Tuberculosis treatment

Repurposed Cancer Drugs May Improve Tuberculosis Treatment.

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Drug combination enhanced delivery of antibacterial medications in rabbits

an image of long blue pill-shaped objects on a black background

Mycobacterium tuberculosis bacteria.

At a glance:

  • A combination of approved cancer drugs may improve tuberculosis treatment.
  • In a rabbit model of tuberculosis, the repurposed drugs enhanced delivery of antibacterial medications.
  • The drugs also promoted antibacterial responses and improved health outcomes in the animals.
  • Next, the combination would need to be tested in patients with tuberculosis.

Researchers have identified a combination of existing cancer drugs that may improve treatment for tuberculosis.

In a study conducted in rabbits and led by Harvard Medical School researchers at Massachusetts General Hospital, the repurposed drugs enhanced delivery of antibacterial medications that target tuberculosis-causing bacteria. Findings published March 27 in PNAS.

Although it is often overlooked in industrialized countries such as the United States, tuberculosis remains one of the deadliest diseases globally, causing millions of deaths every year.

Sometimes, patients die even after being treated, either because tuberculosis bacteria develop resistance to antibacterial drugs or because the ability to deliver medications to infected lung tissue is poor.

To address the latter challenge, researchers repurposed a pair of cancer drugs already approved by the U.S. Food and Drug Administration. The drugs were originally designed to enhance drug delivery to cancer cells by improving the structure and function of blood vessels around tumors, which can be compromised in cancer.

Blood vessel integrity is also an issue in tuberculosis: Often, the disease results in poorly functioning vessels and an overabundant extracellular matrix — the network of proteins and other molecules that surround and give structure to tissues. As a result, blood flow and drug delivery can be reduced in the abnormal lung masses where tuberculosis bacteria reside, allowing the bacteria to evade the body’s immune system.

“Our team is interested in understanding and overcoming physiological barriers to drug delivery” in tuberculosis lung masses, said senior author Rakesh Jain, the Andrew Werk Cook Professor of Radiation Oncology at HMS. “Even the most potent antibacterial drug will fail if it cannot reach the bacteria fueling the disease.”

A multidisciplinary team of engineers, cancer biologists, immunologists, microbiologists, and data analysts used a rabbit model of tuberculosis to test two drugs known as host-directed therapies, or HDTs. One, bevacizumab, acts on blood vessels, and the other, losartan, targets the extracellular matrix.

Previously, Jain and colleagues showed that bevacizumab could improve antibacterial drug delivery to tuberculosis lung masses. Now, they’ve shown that combining bevacizumab with losartan enhances this drug delivery, promotes antibacterial responses, and improves health outcomes. Surprisingly, the HTDs reduced bacteria numbers in lung masses even without antibacterial agents.

To identify the mechanisms involved, the investigators analyzed tuberculosis lung masses and other lung tissue. They found that the HDTs promoted inflammatory responses to tuberculosis bacteria in immune and nonimmune cells.

Also important, bevacizumab and losartan are approved, safe, and affordable, Jain said, so the study lays the groundwork for directly translating the results into the clinic.

A next step, he added, would be “to test these HDTs in patients with tuberculosis for the drugs’ ability to improve outcomes of antibacterial therapy.”

Shortening Tuberculosis Treatment — A Strategic Retreat

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Our current treatment regimen for tuberculosis, which goes by the somewhat ironic name of “directly observed therapy, short course,” is anything but short. Patients are treated, generally on a daily basis, for 6 months, which necessitates an infrastructure to deliver and observe therapy. This logistic burden has led to a push for shorter treatments. Although many initial attempts failed, a recent study suggested that a newer regimen could lead to a similar probability of cure in 4 months.1 This is certainly an advantage, and yet the newer regimen, if widely used, would still require a similarly burdensome infrastructure. Can we do even better and get to a point where the logistics would not be so limiting? The investigators of the TRUNCATE-TB (Two-Month Regimens Using Novel Combinations to Augment Treatment Effectiveness for Drug-Sensitive Tuberculosis) trial,2 the results of which are now published in the Journal, attempted to do that. But rather than focusing on a regimen alone, they chose a treatment strategy.

The trial design is a bit complex and initially had five groups. Participants had to have a nucleic acid amplification test that was positive for tuberculosis with no genotypic evidence of rifampin resistance. The investigators excluded some higher-risk patients initially but then changed the entry criteria to include this population. Participants who were randomly assigned to the control group received standard tuberculosis treatment for 24 weeks (8 weeks of isoniazid, rifampin, ethambutol, and pyrazinamide, followed by 16 weeks of isoniazid and rifampin); this group served as a comparator for a planned noninferiority analysis. Participants in the four other groups received an intensified regimen that contained five drugs. The plan was to drop two of these groups on the basis of early stopping rules. In fact, none of these groups met those standards, so enrollment was stopped in two groups on the basis of logistic criteria (pill burden and regulatory concerns) in order to preserve statistical power. The two remaining groups received either high-dose rifampin plus linezolid or bedaquiline plus linezolid, each in combination with isoniazid, pyrazinamide, and ethambutol.

