Dressed in a dark jacket, rain is pelting Vuyiseka Dubula-Majola’s face as she rushes past bare trees in Geneva, Switzerland. Along with her two children, Dubula-Majola has newly moved into a house in nearby Genthod, from where she commutes to work by train.
In October, the Global Fund to Fight AIDS, Tuberculosis [TB] and Malaria, appointed Dubula-Majola as head of their community, rights and gender department. The Global Fund has allocated tens of billions of dollars around the world to fight HIV since its inception in 2002.
Five weeks into the job, Dubula-Majola tells Spotlight that a big challenge for her will be to hone a new tool – that of diplomacy.
Laughing, the former General Secretary of the Treatment Action Campaign (TAC) says that in the past, diplomacy has not been her greatest strength.
“In this new job, I am required to be diplomatic,” she says. “Basically, diplomacy is being nice in the face of atrocities, and I am not that person. So it will be a huge challenge for me, it’s going to take a shift. I will have to keep asking myself, ‘what value I can add in this position?’ While developing new tools and new ways of fighting, without being the noisy person in the room.”
The power of collective action
Known for not mincing her words, the activist-scholar is talking to Spotlight over Zoom while walking to the Global Fund’s offices in central Geneva. She adds: “Activists don’t like bureaucracies by nature, but you have a voice here. You have political currency to shift things. It’s a tough one, but I’m there.”
In a 2014 TedX talk hosted in London, an inflamed Dubula-Majola told the audience that she is angry – angry with her father, angry with her government, angry at everyone. But that she was using her anger to fuel her work.
While she is in Switzerland, Dubula-Majola’s heart still brims with African proverbs, such as: “When spider webs unite, they can tie up a lion.” She has experienced the power of such collective action first-hand at the TAC, but now she’ll be applying it on a different stage. Indeed, her new job is “to ensure that the Global Fund strongly engages civil society and promotes human rights and gender equality”, with a particular focus on supporting community led organisations.
As a role model for her new diplomatic duties, Dubula-Majola cites American public health official Loyce Pace. “Loyce Pace who runs the health program in the United States government, she is very effective in what she does while hardly saying anything in public. But she is shifting norms – bringing priority to black and poor people. She uses her allies and many other people similar to her to say things louder than she could…I guess this is another step of growth in my activist journey – to still be as effective, as radical, the very same eagerness and passion, but silently.”
‘There was no time to dream’
Dubla-Majola grew up in a village near Dutywa in the Eastern Cape. Aged 22 in Cape Town in 2001, she spiralled with depression after being diagnosed with HIV. But instead of resigning herself to what was then still a death sentence for most people, she joined the TAC – working night shifts at the McDonalds drive-through in Green Point, while by day she joined the fight to bring antiretrovirals and other medicines to South Africa.
“As a 22-year-old, I did not have fun, there was no time to dream,” she recalls. “I was fighting for my life and the lives of others. I never thought I would have children, I never thought I would get married, I never thought I would love again. Because there was also the issue of who infected me, how did this happen? You start resenting relationships.”
At the forefront of social justice activism for most of South Africa’s young democracy – a role model for people living with HIV, and for those fighting inequality – Dubula-Majola lead the TAC from 2007 to 2013, after which she joined Sonke Gender Justice as director of policy and accountability. She holds an MA in HIV/AIDS management from Stellenbosch University; her PhD from the University of KwaZulu-Natal examined “grassroots policy participation after a movement has succeeded to push for policy change,” using MSF’s [Médecins Sans Frontières] pioneering antiretroviral sites in Khayelitsha and Lusikisiki as samples.
‘Build and regain the dignity of poor people’
In 2018, when Stellenbosch University offered her a job as director of its Africa Centre for HIV/AIDS Management, Dubula-Majola was circumspect. Why take up appointment at a white male-dominated institution shackled by slow transformation, in an elitist town? But she took on the challenge to become the transformation she wanted to see.
Dubula-Majola tells Spotlight that while relishing the privilege of academia – a space to reflect – it saw her away from “the heat of the activist fire” for too long. Five years later, a new challenge awaits.
Reflecting on Stellenbosch, she says: “This [job at the Global Fund] is even harder, because it’s not just one country, one university. This is all the continents of the world. All of them facing the same thing, the struggle here is to build and regain the dignity of poor people around the globe.”
Despite her early misgivings about relationships, Dubula-Majola married fellow TAC activist, Mandla Majola. Their children, now aged 10 and 16, are HIV-negative. Presently Majola is helping with their friend Zackie Achmat’s independent campaign for the 2024 general elections, after which he will join his wife in Geneva. The family will unite in Switzerland for Christmas though – “which will be the most miserable and cold Christmas,” says Dubula-Majola, laughing. “It will be our first winter Christmas and our last. As we just arrived a month ago, it doesn’t make sense to travel back to South Africa for the holidays.”
Overall she says she remains hopeful, adding that movements like #MeTo are lessons in global solidarity.
Her thoughts on continuing the fight against HIV: “It is up to HIV positive people, and those who want to remain HIV negative, to steer towards an AIDS-free generation. We must stop complaining, thinking politicians will do everything for us, and do it ourselves.”
Meanwhile, Global Fund representatives have voiced confidence in Dubula-Majola’s ability to lead. Marijke Wijnroks, head of the organisation’s strategic investment and impact division, said in a statement: “Following an extensive search process, I am delighted to say that we found the ideal person for this role. As a person living with HIV, Vuyiseka’s lived experience and leadership style are well aligned to what we need from this critical role.”
Note: Dubula-Majola is a former General Secretary of the TAC. Spotlight is published by SECTION27 and the TAC, but is editorially independent – an independence that the editors guard jealously. Spotlight is a member of the South African Press Council.
A small study published in September found that some ceramic plates and bowls bought from South African chain stores are coated in glaze that contains lead, a toxic heavy metal which can damage multiple organs when consumed. The paper comes in the wake of research that finds that due to its harmful effects on the cardiovascular system, lead exposure is linked to the deaths of somewhere between 2.3 and 8.2 million people a year worldwide (these findings are dissected in part one of this Spotlight special series on lead poisoning).
It is estimated that about 7.8 million children in South Africa (aged 0-14) have lead poisoning, which is about 53% of all young people in that age-range. This means that they have more than five micrograms of lead per 100mL of blood, the clinical threshold for lead poisoning set by the National Institute for Communicable Diseases. Lead increases the risk of health problems at any level, however if a healthcare worker finds that a patient exceeds this threshold then this indicates that the problem is severe enough that they should notify the health department.
But why are children in the country exposed to so much lead?
Scientists from the South African Medical Research Council (SAMRC) have found several sources over the last two decades. These include lead-based paints (which can chip and generate lead dust which people breathe in), certain traditional ayurvedic medicines that contain lead, fishing sinkers (which are sometimes melted down, producing toxic fumes), lead ammunition (which can generate lead dust when fired, and may contaminate hunted game meat), as well as gold mining waste facilities, which can contaminate the surrounding soil.
The recent paper on ceramics adds to a growing body of evidence that cookware and crockery also likely play a role.
Research for the new paper was conducted in 2018, when SAMRC scientists purchased 44 randomly selected plates and bowls from six large retail chain stores in Johannesburg. After testing the glaze, they found that almost 60% of the items contained more than the maximum amount of lead recommended by the United Nations – which is 0.009% of total content. Indeed, the average item contained about 47 times this amount.
Glaze is a liquid coating that is applied to ceramic to make it shinier and more durable. Once it’s coated, the ceramic is fired, leaving it with a glossy sheen. Lead is often used in these glazes to add extra colour and increase water-resistance, but if the ceramic isn’t heated at a high enough temperature then the glaze won’t completely solidify. In the case of ceramic crockery, this means that lead may run off into food or water prepared in these dishes, particularly if they are used for cooking or simply holding acidic foods.
Indeed, this is precisely what has happened throughout parts of Mexico. Research in that country finds that children have higher amounts of lead in their blood if they live in households where food is prepared in lead-glazed pottery (a result which researchers have found repeatedly). Recently, health inspectors in the US linked cases of lead poisoning to the use of ceramic cookware bought in Mexico. After the affected individuals stopped using the ceramics, their blood-lead levels went down.
In order to test whether lead is leaching off the South African ceramics, the SAMRC researchers left an acidic solution in the plates and bowls. When they returned 24 hours later, lead was found to have run off one of the 44 items.
Angela Mathee, the head of the SAMRC’s Environment and Health Research Unit and the paper’s lead author, says that while this is comforting, the results may be deceiving: “our speculative concern is that particularly for people who are poor and keep their ceramic ware for a very long time, that with knocks and cracks and wear and tear over the years, it’s possible that the product could start leaching – even if it wasn’t at the time of purchase. Though that is untested”.
A second caveat is that of the 44 bowls and plates, only one was originally made in South Africa, and it’s this item that released lead.
Additionally, even if lead-based ceramics don’t leach, the production of these items may still cause harm. For instance, a study in Brazil found that children who simply lived near artisanal pottery workshops were more likely to have high amounts of lead in their blood. Caregivers of these children did not report having any lead-glazed ceramics or being involved in pottery making. Thus, researchers suspect that children were simply breathing in lead dust generated by the nearby potters.
