Despite the global emergence of highly resistant strains of gonorrhoea, including untreatable variants, a new antibiotic for the disease has not been developed in more than half a century.
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Despite the global emergence of highly resistant strains of gonorrhoea, including untreatable variants, a new antibiotic for the disease has not been developed in over half a century. In January, a trial began in South Africa and other countries for a new gonorrhoea antibiotic. But what is gonorrhoea? How significant is the problem in South Africa and among those living with HIV? Do we have resistant strains too? Experts report a grim situation, but with hope on the horizon.
South Africa has one of the highest rates of sexually transmitted infections (STIs) in the world, including for gonorrhoea. It is estimated that every year around two million people in the country get infected with the gonorrhoeae bacterium, which is likely to be an underestimate because most women don’t show any symptoms, according to a study published in the journal PLOS ONE in 2018.
The World Health Organisation (WHO) estimates that, globally, there are 87 million cases of gonorrhoea annually, with the African region having the highest burden.
“If you look at the global number, South Africa represents about 2% of the cases which is quite high and could be an underestimate for a number of reasons including under-reporting and that women especially don’t show symptoms,” says Edward Mukwaya, who is the local clinical trial manager for a new antibiotic study being run, and fully funded by, the Global Antibiotic Research and Development Partnership (GARDP).
The trial, being run in partnership with the company Entasis Therapeutics, is investigating whether a new antibiotic called zoliflodacin is a safe and effective treatment for gonorrhoea. New treatments are urgently needed due to gonorrhoeae bacteria becoming resistant to the currently available treatments.
This is a pivotal phase three trial, where the drug will be tested on a large number of people to prove safety and efficacy to support an application for marketing authorisation. According to Mukwaya, the trial is looking to enrol over 1,000 participants from the United States, the Netherlands, Thailand and South Africa. With three sites in SA, there are expected to be between 400 and 600 local participants. Recruitment of study participants in South Africa started at the end of January.
The zoliflodacin trial will not be double-blinded because the oral drug is being tested against the existing standard of care, which includes an injectable drug. This means participants in the control arm will know they are in the control arm if they receive injections.
What is gonorrhoea?
According to the National Institute for Communicable Diseases (NICD) head of STIs, Dr Ranmini Kularatne, gonorrhoea “is a sexually transmitted infection, and is therefore acquired through having genital, oral or anal sex with an infected partner”.
“Neisseria gonorrhoeae (a species of bacteria), the causative agent of gonorrhoea, is the predominant cause of male urethritis syndrome (MUS) in South Africa i.e. of symptoms such as genital discharge in men presenting to primary healthcare clinics,” she tells Spotlight.
“Common symptoms in men are discharge from the penis and burning on urination. If left untreated, complications include pain and swelling of the testes and even male infertility. Symptoms in women include vaginal discharge, which may progress to lower abdominal pain, gynaecological complications such as pus collections in the pelvis and tubal pregnancy and infertility if left untreated. However, most infections in women either do not present with any symptoms or present with mild symptoms only,” says Kularatne.
“We don’t test”
Another reason the two million cases are likely to be an underestimate is because of how the condition is treated and diagnosed in South Africa, says gonorrhoea expert Dr Kevin Rebe, who has previously done work on the disease for the Anova Health Institute and currently runs a private practice in Cape Town.
“One of the biggest issues in countries like South Africa, is that, because of cost, we manage it with syndromic presentation and treatment. We don’t test but rather diagnose gonorrhoea according to symptoms. This means we miss all asymptomatic cases. This is the national strategy in public health facilities but is also often done in private settings,” he says.
The move towards symptomatic management, away from laboratory-based diagnosis, happened about 25 years ago and was based on the high costs of testing and diagnosis and the fact that clinicians could not get results on the same day of testing, says Professor Sinead Delany-Moretlwe, who is also the principal investigator for South Africa for the international trial on zoliflodacin. “In principle, when someone presents with an STI we want to diagnose and treat on the same day so they leave the clinic with a high chance of being cured and interrupting transmission,” she says.
There is a risk of losing patients by telling them to come back for treatment at a later date.