For the groups that received an intensified regimen, the strategy consisted of treatment for 8 weeks and then reassessment for persistent disease (symptoms and a positive sputum smear). If the reassessment was negative, treatment was stopped; if positive, participants continued treatment for another 4 weeks. Those who remained positive could be switched to standard treatment to complete 24 weeks. Those who had a relapse in any group were retreated with a standard regimen with adjustments made according to antibiotic susceptibility testing. Participants were followed closely for evidence of relapse through week 96. The primary outcome was a composite of death, ongoing treatment, or active disease at week 96. For the treatment strategy to be declared noninferior, the upper limit of the confidence interval for the difference between the strategy group and the standard-treatment group in the risk of the primary outcome had to be less than 12 percentage points. This is a somewhat low threshold; for example, a recent treatment-shortening trial used a noninferiority margin of 6.6 percentage points.1 As it turned out, one of the strategy groups failed to meet even that loose criterion, whereas the other would have succeeded at either margin.

The trial enrolled 675 participants at 18 sites in five countries. Impressively, almost all completed the trial and follow-up period. Altogether, 7 participants (3.9%) had a primary-outcome event in the control group, as compared with 21 (11.4%) in the rifampin–linezolid group (adjusted difference, 7.4 percentage points; 97.5% confidence interval [CI], −1.7 to 13.2) and with 11 (5.8%) in the bedaquiline–linezolid group (adjusted difference, 0.8 percentage points; 97.5% CI, −3.4 to 5.1). With these results, only the strategy involving treatment with the bedaquiline–linezolid regimen was declared noninferior to standard treatment. In the bedaquiline–linezolid group, 162 participants (85.7%) did not receive therapy beyond 8 weeks. According to the definitions used in the trial, extension of therapy was not a “failure” but was part of the treatment strategy. Altogether, the mean total length of treatment in the bedaquiline–linezolid group (84.8 days) was less than half that in the standard-treatment group (180.2 days).

One risk that is associated with a shorter course could be the development of antibiotic resistance. There were two cases of acquired drug resistance in the bedaquiline–linezolid group and none in the standard-treatment group. Bedaquiline has a long terminal half-life that generates lingering subtherapeutic concentrations for several months after the end of therapy, which results in de facto monotherapy and a prolonged window for the potential acquisition of drug resistance in cases of relapse. Although a much larger number of patients would need to be treated to detect any significant difference, the small number of cases of drug resistance in this trial does not pose substantial concerns.

In many ways, the results of this trial are not surprising. We have long known that most patients with tuberculosis who are treated even with standard regimens do not have a relapse after 4 months of treatment; in fact, several appear to be cured after only 2 months of treatment.3 And the inclusion of bedaquiline and linezolid in regimens for drug-resistant tuberculosis has allowed for shorter regimens.4-6 What is striking is that each of these drugs has posed considerable concerns about toxic effects in the past. Bedaquiline still carries a black-box warning that resulted from very early trials showing increased mortality among treated patients. Linezolid can lead to dose-limiting toxic effects that have been a substantial issue in other trials. Because of these effects, whether these drugs could be used safely for the treatment of drug-susceptible tuberculosis has been unclear. In the TRUNCATE-TB trial, the toxic effects appeared to be quite limited. In fact, this is one of many trials that suggest that the original concerns about bedaquiline might be overstated, at least for patients who undergo prescreening with electrocardiography.

Will these data change practice? Two months of treatment might not be revolutionary but could be very helpful. However, some obstacles remain. There was a very high degree of adherence to treatment in this trial, far higher than the level likely to occur outside the context of a clinical trial. Lower adherence could mean increased treatment failure at 2 months. In addition, the treatment strategy involved careful assessments of patients to identify those who would receive extended courses of therapy. Although this approach is possible within the confines of a trial, it could require considerable resources that are not now available in many tuberculosis control programs.

Perhaps the biggest accomplishment of this trial is a step forward in the adaptive clinical trial design that may help to accelerate regimen development and to rapidly test many more 2-month therapies that are selected on the basis of recent treatment-shortening trial results.4-7 For shorter treatments, positive results that are similar to the results for standard treatment and are observed across various patient populations, including those with a high burden of cavitary tuberculosis, would garner the confidence needed to influence practice in lower-resource settings.