Lead leaching from cooking pots
Although this is the first time lead has been found in ceramic glazes in South Africa, other kinds of kitchenware products have previously been shown to contain lead. In 2020, researchers published a study in which they purchased 20 cooking pots from informal traders and artisanal manufacturers across South Africa. Each pot was made from recycled aluminium.
They found lead in every pot, and some also contained dangerous amounts of arsenic (a known carcinogenic). The researchers cut the pots up, and boiled a piece from each one in an acidic solution. They found 11 out of the 20 pieces leached more lead than the maximum permissible limit set by the EU. (The experiment was repeated twice more on the same metal pieces, with similar results).
Thus, the authors conclude that artisanal aluminium pots are a likely source of lead exposure in the country. And the issue may extend past individual households, as the SAMRC has documented the use of artisanal aluminium pots in school feeding programmes.
Not only can lead-based artisanal pots cause lead poisoning by leaching into food, but researchers note that simply manufacturing them likely generates lead dust. As demonstrated in a small follow-up study on informal metal workshops in Kwazulu-Natal and Limpopo which found that workers had a lot more lead dust on their hands by the end of the work day than at the start.
It’s also possible that production facilities like this end up contaminating nearby residential areas. A 2018 study in the Johannesburg suburb of Bertrams found that nearly a third of all garden soil samples contained dangerous amounts of lead (i.e. lead levels that exceeded South Africa’s guidelines for safe soil). The scientists hypothesised that one reason may be that various cottage industries, including scrap metal recyclers, are interspersed among suburban homes.
Are regulations on lead being ignored?
South Africa has already taken legislative steps to deal with lead coatings. In the 2000s, a number of alarming studies found lead-based paints covering homes and playground equipment in public parks across several cities. In response, a law came into effect in 2009 that made it illegal to sell household paint or glaze that is more than 0.06% lead. Draft regulations published in 2021 will further slash this limit to 0.009% in line with recommendations by the UN. These will only become enforceable once the finalised regulations are gazetted.
Though evidence is scant, these laws may have had a positive effect. A study last year found that paints produced by large companies being sold in Botswana, but manufactured in South Africa, were all below the lead-threshold set by the 2009 law (and broadly in line with the new draft regulations as well).
However, the research on ceramics suggests the regulations have not always been adhered to, at least when it comes to glazes. The only South African-made piece of crockery which was tested in the study described earlier had a coating that contained over 100 times the amount of lead legally permissible under the 2009 law (despite the tests being conducted nine years after it was passed).
If additional research finds that the problem is widespread, then Mexico’s experience may offer one path forward. There, a ban on lead glaze has long gone unenforced. NGOs in parts of the country have responded by assisting artisanal potters to switch to lead-free glazes and to develop higher-temperature kilns (which would prevent metals from leaching). This has been coupled with public awareness campaigns about the harms of lead-based pottery and a certification program for potters using lead-free coatings.
But stakeholders say the government needs to play its part as well. The South African Paint Manufacturing Association (SAPMA) has previously urged the government to do more to enforce its regulations. In 2021 they stated that “random samples taken from hardware shelves by the government regularly showed that hazardous levels of paint were still being sold. But no report of any offender being charged by the police appeared in the press”.
The National Department of Health didn’t respond to a request for comment about this at the time of publication.
Speaking to Spotlight for this article however, the executive director of SAPMA, Tara Benn, says “I believe manufacturers are adhering to the current regulation and most if not all have already adopted the new regulation of less than 90 parts per million [i.e. 0.009%], but this regulation has not been published as yet”.
Data and investment needed
Except for a few (mostly wealthy) nations like the United States, very few countries run nationally representative blood-lead surveys. In countries like South Africa, researchers have only been able to make very rough calculations about how many people have lead poisoning by pooling together different studies that have been done in particular communities.
As a result, policy makers lack good data about the extent of the problem. National blood-lead monitoring schemes would also allow health officials to work out which communities are most affected, which in turn, could help them identify the sources of lead exposure.
Bjorn Larsen, an environmental economist who consults for the World Bank, explains: “The first thing that needs to be done is we have to get in place routine blood-lead measurements that are nationally representative…This can be done by adding a [blood-lead] module to existing routine household surveys, for example UNICEF’s Multiple Indicator Cluster Survey…countries also have their own routine household surveys, [blood-lead tests] could be added to those”.
In the United States, all children who are enrolled in Medicaid (the government-run insurance scheme) receive blood-lead tests at ages one and two (these can be done via a simple finger-prick test) . This is in addition to nationally representative surveys which are done by the Centres for Disease Control and Prevention (CDC). Overall, the CDC receives about four million lead test results from across the country each year.
In addition, experts are increasingly calling for greater international health financing for the prevention of lead poisoning in low- and middle-income countries. Last month, a group of experts, including researchers from Stanford and officials from UNICEF, released a joint statement on lead poisoning in developing nations. It argues that “despite the extraordinary health, learning, and economic toll attributable to lead, we find the global lead poisoning crisis remains almost entirely absent from the global health, education, and development agendas”.
The statement argues that $350 million in international aid over the next seven years would be enough to make a significant dent in the problem. They provide a breakdown of these funds, which include international assistance with enforcing anti-lead laws, purchasing lead-testing equipment and assisting companies (such as paint manufacturers) with moving away from lead-based sources.
Note: This is the second in a two-part Spotlight special series on lead poisoning. You can read part one here.
For decades, the standard way to prevent people who were exposed to tuberculosis (TB) from falling ill with the disease was to offer them a medicine called isoniazid, taken daily for six or more months. That changed in the last decade with the development of new preventive therapy regimens that are taken for four, three, or even just one month.
One complexity, however, is that both isoniazid and the new regimens are much better at preventing normal drug-sensitive TB than they are at preventing drug-resistant forms of TB. This is not surprising. As explained by Paediatric Infectious Disease doctor and Professor of Global Child Health at Imperial College London, Dr James Seddon, the two drugs that have mainly been used to prevent drug-susceptible TB are isoniazid and rifampicin (rifampicin’s sister drug rifapentine is also used). Now, by definition, he explains multidrug-resistant (MDR) TB is resistant to both these drugs so it’s unlikely to have any impact.
The situation is particularly tricky when it comes to children. In a 2020 statement the World Health Organization (WHO) says that it estimated that worldwide between 25 000 and 32 000 children develop MDR-TB each year, and mainly acquire it through transmission from close contact with an adult or adolescent who has MDR-TB. According to Seddon, while there is some emerging observational evidence on the use of drugs other than isoniazid and rifampicin to prevent MDR-TB, there has been no clinically tested regimen to give to children following MDR-TB exposure.
Now, much anticipated results from a phase three trial has shown that a single antibiotic pill, given daily for six months, is safe and effective to use in children who have been exposed to MDR-TB.
Results from TB CHAMP
The trial, called TB-CHAMP, looked at the efficacy and safety of using the antibiotic levofloxacin to prevent TB in children exposed to MDR-TB. Top-line findings from the study was presented last week at the Union World Lung Conference held in Paris, France.
“The paediatric population is probably the most neglected of all the populations affected by MDR-TB,” Dr Anneke Hesseling, Director of the Paediatric TB Research Programme at Stellenbosch University, told the conference. “Fewer than 20% who develop MDR-TB disease are actually diagnosed and treated, and so to find more cases and prevent more cases is really, really critical…So prevention is really key, and the TB-CHAMP trial is really a phase three efficacy trial looking at levofloxacin to prevent new cases of TB in children and also looking at the safety of levofloxacin.”
Hesseling, who is the Principal Investigator of the study, says that TB-CHAMP is the first trial to provide clinical data on what drug might be used to prevent TB in children who have been exposed to MDR-TB. It was conducted at five sites across South Africa, all with high MDR-TB burdens. The study was led by Stellenbosch University and the Desmund Tutu TB Centre. The findings have not yet been published in a peer-reviewed journal.
922 children were randomised to receive either levofloxacin or a placebo for six months. 453 children got levofloxacin and 469 got the placebo. The primary efficacy data featured data from 916 of those children, with 451 in the levofloxacin arm and 465 in the placebo arm.
Hesseling says that only children who were exposed to an adult in their household with confirmed MDR-TB were included in the study. At first children below the age of five were recruited, regardless of their TB infection status. Later children between the ages of five and 17 were included, but they had to either have a TB infection or be living with HIV. The majority of the children, 90%, were younger than five years. TB infection was confirmed with a blood test.
By 48 weeks, Hesseling says five children in the levofloxacin arm versus 12 in the placebo arm developed TB, which amounts to an incidence rate of 1.1% in the levofloxacin arm, and 2.6% in the placebo arm.
Implication of results
“While TB preventive therapy (TPT) has long been recommended and available for young child contacts of people with drug-susceptible TB, there has not been sufficient evidence to make strong recommendations for treatment that could prevent DR-TB. Therefore, the TB-CHAMP findings are critically important for a number of reasons,” says Professor Guy Marks, President and Interim Executive Director, International Union Against Tuberculosis and Lung Disease (The Union).
“The study provides the first high-quality evidence that DR-TB can be prevented in children by using six months of daily levofloxacin, and that this is a safe medication. Furthermore, this will encourage more community-based contact screening, which will also lead to early detection of children and contacts of all ages who already have disease, and initiate treatment,” he adds.
