inhibitors, such as fluoxetine) cause an elevation in serotonin levels, a key neurotransmitter. This observation led to the idea that antidepressants work because they restore a chemical imbalance, such as a lack of serotonin.

But subsequent years of research showed no significant decrease in serotonin in people with depression. While experts have moved away from this hypothesis due to lack of concrete evidence, this has led to a shift in public opinion on the effectiveness of these medications.

Antidepressants, such as SSRIs and serotonin and norepinephrine reuptake inhibitors (SNRIs), are still effective in alleviating depressive episodes in many patients, however. In a paper published in Molecular Psychiatry, researchers outline a new framework for understanding how antidepressants are efficacious in treating MDD. This framework helps clarify how antidepressants like SSRIs can still be helpful, even if MDD isn’t caused by a lack of serotonin.

Evidence points to a communication problem

“The best evidence of changes in the brain in people suffering from MDD is that some brain regions are not communicating with each other normally,” said Scott Thompson, PhD, professor in the Department of Psychiatry and senior author. “When the parts of the brain responsible for reward, happiness, mood, self-esteem, even problem-solving in some cases, are not communicating with each other properly, then they can’t do their jobs properly,” Thompson said.

“There is good evidence that antidepressants that increase serotonin, like SSRIs, all work by restoring the strength of the connections between these regions of the brain. So do novel therapeutics such as esketamine and psychedelics. This form of neuroplasticity helps release brain circuits from being ‘stuck’ in a pathological state, ultimately leading to a restoration of healthy brain function,” Thompson said.  

Thompson and colleagues liken this theory to a car running off the road and getting stuck in a ditch, requiring the help of a tow truck to pull the car out of its stuck state, allowing it to move freely down the road again. Researchers are hoping healthcare providers will use their examples to bolster conversations with apprehensive patients about these treatments, helping them better understand their condition and how to treat it.

Study aims to reshape the conversation

“We are hoping this framework provides clinicians new ways to communicate the way these treatments work in combating MDD,” said C. Neill Epperson, MD, co-author of the paper and professor of the Department of Psychiatry at the CU School of Medicine.

“Much of the public conversation around the effectiveness of antidepressants, and the role serotonin plays in diagnosis and treatment, has been negative and largely dangerous,” Epperson said. “While MDD is a heterogenous disorder with no one-fits-all solution, it is important to emphasise that if treatments or medications are working for you, then they are lifesaving. Understanding how these medications promote neuroplasticity can help strengthen that message.”

Source: CU Anschutz Medical Campus

Metabolic Parameters Similar in Children Born via Frozen and Fresh Embryo Transfer

No differences in blood glucose, insulin, or cholesterol levels seen in children born via frozen versus fresh embryo transfer regardless of age, gender, or method of assisted conception

Children born via frozen embryo transfer have similar metabolic profiles to those born via fresh embryo transfer, according to a study published June 6th in the open-access journal PLOS Medicine by Linlin Cui and Zi-Jiang Chen from Shandong University, China, and colleagues.

Prior studies have shown inconsistent results on the long-term metabolic health impacts of assisted reproductive technology. Some have shown that children born via frozen embryo transfer have a higher risk of metabolic disorders, such as obesity, and unfavorable lipid profiles. Other studies have failed to find any significant metabolic differences between those born via frozen or fresh embryo transfer.

In this study, researchers compared the glucose and lipid profiles of more than 4000 children between 2 and 5 years of age – approximately half had been born via fresh embryo transfer and half had been born via frozen embryo transfer.

Researchers followed the children for an average of 3.6 years and assessed metabolic factors often associated with heart disease and diabetes, such as fasting blood glucose, insulin, cholesterol, and triglycerides.

They found no difference in any of the metabolic factors among children born via fresh embryo transfer and those born via frozen embryo transfer.

Given the relatively large number of participants in this study, the researchers were able to conduct subgroup analyses. After dividing the children into groups based on gender, age, embryo transfer state, and method of conception, there were still no differences in metabolic factors among the frozen and fresh embryo transfer groups.

The study provides more information to women and couples weighing the pros and cons of different techniques offered for assisted reproduction, but the researchers noted the need for additional data on the effect of assisted reproductive technology on long-term metabolic health.

The authors add, “Frozen embryo transfer shows no significant adverse effects on metabolic profiles in early childhood, providing crucial evidence for counseling couples undergoing assisted reproductive technology treatment on its safety.”

Provided by PLOS