Treatment algorithms such as that used in the TRUNCATE-TB trial are fundamental to tuberculosis control. Although implementing them could be a challenge, any added burden might be offset by reduced costs, better adherence, and increased patient satisfaction. Thus, for tuberculosis, a strategy might be more than just a regimen.

Source: NEJM

Shortening Tuberculosis Treatment — A Strategic Retreat

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Our current treatment regimen for tuberculosis, which goes by the somewhat ironic name of “directly observed therapy, short course,” is anything but short. Patients are treated, generally on a daily basis, for 6 months, which necessitates an infrastructure to deliver and observe therapy. This logistic burden has led to a push for shorter treatments. Although many initial attempts failed, a recent study suggested that a newer regimen could lead to a similar probability of cure in 4 months.1 This is certainly an advantage, and yet the newer regimen, if widely used, would still require a similarly burdensome infrastructure. Can we do even better and get to a point where the logistics would not be so limiting? The investigators of the TRUNCATE-TB (Two-Month Regimens Using Novel Combinations to Augment Treatment Effectiveness for Drug-Sensitive Tuberculosis) trial,2 the results of which are now published in the Journal, attempted to do that. But rather than focusing on a regimen alone, they chose a treatment strategy.

The trial design is a bit complex and initially had five groups. Participants had to have a nucleic acid amplification test that was positive for tuberculosis with no genotypic evidence of rifampin resistance. The investigators excluded some higher-risk patients initially but then changed the entry criteria to include this population. Participants who were randomly assigned to the control group received standard tuberculosis treatment for 24 weeks (8 weeks of isoniazid, rifampin, ethambutol, and pyrazinamide, followed by 16 weeks of isoniazid and rifampin); this group served as a comparator for a planned noninferiority analysis. Participants in the four other groups received an intensified regimen that contained five drugs. The plan was to drop two of these groups on the basis of early stopping rules. In fact, none of these groups met those standards, so enrollment was stopped in two groups on the basis of logistic criteria (pill burden and regulatory concerns) in order to preserve statistical power. The two remaining groups received either high-dose rifampin plus linezolid or bedaquiline plus linezolid, each in combination with isoniazid, pyrazinamide, and ethambutol.

For the groups that received an intensified regimen, the strategy consisted of treatment for 8 weeks and then reassessment for persistent disease (symptoms and a positive sputum smear). If the reassessment was negative, treatment was stopped; if positive, participants continued treatment for another 4 weeks. Those who remained positive could be switched to standard treatment to complete 24 weeks. Those who had a relapse in any group were retreated with a standard regimen with adjustments made according to antibiotic susceptibility testing. Participants were followed closely for evidence of relapse through week 96. The primary outcome was a composite of death, ongoing treatment, or active disease at week 96. For the treatment strategy to be declared noninferior, the upper limit of the confidence interval for the difference between the strategy group and the standard-treatment group in the risk of the primary outcome had to be less than 12 percentage points. This is a somewhat low threshold; for example, a recent treatment-shortening trial used a noninferiority margin of 6.6 percentage points.1 As it turned out, one of the strategy groups failed to meet even that loose criterion, whereas the other would have succeeded at either margin.

The trial enrolled 675 participants at 18 sites in five countries. Impressively, almost all completed the trial and follow-up period. Altogether, 7 participants (3.9%) had a primary-outcome event in the control group, as compared with 21 (11.4%) in the rifampin–linezolid group (adjusted difference, 7.4 percentage points; 97.5% confidence interval [CI], −1.7 to 13.2) and with 11 (5.8%) in the bedaquiline–linezolid group (adjusted difference, 0.8 percentage points; 97.5% CI, −3.4 to 5.1). With these results, only the strategy involving treatment with the bedaquiline–linezolid regimen was declared noninferior to standard treatment. In the bedaquiline–linezolid group, 162 participants (85.7%) did not receive therapy beyond 8 weeks. According to the definitions used in the trial, extension of therapy was not a “failure” but was part of the treatment strategy. Altogether, the mean total length of treatment in the bedaquiline–linezolid group (84.8 days) was less than half that in the standard-treatment group (180.2 days).

One risk that is associated with a shorter course could be the development of antibiotic resistance. There were two cases of acquired drug resistance in the bedaquiline–linezolid group and none in the standard-treatment group. Bedaquiline has a long terminal half-life that generates lingering subtherapeutic concentrations for several months after the end of therapy, which results in de facto monotherapy and a prolonged window for the potential acquisition of drug resistance in cases of relapse. Although a much larger number of patients would need to be treated to detect any significant difference, the small number of cases of drug resistance in this trial does not pose substantial concerns.