“The impact [of the TB-CHAMP results] is potentially tremendous as it would prevent DR TB among child contacts. DR TB is more complex to treat and cure and often children are marginalised, so this study puts the spotlight on an effective way to protect children. This is not just about the life and health of the child but the social, economic and mental health implications for the caregiver and the entire family,” says Dr Priashni Subrayen, Technical Director for TB at The Aurum Institute.
Seddon, who is also one of the Co-PIs for the study, tells Spotlight that it was important to establish the safety of levofloxacin since it belongs to a class of drugs called the fluoroquinolones, which were thought to have terrible side effects when used in children.
Results from TB-CHAMP show that this is not the case.
The side effects were mild, and the regimen was well tolerated, according to Hesseling, with only eight children having a grade one or higher adverse event in the levofloxacin arm compared to four in the placebo arm. Two deaths were reported, one in each study arm, but were unrelated to the study. Overall, six children in the levofloxacin arm discontinued treatment or left the study early.
Researchers from TB-CHAMP collaborated with researchers from the V-QUIN trial – a phase three study that looked at levofloxacin as TB prevention in adults in Vietnam – in order to combine their data which allowed them to show data for levofloxacin across different age groups. Seddon explains: “They’ve applied a novel analytic approach, which uses a Bayesian, or probabilistic, framework, where we take the results of TB-CHAMP and we say well, if we actually use some of the information from V-QUIN to inform the TB-CHAMP results, we can make that a slightly more confident estimate,” he says.
The combined results, according to Hesseling were able to also show that levofloxacin reduced the risk of TB by about 60% across the age spectrum but with a tighter confidence interval, indicating a more precise estimate of the effect.
Seddon tells Spotlight that the combined data showed that there were no serious adverse events, but the adult population experienced more grade one and grade two side effects than the children, but these went away either over time or when the drug was stopped. The side effects included inflammation in the joints and tendons, which is a known side effect of this class of drug.
Not a silver bullet
While the findings could be a game-changer and potentially inform MDR-TB prevention guidelines, particularly in children, the regimen is by no means a silver bullet. Seddon says that while the regimen was safe, when participants were asked whether they liked the medicine, more people said they didn’t like it in the levofloxacin group versus the placebo. Another downside is that the pill was an adult formulation and thus needed to be cut and/or crushed for the kids to swallow.
Seddon explains that the WHO, who have been provided with the data from both studies and expected to meet in early December, would need to consider a variety of factors before deciding what to recommend about the use of levofloxacin for prevention. That includes the fact that you need to treat a lot of children for six months who might not have TB despite being exposed in order to prevent a few cases.
“You have to weigh up the benefits versus the risks and the risks are low, but it is still giving a drug for six months to children and most of them don’t need it. But the consequences of getting MDR-TB are so bad that we really want to prevent that,” he says.
There is also the question around what effect using a broad antibiotic as preventive treatment will have on the microbiome of children and how this might drive resistance to the fluoroquinolones. Seddon says stool samples were collected from the study participants to determine how the drug affected a child’s microbiome and the potential for driving resistance. These data will also be provided to the WHO.
“I think that the evidence base is now very strong on the basis of these two trials. I think you can really say the issue of whether levofloxacin prevents MDR-TB, we’ve put that to bed,” he says. “Are there going to be other studies? Yes. I think that this is not over, levofloxacin is not the perfect drug for preventive therapy.”
Marks adds to this saying: “An important next step for TPT in DR-TB contacts will be studies that evaluate regimens that are shorter than six months – a long time to take medication every day, which can often be challenging. Effective and safe shorter regimens are now being used for child contacts of drug-susceptible TB and we hope the same progress can be made for contacts of DR-TB.”
As Marks has already stated, currently there are no strong recommendations for MDR-TB prevention by the WHO. In the 2020 TB prevention guidelines, it recommends that the preventative treatment for MDR-TB should be either a fluroquinolone or other second-line agent. It does however caution that these recommendations are based on low-quality evidence. Because of this, it recommends that the preventative treatment for MDR-TB should be individualised, and it be based on the drug resistance profile of the presumed contact. The drugs levofloxacin and moxifloxacin- both fluoroquinolones – may be used unless resistance is suspected. For levofloxacin a dosing schedule for both adults and children are proposed in the document.
Subrayen says that in South Africa the 2019 guidelines for the management of Rifampicin Resistant-TB (RR-TB) does indicate the use of levofloxacin as prevention treatment. The guidelines state that for prevention treatment a fluoroquinolone-based, multidrug regimen is preferred (either levofloxacin and high-dose isoniazid or levofloxacin, high-dose isoniazid and ethambutol). And if exposed to fluoroquinolone-resistant RR-TB, then high-dose isoniazid could be given. Delamanid could be considered as a potential option in very select cases. A training manual published this year by the Department of Health suggests that levofloxacin can be given on its own – but also stresses that the evidence base is weak, something that TB-CHAMP has presumably now changed.
Future of TPT
Seddon says that in a perfect world the ideal TB preventive regimen would be a so-called Pan regimen that could be given for a short period of time, to someone who has been exposed to TB and it works regardless of whether they had been exposed to drug-susceptible or drug-resistant TB.
“There are studies planned to use other drugs for prevention. There’s a study planned to use bedaquiline for a month or two and potentially using injectables that you just have to give once every couple of weeks. So, I think although this [levofloxacin] is a good option now, and it’s probably the best option we have now, this is not perfect,” Seddon says.
The study Seddon is referring to is the BREACH-TB study, a phase three trial that will look at whether a one-month treatment regimen of oral bedaquiline could prevent all forms of tuberculosis. It would be given to people exposed to both drug-resistant and drug-susceptible TB, and in people with HIV infection, including pregnant women and children.
Responding to questions from Spotlight earlier this year when this study was announced in the press, Sonya Krishnan, Assistant Professor of Medicine at Johns Hopkins University and Eric Nuermberger, Professor of Medicine at Johns Hopkins University, said that they anticipate recruiting between 1600 and 2 00 people to take part in the study – they expect around 400 to 500 of these will be people living with HIV. They also said that the control arm will receive the current standard of care in the country rather than placebo.
When asked whether any South African study sites will be included in the clinical trial, they said, “We very much plan to partner with study sites in South Africa. South Africa has a long-standing history of research excellence in TB.”
“A shorter regimen that fights both drug-resistant and drug-susceptible TB would be a game-changer for those living with TB and get us closer to our shared goal of ending the epidemic by 2030,” said Dr. Atul Gawande, USAID assistant administrator for Global Health, in a statement on the study. “This clinical trial will lay the foundation for a remarkable innovation in our fight against TB: a single-dose, long-acting injectable medicine.”
Indeed, if the science and development pans out as Gawande suggests it might, the future of TB preventive therapy might well be an entire course of therapy delivered through a single injection rather than a month or more of pills. As indicated in an article in the journal Clinical Infectious Diseases, work is already underway on the development of bedaquline, isoniazid, and rifapentine long-acting injections – though the research is for now still only in mice.
‘Communities need to be involved’
Hesseling raises the point that when treating or preventing TB, more than just the latest research advancement is needed to improve TB outcomes.
“For me treatment follows diagnosis, actually strengthening healthcare services, making communities more aware and creating demand for kids accessing diagnosis, preventive treatment and appropriate treatment, is actually where it starts,” she says. “So tools are amazing, but we actually need to have strong, effective healthcare services and knowledgeable, empowered communities.”
Seddon adds to this saying that results like those from TB-CHAMP are “a bit irrelevant if it is all kind of top down, paternalistic coming from the researchers, coming from the health system”.
“We really need to generate a community demand for this, where individuals living in communities where this is a problem are calling for this and getting angry about this and demanding it in a way that I think we’ve achieved very well with the HIV community,” he says. “It’s all well and good doing the science and then even better to get it [levofloxacin] into a guideline, but until there’s real demand for from the end user, I think it’s only going to have a certain amount of reach.”
Note: The terms DR-TB and MDR-TB are used somewhat interchangeably – Spotlight uses DR-TB to refer to drug-resistant forms of TB in general and MDR-TB to refer specifically to TB that is resistant to isoniazid and rifampicin.
The researchers also found that exposure to lead (a powerful neurotoxin) causes more harm to children’s intellectual development than previously thought. The paper estimates that in developing countries, where the condition is most prevalent, a child with average levels of lead exposure loses nearly six IQ points from the metal in their first five years of life (average IQ is 100).
While only about 2% of those living in wealthy countries have lead poisoning, the situation is very different for those in poorer parts of the world. A 2021 study found that nearly half of all children living across 34 low-and-middle income countries have lead poisoning – which is typically defined as a person having at least five micrograms of lead per 100mL of blood.
It’s estimated that the average child in South Africa is well above this threshold – at about 5.59 micrograms. And worryingly, the metal can still cause harm below the clinical threshold. Indeed, any increase in a person’s blood-lead levels is associated with greater health risks, even at the lowest detectable levels.
The metal can make its way from these products into people’s bodies through a number of routes. In some cases – like with alternative medicines or spices – people directly ingest contaminated goods. In others, people breathe in lead dust, which can be generated by unregulated industrial practices. For instance if lead-acid battery recyclers lack proper safety and environmental standards – as is often the case in developing countries – recyclers may simply pour lead-based battery solution onto the ground, contaminating the soil.
Children are most at risk. For one, they’re more likely to put items that contain lead in their mouths, like toys covered in lead paint, or even a thumb coated in lead dust. Secondly, they’re closer to the ground and therefore breathe in more lead-contaminated dust. The theme of this year’s WHO-backed International Lead Poisoning Prevention Week was “End childhood lead poisoning”.
