ICAAC: Moxifloxacin could cut TB treatment time to four months

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Using the antibiotic moxifloxacin instead of ethambutol in TB treatment increases the cure rate and could cut the length of treatment from six to four months, according to studies from Johns Hopkins University Medical School presented today at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago.

Eight-five per cent of patients who received moxifloxacin had cleared active tuberculosis from the lungs within two months, compared to 68% of those randomised to receive ethambutol. This difference was statistically significant (p=0.02).

The study recruited 170 patients with smear-positive pulmonary tuberculosis in Rio de Janeiro, Brazil, and randomised them to directly observed therapy with moxifloxacin or ethambutol on five days of each week, plus the standard anti-TB regimen of isoniazid, rifampicin and pyrazinamide for all participants. The study was a double-blind trial, so neither doctors nor patients knew which of the two drugs they were receiving.

Glossary

smear

A specimen of tissue or other material taken from part of the body and smeared onto a microscope slide for examination. A Pap smear is a specimen of material scraped from the cervix (neck of the uterus) examined for precancerous changes.

cure

To eliminate a disease or a condition in an individual, or to fully restore health. A cure for HIV infection is one of the ultimate long-term goals of research today. It refers to a strategy or strategies that would eliminate HIV from a person’s body, or permanently control the virus and render it unable to cause disease. A ‘sterilising’ cure would completely eliminate the virus. A ‘functional’ cure would suppress HIV viral load, keeping it below the level of detection without the use of ART. The virus would not be eliminated from the body but would be effectively controlled and prevented from causing any illness. 

p-value

The result of a statistical test which tells us whether the results of a study are likely to be due to chance and would not be confirmed if the study was repeated. All p-values are between 0 and 1; the most reliable studies have p-values very close to 0. A p-value of 0.001 means that there is a 1 in 1000 probability that the results are due to chance and do not reflect a real difference. A p-value of 0.05 means there is a 1 in 20 probability that the results are due to chance. When a p-value is 0.05 or below, the result is considered to be ‘statistically significant’. Confidence intervals give similar information to p-values but are easier to interpret. 

antibiotics

Antibiotics, also known as antibacterials, are medications that destroy or slow down the growth of bacteria. They are used to treat diseases caused by bacteria.

isoniazid

An antibiotic that works by stopping the growth of bacteria. It is used with other medications to treat active tuberculosis (TB) infections, and on its own to prevent active TB in people who may be infected with the bacteria without showing any symptoms (latent TB). 

The TB cure rate was faster in the moxifloxacin group too. Between weeks 1 and 5 significantly more patients in the moxifloxacin group had turned smear-negative, indicating absence of active tuberculosis. During weeks 6 and 7 the difference narrowed, but re-emerged at week 8. The median time to a smear-negative test was 36 days in the moxifloxacin group and 42 days in the ethambutol group (p=0.03).

“It was remarkable to see just how potent moxifloxacin was,” said Prof. Richard Chaisson of Johns Hopkins University School of Medicine. After just two weeks of therapy with moxifloxacin, 21% of the sputum samples were negative and cleared of visible disease, while in the ethambutol study group, it was just 3%. After four weeks, the gap widened to 51% and 29 %, respectively.

“This is the most compelling evidence in nearly 25 years that a novel antibiotic drug combination works better than the current gold standard at curing active TB infection,” said Chaisson.

“Beyond the obvious value of healing patients more quickly, a shorter treatment time could also cut down on transmission of the disease to others and make it easier for health care workers worldwide, who are overwhelmed by large numbers of patients, to treat more people and to treat them faster,” says Chaisson, who started the study in 2003.

History, says Chaisson, shows that shorter regimens boost drug compliance and cure rates, often by as much as 50%. In the 1950s, TB treatment lasted from 18 to 24 months, and nearly a quarter of patients failed to complete therapy. It was not until new drugs appeared in the 1970s and 1980s, when treatment times were shortened to an average of six months, that cure rates shot up.

In a second study the Tuberculosis Treatment Consortium reported on a randomised comparison of moxifloxacin and isoniazid during the first two months of TB treatment.

The study recruited 433 patients with smear-positive pulmonary TB at 26 centres in Africa and the United States, of whom 344 were eligible for the analysis presented today (64% were enrolled in Africa). Eleven per cent were HIV-positive.

After two months of treatment 60% of those treated with moxifloxacin were smear-negative, compared to 55% of those who received isoniazid. This difference was non-significant (P=0.37).

However, the two-month cure rate was better outside Africa (50% vs 72%, p=0.0001), and researchers say more evaluation is needed to explain the discrepancy.

One possible explanation is the fact that the diagnostic tests used to confirm TB clearance produced substantially more discordant results in Africa than in the US. The researchers used both solid and liquid media when attempting to culture TB from sputum samples: the TB germ grows more readily in liquid, leading to earlier diagnosis. Use of both liquid and solid media for diagnosis is standard practice in the US, but not in all African laboratories.

A previous study from the Tuberculosis Trials Consortium, comparing moxifloxacin and ethambutol in American and African TB patients, found an almost identical rate of smear conversion after two months between the two groups (69% vs 70%), but a significantly faster median time to smear-negative conversion for the moxifloxacin group.

Further studies are needed, the investigators say, to define the best partners for moxifloxacin in TB treatment.

Using moxifloxacin as one of the key ingredients in DOTS could also make treatment far less costly overall, allowing TB programmes to expand their coverage. The medication currently costs $10 per day for short-term use, but Prof. Chaisson said the drug’s manufacturer, Bayer Healthcare AG, has promised to make the drug available at affordable prices in poor countries should it gain approval for use in TB.

Moxifloxacin is of particular interest in the treatment of TB in HIV-positive people because it has no interactions with antiretrovirals. The drug is an antibiotic already licensed in over 100 countries, with a well-understood side-effect profile.

Chaisson and his team next plan to investigate a potentially even more potent drug combination that includes traditional DOTS drugs with yet another substitution, rifapentine in place of rifampicin. Rifapentine became available in the United States in 1998 and scientists say it is more effective against drug-resistant strains of TB.

Chaisson and colleagues conducted their research with funding from the U.S. Food and Drug Administration’s Office of Orphan Product Development. The study was part of a series of studies on moxifloxacin that are being coordinated by the non-profit Global Alliance for TB Drug Development (GATB) in collaboration with Bayer.

As part of the research programme, Bayer donated supplies of moxifloxacin.

References

Chaisson RE et al. A randomized, placebo-controlled trial of moxifloxacin versus ethambutol in the initial phase of tuberculosis therapy in Brazil. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, abstract L-736-A, 2007.

Dorman S et al. Moxifloxacin vs. isoniazid in the first 2 months of treatment for pulmonary tuberculosis. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, abstract L-736-B, 2007.