In many ways, the results of this trial are not surprising. We have long known that most patients with tuberculosis who are treated even with standard regimens do not have a relapse after 4 months of treatment; in fact, several appear to be cured after only 2 months of treatment.3 And the inclusion of bedaquiline and linezolid in regimens for drug-resistant tuberculosis has allowed for shorter regimens.4-6 What is striking is that each of these drugs has posed considerable concerns about toxic effects in the past. Bedaquiline still carries a black-box warning that resulted from very early trials showing increased mortality among treated patients. Linezolid can lead to dose-limiting toxic effects that have been a substantial issue in other trials. Because of these effects, whether these drugs could be used safely for the treatment of drug-susceptible tuberculosis has been unclear. In the TRUNCATE-TB trial, the toxic effects appeared to be quite limited. In fact, this is one of many trials that suggest that the original concerns about bedaquiline might be overstated, at least for patients who undergo prescreening with electrocardiography.

Will these data change practice? Two months of treatment might not be revolutionary but could be very helpful. However, some obstacles remain. There was a very high degree of adherence to treatment in this trial, far higher than the level likely to occur outside the context of a clinical trial. Lower adherence could mean increased treatment failure at 2 months. In addition, the treatment strategy involved careful assessments of patients to identify those who would receive extended courses of therapy. Although this approach is possible within the confines of a trial, it could require considerable resources that are not now available in many tuberculosis control programs.

Perhaps the biggest accomplishment of this trial is a step forward in the adaptive clinical trial design that may help to accelerate regimen development and to rapidly test many more 2-month therapies that are selected on the basis of recent treatment-shortening trial results.4-7 For shorter treatments, positive results that are similar to the results for standard treatment and are observed across various patient populations, including those with a high burden of cavitary tuberculosis, would garner the confidence needed to influence practice in lower-resource settings.

Treatment algorithms such as that used in the TRUNCATE-TB trial are fundamental to tuberculosis control. Although implementing them could be a challenge, any added burden might be offset by reduced costs, better adherence, and increased patient satisfaction. Thus, for tuberculosis, a strategy might be more than just a regimen.

Source; NEJM

Sunshine vitamin ‘may help treat tuberculosis’.

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Vitamin D could help the body fight infections of deadly tuberculosis, according to doctors in London.

Nearly 1.5 million people are killed by the infection every year and there are concerns some cases are becoming untreatable.

A study in Proceedings of the National Academy of Sciences showed patients recovered more quickly when given both the vitamin and antibiotics.

More tests would be needed before it could be given to patients routinely.

The idea of using vitamin D to treat tuberculosis (TB) harks back to some of the earliest treatments for the lung infection.

Before antibiotics were discovered, TB patients were prescribed “forced sunbathing”, known as heliotherapy, which increased vitamin D production.

However, the treatment disappeared when antibiotics proved successful at treating the disease.

Drug resistance

There is widespread concern about tuberculosis becoming resistant to antibiotics.

The World Health Organization (WHO) says 3.4% of new cases of TB are resistant to the two main drug treatments – known as multiple drug resistant tuberculosis.

That figure rises to nearly 20% for people who have been infected multiple times in their lives.

One analysis said that in some countries about half of all cases were resistant.

There is also concern about extensively drug resistant tuberculosis, which is resistant to the back-up drugs as well.

The WHO says 9.4% of all drug-resistant TB is extensively drug resistant.

In this study, patients all had non-resistant TB. The researchers said adding vitamin D to treatments may be even more valuable for patients when the drugs do not work as well.

This study on 95 patients, conducted at hospitals across London, combined antibiotics with vitamin D pills.

It showed that recovery was almost two weeks faster when vitamin D was added. Patients who stuck to the regimen cleared the infection in 23 days on average, while it took patients 36 days if they were given antibiotics and a dummy sugar pill.

Dr Adrian Martineau, from Queen Mary University of London, told the BBC: “This isn’t going to replace antibiotics, but it may be a useful extra weapon.

“It looks promising, but we need slightly stronger evidence.”

Trials in more patients, as well as studies looking at the best dose and if different forms of vitamin D are better, will be needed before the vitamin could be used by doctors.

Vitamin D appears to work by calming inflammation during the infection. An inflammatory response is an important part of the body’s response to infection.

During TB infection, it breaks down some of the scaffolding in the lungs letting more infection-fighting white blood cells in. However, this also creates tiny cavities in the lungs in which TB bacteria can camp out.

“If we can help these cavities to heal more quickly, then patients should be infectious for a shorter period of time, and they may also suffer less lung damage,” Dr Martineau said.