According to STI expert Professor Remco Peters from the Foundation for Professional Development and affiliated with the University of Pretoria and the University of Cape Town, this strategy does not allow us to get a proper idea of the total number of people with gonorrhoea, including the asymptomatic burden. It is also a barrier to the country’s knowledge of the level of drug-resistant cases.
The growing threat of drug resistance
Antimicrobial resistance has emerged as a global threat to modern medicine and public health. The WHO has identified gonorrhoea as one of the top ten threats to antimicrobial resistance, but data is lacking for our country and continent.
“Neisseria gonorrhoeae is a smart bug that escapes anything you feed it, it learns and evades every set of antibiotics we throw at it – it’s just a matter of time,” says Rebe.
This is why national treatment guidelines have to change every several years and also why we rely on treatment with two antibiotics as it is hoped resistance will develop less quickly if the bacteria is attacked by two agents at once. In South Africa these two drugs at present are ceftriaxone, which is an intramuscular injection, and azithromycin, taken as two tablets once-off.
Having an injectable agent is not ideal, which makes zoliflodacin, which comes in the form of a single dose oral tablet, even more important.
Peters led a study published in November 2020 in the journal Antimicrobial Agents & Chemotherapy that investigated the level of drug-resistant strains in a high-risk population of men, including men who have sex with men in South Africa. Out of the 51 men recruited for the study, 42 were diagnosed with gonorrhoea. Most strains were resistant to drugs used previously for treatment. About 15% were resistant to azithromycin, but none were resistant to ceftriaxone.
But another study published in the April 2019 edition of the journal Sexually Transmitted Diseases, found a much higher prevalence of azithromycin resistance. “In KwaZulu-Natal, such dual therapy is in fact single-drug therapy because the level of resistance to azithromycin is more than 60%,” wrote the authors, who conducted the study amongst 506 male and 714 female patients appearing with symptoms for gonorrhoea in two sites in the province.
Peters says that, due to the emergence of widespread azithromycin resistance, some countries, such as the United States and the United Kingdom, have already amended their guidelines to stop the drug’s use in favour of mono-therapy. “Some countries are still debating mono-therapy and others have already switched to giving ceftriaxone alone, usually at a higher dose.
“The bottom line is we’re running out of options to treat gonorrhoea. We still have ceftriaxone, but other than that new drugs are needed,” says Peters, adding that this makes having a new option like zoliflodacin even more important.
“Zoliflodacin is the first of a novel chemical class, known as topoisomerase inhibitors, against gonorrhoea. Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases, which play an important role in cellular reproduction and DNA organisation,” explains GARDP’s communications manager Caleb Starrenburg.
Testing high-risk groups
Peters advocates for directed laboratory testing which is the routine testing of high-risk groups because resistance is much more likely to emerge in these groups first for several reasons including that they are likely to have been treated for gonorrhoea before, and resistance develops after exposure.
“It also has to do with sexual networks, frequency of exposure, having STIs more often and being treated more often,” says Peters. He adds that men who have sex with men aren’t the “only high-risk group” but that, for example, “commercial sex workers are at high risk as well” and that there are several high-risk groups.
Another group who should not be overlooked is young women who are both more at risk of gonorrhoea than the general population as well as for its long-term, and severe, consequences, says Delany-Moretlwe. “We know from early pre-exposure prophylaxis (PrEP) studies on girls and women aged 16 to 25 starting PrEP, one in 10 are likely to have gonorrhoea over the course of a year. There are much higher rates in young people. Modelling work has estimated that five in 100 people have gonorrhoea in SA at any given point in time,” she says. PrEP (pre-exposure prophylaxis) involves taking antiretrovirals to prevent HIV infection. PrEP does not protect against other STIs.
Delany-Moretlwe argues that PrEP sites that are enrolling young women and girls should be included as a matter of priority in any high-risk population-directed gonorrhoea testing strategy.
“What we’ve seen after 25 years is that, while the current syndromic approach may work better for men, it doesn’t work for women. Research has shown that, up to 90% – almost all – young women didn’t report symptoms and, in the current South African system, would not be detected and treated,” she says.
Consequences for women can be severe
“The consequences of untreated gonorrhoea in women are severe,” Delany-Moretlwe says. “They can go on to develop upper genital tract infections, pelvic inflammatory disease, chronic pain, ectopic pregnancies [an emergency situation where a fertilised egg attaches somewhere outside the uterus], and subsequently infertility.”