After it’s ingested or inhaled, some lead is excreted, while the rest is absorbed into the bones, teeth and blood. Children absorb more of the metal than adults and once it’s in the blood, lead can be distributed to various organs in the body. This includes the heart as well as the brain, where it can interfere with neurotransmitter systems involved in learning and memory.
The new study in Lancet Planetary Health adds to a growing body of evidence that global lead exposure is far more detrimental to human health than previously thought. While people began understanding that lead was poisonous several thousand years ago, it was only recently that evidence accumulated showing that even tiny amounts of lead can cause damage.
Part of the reason is simply because we didn’t have data on low-level exposure until recently, explains Bjorn Larsen, the study’s lead author. Most people in industrialised countries had very high blood-lead levels during most of the 20th century. For instance, in the late 1970s the average American child had about 15 micrograms of lead per 100mL of blood, which is about 25 times the average today, and three times the present-day threshold for lead poisoning. A major reason was leaded gasoline, which was introduced in the 1920s and phased out from the 1970s onward.
Thus, says Larsen, testing the effects of blood-lead levels that we would now perceive as low wasn’t always possible. For instance, to show that even one or two micrograms of lead per 100ml of blood is harmful, researchers would need to compare people at this (very low) level to those with no lead to observe if they come off worse. But if almost everyone is above two micrograms, this becomes close to impossible as there isn’t anyone to test. And in the absence of data, some simply assumed that the metal was only problematic above a particular threshold.
Bruce Lanphear, a professor of public health at Simon Fraser University, was the lead author of a seminal 2005 paper that showed that lead was associated with declines in IQ even below the clinical threshold set at the time (10 micrograms of lead per 100mL of blood). He explains that by the mid-1990s, when 95% of people were below that threshold, many felt that lead was no longer much of an issue: “my advisors at that point said get out of this line of research, the problem seems to be going away and there won’t be any funding for it. And they were right about one of those two things – I haven’t gotten much funding,” Lanphear says.
As blood-lead levels continued to drop and scientists like Lanphear could study the effects of lead on children’s intellectual development at lower levels, a new consensus emerged. Larsen explains: “Now people are willing to say that in all likelihood the correct way to estimate things is that there is some effect on IQ as soon as we can detect lead in the blood – even at the lowest level these effects start”. Indeed, according to a WHO factsheet, “there is no known safe blood-lead concentration”.
Not only that, adds Lanphear, but research shows that “proportionately, we see greater harms – greater reductions in IQ – at the lowest measurable lead levels”. In other words, the more lead you have in your body, the worse it is, but going from one microgram of lead per 100ml of blood to two micrograms causes more additional harm than going from 15 micrograms to 16. Thus, it’s strangely only through the decline in lead poisoning that its most pernicious effects have been revealed.
Lead ‘poisons’ our cells
As more data is gathered, estimates of the harm caused by lead are constantly being revised upward. The finding that lead is linked to 5.5 million cardiovascular deaths a year is over six times the number previously determined by a 2019 study. It should be noted however that the new estimate is relatively uncertain – the researchers estimate the real value is most likely in the range 2.3 to 8.3 million.
Part of the reason for the updated estimates is that the 2019 research had only looked at the effects of lead on blood pressure, while the new paper considers a wide variety of cardiovascular problems associated with lead.
According to a statement by the American Heart Association from earlier this year these effects include injury to the cells that line the blood vessels, oxidative stress (which can result in cell and tissue damage) and coronary heart disease, which is when the blood flow is restricted, increasing the risk of a stroke or heart attack.
Gervasio Lamas, Chief of cardiology at Mount Sinai Medical Centre and the lead author of the statement, explains that heavy metals like lead can erode cardiovascular health through two broad channels: “one is that toxic metals typically will end up replacing essential metals or ions in vital cellular reactions,” he says.
For instance, lead replaces the calcium in our cells, a mineral which is involved in keeping our hearts pumping, our blood clotting and our heart muscles properly functioning. By removing calcium, lead “poisons these cells,” says Lamas.
He tells Spotlight that the other main route is that toxic metals often interfere with our antioxidant mechanisms. Antioxidants are molecules which deactivate harmful free radicals (chemicals that can attack our cells and DNA). Lead disrupts these antioxidant defences, he says. As a result, free radicals build up, which may cause the blood vessels to harden (called atherosclerosis), blocking blood flow.
Different strands of evidence point in the same direction
To arrive at the conclusion that 5.5 million people died from lead-induced heart conditions, Larsen and his colleague relied on two large observational studies from the United States (where there is lots of data). These studies measured the blood-lead levels of thousands of people and looked at what happened to them over time. They showed that those who had more lead in their blood were more likely to die of heart complications at a younger age, even when controlling for lots of other factors.
Larsen and his colleagues used estimates from these studies to develop a model which calculates the increase in a person’s risk of dying of heart disease at different levels of lead exposure. They then plugged in the blood-lead levels that we observe among people around the world to estimate how much cardiovascular death the metal is linked to.
One contention that emerges from research like this is whether it really shows cause and effect. As Lamas notes, “the populations that are most affected by high lead levels are [more likely] to be underprivileged in some way. They are often either poor or have access to less healthcare or live in areas that are more generally contaminated – things that you would expect would in any case cause [health] problems for them”.
When we find that people who have more lead in their blood die of heart disease more often, this may be due to one of these other factors.
But according to Lamas, there are a number of reasons to be confident that lead is actually the driver of heart disease. The first is that when observational studies (like the ones discussed above) measure the relationship between people’s lead levels and cardiovascular disease, they control for a range of other risk factors, including their socioeconomic status. “Even when you do that, lead still sticks out like a big sore thumb,” Lamas notes.
The other reason is that there are lots of different sources of evidence that all find lead damages cardiovascular health: “there are direct experiments where patients or animals are infused with lead and those show that arterial function [i.e. the ability of our arteries to transport blood] is diminished,” Lamas explains.
Finally, Lamas points to the results of a randomised clinical trial which he and his colleagues published in 2013. In it, they took over 1700 patients who had recently suffered from a heart attack and randomly split them into different groups. One group received a treatment for lead poisoning called EDTA chelation. This is an intravenous medicine that binds with toxic metals in the body before being urinated out. Those who didn’t receive the chelation therapy got a placebo drug.
Five years later, those who got chelation therapy appeared to be better off. They performed better than the placebo group when measured by a composite index that combines factors like patients’ risk of dying and their need to return to hospital for further procedures.
With so many different kinds of research pointing in the same direction, Lamas believes the evidence that lead plays a causal role in heart disease is about as conclusive as in the case of high cholesterol.
And if lead truly is killing 5.5 million people through heart conditions each year, this places it among the top risk factors for cardiovascular disease globally. Despite this, lead poisoning along with exposure to other toxic metals, remains a remarkably overlooked issue. Lamas explains, “at the individual physician level – sitting across from a patient – I’m the only cardiologist I know who routinely checks lead, mercury, arsenic and cadmium”.
Note: This is part one of a two-part Spotlight special series on lead poisoning.
Researchers have been trying to develop antiretroviral medicines that can last for weeks, months or even years per dose. It is thought that such long-acting therapies may eventually end up replacing the daily pills taken by most people living with HIV today.
As pointed out by Dr Anushka Naidoo, a Clinical Pharmacologist and Principal Investigator and Scientist at the Centre for AIDS Programme of Research in South Africa (CAPRISA), three such long-acting HIV medicines have made it to market so far. They are the injectables cabotegravir (CAB-LA) and rilpivirine (RPV-LA) and the dapivirine vaginal ring (DPV-VR). Of these only CAB-LA (two-monthly) and DPV-VR (monthly) have so far been approved by the South African Health Products Regulatory Authority (SAHPRA) for HIV prevention. CAB-LA and RPV-LA have been approved for HIV treatment in the United States, but not yet by SAHPRA.
CAB-LA and DPV-VR are being rolled out as HIV pre-exposure prophylaxis (PrEP) in pilot studies in South Africa. Spotlight earlier this year provided an update on these pilots here.
How do long-acting formulations work?
Dr Sindiswa Maphumulo, a Specialist Virologist and lecturer at the University of the Free State, tells Spotlight that designing long-acting formulations is a very complex and costly process. She explains that when designing any drug, whether it is long-acting or not you need to look at two things – pharmacodynamics and pharmacokinetics. Basically, she says, pharmacokinetics refers to what the body does with the drug in question while pharmacodynamics refers to what the drug does to the body.
“So you’re going to have to know what is the human body going to do to this drug once you’ve administered it and also what is the drug targeting or aiming to do in the human body once it has been given,” she says. For long-acting drugs, studies need to determine what the half-life (how long it lasts in the body) of the drug is so the doses can be timed correctly. It is also essential that different populations are studied to determine how individual’s bodies react to the drug.
“You want to make sure that there is a steady release of that specific drug, which depends on the drug class that you’ve chosen because we target different sites of HIV [with different drug classes],” she adds.
Naidoo tells Spotlight that: “Long-acting drug delivery formulations enable slow drug release after administering a single dose over the course of days, weeks, months or even years, and can maintain a steady pharmacokinetics profile.”