The doctors suggested this might also help in other lung diseases such as pneumonia and sepsis.

Prof Peter Davies, the secretary of the charity TB Alert, said the findings were “excellent” and vitamin D could play “an important role in treating tuberculosis”.

However, he thought there could be an even greater role in preventing the disease.

One in three people have low levels of tuberculosis bacteria in their lungs and have no symptoms, known as latent tuberculosis. However, this would turn to full blown TB in about 10% of people. Prof Davies’s idea is that giving vitamin D supplements, for example in milk, could prevent latent TB developing.

“That would be a massive revolution if it was shown to work,” he said.

Prof Alison Grant, from the London School of Hygiene and Tropical Medicine, said: “Drug-resistant TB is an increasing concern world-wide and so new treatments to reduce the length of TB treatment would be very welcome.

“Vitamin D supplements are often given to patients who are short of vitamin D and these low doses are generally very safe.

“In this study the researchers were giving higher doses of vitamin D, and I think we would need larger studies to be confident that there were no negative effects of this higher dose.”

  • Source: BBC.

CDC Grand Rounds: the TB/HIV Syndemic.

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CDC Grand Rounds: the TB/HIV Syndemic.

This is another in a series of occasional MMWR reports titled CDC Grand Rounds. These reports are based on grand rounds presentations at CDC on high-profile issues in public health science, practice, and policy. Information about CDC Grand Rounds is available at http://www.cdc.gov/about/grand-rounds.

Since Robert Koch‘s 1882 discovery of Mycobacterium tuberculosis, substantial progress has been made in tuberculosis (TB) control. Nevertheless, in the latter part of the 20th century, a long period of neglect of both quality program implementation and research led to persistently high TB incidence rates and failure to develop new tools to adequately address the problem. Today, most of the world continues to rely on the same diagnostic test invented by Koch approximately125 years ago and on drugs developed 40 years ago. The world now faces a situation in which approximately 160 persons die of TB each hour (1.45 million died in 2009), in which a quarter of all deaths in persons with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) (PWHA) are caused by TB, and in which the evolution of the bacteria has outpaced the evolution of its treatment to such an extent that some forms of TB are now untreatable (1). More recently, renewed attention has been given to reducing the global burden of TB (2), but much remains to be done.

Misconceptions Regarding TB

Misconceptions about TB infection and disease impede patient care, program implementation, and policy innovation. The first misconception is that TB infection and TB disease are the same. For TB disease prevention and control purposes, the global population can be divided into three discrete groups: those without TB infection, those with TB infection, and those whose TB infection has developed into TB disease. The lifetime risk that a person with TB infection will develop TB disease is 5%–10%; that risk is much higher among PWHA (3,4). A successful control strategy must, therefore, address each group.

A second misconception about TB is that it is no longer a major public health problem. In fact, of the 7 billion persons in the world, 2.3 billion are already infected with TB, and about 9 million develop TB disease each year. Furthermore, TB causes about 1.4–2 million deaths annually (Figure 1) (1).

A third misconception is that TB can be diagnosed easily by a physician or laboratory. To diagnose TB infection, only two tests are validated currently: the tuberculin skin test (TST) and the interferon gamma blood test. Unfortunately, TST is neither sensitive nor specific for TB infection, and both tests can be difficult to implement in resource-limited settings. To diagnose TB disease, most laboratories examine sputum with a microscope to look for TB bacilli, the same approach that Koch invented. In PWHA, the sensitivity of microscopic examination is low, approximately 40% (5–7). Given the high risk for death in PWHA who have untreated TB, this low sensitivity is a critical challenge that must be addressed. Culture of sputum for M. tuberculosis is considered the gold standard test, but it is difficult to use and, in resource-limited settings, challenging to implement. Culturing M. tuberculosis, a slow-growing airborne pathogen, requires laboratories that employ high levels of biosafety and specialized technicians. In 2010, the Xpert MTB/Rif assay, a sensitive, easy-to-use, polymerase chain reaction (PCR)–based test was validated. With no need for sophisticated biosafety or specialized technicians and a turn-around time of 2 hours for both TB diagnosis and detection of drug resistance, this assay has the potential to improve TB control in the developing world (8). Limiting its current use is the relatively high cost of the necessary equipment and supplies, a lack of evidence that the assay’s use is feasible in routine practice, and the fact that it has not yet been demonstrated to improve patient outcomes in resource-limited settings.

