अब बोर्ड की परीक्षाओं में गणित का प्रश्नपत्र होगा आसान, 2020 में लागू ...

Shorter TB Regimen Misses The Mark

Shorter high-dose rifampicin regimens proved safe for treating pulmonary tuberculosis (TB), but failed to demonstrate noninferiority compared with the standard 6-month regimen, a phase III trial found.

For the primary efficacy outcome, an absolute 6.3% more adults receiving a 4-month regimen that included the highest dose of rifampicin had an unfavorable outcome at 12 to 18 months versus the control group (90% CI 1.1-11.5, P=0.30 for noninferiority), reported Thomas Harrison, MD, of St. George's, University of London, and colleagues.

In the control group, an unfavorable outcome -- a composite that included treatment failure, relapse, or death likely due to TB -- was observed in 7%; with the 4-month regimens, an unfavorable outcome was observed in 13.4% of patients assigned to a 1,800-mg rifampicin dose and 10% of those on a 1,200-mg rifampicin dose, according to the findings in NEJM Evidence.

Current World Health Organization (WHO) guidelines for TB recommend a 6-month regimen that includes rifampicin, a cornerstone of treatment due to its ability to kill Mycobacterium tuberculosis and the mycobacteria thought to be the cause of most relapses. But adherence is often an issue, and high-dose rifampicin regimens have been associated with more rapid lung sterilization, the research team explained.

"In the absence of an effective vaccine, I believe that making TB treatment as accessible as possible and reducing its duration from the current 6 months are our best options for eradicating the disease across the world," said co-author Amina Jindani, MD, also of St. George's, University of London, in a press release.

While a 4-month rifapentine-based regimen has shown noninferiority to the WHO-recommended 6-month treatment, Harrison and colleagues argued that rifampicin may hold certain advantages, including cost, availability, and familiarity given its use across national programs.

Despite missing on the noninferiority endpoint, Jindani said the study "proves that a higher dose of widely available drugs over just 4 months is possible and safe. This is good news for people diagnosed with TB -- it simplifies their treatment meaning they are more likely to complete the full course, giving them the best chance of being cured, whilst slashing the cost which is a huge barrier in developing countries."

Safety outcomes were similar between arms, with grade 3/4 adverse events reported in 4.0% of the control group and 4.4% to 4.5% of patients on the 4-month regimens. Overall, treatment adherence was similar across groups, at 88% to 90%, with the highest rates seen among those with a favorable outcome, at 98%.

Harrison said the 4-month 1,200 mg-dose regimen could benefit those with an earlier form of TB, while individuals with more extensive TB might respond best to a high-dose, 6-month regimen.

From 2017 to 2020, the open-label RIFASHORT (Randomised Trial to Evaluate Toxicity and Efficacy of 1,200 mg and 1,800 mg Rifampicin for Pulmonary Tuberculosis) study enrolled 672 adults with rifampicin-susceptible pulmonary TB across six countries in Africa, Asia, and South America, randomizing them 1:1:1 to three rifampicin-based regimens.

After exclusions for drug resistance, the modified intention-to-treat population included 578 patients who were followed for 18 months from the time of randomization.

All patients received ethambutol and pyrazinamide for 2 months in addition to:

Control: standard WHO regimen of daily rifampicin (10 mg/kg) and isoniazid for 6 months

Rifampicin study regimen 1: daily rifampicin (1,200 mg) and isoniazid for 4 months

Rifampicin study regimen 2: daily rifampicin (1,800 mg) and isoniazid for 4 months

Baseline characteristics were balanced and were reflective of the global TB patient population (median age of about 29 years, roughly three-fourths men), the researchers noted. Sites in Africa contributed the bulk of enrollees, about 70%. Patients with HIV or diabetes were excluded from enrolling.

Prespecified noninferiority criteria was set as a difference of 8 percentage points for an unfavorable outcome in patients who were sputum smear positive at baseline; to control for type I errors, noninferiority was tested for the highest-dose 4-month regimen versus control first, with the 1,200-mg regimen only formally tested if that criteria were met.

Three deaths (1.6%) due to TB as a plausible cause occurred during the treatment phase in the control group, as did four (2.2%) in the rifampicin 1,200-mg group, with an additional death in this group following the treatment period.

For the secondary endpoint of culture conversion, rates were highest early on in the study groups, at 90% to 93% by week 8 versus 86% among controls. By week 12, conversion rates were similar -- 98% across all three arms.

Along with being limited by the exclusion criteria, Harrison and colleagues noted that pharmacokinetic data were not captured. They added that concerns about the higher-dose regimen may have been more likely to prompt treatment changes.

Ian Ingram is Managing Editor at MedPage Today and helps cover oncology for the site.

Disclosures

The study was funded by the MRC/Wellcome Trust/DFID Joint Global Health Trials Scheme, and the Aga Khan Foundation.

Harrison, Jindani, and colleagues reported no conflicts of interest.

