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Some patients with highly drug-resistant tuberculosis could benefit from a shorter treatment with fewer drugs while others may warrant more aggressive therapy, according to the findings of a new study led by an international group of researchers including scientists from Harvard Medical School and conducted across six countries in Asia, Africa, and South America.

The study, partly funded by the National Institutes of Health, is known as endTB-Q, is the first-ever clinical trial to focus exclusively on people with pre-extensively drug-resistant tuberculosis (pre-XDR-TB), a hard-to-treat form of the disease that is more challenging to cure than multi-drug resistant TB but not as extremely impervious to medicines as the most dreaded form of the infection known as extensively drug-resistant TB. Pre-XDR-TB is resistant to rifampin — the most potent first-line drug used against TB — and fluoroquinolone, which thus far has been the most potent second-line TB drug.

The findings, published July 14 in The Lancet Respiratory Medicine, highlight the importance of individualizing therapy to account for patient-to-patient differences and give each infected person a treatment regimen that is the most effective and least toxic for them, the researchers noted.

“This shorter regimen is not a surefire cure for everyone. The big takeaway is that we might need a more tailored approach to treatment of this kind of resistant TB,” said study TB expert Carole Mitnick, professor of global health and social medicine in the Blavatnik Institute at HMS. Mitnick was co-senior author on the study and a member of the endTB project, spearheaded by Partners In Health, Médecins Sans Frontières, and Interactive Research and Development and done in collaboration with researchers and clinicians worldwide.

In recent years, researchers have increasingly found that shorter, less harsh drug regimens benefit certain patients, Mitnick added, but she cautioned that more research is needed on how to select the right patients who would benefit the most, while ensuring that more severe and more drug-resistant forms of the disease do not go untreated or suboptimally treated, leaving patients with lingering or re-emerging disease that is dangerous to their families and communities.

More than 80 years after the first patients were cured of TB using antibiotics, tuberculosis remains the leading infectious cause of death worldwide, killing close to 1.5 million people a year. The disease has a global reach, including in the United States, where more than 500 people have perished from TB per year for the last decade and cases are on the rise.

One reason for this is drug-resistant strains of the disease. Another is that many common regimens are difficult for patients to complete, due to the number of pills required, the length of treatment, and the severe side effects of many established therapies. This means that treatment is cut short in some patients, allowing the infection to roar back.

The aim of the endTB-Q trial was to test whether a shorter, likely better tolerated treatment would be effective against pre-XDR-TB. The trial compared an experimental regimen that used a combination of four drugs (bedaquiline, delamanid, clofazimine, and linezolid) for six or nine months with a long regimen based on the standard of care recommended by the World Health Organization, which included four to six drugs taken for 18 to 24 months.

The results of the trial showed that the shorter regimen might be a promising alternative for many patients with pre-XDR-TB. A favorable outcome was established by two consecutive cultures negative for the TB bug late in the 17-month period of post-randomization follow-up or by favorable bacteriological, radiological, and clinical evolution throughout this follow-up. By this standard, the shorter regimen was 87 percent effective while the longer therapy was 89 percent effective. Both groups of patients received social support including access to nutritious food and transportation, shown to help patients complete TB treatment.

The research was designed to measure “non-inferiority,” a technical term that describes when an experimental treatment is good enough to replace an existing standard of care. In this study, the shorter regimen did not meet that standard across the full study population.

But not all patients responded the same way to the shorter regimen. Those with more advanced lung damage, for example, did not fare as well as those with less advanced disease. For these individuals, the shorter regimen — even delivered for nine months — was not always sufficient to prevent relapse. These patients benefited more from the longer regimen. This could mean treatment needs to be longer in that group or treatment needs to be reinforced with more drugs, the researchers said.

Mitnick noted that other studies of shortened regimens that have included people with this type of drug-resistant TB in their study population did not have enough statistical power to measure the effectiveness of the regimens on people with pre-XDR-TB or to differentiate between those with different degrees of symptoms.

The researchers note that recent guidance from WHO and from North American and European experts, which came out after the endTB-Q trial was underway, recommends six-month regimens irrespective of disease severity. Given the findings of the endTB-Q trial and similar results from other studies, the researchers said, the guidelines should be updated to include consideration of stratified approaches to care based on resistance pattern and extent of disease.

“After millennia of fighting this complex, constantly evolving disease, we know that we need to approach it with great caution and attention to detail,” Mitnick said. “Instead of focusing on the ‘prize’ of shortened treatment, we need to keep our eyes on the true goal of curing as many people as we can.”