TB/HIV Syndemic*

TB and HIV act synergistically within a population to cause excess morbidity and mortality. PWHA are more likely to develop TB disease because of their immunodeficiency; HIV infection is the most powerful risk factor for progressing from TB infection to disease (4). Diagnosing TB disease among PWHA is particularly challenging because PWHA who have pulmonary TB frequently have negative sputum smears and up to one third might have completely normal chest radiographs (5). Furthermore, TB in PWHA often occurs outside the lungs, evading traditional diagnostic tests. Because TB is both common and difficult to diagnose, many PWHA feel ill but are unaware that they have TB. A recent review found that when systematic efforts were undertaken to diagnose TB, approximately 8% of patients who went to HIV care and treatment facilities were found to have TB disease (9), although the exact proportion varies substantially depending on the epidemiology of TB in the area. Finally, TB is a frequent cause of death for PWHA, particularly if HIV disease is advanced and antiretroviral therapy (ART) has not yet been initiated. Persons with both diseases must adhere to complex drug regimens that might interact with each other and might have overlapping toxicities.

Combating the Dual Burden of Disease

TB disease and death can be prevented in PWHA by early TB diagnosis and effective treatment of both diseases. Early diagnosis and treatment ensure that TB treatment is provided before the illness reaches an advanced stage, thereby decreasing mortality, and ensures that the duration of infectiousness is limited, thereby reducing transmission of TB to others. TB disease also can be prevented by treating persons with TB infection. Treatment of TB infection requires reliably excluding the presence of TB disease to avoid the development of drug resistance; drug resistance could emerge if a patient receives a single drug to treat TB infection when the patient, in fact, requires a multidrug regimen to treat TB disease.

Until recently, no internationally accepted, evidence-based, sensitive approach existed to screen PWHA for TB disease, although some preliminary data had begun to suggest that commonly used approaches were inadequate. CDC investigators partnered with the U.S. Agency for International Development (USAID), ministries of health, and nongovernmental organizations in three Southeast Asian countries to derive a TB screening algorithm that would solve this problem. This study concluded that asking patients about three symptoms (i.e., cough, fever of any duration, or night sweats lasting longer than 3 weeks) accurately categorized PWHA for targeted interventions. Patients with none of these three symptoms can be considered free of TB disease and offered treatment to prevent TB disease, if indicated; patients with at least one of these symptoms should have further diagnostic tests performed for TB disease (5,6) These criteria mark a significant improvement over the 2007 World Health Organization (WHO) guidelines in which screening was based primarily on the presence of chronic cough (10). Screening for cough lasting more than 2 weeks was only 33% sensitive for TB disease in this study; screening for the combination of symptoms increased sensitivity to 93% (Figure 2) (5). The increased sensitivity under the new criteria will lead to fewer missed diagnoses of TB disease, at the cost of requiring TB diagnostic evaluation for more people.

Although this approach simplifies TB screening, a comparable approach for simplifying diagnosis of TB disease remains elusive. In the same study, investigators learned that adding liquid culture of two sputum specimens more than doubled the yield of TB case detection among PWHA, compared with microscopic examination alone of the same two sputum specimens, as recommended by WHO at the time (76% versus 31% sensitivity) (6). Unfortunately, liquid culture is not widely available in resource-poor settings and requires high levels of training, biosafety, and supervision. It is hoped that introduction of the Xpert MTB/Rif assay, which is more sensitive than smear but less sensitive than liquid culture, along with other emerging diagnostic techniques, will improve diagnostic accuracy in PWHA who have symptoms of TB (8).

In persons who screen negative for TB disease, treatment of TB infection should be considered. The tuberculin skin test (TST) identifies persons with TB infection who can benefit from isoniazid preventive therapy (IPT), a regimen that involves ingesting isoniazid daily for at least 6 months. In the pre-ART era, clinical trials confirmed that IPT was effective in reducing the development of TB disease in TST-positive PWHA by 64% (11). Subsequently, in 1998, WHO recommended that all PWHA living in TB-endemic countries receive 6 months of IPT, and that TST screening generally was not needed in countries with a high burden of TB. Follow-up studies found that the benefit of IPT waned as early as 6 months after completion of IPT. In 2009, only 0.3% of PWHA globally received IPT (1). ART also can reduce the risk for TB disease in PWHA by 54%–92% and might have a synergistic effect when used with IPT (12). In collaboration with the Botswana Ministry of Health, and with funding from CDC and USAID, CDC conducted a clinical trial in Botswana to evaluate how much better TB could be prevented with a 36-month regimen of IPT in PWHA who had access to government-provided ART. This study found that among those with positive TSTs, 36 months of IPT reduced TB incidence by 74%, compared with persons receiving only 6 months IPT. When the analysis was limited to TST-positive trial participants randomized to the 36-month IPT arm who successfully completed the initial 6 months of IPT, the reduction in TB was 92%. As with previous studies, no significant benefit from IPT was observed for TST-negative participants (Figure 3). ART provided an added benefit to IPT’s protective effect, reducing TB risk a further 50% in all groups (13).

