New anti-TB strategy target: Elimination of the disease

A major shift in the global anti-tuberculosis (TB) strategy was announced at the Stop TB Symposium just prior to the 44th Union World Conference on Lung Health this month in Paris. Instead of setting modest targets for incremental improvements in TB control, which has been the norm for the past few decades, the TB community -- clearly driven by TB/HIV activism -- is now calling for a global effort to eliminate the ancient disease. 

The very ambitious though still preliminary Global TB Strategy 2015-2035, prepared after consultations with key stakeholders including civil society and non-government organizations, will be reviewed by the World Health Organization (WHO) executive board in January 2014 and then proposed for adoption by UN member States at the General Health Assembly next June.

"The mission is a world free of TB. Zero deaths, zero disease, and zero suffering due to tuberculosis," said Mario Raviglione, head of WHO's Global TB Program, at the Stop TB Symposium. "The goal is to end the TB epidemic."

Much of the rest of the symposium -- and indeed, the subsequent conference -- dealt with how to reach this goal.

Improvements in standards of living and implementation of existing TB tools -- including the scale-up of earlier antiretroviral therapy (ART) for HIV -- by emerging middle-income countries such as Brazil, Russia, India, China, and South Africa (the BRICS economies) could get the world part of the way there.

But Raviglione and other speakers stressed that reaching "Zero TB" targets will require major investments in research to develop tools that do not yet exist, such as an effective TB vaccine and better preventive therapies and diagnostics.

This could be a significant challenge, as indicated by a new report from the Treatment Action Group showing that funding for TB research has fallen recently. In addition, as conference-goers would hear, some seemingly promising anti-TB innovations have turned out to be disappointing in late-stage clinical trials.

Success in eliminating TB will therefore depend upon rallying activists and getting researchers, funders, and national governments -- especially in the BRICS countries -- to support the strategy and engage in TB research. Furthermore, scientists at the conference also called for cross-disciplinary approaches to coordinate efforts through modeling, trial designs that test multiple interventions at once, and basic science research that calls into question much of the "old knowledge" about the disease.

The Captain of All These Men of Death

TB has been a major cause of illness and death since antiquity and perhaps before, as all primates are susceptible to the disease. In the 1800s, it was responsible for approximately 25% of all deaths in Europe.

Most of what we know -- or think we know -- about TB was learned by studying the natural history and transmission of the disease between 1882, when Robert Koch identified Mycobacterium tuberculosis as the microbe that causes TB and developed the basic smear microscopy and culture methods to diagnose it, up until the antibiotic era. At that point, effective antibiotic regimens were gradually pieced together that could cure drug-susceptible TB disease in the 1950s-1970s, even though such cures required several months of treatment.

The remaining challenges to TB management appeared to be primarily related to improving adherence and strengthening weak health systems. To address these issues, the DOTS (directly observed therapy-short course) strategy involved securing government commitment for sustained anti-TB efforts, developing monitoring and reporting systems, improved lab testing and facilities for case detection, uninterrupted drug supplies, and, of course, directly observed treatment, which originally meant healthcare workers watching TB patients swallow their pills.

The DOTS strategy also set targets for programs to identify 70% of TB cases and to cure 85% of them. WHO estimated that if these targets were met, there would be a 40% decrease in infected contacts, a 5%-10% decrease in TB incidence (new infections), and an overall decrease in the TB prevalence (total infections).

TB became quite uncommon in wealthy industrialized countries. For a while, at least, the DOTS strategy appeared to be making steady progress against TB where and when it was done well, though there were challenges reaching some populations in poorer parts of the world and wherever drug-resistant TB had taken hold.

Consequently, there was little incentive for further TB research, especially since existing tools and treatments were inexpensive. Smear microscopy remained the first-line TB diagnostic for more than 120 years and until recently there had been no new TB drugs for decades. The number of people with drug-resistant TB was deemed too small to motivate the development of tools to quickly diagnose it or treatments for relatively few patients. As a result, the study of TB became a backwater of infectious disease research.

HIV/TB: A Disastrous Combination with One Silver Lining

In 1992, an outbreak of TB among people living with HIV in New York City helped to uncover a dangerous interaction between these diseases. Soon, in countries with a high burden of the virus, HIV would begin to fuel a re-emergent TB epidemic, particularly in sub-Saharan Africa.