Additionally, she says “pregnant women can pass on gonorrhoea to their children and that has consequences, for example, infection in the infant’s eye which can lead to blindness if untreated”.
According to Peters, another problem with the current syndromic management of STIs is that it adds to the likelihood of resistance developing because relying on symptoms alone which could be caused by another infection “means we over-treat and drive resistance”.
Entangled with HIV
The problem is made even more severe for South Africa because of the interplay between gonorrhoea and HIV, says Rebe.
We are in a situation where the focus on HIV has arguably harmed the attention given to all other STIs yet, certainly in the case of gonorrhoea, the two STIs are interconnected. Having HIV makes one more likely to have gonorrhoea and HIV is more likely to be transmitted if the infected person is positive for gonorrhoea.
“HIV is associated with having or had prior gonorrhoea and chlamydia [another STI] over the past two years,” Rebe says. “The risk of gonorrhoea in someone with HIV is up to eight times the normal HIV risk in some studies. The mechanism is twofold. In someone with HIV and gonorrhoea, the HIV viral load goes up in the genital compartment creating an impact. Gonorrhoeal inflammation of the vagina, penis, anus or mouth causes inflammation of the mucosa and (there is) more potential and (it is) more pliable to be breached by HIV.”
Thus, gonorrhoea makes it more likely for HIV to be transmitted and contracted due to damaged, and more porous, cells in sexual parts of the body.
“Despite this, many sexually active patients don’t get routine STI screening, which I think is a big gap in our health programmes,” says Rebe.
More contagious than HIV
Despite gonorrhoea not appearing in public education campaigns, like we have seen for HIV, it is actually significantly more contagious than HIV.
“HIV is rarely transferred outside of penetrative sex with the penis, vagina or anus, it relies on a lot of things like duration of sex, enough bodily fluid (blood and semen) – all these conditions. But gonorrhoea can be transmitted orally too and more easily with penetrative sex,” says Rebe. “We’ve amplified the HIV message because people are less concerned thinking this can be cured by antibiotics whereas the virus can’t be cured. But doing this, we’ve downplayed the consequences of antibiotic resistance – a lot of bacterial infections are increasingly untreatable.”
Peters adds that South Africa has not really implemented a proper strategy for the management of treatment failures. “If someone is treated and fails treatment in the public sector, we need options to manage patients better or the infrastructure to get a culture and figure out what’s going on, but currently we are limited in what we can do,” says Peters.
It is challenging to diagnose gonorrhoea because it is expensive, takes time (because bacteria has to be cultured in a lab), and because the bacteria do not survive well outside of the body.
“One of the reasons we struggle to diagnose gonorrhoea, even in hospitals with labs on site, is [because] gonorrhoea is a fastidious bacterium that makes it quite difficult to be cultured successfully. It requires very specific conditions. What happens in a hospital or clinic in rural areas, even in an urban area, [is that] you would want to test the gonorrhoea sample but by the time it has reached the lab the sample is no longer alive. There are also specific requirements with regard to sample collections that are more demanding than for other STIs,” explains Peters.
A rapid point of care test for gonorrhoea does not exist. But a test that does not require the same time needed to culture (around an hour versus weeks) exists in the form of the Gene Xpert. These are mostly lab-based machines already widely used in South Africa to test for tuberculosis. These machines take between an hour and an hour and a half to generate results. Importantly, this test can determine whether there is antibiotic resistance.
For now, however, this test is only used in some studies and is not available in the public healthcare system. But, said Peters, there is some hope with recent interest being shown by the National Department of Health. “In the WHO’s global STI strategy there is a call to consider diagnostics for STIs, where resources permit, and the South African government has taken this on in its strategic plan. They are looking into which high-risk groups are the right ones in terms of incidence to start thinking of pilot projects using diagnostics,” says Peters.
Delany-Moretlwe says using the existing PrEP programme as a platform to offer gonorrhoeal diagnostic testing to all people accessing PrEP would be ideal, especially for young women. These women already belong to a high-risk population. The fact that they are using PrEP is also an indicator of higher risk.
Women accessing PrEP would access the health system at least every three months to fill their prescription and therefore can be treated if laboratory testing reveals a positive gonorrhoea diagnosis.
