Tuberculosis Regimens
Tuberculosis (TB) is one of the top ten causes of death worldwide and disproportionately affects the developing world. Though the number of TB deaths decreased from 2000 to 2015, it is responsible for more deaths than HIV and malaria combined. Over the past several years, multi-drug resistant tuberculosis (MDR-TB) has steadily risen. Approximately half a million cases of MDR-TB were reported in 2015. Resistance often develops secondary to patient non-compliance.

Given the complexity and duration of tuberculosis therapy, it is no surprise that many patients struggle to take the medications as directed. Initial first-line therapy consists of isoniazid, rifampin, pyrazinamide and ethambutol. The four-drug regimen must be taken at least five times a week for eight weeks during the initial phase. Then, the patient must continue taking two medications for an additional 18 weeks.

Treatment failure can require eight months of retreatment. If drug resistance develops, treatment can take two years and has a high rate of failure.

Researchers at the University of California at Los Angeles have been working to develop new tuberculosis regimens that could boost the probability of treatment success. Using Parabolic Response Surface (PRS) technology, the team identified drug combinations with higher antimicrobial activity than the Standard Regimen of isoniazid, rifampin, pyrazinamide and ethambutol.

PRS Regimen I includes clofazimine, ethambutol, prothionamide and pyrazinamide. For PRS Regimen II, bedaquiline is used instead of prothionamide.

So far, the new tuberculosis regimens have only been tested on mice, but the results are promising. Differences in efficacy, quantified by the number of colony-forming units, were statistically significant for both PRS regimen groups compared to the Standard Regimen control group.

For both of the new tuberculosis regimens, efficacy was dependent on the pyrazinamide dose. The bedaquiline dose also affected the efficacy of PRS Regimen II.

PRS Regimen I took 12 weeks to achieve 100% relapse-free cure while variations of PRS Regimen II achieved cure in three to four weeks. The Standard Regimen takes 16 weeks to achieve a relapse-free cure. Based on these results, a new tuberculosis regimens could reduce treatment duration by as much as 75%. Such a drastic reduction in length of therapy could facilitate better patient compliance.

The next step is to see whether or not the results in mice can be replicated in human beings. Given the rise of drug-resistant TB, successful treatment of human subjects with these new tuberculosis regimens would be a huge victory for global health.

Rebecca Yu

Photo: Flickr

USAID Defeat Tuberculosis in the Kyrgyz Republic
Hakmiddin lives in a small village in northern Kyrgyzstan. After being diagnosed with tuberculosis several years ago, he never completed a full course of treatment because he had to return to work. As a result, he did not receive the necessary medications. There are many people who share Hakmiddin’s struggle against tuberculosis in the Kyrgyz Republic today.

Kyrgyzstan has one of the highest rates of tuberculosis in Europe. According to the latest data, multidrug-resistant tuberculosis (MDR-TB) is now at 26 percent among new cases, compared to three percent of new tuberculosis cases worldwide. Drug supplies were limited and universal treatment standards were lacking in the country. According to the World Health Organization, only 55 percent of MDR-TB cases were successfully treated in 2011.

In response to this pressing challenge, USAID partnered with the Kyrgyz Republic to manage this deadly disease through improved services, diagnostics, new clinical guidelines, new outpatient treatment and care models. In 2012, led by the KNCV Tuberculosis Foundation, Kyrgyzstan’s National Tuberculosis Program and the Ministry of Health developed new national guidelines on MDR-TB, in collaboration with the USAID-funded TB CARE I project.

The project worked with community groups and non-government organizations to ensure more equitable access to tuberculosis in the Kyrgyz Republic in addition to diagnosis, treatment and a reduction in the social stigma attached to the disease. It also provided training for health care workers and reformed health financing systems to improve tuberculosis treatment in the country.

As a result, patients are able to receive the care they need based on the type of tuberculosis they have, including full outpatient treatment. These efforts resulted in increasing the MDR-TB treatment success rate from 42 percent in 2011 to 57 percent in 2013. In 2014, USAID followed up its previous efforts and developed a five-year project, the USAID Defeat Tuberculosis project, to ease the burden of tuberculosis in the Kyrgyz Republic and strengthen its health care system.