Primary Source

NEJM Evidence

Source Reference: Jindani A, et al "Four-month high-dose rifampicin regimens for pulmonary tuberculosis" NEJM Evid 2023; DOI: 10.1056/EVIDoa2300054.

Please enable JavaScript to view the comments

CDC Details Multidrug-Resistant TB Outbreak In An Unlikely Spot

An outbreak of multidrug-resistant tuberculosis (TB) developed in Kansas in November 2021, and included multiple children who were born in the U.S. And became infected in the state, CDC researchers reported.

The outbreak involved 13 people across four households in Kansas City and spanned 1 year. While a majority of the seven adults identified were born outside the U.S. In a country that had experienced a multidrug-resistant TB outbreak with the same genotype in 2007-2009, most of the six children were U.S.-born, noted Elizabeth Groenweghe, MPH, of the Unified Government Public Health Department in Kansas City, and colleagues in the Morbidity and Mortality Weekly Report.

"This outbreak is ... A cautionary tale, reminding other low TB incidence jurisdictions that sustained declines in TB incidence are not assured," they wrote. "Successful TB treatment and prevention requires ongoing identification and treatment of [latent TB infection] and a swift multifaceted public health response for each person newly diagnosed with TB."

Nine additional people in the four affected households were diagnosed with latent infections, and one child in a neighboring state with an epidemiologic connection to the Kansas outbreak was also identified in July 2022.

All of the active infection isolates were resistant to rifampin, isoniazid, pyrazinamide, and ethambutol -- all first-line treatments -- but susceptible to second-line therapeutics, Groenweghe and co-authors said.

The outbreak began when an infant was hospitalized with pulmonary and meningeal TB. DNA sequencing confirmed that the infective strain was resistant to all four of the first-line drugs. An investigation by the local health department found four latent infections and four more active infections in the same household (household A), including a severely ill adult with pulmonary cavitary disease, who had exhibited symptoms since June 2021.

In January 2022, another case emerged, this time in a young child living in a different household (household B) in the same apartment building. Members of the two families socialized together extensively, shared a car, and commuted together to the same workplace.

The child was hospitalized with pulmonary TB and lymphadenitis; isolates had the same drug resistance profile as those from household A. The child's mother, who was pregnant, was soon diagnosed with pulmonary multidrug-resistant TB. Investigators found four more people in household B with active infection, including a severely ill young adult with pulmonary cavitary lesions, who had been symptomatic since September 2021.

The investigation also identified two additional households (C and D) with connections to households A and B, although located in a different neighborhood. Household C had two latent cases and two active cases, including a teen who had spent time in both households A and B; the teen was diagnosed with pulmonary multidrug-resistant TB and extrapulmonary TB vasculitis. Household D had three adults with latent infections.

Public health officials then investigated other contacts, a school, and a workplace. Potential contacts underwent an interferon-gamma release assay blood test or tuberculin skin test 8 weeks after their most recent exposure to any of those with TB.

Investigators thought the outbreak was contained within these four households until July 2022, when a child in a neighboring state was diagnosed with multidrug-resistant TB (household E).

"Additional investigation confirmed that the young adult from household B was also known to household E and had spent time in the home of household E while infectious," Groenweghe and team wrote.

Clinicians constructed individual treatment regimens for each person. Most of the adults (median age 29 years) and an older teenager in household A received 26 weeks of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM). The pregnant woman was treated with bedaquiline, linezolid, moxifloxacin, and clofazimine. After her baby was born and she stopped breastfeeding, she was switched to the BPaLM regimen for 6 more months.

"The infant, young child, other children, and young teenager presented a unique treatment challenge because BPaLM has not been studied in children aged <15 years," the authors noted.

Three of these children, ages 9-13, received 26 weeks of bedaquiline, linezolid, moxifloxacin, and delamanid. Delamanid is a multidrug-resistant TB medication used in Europe. The FDA granted a compassionate use authorization for these cases.

The infant and young child received bedaquiline, cycloserine, levofloxacin, and linezolid.

Length of treatment was clinically determined and differed in each case, but by September 2023, 13 of the 14 patients had completed treatment.

"One adult who received a clinical diagnosis of extrapulmonary TB disease declined treatment despite extensive measures on the part of public health and clinicians. Local public health staff members continue to maintain careful communication and relationship with this person, should they desire treatment, or should their disease progress further and pose a health risk to the community," Groenweghe and co-authors wrote.

The nine patients diagnosed with latent TB infections were all treated with 6 months of daily moxifloxacin. All completed treatment and none developed disease or complications. Local public health officials will continue to monitor all of the patients every 6 months for at least 2 years. This includes chest x-rays, review of signs and symptoms, and a physical exam.

The CDC's National TB Molecular Surveillance Center performed whole-genome sequencing on isolates from nine of those with culture-confirmed active TB. Whole-genome single nucleotide polymorphism (SNP) analysis showed that these isolates were very similar, differing only by up to three SNPs. This finding supported the investigators' hypothesis that the outbreak was locally transmitted within the social setting of these families.

