Drug-Resistant Tuberculosis

BY SARAH SPAULDING

Throughout much of known human history and prehistory, tuberculosis (TB) has surged and receded along a time scale that challenges much of the accepted scientific understanding of typical epidemic cycles of infectious diseases. Written records of TB appear in Greek literature dating as far back as 460 BCE, with Hippocrates’ description of “phthisis” as the most widespread, almost always fatal, disease at the time1. Since Benjamin Marten’s 1720 conjecture that TB might be spread by “minute living creatures,” 2 the medical community has come a long way in its understanding and treatment of the disease.

Mycobacterium tuberculosis. Source: Flickr.

Today, we know that TB is caused by Mycobacterium tuberculosis, a bacterium that is spread from person to person through airborne transmission. The most common symptoms are weakness, weight loss, fever, and night sweats. Although TB usually affects the lungs resulting in chest pain and coughing of blood, it can also affect other areas of the body, such as the brain, kidneys, and spine.3 Most importantly, it can be extremely fatal; over two-thirds of people ill with TB disease will die without proper treatment.4

Part of the difficulty in tackling TB stems from the sheer complexity of the disease. A person who is exposed to TB bacteria can develop TB disease, as the bacteria multiply and destroy tissue in the body. Alternatively, exposure can lead to the development of latent TB infection, which does not present symptoms of TB disease, but can lead to the development of TB disease in the future.3 However, both types are treatable and curable, though they require differing levels of treatment severity. Depending on an individual’s risk factors for developing TB disease, which can include HIV, diabetes, malnutrition, and tobacco use, latent TB infection can be treated with a series of drugs over the course of several months that are designed to kill TB bacteria. 5 Individuals with TB disease may be treated with a combination of the 10 currently FDA-approved anti-TB agents over the course of six to nine months. 6

As of October 2016, TB is one of the top ten causes of death around the world, and over 95% of TB cases and deaths are in developing countries.7 Currently, approximately one-third of the world’s population has latent TB4, and TB remains a leading killer of HIV-positive individuals, accounting for thirty-five percent of HIV deaths in 2015.7 Additionally, TB treatment is a heavy financial burden on many nations, which disproportionately affects the the health and economies of developing nations more than developed nations. The BRICS nations (Brazil, Russia, India, China, and South Africa), which comprise approximately half of the world’s TB cases, rely on domestic funding for the majority of their financial support. By contrast, 87% of TB financing in low-income nations and 60% in middle-income nations comes directly from international donor funding from organizations such as the Global Fund to Fight AIDS, TB, and Malaria.10 Even so, the $700 million TB received in monetary support from these sources in 2014 are far smaller than that of HIV and malaria, which received $5.4 billion and $1.7 billion respectively in the same year.10 Even more burdensome is the lack of massive reductions in global TB incidence rates needed to push forward TB eradication efforts. Although ending TB epidemic by 2030 is a high priority of the Sustainable Development Goals set forth by the UN, the annual decline in TB incidence would need to reach 4-5% to reach the 2020 milestone of the “End TB Strategy.” Since 2000, the rate of incidence has only fallen by 1.5% per year on average.7

Further complicating the issue is the rise of drug-resistant TB. In one of the earliest comprehensive studies of drug-resistant TB, conducted in 2006, several global health organizations including the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) found that 20% of Mycobacterium tuberculosis isolates were resistant to multiple first-line anti-TB agents. Furthermore, the report found that extensively drug-resistant TB (XDR-TB) was identified in each of the 25 reference laboratories around the globe that contributed data to the study.8,9,10 Furthering the crisis in the rate of drug-resistant TB incidence, a major impediment to the reduction of this rate stems from the severe lack of access to adequate treatment for drug-resistant TB. According to the 2016 WHO Global TB Report, of the 580,000 individuals with MDR-TB who became eligible for treatment in 2015, only 20% were enrolled.10