Reference: Guglielmetti L, Khan U, Velásquez GE, et al. Bedaquiline, delamanid, linezolid, and clofazimine for rifampicin-resistant and fluoroquinolone-resistant tuberculosis (endTB-Q): an open-label, multicentre, stratified, non-inferiority, randomised, controlled, phase 3 trial. Lancet Respir Med. doi: 10.1016/S2213-2600(25)00194-8

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New data from Denmark shows the HPV vaccine’s powerful long-term impact, while also revealing why cervical cancer screening is still essential.

Study: Human papillomavirus prevalence in first, second and third cervical cell samples from women HPV-vaccinated as girls, Denmark, 2017 to 2024: data from the Trial23 cohort study. Image credit: Halfpoint/Shutterstock.com

A Danish study published in the journal Eurosurveillance reports that women who received the human papillomavirus vaccine in their adolescence are significantly less likely to develop human papillomavirus infections later in life.

Background

Prolonged infection with human papillomavirus (HPV) is associated with an increased risk of developing cervical cancer. Early screening and vaccination against HPV are effective strategies to prevent this cancer type.

Screening for precancerous lesions has been a widely considered strategy for secondary prevention of cervical cancer in Europe. Vaccines covering both high-risk and low-risk HPV types have been introduced as a primary preventive intervention at the end of the 2000s.

In Denmark, free public HPV vaccination (4-valent vaccine) was initially offered to all girls aged 13 to 15 in October 2008. It was later introduced to all girls turning 12 in January 2009. In November 2017, a 9-valent vaccine, which covers high-risk HPV types responsible for up to 90% of cervical cancers, was introduced in the country.

Cervical cancer screening is offered to women living in Denmark from the age of 23 years until the age of 64 years. One of the first groups of women who received the 4-valent HPV vaccination as teenage girls in 2008 reached the screening age of 23 years in 2017.

To carefully monitor screening outcomes in these vaccinated women, Trial23, a public health study embedded in the Danish national cervical screening program, was designed to determine the prevalence of HPV infection in cervical cell samples collected during three consecutive rounds of screening invitations.

In the current study, researchers assessed the prevalence of HPV infection in these consecutive cervical samples and the changes in HPV persistence and incidence between the first, second, and third samples.

Key findings

A total of 17,252 women with at least one cervical cell sample were registered in the Trial23 between February 2017 and February 2024. In this study, researchers analyzed 16,955 cervical samples collected from 8,659 women.

The prevalence of any high-risk HPV infection in the first, second, and third rounds of cervical samples was 32%, 28%, and 31%, respectively. The prevalence of HPV types 16 and 18 (high-risk viruses covered by the 4-valent HPV vaccine) remained low over time in all analyzed samples.

The comparison between vaccinated and unvaccinated women revealed significantly lower prevalence of HPV types 16 and 18 in vaccinated women. The prevalence of this virus type was 15 to 17% before vaccination, which reduced to less than 1% in vaccinated women by 2021.

Notably, the study found that about one-third of women still have infections with high-risk HPV that are not covered by the vaccine, and that the incidence of these infections was significantly higher in vaccinated women compared to unvaccinated women. However, the prevalence differences were not statistically significant.

Regarding HPV infection persistence and incidence, the study found a high persistence for both vaccine-covered and non-covered virus types, irrespective of vaccination status. The incidence of HPV types 16 and 18 was significantly lower in vaccinated women compared to that in unvaccinated women. However, the incidence, but not prevalence, of non-covered high-risk HPV types was significantly higher in vaccinated women compared to that in unvaccinated women, a pattern the authors suggest may be due to type replacement or unmasking.

Study significance

The study reports the prevalence of HPV infection in three sets of cervical cell samples collected consecutively from young Danish women who received the 4-valent HPV vaccination in their adolescence.

According to the findings, the prevalence of infection with HPV types 16 and 18 in vaccinated women is currently less than 1%, a significant drop from the pre-vaccination prevalence. In unvaccinated women, the prevalence is 5%, which is also much lower than the pre-vaccination prevalence. The drop in prevalence in unvaccinated women indicates population immunity.

Regarding infections with high-risk HPV types that are not covered by the vaccine, the study reports a prevalence of 30% in vaccinated women and 27% in unvaccinated women, which is a non-significant difference. A persistently high prevalence of non-vaccine high-risk HPV types in both vaccinated and unvaccinated women highlights the need for continuous screening of these generations until women vaccinated as girls with the 9-valent vaccine covering all major HPV types reach the screening age. At this point, the screening model might be reconsidered, with the study suggesting that less intensive but continued screening could be appropriate.  

