PI Perspective #45

April 2008     View PDF     En español

The growing renaissance in TB drug study

by Alan McCord

Nearly one-third of the world’s population is infected with Mycobacterium tuberculosis (TB). Each year, about 9 million develop the active disease and about 2 million die. Globally, it’s also the leading cause of death in people with HIV. Over the years, TB has developed resistance to several of the antibacterial drugs used to cure it. World health personnel are scrambling for answers as they now face multi-drug resistant (MDR) and extensively drug resistant (XDR) strains of TB.

Treating standard TB in people living with HIV is difficult, let alone treating MDR-TB. Those with active TB disease must take up to 4 drugs (rifampin, isoniazid, ethambutol and pyrazinamide) and treatment lasts 6 months, often with side effects and often interfering with treating HIV disease. Many do not complete the course of treatment. In many cases, people are given the drugs under the supervision of a health provider, called directly observed therapy, which can tax a person’s lifestyle and which is not possible in some communities.

In resource-poor countries, properly treating TB is a great challenge, as health care infrastructures do not exist or are not sufficient. Some areas do not have the medical staff to treat or observe everyone; some encounter poor adherence which results in more resistant TB; and some simply don’t have enough drugs.

These, among other reasons, have spurred global interest in developing new drugs for TB as well as using other antibiotics in more effective ways. The current TB drugs date back to the 1960s. Below is hopeful information on the TB drugs now in study. The main goals for developing these new drugs and schedules are to offer a shorter course of treatment, improve adherence, fewer interactions with HIV drugs, and perhaps reduce the pill or dose count.
                                                                 
Rifapentine
This drug was originally studied in 1998 to treat TB, but was found to be less effective than rifampin at its then-studied dose. Its TB use was abandoned, though it is widely available as an antibiotic. Currently, rifapentine is being studied in mice at higher doses and more frequent dosing. So far, results are very encouraging.

A study compared the approved three-drug TB regimen (rifampin, isoniazid and pyrazinamide) to a regimen with rifapentine (in place of rifampin) and moxifloxacin (in place of isoniazid). After two months, the rifapentine regimen showed lung tissue without TB while the standard regimen still showed TB. After three months of treatment, the mice showed no TB relapse on rifapentine. The mice on the standard regimen needed six months of treatment to prevent relapse. Rifapentine appeared well tolerated.

It will take more study in humans to see if the same or similar results occur. With these results, rifapentine may still be potent given three times a week rather than daily, or even given with other drugs like isoniazid in place of the moxifloxacin. So far, using rifapentine shows great promise by potentially cutting in half the time a person with TB would be on therapy. Phase II studies should begin by mid-2008 to gauge its safety and effectiveness.

Moxifloxacin
This antibiotic is in large scale phase III human study. It’s already approved for treating other lung conditions. Research hopes to show that as part of a four-drug regimen moxifloxacin will reduce treatment time from six months to four months or less.

Moxifloxacin affects TB in a different way than other first line TB drugs. It also doesn’t interact with the P450 liver protein that’s used to break down many HIV drugs, which results in fewer drug interactions and side effects.

A current study, called REMoxTB, will use the standard four-drug, six-month treatment against a four-drug regimen with moxifloxacin instead of ethambutol or isoniazid. Results will be forthcoming.

Gatifloxacin
This antibiotic is used to treat various bacterial infections and has shown fairly good activity against TB in both the lab and in mice. It is believed that gatifloxacin will work well with HIV drugs. Current studies in mice are comparing various regimens of gatifloxacin to the standard TB regimen. The hope is that gatifloxacin could reduce the standard regimen from six months down to four or less.

One study compared two regimens of gatifloxacin to isoniazid. The second regimen (100mg/kg gatifloxacin + 10mg/kg rifampicin) was more effective than rifampicin + isoniazid after 12 weeks. Though TB was not found in lung tissue, the regimen did not reach a durable cure, which means relapse was likely. Another study compared gatifloxacin + ethionamide with or without pyrazinamide. After 12 weeks of therapy, the regimen with all three drugs produced a durable cure, with no relapse within the next 8 weeks.
                                       
The role that gatifloxacin plays in treating TB is not well defined from these studies. It appears the drug works against active but not latent TB. This may limit its usefulness for improving the treatment regimens for TB, though it may offer an alternative to TB-resistant drugs like isoniazid or rifampin. More study is needed to see how gatifloxacin fits into TB therapy.

