Letting Sleeping Dogs Lie:

Tuberculosis becoming the Global Threat it Never Should Have Been

15 January 2013

For tens of thousands of years, humankind has fought Mycobacterium tuberculosis, the bacterium that causes the infectious disease tuberculosis. Modern strains of the bacterium likely originated 20,000 years ago in East Africa then spread from there as people migrated out of Africa and throughout the rest of the world. Throughout history, tuberculosis has epidemically popped up and receded again in cycles, but what distinguishes it from other diseases is the extent of the time scale with which tuberculosis has done this. Ancient mummies in Peru and Egypt show evidence of tuberculosis infections, and references to the disease appear in Chinese and Indian texts several millennia in age. Europe during the Middle Ages and the Renaissance was no exception, where tuberculosis, or consumption, became a new topic of study for European scientists. By the 19th century, cities in Europe and the United States had become urbanized, densely populated, and terribly unsanitary, resulting in high incidence and mortality rates of tuberculosis(Daniel, 2006). Around this time, scientists made great progress in solving the riddle of the causes and cures of infectious diseases. In the 1880s, Robert Koch provided the breakthrough with his theory that small microorganisms were the cause of tuberculosis and other infectious diseases. In 1921, Albert Calmette and Camille Guerin developed the tuberculosis vaccine Bacille Calmette-Guerin (BCG), which then became the standard vaccination and is still in use today. After World War II, the World Health Organization, under the newly created United Nations, began its first disease control program by administering the BCG vaccine in several European countries. Around this same time, the first antibiotic compound effective against tuberculosis, streptomycin, was discovered and

successfully tested in tuberculosis infected humans, and several other major drugs (isoniazid and rifamycins) followed in the subsequent decade (Daniel, 2006). Compared to a century ago, tuberculosis incidence in the world as a whole has fallen dramatically. However, the fight against the disease is far from won. In 1993, WHO declared a global health emergency after years of tuberculosis neglect, a sustained tuberculosis burden in low and middle income nations, and resurgences of epidemics in high income nations (Lnnroth, 2009). When looking at the general statistics on tuberculosis since the renewed efforts against it, it would seem that humans have been winning the battle. From 1995 to 2011, 51 million people in countries working with WHO were treated successfully for tuberculosis (WHO, 2012). The number of new tuberculosis cases reported every year has fallen consistently since 2005, and the tuberculosis mortality rate has dropped by 41% since 1990. Regardless of the advances of the past decades, tuberculosis still remains a significant killer among infectious diseases. Last year saw 8.7 million new cases of the disease, with 1.4 million patients dying from it. Many of these cases are the ones curable with standard, first line drug treatments. However, lurking in the numbers are the rise of Multi-Drug Resistant (MDR-TB), Extremely Drug Resistant (XDR-TB), and Total Drug Resistant (TDR-TB) strains of tuberculosis. They are becoming harder and more expensive to treat, and many people in high tuberculosis burden countries are left with little hope of surviving their resistant forms of tuberculosis. Overall, the rise of the resistant strains of Mycobacterium tuberculosis has occurred as a result of the failure of governments, public and private institutions, and international bodies to adequately regulate and guide the fight against tuberculosis.

Drug resistant tuberculosis is a problem that threatens efforts to combat the disease, but the rise of these strains did not come without warning. Sir John Crofton, in an address to a meeting of the British Medical Society in 1958, warned of the dangers of drug resistant tuberculosis and suggested the need to take action: A recent survey . . . has shown that no less than 5% of newly diagnosed patients were infected with organisms resistant to at least one of the three main drugs. If physicians come to apply thoroughly the present knowledge about preventing drug resistance, this percentage should steadily diminish (Andre, 2012). However, his words went unheeded, and rather than diminish, the resistant strains grew. Half a century later, 84 countries have reported cases of XDRTB with 440,000 drug-resistant cases worldwide (WHO, 2012). Compounding this concern, the first cases of TDR-TB were reported in Italy in 2007 and subsequently in Iran and India (Udwadia, 2012). The handling of the tuberculosis crisis of the past decades is a prime example of both public and private sector culpability in the rise of TDR-TB , all in all a clear example of iatrogenesis, or an inadvertent induction of a disease by a medical treatment. As a rapidly developing nation with the largest tuberculosis burden in the world, India provides a perspective into healthcare mistakes that paves the way for future issues. The Indian health care system has dramatically improved its treatment of patients with non-drug resistant tuberculosis since the early 1990s, despite frequent drug shortages and low rates of treatment (WHO, 2010). In 1993, the Indian government carried out a pilot program, the Revised National Tuberculosis Control Programme (RNTCP) modeled after directly observed treatment short course (DOTS), the then-WHO recommended strategy for tuberculosis control (WHO, 2010). With the help of WHO and a number of international 3

