Shorter Course Drugs Against TB May Multiply Long-term Benefits

Photo by Steve Gilbert Joshua Salomon and his colleagues modeled the effect of potential tuberculosis drugs that could be taken over two months rather than six or more, and they found the limited regimen could save millions of lives.

For many years, the burden of tuberculosis around the world became steadily lighter. Today, however, new challenges—including HIV and multidrug-resistant TB—allow the disease to persist and even increase in many regions. “There are a lot of factors that conspired to reverse the historical progress against tuberculosis,” said Joshua Salomon, HSPH assistant professor of international health. He and colleagues use computer models to examine variables in tuberculosis treatment that may help advance global control of the disease.

In a study published in the August 2006 online issue of PLoS Medicine, Salomon and colleagues describe a mathematical model developed to study the potential impact of new drugs that could shorten the duration of TB treatment. The model examined effects on tuberculosis incidence and mortality in Southeast Asia, revealing that an effective two-month course of treatment introduced by 2012 could reduce new cases by as many as 11 million and avert up to five million deaths by 2030.

DOTS as a Starting Point
Tuberculosis, though curable, infects eight million and kills nearly two million people each year, most of them in Africa and Southeast Asia. Among the most vulnerable are HIV patients, whose weakened immune systems increase their susceptibility. In some areas, historically poor implementation of control efforts has resulted in high levels of multidrug-resistant (MDR) TB that is far more difficult to treat.

Current tuberculosis therapy centers on the DOTS approach implemented by the World Health Organization, in which workers watch patients take their daily medications for six months or more. The drugs in current treatment cocktails, however, were developed decades ago, with no new first-line drugs introduced in more than 30 years.

Nevertheless, several new drug candidates could result in a cure over shorter treatment periods. Minimizing the duration of therapy could enhance compliance, assuring that more patients complete the full course and limiting chances for drug resistance or the spread of disease from partially treated patients.

Salomon’s computer model compared the potential effects of two-, four-, and six-month treatment regimens. The researchers created a general model of the relationships between treatment duration and tuberculosis dynamics, then specifically calibrated this to reflect a region of Southeast Asia including India, Bangladesh, Burma, Thailand, and Indonesia.

Certain features of the disease make it conducive to this type of modeling, said Salomon. Tuberculosis epidemics unfold over a more extended period of time than other, more rapidly transmitted infectious diseases—infecting many, but often remaining dormant. To accurately fit the model to Southeast Asia and replicate observed disease patterns and trends, the researchers pulled specific data from the extensive records kept by the DOTS program in that region. They examined the period from 2005 to 2030 under two scenarios: one in which current DOTS programs remain stable and another in which the programs keep pace with WHO targets for expansion.

The computer model revealed that shorter treatment regimens accelerate reductions in new cases and deaths from the disease. Assuming that a two-month treatment became available in 2012, annual incidence would decrease by 9 percent in 2015 and 39 percent in 2030, compared to a baseline scenario in which DOTS implementation with current regimens remained stable. Deaths caused by tuberculosis were expected to decline by similar rates.

Though the model applies two-month drug regimens beginning in 2012, achieving this in the real world presents an ambitious target, Salomon explained. Though several new drugs for tuberculosis are now in development, attention to new approaches against the disease has ramped up only recently. “Every few years represents a missed opportunity to have a bigger impact against the epidemic,” said Salomon. The model demonstrates that nearly 75 percent of the benefit of a two-month regimen would disappear if its debut were delayed from 2012 to 2022.

Rebalancing Resources
The researchers also modeled a more speculative what-if scenario for Southeast Asia, considering the possible indirect benefits of shorter regimens. In this version of the model, the team assumes shorter treatment reduces the resources, such as personnel, required to care for each patient and allows for reallocation of these resources to enable wider detection of new cases. In this scenario, reductions in incidence and mortality would be 40 to 50 percent greater than those calculated without considering these added benefits. This translates into the prevention of up to 11 million new cases and five million deaths. With the limited availability of resources, however, efforts to develop new drugs and technologies must be balanced against the current emphasis on expanding the reach of DOTS. “It’s important to strike a reasonable balance between getting more out of available tools to help people in need right now and longer term investments that will make a difference over the next several decades,” said Salomon.

This study also reflects recent shifts in the way researchers look at tuberculosis treatment. Once satisfied with DOTS, they are now searching for ways to build upon it. “The way that conventional wisdom on tuberculosis control has evolved over the last few years is interesting,” said Salomon. “Until very recently, there was inadequate attention to what besides DOTS is needed to strengthen tuberculosis control.”

This is starting to change. “DOTS is a good strategy,” said Edward Nardell, HMS associate professor of medicine and of social medicine at Brigham and Women’s Hospital, “but there are many things that are problematic about it.” One improvement has already occurred with the advent of a DOTS-plus program, now rolled into the core DOTS program, which addresses multidrug-resistant tuberculosis. “More and more sites are beginning to do DOTS-plus, and that’s a major victory,” said Nardell. “We’re realizing that treatment of tuberculosis involves treatment of AIDS and of multidrug-resistant tuberculosis, and working all of these into one program.”

Models such as Salomon’s show how additional improvements might shape the future of TB treatment. Though inherent uncertainty exists in this type of study because it forecasts the trajectories of many variables, “these models are extremely useful. You’re very likely to get something informative,” said Nardell. “Since we have no other way of predicting the future, this type of modeling is critical.”

—Kathleen Fink

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