TMC-207
Study of this new antibiotic has shown it has many desired qualities for treating TB. These include potency against drug sensitive and resistant strains of TB; no cross-resistance to other TB drugs; potency against active and latent TB; a long half life making it possible for once weekly dosing, cutting the course of treatment perhaps by half; and low likelihood for drug interactions, which is important for those taking HIV drugs.

Study in mice has shown that TMC-207 is not only potent on its own but especially when used with other TB drugs. In the combination regimens, TMC-207 was as effective within one month as what the standard TB regimen was within two months.

An Irish study has enrolled 60 people and will examine three different doses of TMC-207 compared to two other regimens, one with isoniazid and one with rifampin. The safety and effectiveness of 25mg, 100mg and 400mg TMC-207 once a day will be evaluated over 7 days in people who have never used TB drugs. Results will be forthcoming.

PA-824
This new antibiotic is in phase II study in South Africa. Its novel mechanism shows promise for treating drug sensitive and drug resistant TB as well as active and latent TB. It appears more potent than isoniazid and rifampin. Researchers are hoping to greatly shorten the standard six-month regimen to three months or less, though there are no clear data yet to support this.

Early study using PA-824 in healthy volunteers showed that it’s well-tolerated. It does not appear to affect the liver’s P450 protein, which reduces possible interactions with HIV drugs. A current study is evaluating its short-term potency by giving volunteers PA-824 only or the standard four-drug regimen for 14 days. Should the drug prove potent, it will move on to test for safety and effectiveness.

OPC-67683
This new antibiotic is being developed by Japanese researchers, though not much is known about it. What has been reported so far is that OPC-67683 prevents TB from multiplying in the lab and in mice. It has shown to be highly potent against TB and was also able to fight drug resistant strains.

OPC-67683 was used with two approved TB drugs (isoniazid and rifampin) and showed a quicker response than the standard four-drug regimen. So far, the compound does not affect the P450 protein, which is good news for people with HIV. If proven effective in human study, OPC-67683 will likely be taken with other drugs to prevent drug resistance, as will all the other drug candidates in the pipeline.

SQ109
Early lab study shows that this promising new antibiotic contributes good potency when combined with the first line TB drugs isoniazid or rifampicin. It also showed potency against TB resistant to rifampicin. However, it was not as effective when combined with the other standard drugs, ethambutol or pyrazinamide.

One study in mice compared SQ109 to isoniazid and ethambutol. Results showed that SQ109 is as potent as isoniazid and was superior to ethambutol. Another animal study showed about the same results when using isoniazid and rifampicin with SQ109 instead of ethambutol, with or without pyrazinamide. After 8 weeks, the SQ109 regimen showed significantly lower levels of TB in lung tissue. More study is ongoing.

Macrolides and ketolides
In the late 1990s, research ushered in high hopes for using these types of antibiotics to treat TB. Common examples of macrolide antibiotics are azithrocmycin, clarithromycin and erithromycin. Although lab research has shown some activity against TB, none of the macrolide candidates has proved more effective than the drugs isoniazid and rifampin. More study is ongoing to create a macrolide that has broader control over TB.

Another type of antibiotic called ketolides has also been suggested for treating TB as they are similar to macrolides. They’re currently used to treat respiratory infections that are resistant to macrolides. So far, early study has not been favorable in finding one that is potent against TB.

Pyrrole LL-3858
An Indian company is researching this compound for possible activity against TB. So far, no public information has been made available on it.

Commentary
This renaissance in TB drug study shows a great deal of potential in making regimens shorter, more effective, and with fewer side effects. For people living with HIV and TB, new drugs that don’t interact with their HIV regimens are critically needed. Many of these drugs hold promise for them.

Though the world TB epidemic needs new drug solutions today, the soonest that one of them is likely approved may not be until 2010 or 2011. The research process is a difficult one for TB. Clinical study in humans must compare the new drugs against current therapy. Given that the current course of treatment lasts six months and standard time checking for relapse is another two years, TB study takes time to complete.

Although the US does not have as high a level of concern with MDR-TB, better regimens will benefit everyone, especially those countries without the health care infrastructures that are necessary to fully combat this disease. As promising as this research is, much more study still needs to be conducted, especially in people with HIV and other co-infections such as hepatitis C.

For more information on TB disease, read Project Inform's publication, Tuberculosis and HIV disease.

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