Naidoo says that long-acting drugs are formulated so that they form a “depot” of the drug, either through the way the drug is released into the body or the way device that contains the drug is designed to slowly release it over time. Several ways of achieving this has been investigated, including long-acting injectables, implants, infusion pumps, and patches. Long-acting injections and implants, for example, are already widely used in South Africa as contraceptives.
For HIV this means that ARVs can either be stored in the body and slowly absorbed or be stored in a device that is placed in the body which releases consistent drug levels over time. For example, “long-acting injectables are usually the same medication that is taken in pill form but when injected they allow for the slow release of medication into the blood over a longer period of time,” says Naidoo.
How CAB-LA works
Maphumulo explains that CAB-LA and DPV-VR fall under different drug classes which target different stages of the HIV viral replication cycle inside the human body. Cabotegravir is an Integrase Strand Transfer Inhibitor (INSTI) – which is to say it targets the integrase enzyme that allow HIV to integrate itself into a cell’s DNA.
“Cabotegravir’s unique physiochemical and pharmacokinetic properties have permitted its formulation and delivery both as an oral tablet for daily administration and as a long-acting nanosuspension for monthly to quarterly intramuscular injection,” Naidoo says.
“Cabotegravir LA is made from the free acid form of cabotegravir, which has a low water solubility, a long systemic half-life and high antiviral potency,” says Emmanuella Chinonso Osuala, a Research fellow and PhD student based at CAPRISA.
She explains that the properties of this drug make it suitable for a so-called nanosuspension delivery system and allows for high levels of the drug be contained in a small volume that can be administered through an intramuscular injection. This is achieved by manufacturing cabotegravir, through a process called wet-bead milling, to form nanocrystals – approximately 200nm in size. These have a large surface which allows for “a slower and controlled release of the drug over time”.
“[The] drug is released from the injectable suspension over several months due to the slow dissolution of crystals from the suspension,” Osuala explains.
How DPV-VR works
Naidoo explains that DPV-VR is a ring made of “a flexible silicone polymer” and contains the drug dapivirine, which is slowly released over the course of a month and can be inserted and replaced by the women themselves each month. A three-month ring is also currently in development.
“The ring delivers dapivirine directly at the site of potential infection, with low systemic exposure (it acts at the site of action in the vagina and is not released in significant amounts into the blood circulation), which could minimise side effects…and reduce the risk of developing HIV (drug) resistance,” she says.
Dapivirine, according to Maphumulo is part of a drug class called Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), which block the reverse transcriptase enzyme on the HIV virus that allows for the transcription of HIV – which is an RNA virus into DNA. It is this transcription which would allow HIV to enter the human cell nucleus and replicate there.
Making current treatments long-acting
While long-acting forms of cabotegravir and dapivirine are clearly useful, these are far from the most widely used ARVs. Most HIV treatment in South Africa today is with a combination of three drugs, with the key one being dolutegravir. Earlier this year we reported on how more than 4.7 million people in the country have started or switched to dolutegravir-based HIV treatment in the last five years.
One group of researchers are trying to develop long-acting formulations of these commonly used ARVs. Using so-called drug combination nanoparticles (DcNP) they have developed a long-acting formulation of the ARVs tenofovir, lamivudine, and dolutegravir (LA-TLD) that shows some promise as a monthly injection. Early findings presented at this year’s International AIDS Society (IAS) conference in Australia and published in the journal AIDS suggest that the formulation achieves sufficient drug concentrations in non-human primates to allow for monthly dosing.
Dr Rodney Ho, an expert in biomedical science and pharmacology based at the University of Washington in the United States who led the research, tells Spotlight the study wanted to address a seemingly impossible question.
“Can we make three incompatible oral antivirals – tenofovir, lamivudine (which are water soluble) and dolutegravir (which is oil soluble and water-insoluble) – compatible and create a long-acting drug combination injectable product? With creativity and hard work, our team finally found a way to make this happen,” he says.
He explains that the three drugs were bound to lipid (fatty) nanoparticles using DcNP technology, which stabilises them so that the combination of drugs do not get released at the injection site immediately. Instead, the drugs are taken up by the body’s lymph and lymph nodes, which allows the drug to be metabolised within the body’s cells, which host the HIV virus, before it is taken up in the blood stream.
“As a result of this intentional design, LA-TLD has now provided data verifying that we are able to provide the necessary long-acting drug profile while achieving targeted drug exposure in cells and tissues of interest for an extended time,” Ho says.
“These results verified that a stable and scalable long-acting product, previously considered impossible, is now proven to be possible. This novel LA-TLD product can be administered via subcutaneous injection and will reach therapeutic drug levels within hours (not days which is needed for CABENUVA – LA-CAB and LA-RPV taken as HIV treatment). Thus, two-month oral leading doses may not be necessary,” he says.
Challenges around long-acting formulations
Osuala says there are several scientific challenges when it comes to long-acting formulations. This includes ensuring that: the drugs remain stable when released over long periods of time; sustained drug release is maintained; and the biocompatibility of the materials used in the product. Other challenges include issues around drug potency, as the amount of drug required for the formulation depends on its potency; as well as the cost and access to the formulations, as it is currently expensive to develop and manufacture which may hinder the accessibility of these products in low-and-middle-income (LMIC) countries.
Further challenges, according to Naidoo include the added complication that if adverse events occur for long-acting injectables, “one cannot simply stop taking the medication like one can with daily pills” since the drug will continue to be released into the body. One way to reduce this risk is through having an oral lead-in period where the drugs, like cabotegravir and rilpivirine that are set to be injected are first taken in pill form for four weeks, which can be stopped if an adverse event like hypersensitivity, an allergy or a severe side effect occurs.
Other challenges include the cold-chain storage requirements that some long-acting formulations and injections have, Naidoo says, “which can be challenging in LMIC settings so formulations without cold chain needs are needed.”
“The development of long-acting injectable formulations are a complex, time-consuming, and costly process. One of the challenges in the development of long-acting injectable formulations is the limited selection of ‘polymers’ and ’excipients’ (materials used to formulate the long-acting injectables that are available). As a result, some innovator companies develop proprietary excipients for use in long-acting injectable formulations, which can delay the development of generic long-acting injectable products,” she adds.
Already long surgical waiting lists in the Northern Cape appear to have ballooned in recent months. In May, the province’s MEC for Health Maruping Lekwene told the province’s legislature that surgical waiting lists in the province stood at just under 4000. According to more recent figures from the Northern Cape Department of Health’s 2023/24 First Quarterly report, the surgical backlog stands at 6373 – an increase of more than 50% on the figure given in May.
Lulu Mxekezo, Northern Cape Department of Health Spokesperson, confirmed to Spotlight last week that the surgical backlogs had indeed increased from around 4000 to around 6000. She said that the numbers fluctuate as the need continues to increase on a daily basis.
“The shortage of specialised theatre staff makes it impossible for us to utilise all theatres daily to perform the procedures,” said Mxekezo, adding that the department will not compromise the safety and lives of patients and operate in theatres with no specialised theatre staff.
The increase in the backlog came despite the outsourcing of some surgical services in the province. Lekwene told the legislature that the Northern Cape Department of Health pays Gauteng-based Medicomed (captured as Medicore-Mets in the legislature minutes) R400 000 per month to assist with orthopaedic surgeries at Robert Mangaliso Sobukwe (RMS) Hospital in Kimberly on a month-to-month basis. He said the company supplies the department with specialised theatre nurses which is a scarce skill in the province. In May, Lekwene told legislators that the company had assisted with 57 surgeries over a two-week period.
Lack of theatre staff
The quarterly report stated that the backlog is fuelled by the lack of theatre staff at RMS hospital, and that the private sector was called in to fill this gap.
When asked by Izak Fritz, Democratic Alliance member of the Provincial Legislature, why the department does not appoint specialist nurses instead of outsourcing these services, Lekwene answered that there are unfortunately not enough theatre specialist nurses in the province.
“For us to take this route, it means that we need to have internal capacity. For instance we will have a neurosurgeon but we will not have an anaesthetist. We have nurses, but we do not have theatre specialist nurses,” he said.
He said they do not enjoy outsourcing, but that because of the urgency and the growing backlog the department has to act swiftly. “However as soon as the backlog has been reduced, we will then try to use our internal staff,” he said.
Lekwene also told the legislature that the backlog was mostly caused by the Covid-19 pandemic. “Remember that for two years during Covid-19, hospitals were closed,” he said.
Some workers at RMS said the long waiting list has left many patients frustrated and stranded. One doctor described the situation to Spotlight as “dire”. “The hospital has four fully equipped theatres but patients do not get help,” he said. He asked not to be named for fear of losing his job.
“Yes, we do have a shortage of nurses, but it is not as bad as they say. We are available as doctors, but without the help from nurses we are unable to perform surgeries at all,” he said.
The doctor said that currently the list of patients that need to receive emergency surgery is longer than 30. He said that for ordinary surgeries such as hip replacements there are patients who have been in hospital for more than 18 months, while some have been waiting for cataract surgery for five years.
A strain on staff and patients
Dennis Segano, provincial chairperson of Health and Other Services Personnel Trade Union in South Africa (HOSPERSA) said the surgery backlog is putting a strain on both nurses and patients.
He said the main problems that they see at RMS is the shortage of specialised theatre nurses and a lack of equipment. “When you enter the theatres there are enough doctors but not enough nurses,” he said. “We have a problem with our theatre nurses who are often outsourced by the service provider to work during their surgery marathons at the RMS hospital but have to wait three months or sometimes even six months before they can get paid.”
