The recent Union World Conference on Lung Health in Copenhagen, Denmark, showcased a study on preventive therapy pills and a potential new drug, sorfequiline, that may shorten treatment duration while addressing drug resistance, writes Elri Voigt for Spotlight, who highlights some of the most interesting findings at the event.
1. Better results if all TB pills dispensed at once
An important question is how to best prevent people from getting ill if they’ve been exposed to the bug. While effective treatments exist, uptake has generally been poor.
Now, researchers have found that dispensing all of the pills in a three-month course of TB preventive Therapy (TPT) at once, instead of people having to collect pills at the clinic every few weeks, led to more patients completing the course.
The study, called ThiPhiSA, was conducted in four clinics and communities in KwaZulu-Natal, where 268 households who qualified to receive TPT were enrolled in the trial. More than 301 participants were randomised to one of two arms, said Dr Adrienne Shapiro, Assistant Professor of Global Health and Infectious Diseases at the University of Washington.
In the first arm, 159 people were given a two-week supply of the standard of care 3HP (isoniazid and rifapentine, taken once weekly for three months). They then had to go to clinic to receive their refills. They received weekly SMS reminders to take their pills and were visited by researchers at month one and two and at the study’s end.
In the second arm, 142 people were given all the pills for the three-month course of 3HP at once. While no clinic visits were required, they were remotely registered at their clinics in case they had to visit the clinic. They also got weekly SMS reminders to take their pills and were visited at month one and two and at the study’s end.
They were assessed through self-reporting, as well as a calendar dosing diary, pill count and assessment of urine colour change if the visit were on a day when they had recently taken a dose of 3HP.
For those who had to go to the clinic to collect their pills, only 28% completed their course. By contrast, 86% of those who had the full course dispensed at once completed their treatment.
Mainly this was due to some people in the prior group not going to the clinic every time to collect pills. There was also a drug stockout at one clinic – which skewed the results, but not enough to change the fact that people were more likely to complete treatment if they got all of the pills at once.
Dispensing a full course at once was safe, said Shapiro, with no serious adverse events recorded.
2. New medicine might help shorten treatment
Much TB research in recent years has focused on reducing the treatment duration – it typically takes six months. Additionally, researchers have also been looking for medicines with fewer side effects. Growing resistance to some existing drugs is also a concern.
One of the big talking points was data on an experimental new drug called sorfequiline. It is thought this could be a replacement for bedaquiline, arguably the most important TB drug developed in recent decades. This is because sorfequiline appears to be more potent than bedaquiline and because of worries over TB strains that are resistant to bedaquiline.
The new data are from a phase 2 trial of sorfequiline used in combination with two other drugs – pretomanid and linezolid – to treat drug susceptible TB. The regimen is called SpaL for short.
A total of 309 participants with newly diagnosed TB were either given the standard of care first-line drugs isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) for 26 weeks, the BPaL regimen consisting of the drugs bedaquiline, pretomanid and linezolid for 26 weeks (not all drugs in these first two arms are taken for the entire period), or one of three different doses – 25mg, 50mg or 100mg – of sorfequiline along with linezolid and pretomanid for eight weeks.
Once those in the sorfequiline arms completed the initial eight-week course, they had to take isoniazid and rifampicin (HR) for another seven weeks and were then tested for TB again. Meaning at this point they had received treatment for 15 weeks. If they tested negative and had no TB symptoms, they could stop treatment.
But if they tested positive for TB and had symptoms then they’d have to continue taking isoniazid and rifampicin.
Among the participants who got sorfequiline, 64% in the 100mg arm were able to stop treatment after 15 weeks, compared with 46% in the 50mg arm, and 28% in the 25mg arm.
Study participants gave regular sputum samples tested for the presence of TB bacteria. The researchers then estimated the probability of a “stable sputum culture conversion at week eight”. In simple terms, this means the researchers wanted to find out what the probability is that all the TB bacteria had been killed by the different regimens after eight weeks of treatment.