These findings have enormous implications for controlling the TB epidemic in countries with a high burden of HIV. If 36 months of IPT were provided to all TST-positive PWHA in Botswana, countrywide TB incidence would decline 45%†(Figure 4). A cost-effectiveness model of 10,000 PWHA in Botswana demonstrated that providing 36 months of IPT for PWHA with a positive TST result, in addition to ART for those with CD4 <250 cells/µL, could avert more incident TB cases with fewer resources than increasing the threshold for ART initiation alone (CD4 <350 or 500), suggesting any cost-effective TB prevention strategy should include the provision of IPT for TST-positive PWHA.

From Evidence to Guidance to Global TB Control

The strong evidence provided by the studies described above has been combined with results from other studies to update the global guidelines for TB screening and prevention (14). A recent WHO publication outlines four updated recommendations for resource-constrained settings: 1) PWHA should be screened with the new symptom-based algorithm, and those who do not report current cough, fever, weight loss, or night sweats are unlikely to have active TB and should be offered IPT (a minor modification to the algorithm developed in the CDC Southeast Asia study); 2) PWHA who report any of the aforementioned symptoms are considered suspects for TB disease and should be evaluated further for TB and other diseases as clinically indicated; 3) PWHA who are TST positive or have unknown TST status and are unlikely to have TB disease based on symptom screening should receive IPT for at least 6 months; and 4) in settings where feasible, PWHA should receive IPT for at least 36 months, or even lifelong. Where feasible, TST should be used to help identify those who would benefit most from IPT (15).

TB control relies on an international strategy known as “DOTS” (directly observed treatment, short course) that includes finding as many highly infectious patients with TB as possible, initiating effective treatment, directly observing drug ingestion to ensure adherence, and standardized monitoring, evaluation, and reporting. DOTS has saved approximately 7 million lives globally since 1990 (1). In the United States, the experience in New York City provides an example of the progress that can be made through full implementation of the DOTS strategy (16). However, although TB prevalence and deaths around the world did fall in the period after widespread global DOTS implementation, treatment programs generally have not resulted in a rapid reduction in global TB incidence (17). Multiple factors explain this phenomenon: insufficient resources and commitment to implement DOTS, in part because TB occurs predominantly in the poorest populations; a focus entirely on treatment of TB disease but not TB infection; the HIV epidemic; the emergence of multidrug resistant TB strains; and limited attention to the social determinants of sustained TB transmission and reactivation. Modeling studies suggest that detecting more infectious TB cases and successfully treating them will, on its own, be insufficient to drive down TB incidence and prevalence quickly and that the global TB strategy must address the large burden of latent TB infection that exists globally (18). The simplified symptom-based screening approach derived in the Southeast Asian study and the effective approach to chemoprophylaxis documented in the Botswana clinical trial help address this need.

The Way Forward

In a 2010 “call to action,” global leaders in TB control outlined crucial areas that must be addressed to accelerate the decline in global TB incidence to more than 1% per year and to meet the target for the 2015 Millennium Development Goal (Figure 5) (19). Achieving this will require fully implementing the DOTS strategy globally, and it will also require going far beyond that to address the limited impact that would be expected with DOTS alone, as outlined in WHO’s latest STOP TB strategy (20). WHO calls for improvements in TB screening and diagnosis, including the use of newer TB diagnostic assays. In addition to these steps, treatment of latent TB infection also is needed (18). In settings with a high prevalence of HIV infection, implementing IPT can reduce TB incidence greatly. Finally, scientific advances are needed in three key areas to develop 1) an effective TB vaccine; 2) a shorter, simpler anti-TB drug regimen with efficacy against both drug-susceptible and drug-resistant TB; and 3) new diagnostic tests that can simply and accurately diagnose both TB infection and disease (21).

The fundamentals of TB control are early and accurate TB diagnosis, effective treatment, and prevention. The gap between what we know and what we need to know is large, but the gap between what we know and what we are implementing in practice is both larger and more harmful. By closing both our knowledge gap and our implementation gap, we can eliminate this deadly syndemic.

Reported by

Haileyesus Getahun, MD, PhD, Mario Raviglione, MD, World Health Organization, Geneva, Switzerland. Jay K. Varma, MD, Global Disease Detection Br, Center for Global Health; Kevin Cain, Div of Tuberculosis Elimination, Taraz Samandari, Div of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention; Tanja Popovic, MD, PhD, Thomas Frieden, MD, Office of the Director, CDC. Corresponding contributor: Kevin Cain, kcain@cdc.gov, 404-639-2247.