Spotlight asked Mxekezo about the late payment allegations but had not received a response by the time of publication.
“We don’t know why the government is not appointing the nurses instead of paying a service provider,” Segano said. “The system is burdened, the nurses in orthopaedic wards are burdened and we feel sad for the patients who have to spend months in hospital. “As a patient when you have a fracture, you must be able to go to theatre immediately, but in this province, you have to wait months before you receive help.”
“Stakeholders are also assisting us in performing theatre marathons to deal with the backlog,” Mxekezo said.
For example, in October last year, disaster relief organisation Gift of the Givers sent a team of theatre nurses and anaesthetists to assist with the backlog at RMS. According to Ali Sablay, the organisations project manager, they performed 72 operations on 72 patients during the catch-up drive.
When asked what the department’s long-term plans are to reduce the pressure, Mxekezo explained that the operationalisation of theatres in district hospitals with specialised theatre staff will assist in minimising the backlog at RMS as many patients are transferred from districts.
Segano agreed that a long-term solution is to equip district hospitals with decent theatres and specialised theatre nurses.
“Minor fractures must be dealt with at district hospitals. RMS Hospital must only perform serious surgeries,” he said. “If the department can prioritise Harry Surtie Hospital and De Aar Hospital with theatre staff and equipment, RMS Hospital will operate much better and the patients will be helped. It is incorrect to send all patients of the Northern Cape to one hospital in Kimberly. They will not succeed.”
“Permanent employment of theatre staff will also assist in stabilising the surgical backlogs,” Mxekezo said.
Fritz told Spotlight the DA is very concerned about the growing backlog in the Northern Cape and that they have repeatedly highlighted surgery backlogs at the provinces only tertiary facility (RMS).
“When one looks at nursing appointments at the RMS hospital, we see a trend whereby more nurses’ contracts are terminated each year than the amount of nurses who actually get appointed,” he said. “In effect, the hospital only operationalises four of its nine theatres.”
“Despite agreements with private agencies for surgery marathons to help tackle the backlogs, this only has a limited impact because of the inability to operationalise more theatres and to ensure there is an availability of more beds for recovery,” he said.
Fritz said the reality is that the people who require elective surgery often have to wait years to be attended to while their condition progresses. “Only when their case becomes an emergency can they be bumped up the list, and by that time their disease has become worse and their hopes of a full recovery is minimised,” he said.
Wynand Boshoff, the Freedom Front Plus’s (FF+) Northern Cape Provincial Leader, said in an interview with Spotlight last week that the problem with the department is that it is an entity that is riddled with mismanagement and a culture which aims for anything but service delivery.
He said the FF+ is not only approached by patients, but also by doctors on a regular basis who want to leave the health department because of management that he said has completely abandoned services.
“It is clear that more is needed than the appointment of a new minister or a new Head of Department, as the legacy of mismanagement overwhelms individual role players. A comprehensive investigation and steadfast disciplinary action is needed,” he said. “Repeat offenders should not be tolerated in the department, not even in the most humble of positions.”
As Spotlight previously reported, the Northern Cape Department of Health has had several acting heads in the last three years and several senior officials have and are facing charges in court. The current Head of Department is Dr Alastair Kantani, who has been acting in the position since 8 September following the arrests of seven officials, including former head Dr Dion Theys who now occupies the post of Medical Director in the department. In a statement issued by the department on 13 September Lekwene said this action is informed by the constitutional responsibility to ensure relative stability in the delivery of healthcare services in the province.
Newly announced results of a pivotal phase 3 trial have demonstrated the effectiveness of a new one-dose treatment for gonorrhoea. The medicine, called zoliflodacin, is the first new drug developed to treat gonorrhoea in over 30 years. More than half of the 930 patients included in the trial were from South Africa, including women, adolescents, and people living with HIV.
Zoliflodacin, which was shown to be non-inferior to (as good as) the currently used treatment in treating uncomplicated gonorrhoea, provides an important new tool to combat rising rates of drug resistant gonorrhoea. It was found to be generally well tolerated and there were no serious adverse events or deaths recorded in the trial. So far, only top line results have been shared in a media release and the findings have not yet been published in a medical journal. (You can see some technical details of the study design on ClinicalTrials.gov)
The World Health Organization raised the alarm about increasing rates of drug resistant gonorrhoea in 2017, noting the emergence of cases of untreatable gonorrhoea resistant to all available antibiotics. According to the United States Centers for Disease Control and Prevention “medication to treat gonorrhoea has been around for decades, but the bacteria has grown resistant to nearly every drug ever used to treat it”. They say: “only one class of antibiotics known as cephalosporins remains to treat the infection”.
As a drug from a new class of antibiotics, zoliflodacin, offers a new potential treatment for patients whose gonorrhoea was previously untreatable, as well as a new tool for safeguarding the ongoing effectiveness of currently available antibiotics.
How zoliflodacin may change gonorrhoea treatment
Professor Sinead Delany-Moretlwe, Director of Research for Wits RHI and the National Principal Investigator for the trial in South Africa, told Spotlight that while zoliflodacin may be used to treat drug resistant gonorrhoea, it also provides an attractive new treatment option for first-line treatment of gonorrhoea in some countries (in other words, gonorrhoea that is not resistant to other treatments).
Zoliflodacin, which is taken as a single oral dose, is simpler to administer than the current standard of care, which involves a combination of injectable ceftriaxone and oral azithromycin. Removing the need for an injection could simplify the administration of gonorrhoea treatment and improve its uptake.
Using zoliflodacin as first-line gonorrhoea treatment can also help safeguard the ongoing effectiveness of cephalosporins (including ceftriaxone), according to Delany-Moretlwe, which she adds are needed not just for treatment of gonorrhoea, but also other infections.
According to Delany-Moretlwe, because zoliflodacin is the first of a new class of antibiotics with novel mechanisms of action and without existing cross resistance, the hope is that widespread use of zoliflodacin as first-line gonorrhoea treatment will slow the emergence of resistance compared with the medicines currently being used.
The Global Antibiotic Research and Development Partnership (GARDP), a non-profit that sponsored the trial, points out that: “Antimicrobial resistance [AMR] has been around for millions of years, long before the first man-made antibiotics. So, drug-resistant bacteria are inevitable and will eventually affect all antibiotics”. They state: “to beat AMR we need a steady supply of new antibiotics to be developed that are effective against drug-resistant bacteria, particularly for priority pathogens that have the greatest public health impact.”
Gonorrhoea in South Africa
South Africa has incredibly high rates of gonorrhoea, with an estimated 2 million new cases annually. While data on rates of drug resistance in the country is limited, the data that is available indicates that ceftriaxone resistance in the country is low, but azithromycin resistance is concerningly high in some parts of the country.
As there is no routine screening for gonorrhoea in South Africa, linkage to treatment remains a challenge. Currently, diagnosis is largely done through symptomatic reporting by patients. But this approach misses many cases as some patients do not self-report symptoms and some cases of gonorrhoea are asymptomatic.
In 2022, the Southern African HIV Clinicians Society released new guidelines for the management of sexually transmitted infections which called for provider-initiated symptomatic screening and provider-initiated diagnostic screening in high-risk populations.
The country’s new National Strategic Plan on HIV, TB and STIs has set a target to increase the number of pregnant women tested for gonorrhoea from 10% in 2023 to 80% by 2028 and has committed to implementing diagnostic testing in other priority populations, including adolescent girls and young women.
How will new gonorrhoea treatments be commercialised?
Zoliflodacin was developed by GARDP in collaboration with the company Innoviva Specialty Therapeutics. According to GARDP, it holds the rights to register and commercialise zoliflodacin in more than three-quarters of the world’s countries, including all low-income countries, most middle-income countries, and several high-income countries. While, Entasis Therapeutics Limited, an affiliate of Innoviva Specialty Therapeutics, “retains the commercial rights for zoliflodacin in the major markets in North America, Europe, Asia-Pacific, and Latin America”.
South Africa is one of the countries in which GARDP holds the rights to register and commercialise zoliflodacin. It is anticipated that this will be done through selection and licensing of companies to manufacture and supply zoliflodacin in South Africa and other countries where GARDP holds commercialisation rights.
GARDP recently launched a request for proposals from partners that are interested in commercialising zoliflodacin. GARDP has also signed a memorandum of understanding with two generic producers to explore opportunities to commercialise the medicine in low-and-middle-income countries.
While the price that will be offered by commercial partners for the product remains to be seen, it is anticipated that products will be made available at affordable prices in line with GARDP’s goal to ensure that “all GARDP products are available, affordable, and appropriately used across populations that need them”.
“This is the first study to address a World Health Organization priority pathogen that has been sponsored and led by a non-profit organization,” says GARDP.
“This demonstrates that GARDP’s model can play a crucial role in helping to fix the public health failure at the heart of the global AMR crisis,” says Professor Glenda Gray, GARDP board member and President of the South African Medical Research Council.
According to GARDP, South Africa had the highest number of participants in the global trial, across six sites in four provinces: Wits RHI in Hillbrow, Johannesburg; the Desmond Tutu HIV Foundation in Masiphumelele, Cape Town; Setshaba Research Centre in Soshanguve, Gauteng; the SAMRC’s clinical research sites in Botha’s Hill and Tongaat in KwaZulu-Natal; and Ndlovu Research Centre in Groblersdal, Limpopo.