The project offered support for quality improvement and standardization of laboratory services. To jumpstart this process, the USAID Quality Health Care Project introduced a Quality Management System in laboratory networks in Kyrgyzstan. Seventeen lab quality control specialists in Bishkek and Chui Oblast participated in relevant training sessions. Undergraduate and continuing education institutions also integrated some tuberculosis training modules with the project’s support.

Today, 30.6 percent of the population still lives below the national poverty line and 42.7 percent of the employable population is unemployed. Therefore, providing affordable tuberculosis diagnosis and treatment for patients and reducing prolonged hospitalization to ensure people’s productivity are still challenging tasks that the country needs to address in the future.

With two more years left, the USAID Defeat Tuberculosis Project will focus more on advocating childhood and adolescent tuberculosis diagnosis and treatment, as well as the prescription of child-friendly drug formulas in the country.

Yvie Yao

Photo: Flickr

While medication treats an ailment, it is the rapid diagnosis of the ailment that is critical to saving many lives. With the rising rate of antibiotic-resistant infections, the need to diagnose quickly and correctly to facilitate accurate choice of medication has grown exponentially. The rapid diagnosis issue is compounded in resource-poor settings that are mired with lack of easy access to affordable healthcare and infrastructure.

Consider the example of tuberculosis (TB), a deadly infectious disease that can take up to six months or more to treat completely. In 2013, there were more than nine million new cases of TB. Most of these occurred in Africa and Asia. The standard-of-care diagnostic, a sputum smear, is slow and can take multiple health visits, which many people can ill afford. Additionally, the sensitivity of the test is variable and is worse when the patient is HIV positive, which almost 13 percent of TB patients are.

Now multiple-drug resistant TB (MDR-TB) infections, where most of the available antibiotics are no longer effective, are a huge concern. MDR-TB develops because of the incorrect use of antibiotics. The more rapidly TB is diagnosed and the more often correct treatment is prescribed, the less the incidence of MDR-TB and the less the chance of it spreading. As the ceiling of new antibiotic development is being pushed, drug-resistant infections urgently need to be controlled.

Rapid and accurate diagnosis is a necessity not just for TB but for everything ranging from malaria to diabetes. Both academics and the industry are hard at work to develop techniques that can provide results in a matter of hours. Some, especially those related to telemedicine like new iPhone blood glucose testing, can do this from the convenience of one’s home. However, the real conundrum has been how to make this cheap to manufacture, affordable to buy for resource-poor populations who need it and easy to use when there is no infrastructure in place.

Diagnostics For All is a nonprofit organization that aims to produce technology particularly for the 60 percent of the developing world that lack easy access to healthcare. Its projects range from a simple, easy-to-use liver function test to monitor the efficacy of HIV anti-retroviral therapy, to detecting micronutrient levels in children so that appropriate nutritional supplements can be provided. Its systems are based on a patterned paper technology developed at Harvard University. Since the paper takes up the test sample easily and micro channels made on the paper allow the sample to flow into tiny wells of chemical indicators, there is no need for any external power. The indicator changes color based on a component in the sample, allowing an easy read out. The patterned paper can be manufactured cheaply on large scale. Diagnostics For All supports its work with philanthropic grants and partnerships with the for-profit sector.

Foundation for Innovative New Diagnostics (FIND) is another international nonprofit organization that builds partnerships with enterprises and assists in developing novel diagnostic techniques through expertise and capacity building. It supports the discovery and scale-up of diagnostic tools bridging the gap between development and delivery, and ensures that these technologies are made available to high-burden countries at preferential pricing. It has developed several techniques among which are an HIV viral load detection system co-developed with California based, Cepheid and malaria and sleeping sickness diagnosis methods with Massachusetts based, Alere.

There are several other organizations out there, including those making strides in telemedicine, that are working to make diagnosis faster, cheaper and more accurate. As science makes progresses towards developing these new techniques, markets, nonprofit and for-profit business models, and governments all have to play their part in keeping up with strides being made and ensuring that these new methods are realized in practice.