Two main sectors of drug-resistant TB exist: multi drug resistant TB (MDR-TB) and extensively drug resistant TB (XDR-TB). MDR-TB is caused by bacteria that do not respond to the two strongest first-line anti-TB drugs: isoniazid and rifampicin. However, MDR-TB can be cured through treatment with second-line drugs, which are typically less effective, more expensive, and toxic compared to first-line drugs. By contrast, bacteria that causes XDR-TB is unresponsive to even the most powerful second-line anti-TB drugs. As a result, individuals with drug-resistant TB face more difficult treatment options, which typically include a combination of chemotherapy and extremely potent drugs. Additionally, individuals treated for drug-resistant TB face more extensive treatment periods and drawn-out recoveries: typical MDR-TB treatment periods are 20-26 months, and XDR-TB treatment takes 32 months for completion. This lays a heavy burden on individuals treated for drug-resistant TB. On top of the severe side effects of treatment (which can include depression, psychosis, hearing impairment, hepatitis, kidney impairment, loss of mobility, vision impairment, and seizures), 73% are hospitalized, 37% require home isolation, 27% must stop working due to the sickness. As a result, this productivity costs an average of $134,000 for MDR-TB patients and $184,000 for XDR-TB patients.11

Several avenues for the emergence and proliferation of drug-resistant TB have collectively contributed to the current crisis in rates of MDR-TB and XDR-TB emergence. Since the first antibiotic treatment of TB in 1943, random genetic changes have allowed for the development of drug resistance in certain strains of TB. This process is further accelerated by poor management of TB treatments on a single patient basis. Within individual cases of TB, there are two methods by which an individual can obtain drug-resistant TB. Inadequate TB treatment, due to a number of things including failure to maintain proper TB treatment regimes and improper or substandard prescription of anti-TB drugs, can result in acquired drug-resistant TB. Moreover, drug-resistant TB can be directly transmitted from one individual to another.12

Despite a collective worldwide effort to end TB, such as the 2035 WHO milestone which aims to reduce TB deaths by ninety-five percent and TB incidence by ninety-percent, many global programs neglect to adequately address the incidence and prevention of primary drug-resistant TB, if at all.7 Additionally, eradication efforts are further complicated by the recent emergence of a strain of totally drug-resistant TB (TDR- or XXDR-TB), which is resistant to all first-line and second-line anti-TB agents,13 as well as the current coepidemics of TB and HIV/AIDS in African countries, which were predicted to fuel each other to “crisis proportions” in a recent study.14 The most essential elements in the fight against drug-resistant TB are expansion of preventative treatment, more comprehensive global TB data, increases in TB funding, and major advancements in clinical research.

A handful of antibiotics. Source: Flickr.

In 2015, only 7% of HIV-positive individuals eligible for preventative TB treatment were started on a treatment course.10 These numbers leave the door wide open to major improvements in access to preventative TB measures. Similarly, one of the most essential elements in drug-resistant TB eradication efforts is drastically improved data on global TB rates. 2015 marked the first year that 10 countries, including Kenya, reported data for rates of TB preventative treatment given. Although this trend is promising, more than two-thirds of the countries with the highest rates of TB in HIV-positive individuals did not report any quantitative data concerning the disease.10 Until we can implement national “notification and vital registration systems” as outlined in the 2016 WHO Global TB Report, comprehensive data from each country through prevalence surveys will be invaluable; not only does it provide crucial information regarding the relative burden each nation faces, but it allows for tailored TB eradication efforts specific to each nation’s situation.10 For example, the most recent Global TB Report showed six nations, India, Indonesia, China, Nigeria, Pakistan, and South Africa, were responsible for 60% of 10.4 million new TB cases in 2015 worldwide. As a result, the WHO has been able to give special attention to targeting the current state of TB prevalence in these nations when designing their future efforts in TB eradication. Lastly, substantial progress in TB-related clinical research is essential to the reduction of drug-resistant TB. Until the development of a universal TB vaccine that protects against all strains of TB, research efforts in drug susceptibility testing and the development of effective second-line drugs to treat MDR-TB and XDR-TB will prove essential.