References

  1. World Health Organization. Global tuberculosis control: WHO global report 2010. Geneva, Switzerland: World Health Organization; 2011. Available at http://www.who.int/tb/publications/global_report/archive/en/index.html. Accessed June 27, 2012.
  2. CDC. Ten great public health achievements—worldwide, 2001–2010. MMWR 2011;60:814–8.
  3. American Thoracic Society. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161(4 Pt 2):S221–47.
  4. Getahun H, Gunneberg C, Granich R, Nunn P. HIV infection-associated tuberculosis: the epidemiology and the response. Clin Infect Dis 2010;50(Suppl 3):S201–7.
  5. Cain KP, McCarthy KD, Heilig CM, et al. An algorithm for tuberculosis screening and diagnosis in people with HIV. N Engl J Med 2010;362:707–16.
  6. Monkongdee P, McCarthy KD, Cain KP, et al. Yield of acid-fast smear and mycobacterial culture for tuberculosis diagnosis in people with human immunodeficiency virus. Am J Respir Crit Care Med 2009;180:903–8.
  7. Frieden TR, ed. Toman’s tuberculosis: case detection, treatment and monitoring: questions and answers. 2nd ed. Geneva, Switzerland: World Health Organization; 2004. Available at http://www.who.int/tb/publications/toman/en/index.html. Accessed June 29, 2012.
  8. Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med 2010;363:1005–15.
  9. Kranzer K, Houben RM, Glynn JR, Bekker LG, Wood R, Lawn SD. Yield of HIV-associated tuberculosis during intensified case finding in resource-limited settings: a systematic review and meta-analysis. Lancet Infect Dis 2010;10:93–102.
  10. World Health Organization. Improving the diagnosis and treatment of smear-negative pulmonary and extrapulmonary tuberculosis among adults and adolescents: recommendations for HIV-prevalent and resource-constrained settings. Geneva, Switzerland: World Health Organization; 2007. Available at http://www.who.int/hiv/pub/tb/pulmonary/en/index.html. Accessed June 26, 2012.
  11. Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev 2010;(1):CD000171.
  12. Lawn SD, Wood R, De Cock KM, Kranzer K, Lewis JJ, Churchyard GJ. Antiretrovirals and isoniazid preventive therapy in the prevention of HIV-associated tuberculosis in settings with limited health-care resources. Lancet Infect Dis 2010;10:489–98.
  13. Samandari T, Agizew TB, Nyirenda S, et al. 6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial. Lancet 2011;377:1588–98.
  14. Getahun H, Kittikraisak W, Heilig CM, et al. Development of a standardized screening rule for tuberculosis in people living with HIV in resource-constrained settings: individual participant data meta-analysis of observational studies. PLoS Med 2011;8:e1000391.
  15. World Health Organization. Guidelines for intensified tuberculosis case finding and isoniazid preventive therapy for people living with HIV in resource constrained settings. Geneva, Switzerland: World Health Organization; 2011. Available at http://www.who.int/hiv/pub/tb/9789241500708/en/index.html. Accessed June 29, 2012.
  16. Frieden TR, Fujiwara PI, Washko RM, Hamburg MA. Tuberculosis in New York City—turning the tide. N Engl J Med 1995;333:229–33.
  17. Dye C, Lonnroth K, Jaramillo E, Williams BG, Raviglione M. Trends in tuberculosis incidence and their determinants in 134 countries. Bull World Health Organ 2009;87:683–91.
  18. Dye C, Williams BG. Eliminating human tuberculosis in the twenty-first century. J R Soc Interface 2008;5:653–62.
  19. Marais BJ, Raviglione MC, Donald PR, et al. Scale-up of services and research priorities for diagnosis, management, and control of tuberculosis: a call to action. Lancet 2010;375:2179–91.
  20. Raviglione MC, Uplekar MW. WHO’s new Stop TB strategy. Lancet 2006;367:952–5.
  21. Abu-Raddad LJ, Sabatelli L, Achterberg JT, et al. Epidemiological benefits of more-effective tuberculosis vaccines, drugs, and diagnostics. Proc Natl Acad Sci USA 2009;106:13980–5.

* Additional information available at http://www.cdc.gov/nchhstp/programintegration/definitions.htm.

† Assuming provision of antiretroviral therapy to all PWHA if CD4 <200 cells/µL.

Three recent studies highlight the importance of maintaining a healthy gut to avoid disease and optimize your health. The first, published in the journal Celli, shows that “host-specific microbiota appears to be critical for a healthy immune system.”

Source: CDC.