For the 25mg arm, there was 31% stable culture conversion, in the 50mg arm 48%, and in the 100mg arm 59%. For both HRZE and BPaL it was 45%. In other words, 100mg of sorfequiline plus pretomanid and linezolid showed better stable sputum culture conversion after eight weeks than HRZE, the regimen currently used to treat drug-susceptible TB in South Africa and most other countries.
“We believe that SPaL is a promising four-month regimen,” said Dr Morounfolu Olugbosi, the medical lead for the study, which is being conducted by the non-profit TB Alliance.
The regimen was well tolerated at all dose levels, according to Olugbosi, with no difference in safety signals in the sorfequiline arm compared with the other treatment arms. “So that lack of observable difference is what we consider positive news,” he said.
While this trial looked at people with drug susceptible TB, the research team will be investigating how well it works for drug resistant TB in an upcoming phase 3 study, said Dr Maria Beumont, the Chief Medical Officer at TB Alliance, during a press conference.
Indeed, while these phase 2 results are promising, the real test for this drug will be in the larger phase 3 study to come.
3. Co-morbidities are critical when people have TB
A prospective cohort study in South Africa looked at the burden of co-morbidities and the impact it has on TB mortality. The researchers followed about 2 000 adults with pulmonary TB, diagnosed with Gene Xpert (a molecular TB test), and looked at mortality rates for 1 896 of them after 15 months.
Of those, 272 people (14.3%) had passed away during the study duration.
Study presenter Dr Greta Wood, a Clinical Research Fellow in Infectious Diseases at the University of Liverpool, said the prevalence of TB multimorbidity among the whole study group was 86%. Meaning most had TB as well as another illness or risk factor.
The researchers looked at five key co-morbidities identified by the WHO – HIV, smoking, under-nutrition, diabetes and alcohol use.
“These five alone explained more than half of the mortality that we saw in this cohort,” Wood said.
The researchers found that the more co-morbidities a person had, the higher their risk of dying when they TB: the risk of death was 19% if they had three or more co-morbidities compared with 16% if they had two, and 11% if they had no co-morbidities.
The key conditions driving mortality in this group are HIV and under-nutrition. Under-nutrition in particular was flagged, as in this setting it was responsible for around one in five TB deaths in people under 40, Wood said.
“In this cohort, we didn’t find an association between diabetes, smoking, alcohol and mortality, but that has been demonstrated in other settings,” she added.
These data should lead to urgent action, concluded Wood, saying that “to reduce the risk of death, we need to urgently start operationalising screening for these key five comorbidities and linking people into treatment”.
4. Point-of-care testing leads to starting treatment faster
As shown in several studies at the conference, the details of how TB services are delivered can make a significant difference to outcomes.
One such study, led by University of Cape Town researchers, explored whether it made a difference if someone had a TB test done at a mobile van, or had their sputum sample collected and sent to a lab. In other words, did it makes a difference if someone gets a test result right after testing, versus having to wait a day or two to be contacted with a result.
The study, of more than 7 000 people, was conducted in South Africa, Zambia, Zimbabwe, and Mozambique. Around half of those screened in were at high risk for TB and randomised to either receive point of care testing on a GeneXpert machine in a mobile van or centralised GeneXpert testing at a laboratory.
In the point of care arm, results were available for 1 641 people, and of those 55 (3.3%) had microbiologically confirmed TB. While 67 (4.1%) of the 1 632 tested in the centralised testing arm had microbiologically confirmed TB. Overall, across both arms, 93 of the people diagnosed with TB (76%) were successfully linked to care.
“When compared with those who had their Xpert performed at a central laboratory, those who had their Xpert done at point of care had a 43% lower probability of treatment initiation failure and initiated treatment twice as fast,” said presenter Tahlia Perumal, a researcher at UCT. Participants in the point of care arm on average started treatment four days sooner than those whose TB tests were done in a centralised lab.
“There is an argument to be made about the clinical significance of a four-day reduction. We are currently doing transmission modelling to be able to provide more granular details about the difference this may make in active case finding models in larger population sizes,” she said.