donors, the RNTCP expanded rapidly and, by the 21st century, covered a majority of Indias population while reducing new cases of tuberculosis from 190 cases per 100,000 people in 1995 to 100 per 100,000 in 2007 (WHO 2010). Regardless of success with general strains of tuberculosis, drug resistant tuberculosis brought new problems that were left neglected. For years, the RNTCPs methodology of treatment was as follows: patients whose tuberculosis did not improve after a regimen of the DOTS category 1 drug treatment were given a category 2 treatment, which essentially added only a single extra drug to their existing regimen (Udwadia, 2012). This merely amplified the resistance of tuberculosis strains and widened the window of time during which these patients could spread their drug resistant tuberculosis to others in the booming, crowded urban areas and slums of India. It was only after this category 2 treatment failed that the RNTCP ordered drug susceptibility tests. Then, of these people diagnosed with MDR-TB, less than 1 percent were offered a regimen of second-line tuberculosis drugs, with the rest left to futilely search other means (i.e. the private sector) as their tuberculosis continued to strengthen (Udwadia, 2012). Furthermore, despite numerous studies and the WHOs strong recommendations for a daily regimen of drugs during the first months of tuberculosis treatment, India implemented an intermittent, thrice-weekly regimen, effectively halving a patients treatment potency; India is the only high burden country with this intermittent program (Dasgupta, 2012). Along with its strong recommendation for a daily regimen, the WHO noted that rates of acquired drug resistance were higher among patients receiving three times weekly dosing throughout therapy than among patients who received daily drug administration throughout treatment (Dasgupta, 2012). Overall, despite empirical evidence supporting the use of a daily regimen to treat tuberculosis, India continues to 4

promote a less effective, intermittent regimen that puts the lives of patients, especially those with drug resistant tuberculosis, at risk. Public policy is hardly the only factor contributing to Indias MDR-TB and XDRTB epidemic; the private sector cannot escape blame. The private sector is a dominating force in Indian healthcare: 80% of doctors and 60% of hospitals are in the private sector, and private sector spending has accounted for 80% of total health expenditure in India (WHO, 2010). Consequentially, a majority of tuberculosis patients (86%) end up turning to private practitioners both before approaching the RNTCP and after treatment in the public sector failed (Wells, 2011). While many flock to the private sector, they hardly find much better care there than what is available through the RNTCP, and a large part of this is private practitioners lack of the expertise necessary to treat tuberculosis, especially its drug resistant strains. In the 1990s, a study was conducted on the tuberculosis drug prescriptions of 100 private doctors, finding that they gave 80 different regimens; a decade later, a study of 105 doctors provided 79 different prescriptions (Udwadia, 2010). Furthermore, in a study conducted in 2007, less than 5% of the doctors tested were able to write an appropriate prescription of second line drugs in the correct doses and durations for MDR-TB cases. Consequences of this inability are evident with the example of the antibiotic fluoroquinolone, which was prescribed in 70% of the doctors incorrect prescriptions and to which 30% of all tuberculosis cultures (from the P D Hinduja Hospital, taken over a nine year period) were resistant (Udwadia, 2010). Because of the absence of a uniform and regulated treatment method for private practitioners, attempts to rein in drug resistance have been stymied and will likely continue to fail without guidelines set by the RNTCP. 5

Thirdly, drug resistant tuberculosis has become a major health threat in part due to years of stagnation in developing new tuberculosis drugs while strains gained resistances to traditional antibiotics. When it comes to research and development of new drugs, those in lower income nations tend to receive the short end of the stick. In the last two decades of the 20th century (the time frame when tuberculosis became noticed as a global threat), of the 1,223 drugs approved for global marketing, fewer than 1% targeted diseases predominately affecting developing nations, and only a handful of these were products of pharmaceutical company research (OBrien, 2001). Furthermore, of the $35 billion invested into research by pharmaceutical companies in 1999, only 10% was spent on infectious diseases and only $70 million spent on malaria and tuberculosis combined (Trouiller, 2002). There are a number of possible explanations for this, one being that the complete pathology of tuberculosis makes drug development difficult. The bacterium in question, M. tuberculosis, has an array of resistance mechanisms, including a tough cell envelope, several drug-modifying enzymes, and efflux systems (Cole, 1998). Additionally, the lack of understanding of the mechanisms of metabolism during the M. tuberculosis dormant states proves to be a hindrance to identifying new compounds as antibiotic candidates. Another possible reason for the absence of tuberculosis drug development of the past decades is the low prospect for profit and small market size in low income nations. Among the OECD member nations, public spending on drugs was $239 per capita per annum (made possible by government health insurance programs and incentives), while spending in developing countries was less than $20 per capita per annum (Trouiller, 2002). Thus, pharmaceutical companies have a much larger incentive to invest into the type of 6

