New generation of drugs show early efficacy against drug-resistant TB


Date:
August 12, 2020
Source:
Harvard Medical School
Summary:
New drug regimen for multidrug-resistant tuberculosis shows early
effectiveness in 85 percent of patients in a cohort including many
with serious comorbidities. The results suggest a global need for
expanded access to two recently developed medicines, bedaquiline
and delamanid.

Study cohort included many people who would have been excluded from
trials because of comorbidities, severity of disease or extent of
drug resistance. Findings highlight the importance of innovative
regimens to improve outcomes for patients with multidrug-resistant
tuberculosis.



FULL STORY ==========================================================================
New treatment regimens for multidrug-resistant tuberculosis (MDR-TB)
have shown early effectiveness in 85 percent of patients in a cohort
that included many people with serious comorbidities that would have
excluded them from clinical trials, according to the results of a new international study.


==========================================================================
The results, based on observational data from a diverse cohort of
patients in 17 countries, underscore the need for expanded access to the recently developed TB medicines bedaquiline and delamanid. By contrast,
the historical standard of care, still in use in much of the world,
has approximately 60 percent treatment efficacy globally.

The study was published July 24, 2020, in the American Journal of
Respiratory and Critical Care Medicine.

"This is important evidence that these new regimens will work well for
the true population suffering from this disease," said lead study author
Molly Franke, associate professor of global health and social medicine
in the Blavatnik Institute at Harvard Medical School.

The research was conducted as part of endTB, an international partnership
with leaders from HMS, Partners In Health, Me'decins Sans Frontie`res, Interactive Research & Development, the Institute of Tropical Medicine
in Antwerp and Epicentre.

"Our findings underscore the need for urgent expanded access to these
drugs," said Carole Mitnick, associate professor of global health and
social medicine in the Blavatnik Institute at HMS and a co-author of the
study. While recent announcements of a price reduction for bedaquiline
and an expected reduction for delamanid are welcome, the researchers
said, more must be done to improve treatment guidelines worldwide and
to scale up treatment with these new regimens.



==========================================================================
The need for better treatments for MDR-TB is dire. The WHO estimates
that there are nearly 500,000 new cases of MDR-TB per year and that
nearly 200,000 people die of the disease each year . In 2018, only one
out of three patients were given an effective treatment, and only half
of these were cured.

In the early 2010s, regulatory agencies approved the first new TB drugs
in 50 years, bedaquiline and delamanid, offering hope for more effective
and less toxic MDR-TB treatment. With the historical standard of care
and some newer regimens, certain subgroups of patients, including those
with HIV or hepatitis C or diabetes experience worse treatment outcomes
than patients without these conditions. In addition, these conditions
preclude patients from participating in clinical trials for these drugs.

It's important to examine whether these subgroups experience any
benefit from the new regimens that might be observed in healthier study participants, the researchers said. They noted that only a large cohort
study has the statistical power to explore these differences.

The endTB study showed that for the new regimens, early treatment
response was similar for patients without serious comorbidities or other complicating factors and for those with diabetes, hepatitis C and severe
drug resistance.

Patients with severe TB disease when they started treatment had worse
outcomes than patients with less severe disease. Sixty-eight percent
of people with severe disease had early favorable responses to the new
regimen, compared to 89 percent without severe disease. Among patients
with HIV coinfection, early outcomes on the new regimens were favorable
in 73 percent, compared to 84 percent in those without HIV.



==========================================================================
The results are based on an analysis of early treatment results from
more than 1,000 MDR-TB patients who were enrolled in the study between
April 2015 and March 2018. The study examines outcomes after 6 months
in a treatment that lasts 15 months or longer. Long-term effectiveness
will be measured at the end of treatment and during follow-up.

For this study, the researchers counted how many of those patients, within
the first six months of treatment with regimens containing bedaquiline, delamanid, or both, experienced culture conversion, a state in which
the bacteria that cause TB can no longer be found on a sample. Previous
studies have shown this to be a strong predictor of successful treatment outcomes.

Confirmation with end-of-treatment outcomes will be important and more
work needs to be done to ensure successful treatment in these populations,
the researchers said.