“We have also been able to leverage our HIV experience to build capacity for trials of novel STI technologies, a previously neglected area. Undertaking this vital work on a new treatment for gonorrhoea has also given us the opportunity to focus sharply on the local situation in South Africa,” says Delany-Moretlwe.
By Matshidiso Lencoasa and Dominic Brown for Spotlight
In the context of weak economic growth, lower-than-expected tax revenues, and the implementation of measures to reduce public spending, there is “rising panic” ahead of this year’s Medium Term Budget Policy Statement (MTBPS). The concern for health care provision is palpable as anticipated budget cuts threaten the country’s already fragile and understaffed public healthcare system. There is only one nurse for every 224 patients in the public health system, and over 5 000 nursing posts remain unfilled (something primarily attributed to funding constraints).
In times of poor economic performance, difficult policy choices and trade-offs arise, and it may be tempting for fiscal policymakers to slash public health spending. However, without meaningful consideration of the impact of these decisions on our people and our constitutional right to access healthcare, the MTBPS risks exacerbating the hardships faced in our country.
South Africa’s economic outlook has been riddled with challenges permeating our healthcare system. Over the past decade, the country’s economic growth has underperformed, falling in real terms from 2.3% in 2013 to 0.1% in 2023. National Treasury has responded to this with cuts to social spending, including healthcare. Public health is receiving fewer resources in real terms, and our government spends more on debt-servicing (R340.5 billion in the 2023/24 Budget) than on healthcare (R259.2 billion in the 2023/24 Budget). Moreover, healthcare’s allocation of R259 billion in 2023/24 was the same as last year’s allocation, meaning that the value of resources allocated to healthcare this year is eroded by Consumer Price Index (CPI) inflation, which was projected to be 4.9% at the time of the Budget Speech in February this year.
According to the Public Economy Project, after accounting for inflation and population growth, the spending per healthcare user fell from approximately R4600 in 2012 to R4300 in 2018. Based on current budget estimates, it is projected that real per capita public health spending will fall below R3 900 by 2024/25.
Implications for health care staffing
Although the 2023/24 budget proposed a measly 1.5% nominal increase to the public sector wage bill, President Cyril Ramaphosa approved a 3.8% increase for this year. However, Treasury’s cost containment measures have stipulated a hiring freeze for the rest of the 2023/24 financial year and no further allocations towards personnel expenditure. This is despite the Department of Health’s 2030 Human Resources for Health Strategy quantifying that 96 586 additional health workers are required to bolster the healthcare of all provinces to the same standard as the third-ranked province by 2025. This requires an additional cost of nearly R40 billion in total.
Health budget cuts disproportionately burden women. This burden is evident in the inordinate risk and prevalence of HIV that women face in the country. It is exacerbated by women’s higher and differentiated health needs (including those for reproductive and maternal health). Women-led households are 40% poorer, and unemployment is most prevalent among women. These socioeconomic factors make women more dependent on the public health system.
Budget cuts and underspending clearly have implications for gender equity in the country.
Furthermore, the Department of Health has recognised the healthcare workforce as a critical driver of inclusive economic growth and a means to create decent work for women, especially in rural and underserved communities. Over 90% of nurses in our public health system are women, and in our society of unequal gendered norms, it is also women who carry the care work burden in the home. Many will likely interpret any proposed MTBPS cuts without factoring gender equity implications as an under-appreciation of women’s labour in making a fragile healthcare system and society work.
A case for human rights budgeting
Although improving the country’s economic outlook is imperative, without consideration of the power that fiscal policy has in advancing human rights in the country, there is a likelihood of tabling an MTBPS that impedes the realisation of constitutionally guaranteed human rights in the country.
More than ever, our health system requires inculcation of human rights impact assessments as recommended by the UN Committee on Economic, Social and Cultural Rights, to which South Africa is a party. These assessments could compel policymakers to outline how the resources allocated will protect the right to access healthcare for all in the country, especially when budget cuts are considered. Including these considerations in budget policy may further advance meaningful public participation processes in fiscal policy.
Furthermore, a gender-responsive MTBPS is long overdue and a powerful means to protect the most vulnerable people in the country from reduced social investment. The health budget could be tagged to identify programmes with gender as a principal or significant objective and areas which would need to be protected and consideration of the gendered experience of healthcare to prevent fiscal policy from worsening gender inequities in the country. Budget policymakers should further promote the collection of gender-disaggregated data and establish indicators and benchmarks on gender and other socio-economic factors to advance a more equitable funding allocation.
Lastly, authentic public engagement will allow National Treasury and budget policymakers to solicit and table more equitable fiscal expansion alternatives. Increased public consultation could include extending the pre-budget consultations with the public.
The Financial Intelligence Centre estimates that between $15 billion and $25 billion is shifted out of our country to tax havens yearly. We call for greater urgency towards implementing publicly disclosed beneficial ownership registries based on country-by-country reporting and the automatic exchange of information, strengthening capital and exchange controls, and increasing South African Revenues Services (SARS) capacity to investigate corporations suspected to be involved in IFF and BEPS. These essential measures can contribute to curbing profit shifting, resulting in more than R100 billion in revenue each year.
The upcoming MTBPS will find National Treasury in a challenging position where various trade-offs will likely be made. In this harsh economic climate, if something has to give, it cannot be the constitutional right to health care for all in this country.
*Lencoasa is a Budget Researcher at SECTION27 and Steering Committee Member of the Budget Justice Coalition. Brown is Director of the Alternative Information and Development Centre and member of the Budget Justice Coalition.
Over the last decade, the National Health Department has rolled out a range of electronic surveillance systems to monitor medicine stocks throughout the country’s healthcare facilities. Many healthcare workers feel the new systems are making a positive impact, but stockouts persist due to a host of ongoing supply challenges.
“My problem with the clinic is that I get there as early as 7am and leave around 3pm. I [went] to the clinic to collect my hypertension tablets. We get into a long queue only to be told that they don’t have hypertension tablets. Not having my tablets poses a danger to my life. I get dizzy and I am unable to work. I [asked] for the day off from work to come [that day], then [had] to ask for another day off to do the same thing,” says a Klerksdorp resident interviewed by the community healthcare monitoring group Ritshidze.
According to a recent report from Ritshidze, between May and June this year, there were over 400 unique medicine stockouts reported in just 72 healthcare facilities across the North West province. In roughly the same period, doctors in the Eastern Cape reportedly struggled to treat patients with bone marrow cancer due to province-wide shortages of crucial chemotherapy drugs. And in August, Africa’s largest hospital, Chris Hani Baragwanath, allegedly faced a stockout of adrenaline for two days.
Though the problem is not exclusive to South Africa, recent news about medicine stockouts paints a gloomy picture of the country’s capacity to manage essential medicines. But the National Health Department’s Khadija Jamaloodien says these reports shouldn’t overshadow a broader trend. Instead, she argues that the health department has made significant strides to improve medicines availability through a series of national drug stock surveillance programs. (You can see Jamaloodien’s full and very informative response here.)
But what are these systems, and are they as effective as the health department claims?
Health department ramps up surveillance
In November 2013 a nation-wide survey of hospitals and clinics conducted by the Stop Stockouts Project found that more than 1 in 5 had experienced stockouts of ARVs or TB drugs in the previous three months alone. The National Health Department appeared to have little understanding of the severity of the problem – in April, 2014 they claimed that in the last 12 months there had been only a few stockouts of ARVs, restricted to two provinces.
As media attention on shortages grew, the department began to prioritise the issue and developed an extensive surveillance system to better monitor medicine levels throughout the country’s public healthcare facilities. One key program is RxSolution, a computer-based stock management system that pharmacists and nurses use to record the quantities of drugs that have been ordered, received and dispensed at their facilities.
The software was rolled out incrementally at hospitals from 2014 and is now used in healthcare facilities across the country. The data feeds back to a series of national, provincial and district-level dashboards which show medicine levels across facilities.
The central software platform that hosts these dashboards is called the National Surveillance Centre. According to Jamaloodien the platform “allows stakeholders at national and provincial levels to quantify or predict challenges in medicine supply…”.
Additionally, RxSolution generates reports which advise hospital staff on how much of a particular drug they need to order to prevent shortages or overstocking, and which medicines are due to expire.
A similar online tool is the Stock Visibility System, which is used to measure medicine levels at primary healthcare facilities across the country. Unlike RxSolution, it’s accessed on a cell phone app and the data is stored in the cloud (RxSolution requires an in-house server). Healthcare workers scan medicines using the app to capture stocks.
SA better at managing ARVs – trends unclear for other drugs
Evidently, shortages remain, but according to Jamaloodien, these systems have made a positive impact: “Good surveillance systems are one factor in a multifactor situation but do play an important role in reducing stockouts. This can be seen in the downward trend of major stockouts since introducing the surveillance systems…”
Verifying this is difficult however as the health department wasn’t able to provide data over a long period, and independent research has historically focused only on TB drugs or ARVs. Shortages of the latter do appear to have become less common. In 2013, a national survey found that 19% of healthcare facilities had a stockout of ARVs in the past three months. By contrast, interviews that were done with healthcare workers this year suggest that, depending on the quarter, only 5% to 9% could recall shortages of HIV medicines in the past three months.