A reliable source who asked not to be named said the national department “is busy putting together these plans and hopes to have some pilot work started within the next couple of years”. “They have a road map and are going to look at syphilis first, and I’m sure gonorrhoea will follow.”
Will we be able to get zoliflodacin if it works?
Will people in South Africa be able to access zoliflodacin if the phase three study is successful and what does access mean in the context of gonorrhoea — a bug known for its ability to over time evade any antibiotic regimen thrown at it?
According to GARDP’s Amir Shroufi, who is the organisation’s Medical Affairs Expert Advisor for southern Africa, GARDP is exploring innovative funding mechanisms that can help to make sure medicines effective against antimicrobial-resistant organisms are available to those who need them most, and that GARDP is working to ensure that access is not constrained by affordability.
“We would like South Africa to have access to the product, of course, but it is quite difficult to say when and how at this point as we still have to have the conversation about who will be able to access it and how will it be made accessible to countries like South Africa. That work still needs to happen, but we have time. Phase three trials have only just started,” explains Shroufi.
He adds that the advantage of zoliflodacin is that it was not developed by a drug company motivated by profit. “We are not a commercial entity, so the model of a drug company – to sell more of the product to make more profit – doesn’t apply to us. In terms of guarding against resistance, it is not always the case that we want to be using a drug as widely as possible. We need to think carefully about how we use it,” says Shroufi.
“In terms of South Africa, gonorrhoea is still treatable with existing drug regimens. But we’ve seen the emergence of resistance in other countries and, based on what we know about how resistance spreads, it will emerge in South Africa – we just don’t know when,” he says.
Access could also hinge on resistance being confirmed by testing, something that is lacking in South Africa and will remain lacking, at least, for our immediate future.
With the future accessibility of zoliflodacin and when drug-resistant strains will emerge in the country both being unknown, Rebe points out there are other obstacles regarding improving the fight against gonorrhoea – some easier than others to overcome.
“I think the way we deal with STIs other than HIV is conservative and reflects the taboo nature of STIs in our community. For example, if a patient is treated for gonorrhoea in our public sector, they are still given a case partner notification slip that they are expected to take to their husband or wife. That is so 1970s. We know [many] people have sex outside of formal relationships. The reality for some people is that they may not know their most recent partner’s name or telephone number,” he says.
Rebe tells Spotlight that contact tracing needs to become more sophisticated and innovative to work in line with today’s realities. He suggests the use of online and cellphone-based platforms like the ones used for Covid-19.
While we are over-treating, as mentioned by Peters, Rebe notes that we are also undertreating [by] “not finding enough of the cases to treat”.
“Gonorrhoea is a hidden disease. Nobody gets trained on how to deal with it properly. There is no interest in it and, consequently, it has been neglected. Millions of cases happen every year and probably the majority are being treated without being tested, so who knows the true nature of the epidemic? There are huge gaps in our knowledge, but I still think it’s possible to put together a coherent programme to address it,” he says.
In its mandate to guide the formulation of the government’s National Strategic Plan (NSP) on HIV, STIs and TB, the South African National Aids Council (Sanac) admits to Spotlight that there are challenges setting specific targets for individual STIs resulting in the fact that there is no target in the current, and upcoming NSP, on gonorrhoea.
“Globally, target setting for STIs remains a challenge, therefore there are no specific targets for any particular micro-organism [outside of HIV and TB],” says Sanac CEO Dr Thembisile Xulu.
The general STI targets in the NSP include increasing condom awareness, intensifying case finding, enhancing the role of traditional health practitioners, strengthening data management and “exploring the use of mHealth tools and social media”.
Rebe says that there “aren’t a lot of [STI] researchers in SA” and that “it’s not an easily fundable topic”.
“The NIH [US-based National Institute of Health], for example, will be much more likely to fund a study on HIV or Covid-19 than one about gonorrhoea. I’m not aware of young doctors wanting to be STI specialists, outside of HIV. It’s not on the research agenda. That’s a problem. If it can’t get funded and mentors aren’t teaching about it, then no one is going to develop a passion about it. Despite its significance, it is not a very sexy disease.” DM
This article was produced by Spotlight – health journalism in the public interest.
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