"The early results from these studies offer convincing evidence that these
new regimens offer a very promising alternative to the historical regimens
that achieve approximately 60 percent success at end of treatment, and to
other new treatments that are becoming available," said Mitnick, who is
a senior researcher at Partners In Health and co-principal investigator
of the clinical trials being conducted by endTB.

"We're eager to follow these patients as they progress through treatment
in order to verify the effectiveness of these new regimens," she added.

Observational research makes so many important contributions to improving treatment outcomes for complex illnesses in complicated populations that
it is critical to continue research efforts past the stage of clinical
trials in illnesses like tuberculosis, the researchers said.

While tuberculosis has nearly disappeared in wealthier populations,
it remains a critical threat in communities with fewer resources. A
big part of the challenge of treating MDR-TB is finding regimens that
will work in low-resource settings with complex populations that often
include great diversity and many people who might be undernourished or
sick with other illnesses.

The partnership is also studying the safety of the new
regimens. Preliminary results suggest that side effects from the new
regimen may be much less severe than those seen with the historical
treatment, which has been known to cause deafness and psychosis.

"TB is well-controlled where control is easy," Mitnick said. "We need to
find better ways to treat it where it's difficult." The global reach of
endTB has now provided clinicians with invaluable hands-on experience
with bedaquiline and delamanid and helped change country guidelines,
getting the new drugs registered for use in more than half of the17
endTB countries, the researchers said. The endTB observational study has contrinuted to changing global guidelines, including new recommendations
for concomitant use of bedaquiline and delamanid and extended use of
each drug.

The endTB partnership is using the same model for promoting innovation
to prepare for what researchers hope will be the next change on the
horizon in care for MDR-TB: all-oral, shortened regimens, which are
being studied in the current phase of endTB's clinical trial. While the implementation program continues to roll out and reaches new patients,
the endTB trial has enrolled 465 patients with MDR-TB in new all-oral
regimens that could transform care for MDR-TB.

The all-oral regimens used in the endTB observational study and the
all-oral, shortened regimens studied in the trials would be particularly helpful during international health crises like the coronavirus pandemic,
the researchers noted. These all-oral regimens are much easier to deliver
in routine times and especially so in times of extreme crisis that burden health systems.

"If the ongoing trials demonstrate reduced toxicity of the all-oral,
shortened regimens, this is another huge benefit for their delivery in
good times and bad," Mitnick said.

The project also transformed the landscape for TB trials by running in six countries (Georgia, Kazakhstan, Lesotho, Pakistan, Peru, South Africa)
on four continents. This is the first time a clinical trial has taken
place in some of these sites, the researchers said.

"In global health we see many vicious cycles, where poverty and lack of
access to care combine to make diseases worse," Franke said. "On the other hand, bringing care delivery, training and research together the way we
are in the endTB project can be a kind of virtuous cycle, where each turn
of the wheel brings better care, improved health and greater well-being."

========================================================================== Story Source: Materials provided by Harvard_Medical_School. Original
written by Jake Miller.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Molly F Franke, Palwasha Khan, Cathy Hewison, Uzma Khan, Helena
Huerga,
Kwonjune J Seung, Michael L. Rich, Khin Zarli, Nazgul Samieva,
Lawrence Oyewusi, Parvati Nair, Mishaz Mudassar, Nara Melikyan,
Putri Lenggogeni, Leonid Lecca, Andargachew Kumsa, Munira Khan,
Shirajul Islam, Kerow Hussein, Wisny Docteur, Nino Chumburidze,
Elmira Berikova, Hakob Atshemyan, Sidney Atwood, Manzurul Alam,
Saman Ahmed, Mathieu Bastard, Carole D Mitnick. Culture Conversion
in Patients Treated with Bedaquiline and/or Delamanid: A Prospective
Multi-country Study. American Journal of Respiratory and Critical
Care Medicine, 2020; DOI: 10.1164/rccm.202001- 0135OC ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200812161316.htm

--- up 4 weeks, 1 hour, 55 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1337:3/111)