The study finds no significant differences in the persistence of HPV 16 and 18 infections between vaccinated and unvaccinated women, which indicates that the 4-valent vaccine, which covers high-risk HPV types 16 and 18 and low-risk types 6 and 11, is a prophylactic (preventive) vaccine and not a therapeutic vaccine. The conclusion supports the finding that persistence rates were similar regardless of vaccination status.

Overall, the study findings highlight the long-term protective efficacy of the HPV vaccine and advise close monitoring of factors associated with vaccine hesitancy and low vaccine coverage, such as perceived side effects of the vaccine.

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In utero exposure to two liquid ingredients in e-cigarettes – minus the nicotine that drives addiction – can alter skull shape during fetal development, a new study in mice has found. 

In a series of experiments, pregnant mice were exposed to a combination of two liquids used to create vaping’s throat hit and smoke plume. Compared to two other experimental conditions, the offspring of mothers exposed to a specific ratio of these compounds weighed less and were born with narrowed facial features and shortened skulls.

The finding was surprising to researchers not only because no nicotine was present, but because the ratio of chemicals that produced the skull defect was designed by the e-cigarette industry to be a safer available option than the proportions in earlier products.

“This had no nicotine, and it’s still having effects on the development of the skull in our model, which was not anything we expected,” said lead study author James Cray, professor of anatomy in The Ohio State University College of Medicine.

The research was published recently in the journal PLOS One.

Cray’s developmental biology lab has studied the effects of in utero exposure to nicotine on head and face development for years, reporting in 2020 that exposure to nicotine through breastmilk caused skull defects in mice. About 3% of babies are born annually with a birth defect, according to the Centers for Disease Control and Prevention, and alterations to the head and neck are among the most common – particularly cleft lip and/or cleft palate.

In this study, the team was developing a model to serve as an experimental control for comparison to animals exposed in utero to nicotine through vaping.

Pregnant mice were exposed to either filtered free air or two humectants – hydrating substances that function as carriers of other e-cigarette contents – at differing concentrations: 50% each of propylene glycol and glycerol (also called vegetable glycerin), or 30% propylene glycol and 70% glycerol (30/70 PG/VG).

Because propylene glycol in e-cigarettes has been linked to increasing uptake of nicotine, Cray said, “a lot of companies have moved toward getting away from a high percentage of propylene glycol toward more glycerol, trying to position this as a safer alternative.”

Female mice were exposed to these three different conditions at a rate of one puff per minute, four hours per day on five days each week during the roughly 20-day pregnancy.

The cranial width and height of mouse pup skulls were scanned two weeks after birth. The analysis showed statistically significant reduced measures in the offspring of pregnant mice exposed to the presumed safer 30/70 PG/VG mixture compared to mice exposed to free air and the 50/50 formula.

“What we see is a consistent narrowing of all of the facial features, and the same thing as we move back into the cranium as well. So globally they’re narrower and a little bit shorter-headed, which does mimic some observable changes that we see in children,” Cray said. “We also saw a bit of a reduction in weight. These animals were within the normal range of an animal that age, but they still weighed less.”

The findings were consistent across several litters of mice and in both biological sexes.

“The 50/50 mixture had no dramatic statistical changes – and that’s where we were looking for the difference. We thought heavier propylene glycol should be causing more effects, and it was the exact opposite,” Cray said.

The Food and Drug Administration began regulating electronic nicotine delivery systems in 2016, but has faced legal pushback from e-cigarette companies – which prevailed in a June 20 U.S. Supreme Court ruling that makes it easier to sue the FDA over efforts to block products from the market. In April, the court sided with the FDA’s crackdown on sweet-flavored products after a major increase in teen vaping.

Though researchers continue to study the health effects of multiple ingredients detected in e-cigarettes, many unknowns remain as the products grow in popularity.

“The majority of users are young adults and teenagers, so we are talking about people who are in peak reproductive years. And with development of the head happening very early in fetal development, people could be using these products and not even realize that they are pregnant, which is of great concern,” Cray said.

“This is a small study that speaks to the possibility that nicotine-free vaping is not safe. And it’s a sign that we probably should study the nicotine-free products as much as we study the nicotine-laden products.” 

Reference: Richlak E, Shope L, Leonard E, et al. In utero exposure to electronic cigarette carriers alters craniofacial morphology. PLOS ONE. 2025;20(6):e0327190. doi: 10.1371/journal.pone.0327190

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