– Mithila Rajagopal

Sources: Alere, NCBI, Sanofi, San Francisco Business Times, WHO 1, WHO 2
Photo: Fashion For A Cause

drug resistant bacteria

The White House has said President Barack Obama will call for $1.2 billion in funding for research on drug-resistant bacteria in his upcoming budget proposal. If the funding is approved, the total would double last year’s funding for the same research, marking it as an administration priority in healthcare.

The rise of bacteria that is resistant to normal antibiotic treatments has been of concern for some time. The Centers for Disease Control and Prevention say that drug-resistant bacteria, sometimes called “superbugs,” account for a probable two million illnesses and 23,000 deaths in the United States alone each year.

The funding would pay for research in government agencies on drug resistance and how bacteria becomes immune to antibiotics. Additionally, it would fund researchers looking for new treatments for drug-resistant bacterial illnesses.

Drug resistance has become a problem because of the over-prescription and misuse of antibiotics. This is a naturally occurring phenomenon that has been accelerated by human intervention. Drug-resistance threatens both prevention and treatment of a wide array of illnesses including malaria, pneumonia, gonorrhea and bloodstream infections.

Particularly pressing are multi-drug resistant, or MDR, and extremely drug-resistant, or XDR, tuberculosis. In 2012, there were approximately 450,000 new cases of MDR tuberculosis around the world. MDR TB cases now make up about six percent of new TB cases. XDR TB cases have been identified in 92 countries, in all regions. Because XDR TB cases are underreported, research and treatment are difficult.

The interconnectedness of today’s world makes drug-resistant bacteria even more threatening. While the root causes of drug-resistance may be local, that bacteria can easily move through trade and travel, spreading far quicker than previously possible.

Some of the riskiest drug-resistant bacteria are methicillin-resistant Staphylococcus aureus; hospital borne bacteria like Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas and Enterobacter; foodborne bacteria like escherichia Coli and salmonella; sexually transmitted infections like gonorrhea and chlamydia; and tuberculosis.

– Caitlin Huber

Sources: Washington Post, CNN, World Health Organization

Photo: Rawstory

In 2013, five percent of global tuberculosis cases were known as multi-drug resistant tuberculosis. MDR TB is a form of tuberculosis that does not respond to the standard first-line drugs of Isoniazid and Rifampicin, which are used to treat TB.

Multi-drug resistant tuberculosis is on the rise around the world. There are 27 high MDR TB burden countries. A large majority of these are also high burden countries for regular TB as well. MDR TB rates are extremely high in Eastern Europe, where as many as 28 percent of new TB cases are MDR. Two countries, India and China, carry the most incidences of MDR TB.

Multi-drug resistant tuberculosis is a man-made problem created by inadequate or improper administration of TB drugs. Because of the length of treatment required for TB, improper drug use is common. As patients start to feel better, they stop taking their medication. The TB bacteria are still not eradicated from the body so the TB builds resistance to the first-line drugs that the patient has already taken. When the patients fall ill again, their TB strain will not only not respond to first line drugs, it will be highly contagious.

Weak TB control programs at the country-level contribute to drug resistance because they allow for improper TB treatment. Because of the risk that patients will not finish the TB treatment cycle, TB control programs are designed to create a system of observation by health professionals that insures proper treatment. However, countries with low health infrastructure and limited resources cannot follow the progress of every TB patient.

A growing concern is not the new instances of MDR TB cases but the infectiousness of the people who already have it. Because TB disproportionately affects the poor, who live in crowded, unsanitary conditions, the threat of contagion is much greater. This is especially true in high-burden countries like India and China, where the living conditions of the poor are extremely crowded.

The treatment for MDR TB is extremely expensive and much harder to access. The treatment cycle can last upward of two years and includes a daily injection for a period of six months, increasing the risk of patients not finishing the treatment even more than regular TB treatment. Patients who do not finish treatment create resistance to the second-line drugs.

A new phenomenon emerging is an extremely drug resistant, or XDR, strain of TB. XDR TB cases only make up five percent of MDR TB cases. XDR TB is resistant to any fluoroquinolon, at least one of three second-line drugs and both first-line drugs. Research and infrastructure dealing directly with XDR TB are very limited and resource consuming. For least-developed and developing countries with limited medical resources, XDR TB is almost impossible to treat.

Caitlin Huber

Sources: E-Medicine Health TB Alliance, WHO
Photo: The Guardian