However, the phenomenon of HIV/TB also resulted in an infusion of new activist energy into the TB community. One of the activists' first targets was DOTS, which was clearly inadequate to control HIV-related TB in high-burden settings.  In 2005, Zachie Achmat of the Treatment Action Campaign gave the opening plenary presentation at that year’s Union World Conference, complaining that DOTS was "a patriarchal approach that does not empower patients."

While this seemed to challenge the orthodoxy of the TB world, many TB specialists were eager for activists to work the same sort of magic for TB as they had for HIV.

More recently, complaints about DOTS have focused on what activists see as the unambitious targets that have been set. These seem to betray complacency, perpetuating TB at near current levels, with 1.2 million people dying of the disease last year.

"Where are we in TB? We’re saying '1.2 million deaths is okay'," exclaimed Colleen Daniels of the Treatment Action Group during an action in which activists took over the stage at this year's Stop TB Symposium. "It's not okay. We are demanding that you all in this room have vision, that you all in this room decide that we are not going to control TB, but we are going to eliminate TB."

Raviglione and other leaders in the community happily put on the activists' T-shirts. While the activists are calling for "Zero TB" a bit sooner -- by 2025 instead of 2035 -- the TB world is finally setting its sights higher than simply controlling the disease.

What Will It Take to Eliminate TB by 2035?

What is required to eliminate TB by 2035, the ending date of the forthcoming Global TB Strategy? Between now and 2025, it will take improvements in the control of TB in high burden middle-income countries, as well as a major push for research to develop new anti-TB tools that do not yet exist. After 2025, there will need to be rapid scale-up of these new tools.

"We believe it is possible to reduce the incidence of TB by an average 10% per year," said Raviglione. "If it were possible in Europe half a century ago, it must be possible [today] in the BRICS countries and other middle-income countries -- many of the countries that are dominating the epidemic in the world."

The reduction in TB incidence in industrialized countries during the 20th century required improvements in living conditions, nutrition, and access to health care. The Global TB Strategy is counting on similar improvements in middle-income countries -- especially Russia, India, China, and South Africa, which together account for 45% of the global TB burden.

These countries have significant capacity to mobilize domestic resources and will need to continue scaling up existing TB interventions. These include HIV-related activities such as the continued scale-up of ART -- which reduces the risk of developing active TB in people with HIV by 67% -- as well as the "Three I's for HIV/TB": intensified TB case finding, TB infection control, and isoniazid preventive therapy (IPT).

A few presentations at the Union World conference looked at the potential impact these interventions could have on TB incidence in southern Africa.

Carel Pretorius from the Futures Institute in South Africa shared results of a modelling exercise to study the impact of ART expansion on TB in South Africa. The researchers took models from 3 groups that had been developed to look at the effects of different ART expansion approaches on the HIV epidemic, and adapted them to look at the impact on TB incidence (complete findings will be reported in The Lancet Global Health in December).

"When we combined universal ART eligibility (in other words, that CD4 cell counts are not a criteria for starting ART), as well as expanded access (the maximum coverage we thought possible), we found that by 2033 there would be 28%-37% reduction in TB incidence and 36%-42% reduction in TB mortality," Pretorius said. "So our overall finding is that there will be a significant impact on the TB burden...but ART expansion alone won’t achieve TB control in South Africa."

According to Francine Tjituka, the HIV Program Manager from Namibia, programmatic data demonstrate that implementing an HIV and TB care service package already seems to be having a significant impact on the HIV and TB burdens in her country.

In addition to an ambitious national scale-up of ART -- after 2010, to all HIV positive people with CD4 counts less than 350 cells/mm³ or with active TB -- a TB/HIV technical working group was established and collaborative TB/HIV activities were incorporated in both the HIV and TB strategic plans and guidelines. These included HIV testing in TB clinics, initiation of ART for those who test HIV positive while they are still on TB treatment, and implementation of the Three I's for HIV/TB.