5. Promising signs for a portable TB test
In the above study, point-of-care testing was done in a relatively large machine in a mobile van. We may, however, be able to go much smaller.
Tessa Mochizuki, a Research Scientist at University of California-San Francisco, presented results from a multi-country study evaluating how accurate a portable, battery-operated testing device, called MiniDock MTB, was at diagnosing TB from sputum swabs and tongue swabs.
A total of 1 380 people, aged 12 and older with presumptive TB, were enrolled across seven countries – South Africa, India, Nigeria, the Philippines, Uganda, Vietnam, and Zambia. Sputum samples were tested using two MIDGIT cultures (a test in which the bug will grow if present), smear microscopy (where the bug is looked for under a microscope), and GeneXpert Ultra (a molecular test).
Results were then compared with results from the MiniDock MTB machine.
For the tongue swab test, a healthcare worker runs a swab over the participant’s tongue for 30 seconds, then it is put it into a buffer liquid, mounted on a testcard which is run through the portable machine. For the sputum swab, a swab is dipped into a test tube that contains sputum for about 15 seconds, put into a buffer liquid and mounted onto a testcard and run through the portable machine.
When comparing sputum swabs results to the Xpert Ultra results there was not a statistically significant difference, said Mochizuki, as sputum swabs showed 87% sensitivity compared with GeneXpert Ultra’s 89%. Sensitivity is a measure of how likely the test is to detect a bug if the bug is present in the sample.
Tongue swabs performed worse, with 81% sensitivity. However, this was much better than the 62% with microscopy. Microscopy is rarely used for TB diagnosis in South Africa, but this finding could be important in other countries where health systems haven’t switched over as fully to molecular testing as we’ve done here.
All sample types and tests achieved 98% specificity – an indication of how likely a test is to give a negative result if the bug being tested for is not present in the sample.
These findings meet the WHO target product profile requirements – a minimum of 85% sensitivity and 98% specificity for sputum tests, and a minimum of 75% sensitivity and 98% specificity for non-sputum tests.
“We submitted these data to the WHO guideline development group that convened last week, and look forward to news on any official recommendations next year,” Mochizuki said. “These results show we can achieve high accuracy with a low-complexity platform, bringing molecular testing closer to people seeking care without sacrificing performance.”
6. A mask that can help diagnose TB
An even more interesting idea on which some researchers have been working is using a diagnostic mask to ID TB.
Dr Rouxjeane Venter, a researcher from the Clinical Mycobacteriology and Epidemiology (CLIME) research group at Stellenbosch University, presented a proof-of-concept study testing whether a mask – the Avelo Mask – can be used to diagnose whether TB bacteria is present in the air a person breathes out.
A total of 58 adults, from four clinics in Cape Town who had TB symptoms and tested positive for TB on a molecular test, were given the mask to wear for 45 minutes. Its filter can trap tiny particles from .3 micrometers and above – meaning it can trap viruses and bacteria. This filter is then pushed into a buffer tube using a sample stick, where it can be stored or tested directly.
The mask as well as the stick and buffer tube are part of the Avelo kit developed by Avelo Diagnostics.
For this study, the researchers used a qPCR test – a rapid test that looks for TB DNA – to detect TB bacteria.
When the mask filters were tested, 34 people were found to be negative for TB bacteria and 24 were positive. Compared with their Xpert Ultra sputum results, two were false positives.
Overall, according to Venter, the mask had a sensitivity of 71% compared with GeneXpert Ultra, and 65% when compared with the Microbiological Reference Standard and a specificity of about 92%.
People with higher bacillary loads in their sputum were more likely to be positive, but there was still a large percentage of participants with low or very low bacillary loads that were detected by the mask.
These numbers aren’t nearly as good as those for the MiniDock MTB, but it is positive that masks like these are showing promise. A long-standing problem in TB diagnosis is that not everyone can produce sputum samples. The more alternatives available, be it tongue swabs or masks, the better.
Spotlight article – Six striking findings from major TB conference (Creative Commons Licence)
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