Tuberculosis (TB) is the leading killer of people with HIV worldwide, accounting for more than quarter of all HIV deaths in 2008 according to the World Health Organization (WHO). That same year, more than 5% -- that is, 500,000 -- of all recorded TB cases were confirmed as multidrug-resistant (MDR), meaning those individuals were infected with a form of the disease that has developed resistance to the two most common and powerful first-line TB drugs, isoniazid and rifampicin. Most cases of MDR-TB are never diagnosed because many laboratories -- particularly those where lots of people with TB and HIV live with limited resources -- lack the proper diagnostic tools, trained staff, and infrastructure to detect drug resistance. Reported cases of MDR-TB are just the tip of the iceberg, and a scant 3% of people with MDR-TB receive proper treatment, in accordance with WHO guidelines.
While first-line treatment for drug-susceptible TB has a cure rate of 95% in well-functioning TB programs, treatment for MDR-TB cures only 50-70% of cases, and requires 18-24 months of complicated, expensive, and often toxic combination therapy. Depending on the drug sensitivity profile of the TB bacteria, as well as country-specific drug availability, a person may be required to take up to six different pills multiple times per day, as well as a painful injection. This complex treatment regimen can cause a long list of side effects, not the least of which includes psychosis. The need for better, shorter, more effective, and more tolerable treatment for drug-susceptible and drug-resistant TB is urgent and acute.
Since the heyday of TB drug development in the 1950s and '60s, no new class of TB drugs has been approved to treat the disease. However, over the past few years TB drug development has experienced a minor renaissance. Seven drug candidates with novel mechanisms of action against TB are in human studies, most to treat MDR-TB, and two broad-spectrum antibiotics are under wide-scale evaluation for drug-susceptible TB. Two of the drugs farthest along in the TB pipeline are Tibotec Pharmaceuticals' TMC207 and Otsuka Pharmaceuticals' OPC-67683. Both drug candidates are in phase II clinical studies for treatment of drug-resistant TB. The Global Alliance for TB Drug Development (aka the TB Alliance) is planning to initiate phase II studies of its nitroimidazole, PA824, within the year. The other three new compounds in phase I human trials are Sequella's SQ-109, which is a diamine, Pfizer's PNU-100480, and AstraZeneca's AZ5847, which are both oxazolidinones, along with the already approved (for sepsis) linezolid (Pfizer's Zyvox), which is being looked at in low doses for MDR-TB.
TMC207, a diarylquinoline, and OPC-67683, a nitroimidazole, are from wholly new treatment classes (as are the oxazolidinones); thus it is possible that these two drugs could potentially be combined to enhance treatment of drug-resistant TB. Since four out of these seven drugs are from new and different classes there is potential for synergy among them against both drug-susceptible and drug-resistant TB.
Tibotec released promising, preliminary data from the first stage of a phase II study showing that adding TMC207 to a standard MDR-TB treatment regimen reduced the amount of TB bacteria faster than the standard regimen alone after eight weeks of treatment. A second stage is evaluating TMC207 plus a standard background regimen versus placebo plus a background regimen for 24 weeks. Any volunteers diagnosed with extensively drug-resistant TB, before the six-month treatment period is over will be given open-label TMC207.
For the first time in history, Tibotec has begun an open-label safety study for a TB drug. The study currently has three sites up and running in South Africa, with other potential sites in Russia, Eastern Europe, and Asia. The trial will enroll up to 225 people with confirmed MDR-TB. Enrollment has been slow, and local regulatory requirements have proven to be a challenge to scale-up studies. In addition, the lack of data on drug-to-drug interaction between TMC207 and certain antiretroviral (ARV) drugs has delayed enrollment of people who are taking ARVs. The US Adult AIDS Clinical Trials Group (AACTG) is looking at the pharmacokinetic (PK) interactions of TMC207 with one of the most commonly used ARVs, efavirenz, and Tibotec is conducting PK studies of TMC207 with nevirapine and (separately) with lopinavir/ritonavir (Aluvia, Kaletra).
Sponsors need to accelerate the PK studies that will make it clear which ARV drugs can be used safely with the new TB drugs, as the interaction between TB disease and advanced HIV can be fatal unless both diseases are effectively treated together.
Each country has its own regulatory agency and process, and therefore its own rules and requirements for approving and registering new treatments. Sponsors clarity on local regulatory requirements (particularly in high-burden settings) as a major impediment to the rapidity of initiating clinical trials. Because there has not been a TB drug registration trial since the 1960s, there is little to no experience in conducting and monitoring these type of studies in the TB field.
Because so few people can enter controlled clinical trials, TAG and other activists including the Treatment Action Campaign (South Africa) and the European AIDS Treatment Group (EATG) have called for TB drug developers to conduct, when enough safety data exist, open-label safety studies for those without other treatment options and who cannot enroll in controlled trials. This early form of expanded access was used in the early days of AIDS drug development and was known as compassionate use (while later, broader expanded access programs opened to a broader population when drug activity became clearer). Given the low success rate of treatment for drug-resistant TB, the high burden of disease, and the increased risk for death among people coinfected with HIV and TB, these new compounds that may shorten treatment and result in better treatment outcomes should be made available to those who are not eligible for trials but are in desperate need of effective treatment. The reluctance to make these newer compounds available through compassionate-use programs stems from the fear that releasing them will lead to unregulated use and development of drug resistance before the drugs even make it to market. This is compounded by a lack of access to drug susceptibility testing (DST) in many high-burden settings, making it difficult to determine the most effective regimen for each person.
These concerns are valid, yet there is a need to confront these challenges and strategize on how best to introduce new compounds while maximizing their benefit without jeopardizing future use. Expanded-access issues are new to TB programs and service providers as there have not been any new compounds to consider for treating TB in either its drug-susceptible or drug-resistant forms for many years.
Given the dearth of effective treatment options, the time has come to make these treatments more readily available -- especially for those with hard-to-treat MDR-TB disease, in program settings with good patient care, DST, and appropriate background combination treatments.