Despite a challenging situation, current efforts to eliminate TB are promising. Since 1990, global TB mortality rates have fallen by 47%.15 Additionally, increasing efficacy in diagnosis and treatment of TB has saved over 49 million lives since 2000.10 Current TB research shows great potential for drastically shortening treatment times and minimizing debilitating side effects for individuals with drug-resistant TB.16 Although drug-resistant TB is an exceptionally complex issue in global health, as eradication efforts and advancements in medical research continue, we will be able to look forward to a TB-free future.

Sarah Spaulding is a junior in Jonathan Edwards College double majoring in Environmental Engineering and Ecology & Evolutionary Biology. Contact her at sarah.spaulding@yale.edu.

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References:

  1. Daniel, T. M., Bates, J. H., & Downes, K. A. (2006). History of Tuberculosis. Tuberculosis,100(11), 1862-1870. doi:10.1128/9781555818357.ch2
  2. History of Tuberculosis. (2015). Retrieved March 6, 2017, from Rutgers Global Tuberculosis Institute, http://web.njms.rutgers.edu/ntbcweb/abouttb/historyoftb.html
  3. CDC. (2011, October 28). Tuberculosis: General Information. Retrieved March 6, 2017, from Centers for Disease Control and Prevention, https://www.cdc.gov/tb/publications/factsheets/general/tb.htm
  4. WHO. (2016, October 13). What is TB? How is it treated? Retrieved March 6, 2017, from World Health Organization, http://www.who.int/features/qa/08/en/
  5. CDC. (2016, April 5). Treatment Regimens for Latent TB Infection (LTBI). Retrieved March 6, 2017, from Centers for Disease Control and Prevention, https://www.cdc.gov/tb/topic/treatment/ltbi.htm
  6. CDC. (2016, August 11). Treatment for TB Disease. Retrieved March 6, 2017, from Centers for Disease Control and Prevention, https://www.cdc.gov/tb/topic/treatment/tbdisease.htm
  7. WHO. (2016, October 13). Tuberculosis Fact Sheet. Retrieved March 6, 2017, from World Health Organization, http://www.who.int/mediacentre/factsheets/fs104/en/
  8. CDC. (2013, January 18). Extensively Drug-Resistant Tuberculosis (XDR TB) Fact Sheet. Retrieved March 6, 2017, from Centers for Disease Control and Prevention, https://www.cdc.gov/tb/publications/factsheets/drtb/xdrtb.htm
  9. CDC. (2013, January ). TB Elimination: Extensively Drug-Resistant Tuberculosis (XDR TB). Retrieved March 6, 2017, from Centers for Disease Control and Prevention.
  10. WHO. (2016). 2016 Global Tuberculosis Report. Retrieved March 6, 2017, from World Health Organization.
  11. CDC. (2016, October). The Costly Burden of Drug-Resistant TB in the U.S. Retrieved March 6, 2017, from Centers for Disease Control and Prevention.
  12. Kanabus, A. (2015, April 13). Drug resistant TB | Types, Statistics & Global Control. Retrieved March 6, 2017, from TB Facts, http://www.tbfacts.org/drug-resistant-tb/
  13. Kanabus, A. (2015, April 13). Totally Drug Resistant TB | Extremely, XXDR, TDR. Retrieved March 6, 2017, from TB Facts, http://www.tbfacts.org/xxdr-tb/
  14. Fauci, A. (2008). Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis: The National Institute of Allergy and Infectious Diseases Research Agenda and Recommendations for Priority Research. The Journal of Infectious Diseases, 197(11), 1493–1498. doi:10.1086/587904
  15. WHO. (2015). 2015 Global Tuberculosis Report. Retrieved March 6, 2017, from World Health Organization.
  16. MSF. (2017, January 19). Uzbekistan: Pioneering Clinical Trial for Drug-Resistant Tuberculosis Starts. Retrieved March 6, 2017, from Medecins Sans Frontieres, http://www.msf.org/en/article/uzbekistan-pioneering-clinical-trial-drug-resistant-tuberculosis-starts
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