The whole-genome SNP analysis also genetically tied the isolates to outbreaks that had occurred in the Federated States of Micronesia during 2007-2009 and Guam during 2009-2016. Some of the adults in the outbreak lived in those regions during those times.

"Both sentinel events of TB disease in the infant and young child included a plausible source within the household (i.E., a non-U.S.-born adult with a lengthy illness course and infectious period)," Groenweghe and team wrote. "At least one of these adults was likely infected overseas years earlier and then experienced progression to active TB disease after moving to Kansas. Unfortunately, neither of the plausible source persons received a diagnosis for many months, leading to further transmission."

"This outbreak in an urban, at-risk community resulted in tremendous financial, staffing, and capacity strain on the local public health department, where capacity was already diminished after nearly 2 years of COVID-19 pandemic response; however, recent collaborations established during COVID-19 prevention activities led to many positive working relationships with community partners such as the schools and hospitals, which facilitated efficient coordination of the outbreak response," the authors noted.

Disclosures

Groenweghe had no financial disclosures. Co-authors disclosed relationships with the Pacific Islands Tuberculosis Controllers Association Conference, the Heartland National Tuberculosis Center, the American Academy of HIV Medicine, the Advisory Counsel for the Elimination of Tuberculosis, and the Kansas Department of Health and Environment.

Primary Source

Morbidity and Mortality Weekly Report

Source Reference: Groenweghe E, et al "Outbreak of multidrug-resistant tuberculosis -- Kansas, 2021-2022" MMWR 2023; DOI: 10.15585/mmwr.Mm7235a4.

Please enable JavaScript to view the comments

Cost Of Tuberculosis Treatment Halved In Deal To Permit Generic Versions

The cost of a crucial tuberculosis treatment has been halved after an agreement was made to allow the sale of generic versions of the drug.

Johnson & Johnson's price for bedaquiline, considered the backbone of treatment for drug-resistant TB will drop from $289 (£227) to $130 for a six-month course until December 2024.

Johnson & Johnson had previously been the only supplier of bedaquiline but in July agreed to allow generic versions to be supplied to poorer countries.

The move allows the Stop TB Partnership's Global Drug Facility (GDF), the world's largest procurer of TB medicines and diagnostics, to source the drug from cheaper manufacturers for 44 low and middle-income countries.

"No one should have to suffer from drug-resistant tuberculosis simply because they cannot afford treatment," said Dr Atul Gawande, the assistant administrator of the Global Health Bureau of USAid. "This historic price reduction will broaden access to this life-saving drug and keep us on the path to end TB by 2030."

The Indian drug manufacturer Lupin has also agreed to reduce the cost of its TB treatments by a third to $194 for a six-month course.

The Stop TB Partnership said the price reductions, announced on Wednesday, should save $8m and allow 51,000 more bedaquiline treatments to be purchased.

A Médecins Sans Frontières protest calling on Johnson & Johnson to lower the cost of bedaquiline for people with drug-resistant tuberculosis in New York in 2020. Photograph: Justin Lane/EPA-EFE

While Johnson & Johnson's main patent for bedaquiline expired in July, it had faced criticism for using secondary patents – in which small modifications are made to a product to extend a patent and prevent a product from being sold by competitors.

At the time, a J&J spokesperson said it uses money made through patents to pay for other drugs to be developed, which generic manufacturers do not usually do.

GDF's chief, Brenda Waning, said she expected the prices to drop further as generic manufacturers improved production.

Bedaquiline is considered the key component of the World Health Organization's recommended cocktail of treatment for multi-drug-resistant tuberculosis.

"Every person diagnosed with drug-resistant TB should be ensured access to the non-injectable, six months treatment regimen and this reduced price takes us exactly in that direction," said Austin Arinze Obiefuna, the vice chair of the Stop TB Partnership board. However, he said he hoped further reductions could be achieved.

Cheaper TB drugs for millions after global deal on patent rights agreed

Read more

Dr Chukwuma Anyaike, Nigeria's director of public health, said the price drop was well timed, as the country was planning to scale up its TB programme.

But he warned: "We still have the challenge of the financial gap required to treat the expected huge number to be identified in the TB response. I know am not speaking just for myself, but for all leaders of TB programmes in the world."

A tuberculosis patient receives medical treatment at a hospital in Peshawar, Pakistan. Photograph: Bilawal Arbab/EPA

Médecins Sans Frontières (MSF) welcomed the price cut but said Johnson & Johnson should drop its secondary patents, as the deal did not cover a number of countries with high burdens of TB.

Christophe Perrin, a TB advocacy pharmacist at MSF, said: "The J&J/GDF deal is still a short-term solution, as high TB burden countries in eastern Europe and central Asia – that remain excluded from the deal – will be blocked from procuring lowest-priced generics in the long run due to patent barriers.

"J&J could easily remedy this by withdrawing now its secondary patents on bedaquiline in all high-burden countries."

---