In TB facilities, HIV testing increased from 16% in 2005 to 89% in 2012, while ART coverage among HIV positive TB patients went from 17% in 2007 to 72% in 2012. This has had been associated with a decline in HIV prevalence among TB patients, from 67% in 2007 to 47% in 2012, as well as a decrease in the national burden of TB overall, from 822 cases per 100,000 people in 2004 to 529 per 100,000 in 2012.

"A package of TB and HIV prevention and care services is associated with a decline in HIV-associated TB and also will have a long term impact on the TB epidemic," Tjituka said. "Further research is required to see which of these interventions had the greater effect on the TB epidemic." She added that they are hopeful that the impact will increase as the country raises its ART eligibility threshold from 350 to 500 cells/mm³.

However, a third study by UNAIDS consultant Somya Gupta and colleagues suggests that a full package of interventions will be required to achieve the greatest impact. This study used a decision-analytic model to evaluate the number of TB cases, costs, and cost-effectiveness under different TB prevention policy scenarios, using cost data from South Africa.

This study found that expanding ART coverage alone would only decrease the TB case rate by 100 cases or so (from a base rate of around 1300 cases per 100,000 people per year). Under a scenario in which the recently launched Xpert MTB/RIF test is used to diagnose TB, ART is started at a threshold of 500 cells/mm³, infection control is implemented, and IPT is used for 36 months, 450 TB cases were prevented, at an incremental cost of US $7,200.00 per case averted.

"Our study found that a combination TB prevention strategy was more cost-effective when compared with individual strategies," Gupta said. "So to reduce the burden of TB in people living with HIV and [achieve] related other health benefits, we need to accelerate the scale up of early ART and the Three I's for HIV/TB."

More and Better Research

Gupta's model would still leave a very high TB case rate in South Africa -- around 815 cases per 100,000 people per year. To do better, TB treatment program fundamentals will need to be strengthened and, as Raviglione stressed in his opening talk, research and development of new tools will be necessary, including an effective vaccine, better preventive therapies, and shorter treatment regimens.

Unfortunately, recent research on some of these new tools has been disappointing. Results presented earlier this year on the first major TB vaccine study in infants since 1921 suggest that researchers may have to re-evaluate underlying assumptions about what type of immune response will be needed for an effective vaccine. Although the MVA85A vaccine was safe and induced modest cell-mediated immune responses, it failed to protect children from becoming infected with M. tuberculosis or from developing active disease.

Another example is the effort to shorten the course of TB treatment by substituting newer fluoroquinolonessuch as gatifloxacin or moxifloxacin for older drugs currently used in first-line TB regimens.

The RIFAQUIN study, presented at this year's Retrovirus conference, showed that although a 2-drug combination of rifapentine and moxifloxacin could effectively be administered once-weekly during the 4-month continuation phase of TB treatment, this did not allow the total duration of therapy to be shortened from 6 to 4 months.

Disappointing results were also released at the Union World Conference from the OFLOTUB trial, in which gatifloxacin was substituted for ethambutol during the 2-month intensive phase of TB treatment, then added to rifampicin and isoniazid during a 2-month continuation phase. The study found that the standard 6-month regimen was superior, at least at the gatifloxacin doses currently used.

"If we do not invest in research now, we are not going to the point in 2025 -- which is a milestone in our strategy -- with the weapons that we need to really pursue elimination of TB," Raviglione cautioned.

In other words, these tools really need to be developed and in use by 2025 in order to help push the incidence of TB down more sharply and to reach the new Global TB Strategy goals of a 90% reduction in TB incidence and a 95% reduction in death by 2035.

"This is not about academic research for research's sake," said Gilla Kaplan from the Public Health Research Institute Center of Rutgers New Jersey Medical School, speaking at a Stop TB Symposium session on research needed to control TB in the post-2015 era. "This is about harnessing the intellectual and academic capability of all of those communities that are involved in TB research and then getting them to work together with vaccine development, drug development, diagnostic development, epidemiology, survey, and operational research focusing on stopping infection, stopping transmission, and stopping the epidemic rather than merely treating those who are infected and have the disease today."

Source

44th Union World Conference on Lung Health (http://www.worldlunghealth.org/conf2013/). Paris. October 30-November 3, 2013.

Source: HIVandHepatitis.com