Whether the surveillance systems played any role in this decline, and whether the same trend holds for stockouts of other drugs, is unclear.
Healthcare workers say software reduces stockouts
A paper published in June assessed the attitudes of 114 users of the National Surveillance Centre. These individuals, mostly managers and pharmacists at different levels in provincial health systems, are responsible for monitoring drug stocks and reporting shortages. Two-thirds of them said the introduction of the National Surveillance Centre in 2016 had improved medicines availability, as having so much data on drug stocks allowed them to be more proactive – for instance by redistributing stocks from facilities that contained an excess of a particular medicine to those with shortages.
Prior to the rollout of this system, many of these individuals had monitored medicine stocks by physically going to facilities or waiting for healthcare workers to notify them of a stockout.
Another paper published in May found positive attitudes toward the Stock Visibility System among healthcare workers who used the system at clinics in Kwazulu-Natal (mostly nurses and pharmacists). Almost three-quarters of the 206 surveyed staff felt that the phone app had improved stock management at their facility, though it had reportedly increased their workload.
This lines up with a national survey in 2017 which found that 87% of healthcare staff reported that the Stock Visibility System had reduced the frequency of stockouts.
Mncengeli Sibanda, a pharmacy expert at Sefako Makgatho Health Sciences University, says the application has clear benefits: “In the past we’d have to count stocks physically and write it by hand, now it’s captured electronically, limiting capture errors and allowing stock counts to be done more regularly…And at a national level, they can intervene [to prevent shortages] because they have data on stock levels at [most] clinics”.
Loadshedding hinders rollout
RxSolution – which is PC-based – appears to have been similarly well-received among some healthcare workers. Phelelani Dludla, the acting clinical manager of Benedictine hospital in Nongoma in KwaZulu-Natal, says that when the system was introduced at Benedictine in 2019 “it would assist us in making orders before we ran out of stock”. He explains that: “it would tell us [which] stocks would run out and so we’d…reorder them a week earlier than our usual routine”.
Dludla adds that it also assisted in reducing waste: “it helped with finding out which drugs we should cut down on in terms of spending, because they were frequently expiring and being sent back”.
But particularly for rural hospitals like Benedictine, infrastructural problems can pose obstacles. Dludla says that since 2021, network problems caused by loadshedding have prevented the use of RxSolution throughout the hospital. Today, the software is only used in the pharmacy. Sibanda explains that “ideally RxSolutions should be [in each section of the hospital], but there have been challenges”. Aside from loadshedding “some hospitals can’t get a computer into each and every ward,” he says.
The National Health Department has also been monitoring drug suppliers. Jamaloodien says that companies that are awarded national tenders to provide medicines are “contractually bound to [provide] up-to-date production pipeline data for products that they supply. The mandatory six-month pipeline window allows for proactive prediction and management of looming supply challenges.”
Policies like this have good international precedent. Preliminary evidence found that Canada managed to reduce drug stockouts by forcing pharmaceutical companies to notify them of any supply interruptions. To work, they need to be implemented effectively however, and the National Health Department has previously complained that companies weren’t routinely notifying them of supply interruptions.
Yet if the health department has generally been making such positive strides toward reducing shortages, why are there still so many stockouts?
Part of the problem is international, says Andy Gray, a pharmacy expert at the University of KwaZulu-Natal: “globally, there is a problem with the security of supply in the pharmaceutical industry. For example there are a number of older cancer drugs that are out of stock in the US at the moment, and the UK has had persistent problems with antibiotics.”
Indeed, last week the European Union announced details of a “solidarity mechanism” in which member states who face drug shortages can now request donations from other European countries if they have exhausted all other options. This was after Europe faced repeated shortages of key medicines over its winter.
If a single factory runs into a problem, this can disrupt global supply, including in South Africa, where locally made drugs usually require active ingredients from abroad. Indeed, a 2020 paper found that pharmacists in Gauteng’s hospitals were often left waiting for medicine orders for months after the delivery deadline and many believed that this was due to contracted suppliers facing shortages of active pharmaceutical ingredients.
According to Gray, another issue is the overreliance on individual companies: “all too often the contract [to supply a particular drug] is awarded to a single supplier”. The conditions of pharmaceutical tenders often stipulate that if the company can’t meet its contractual obligations, the government can turn to alternative suppliers. But that’s easier said than done, says Gray: “If that single supplier is unable to meet demand…the alternative suppliers in the country simply don’t have the volumes to substitute…especially if there’s no prior warning that there is going to be a problem in supply”.
Jamaloodien argues that: “many contracts are currently awarded with…quantities split among suppliers”. However, doing so more frequently would present its own problems, as requiring several companies to produce small amounts of drugs “can invite higher prices because the price is largely related to economies of scale”. In other words, it’s cheaper for one company to supply all the drugs.
Gray acknowledges this but argues that the trade-off needs to be made more often in certain cases: “Vital medicines for which there are no alternatives are being given to maybe one or two suppliers”. The vulnerability this creates can come at enormous cost to patients.
He urges: “for vital medicines we need more split tenders”.
Disclosure: Spotlight editor Marcus Low was a member of the Stop Stockouts Project steering committee for several years in the mid-2010s. Also, Ritshidze is mentioned in this article. Spotlight is published by SECTION27 and the Treatment Action Campaign (TAC) and TAC is a Ritshidze member organisation. Spotlight is however editorially independent – an independence that the editors guard jealously. Spotlight is a member of the South African Press Council and subject to the Press Code.
It is often enlightening for us at Spotlight to ask how and why certain services differ in the ways they do between the private and public healthcare sectors.
Take something as simple as needing medical help when you have a flu that just won’t go away. As a private sector patient, I’d call my GP’s office and make an appointment. Providing I get there on time, chances are I would at most be asked to wait for 10 or 20 minutes in a comfortable waiting room. By contrast, at many public healthcare facilities, you are not able to make an appointment, and often have to wait for long hours in a poorly ventilated and overcrowded waiting area and will likely end up seeing a nurse rather than a GP.
Some aspects of such differences are understandable, albeit deeply problematic. The shortage of doctors is much more acute in the public sector than in the private sector. There is a moral imperative to address this imbalance, but as previously argued, the current NHI plans are just one way to address it.
Why some public healthcare facilities still do not use appointment systems is harder to explain. Even if some users prefer to queue rather than to have appointments, it is odd that all facilities do not at least have hybrid systems with some appointments and some queueing. Having appointment systems is not rocket science and doesn’t have to cost millions.
There are, of course, other examples. As a private healthcare user, it is relatively trivial for me to get a six-month chronic medication script from my GP and to arrange for the medicines to be delivered to my home. Though there has been significant progress in this direction in the public sector, many people still find it hard to get scripts and collect their medicines.
Of course, differences in available resources are a large part of what is going on here, but it is not the whole story. As a private healthcare user, my needs, my preferences, and my time are generally respected in a way that seems rare in the public sector. To be clear, there are many committed healthcare workers in the public sector who show exemplary respect for their patients, but at a systemic level, as in the decision not to have appointment systems or not to allow for extended medicine refills, people’s time and needs are being disregarded.
Apart from the risk of corruption and mismanagement, much of the middle-class resistance to NHI may well have to do with the fear that people who can now access private healthcare services will become subject to precisely this kind of systemic indifference to their needs. And indeed, while the rhetoric around NHI has often been about ideals like the need for greater social solidarity, we haven’t really seen a vision presented of NHI as offering better, more respectful, and more personalised healthcare.
But, with a bit of flexibility, this could change.
Consider annual checkups. Rather than asking public sector patients to go to overcrowded clinics with long queues for tests, why not give public sector users the option of getting their basic screening tests for HIV, TB, hypertension, and diabetes done at private sector pharmacies along the lines of Discovery Health’s Annual Health Checkup. Of course, data systems will have to be developed to support this and it will have to be budgeted for, but the extra convenience will no doubt make a big difference for many and could help with early detection of these diseases. (We previously wrote about the idea of such an expanded annual checkup programme here.)
Getting the state to pay for such checkups at private sector pharmacies is not exactly NHI as set out in the bill, but the idea certainly shares some DNA.
To be fair, there are at least some exceptions that show such innovation is possible. Maybe most notably, these days many public sector patients can collect their chronic medicines at private pharmacies or other pickup points. Though still a work in progress, the evolution of the public sector medicines distribution system shows that we need not wait for the NHI Bill before taking steps to make things easier and more convenient for users.
In addition, with the NHI pilot projects we have seen at least some awareness that there is a need to try new things and learn from them. Unfortunately, on the whole the NHI pilot projects didn’t meaningfully pilot the key aspects of NHI, and where they did, as with GP contracting, it didn’t go well. And here one gets to the rub. From the outside one gets the impression that those who wanted to run pilots we could actually learn from lost out to those who consider the pilots just another step toward building political support for NHI.
As for the NHI Bill itself, the fact that the ANC and much of the portfolio committee on health, has been intent on reducing almost all discussion on the Bill to a simple for or against shows a clear disdain for meaningful engagement. Indeed, whatever its merits, the ANC’s version of NHI has become fundamentally associated with an overdose of ideology and an absence of curiosity and critical thinking.
But we don’t have to buy into the ANC’s sclerotic thinking.
There are many possible ways to reform and improve our healthcare system. Some will be affordable, some won’t. Either way, it would be foolish to simply turn our backs and pretend they are not there.