drugs that target high-income nation markets. In the low-income nations where new tuberculosis drugs are most needed, it is assumed that there would not be a large enough market capable of affording to buy a new drug. Without a high enough chance for a profit margin, pharmaceutical companies would rather not take the risk of investing hundreds of millions of dollars. Also, pharmaceutical companies face a risk developing drugs for low income nations from the perceived lack of patent security. An example of this arose from the AIDS crisis leading to the Doha Declaration in 2001, which gave governments interpretive flexibility with the World Trade Organizations Agreement on Trade-Related Aspects of Intellectual Property Rights regarding pharmaceutical patents in times of national health crises, thus allowing for generic drug manufacture, parallel importation, and price controls (Lucchini, 2003). Losing patent protection indicates a loss of potential profit, a risk that pharmaceutical corporations might not have been willing to make. Overall, several factors, most notably pharmaceutical unwillingness to take on risky ventures, have contributed to the last decades lack of the new generation of antituberculosis drugs needed to fight drug resistant strains. A look into Indias history with pharmaceutical patents reflects the issues of the deficiency of drug development in the late 1900s. The passing of the 1970 Patent Act prohibited patents on drug compounds but allowed for patents regarding methods of manufacturing those drugs. Thus, one simply had to take an already-developed drug, reverse engineer the compound, and find an alternative way of efficiently producing that same compound. This hole in Indian patent law allowed for the growth of a large generic drug industry, reaching the size of 16,000 firms and selling the generics for a fraction of their price in other nations. Further, the 1970 Patent Act granted the Indian government the 7

power to place strict price ceilings on certain drugs. It was not until 2005 that India, as a member of the WTO, expanded patent protection to the drug compounds themselves (Gupta, 2004). Even then, the Indian government placed a large number of exception clauses and restrictions on patenting, allowing the Indian generics industry to continue operating (Mueller, 2007). When it comes down to why tuberculosis was allowed to grow stronger in the absence of new treatments, blame can be laid to all sides. It is easy to blame the pharmaceutical corporations for caring only for profit margins and not the greater good, but they are private for-profit businesses, and as such are not so eager to take huge investment risks for minimal gain. These past years of fighting tuberculosis have yielded mixed results, with huge improvements made in treating non-resistant tuberculosis but also allowing for the rise of drug resistant tuberculosis strains. Today, this fight continues both with efforts to correct past mistakes and with new challenges to overcome. For example, tuberculosis is a major cause of death among HIV patients, as compromised immune systems open windows for widespread and infectious disease to take hold. In particular regions, notably sub-Saharan Africa, the HIV epidemic has increased the tuberculosis caseload by a factor of five (Williams, 2005). Furthermore, the combination of MDR-TB/XDR-TB and HIV proves to be a particularly deadly where premium health care is unavailable; one outbreak in Tugela Ferry, South Africa, killed 98% of the infected, with a survival length of just weeks from the time of infection tests (Havlir, 2008). To add, simultaneous treatment of both HIV and tuberculosis presents a hazard, as one of the primary tuberculosis first line drugs, rifampicin, has been shown to reduce the potency of co-administered antiretroviral therapy drugs targeting HIV and to increase the chance of resistance development (Maartens, 8

2009). In many cases, patients and doctors have to decide how to balance treatment for HIV and tuberculosis in order to avoid the risks posed by simultaneously administering drugs for both infections. With the current global HIV epidemic rendering many people vulnerable to an infectious disease as opportunistic as tuberculosis, dual infection of HIV/ TB presents an ongoing challenge, especially in low income countries where both are problematic. Regardless of these obstacles to beating back tuberculosis, correcting the mistakes of the past indicates a promising step forward. One part of this is adding to and improving upon the arsenal of antibiotics used to treat tuberculosis. The current first-line drugs still used today are already over half a century old, and treatment for drug resistant tuberculosis involves 20 months of second-line drugs that are associated with several negative, and sometimes serious, side effects (WHO, 2012). In the past, there would be little hope for correcting these issues due to the lack of investment into research and development of new tuberculosis drugs. But, as of last year, the development pipeline for drugs was filled with promising compounds, many of which were already progressing through the clinical phases (WHO, 2012). Clinical trials for new drugs are costly, as they include follow-up treatments for subjects, tests in combinations with a number of existing drugs, and strict regulations that must be met to receive approval. While such investments were rarely made before, a number of international research groups and projects, such as the NIH-funded AIDS Clinical Trials Group and the Critical Path to New TB Drug Regimens initiative are contributing laboratory and clinical trial site capacity to the progress of new drugs. Moreover, new tuberculosis vaccines are in developmental stages to replace the centuryold BCG vaccine, now used for infants and unreliable for adults. Several vaccines have 9

already been clinically tested in countries like Tanzania, South Africa, and Kenya, and results are expected in mid-2013 (WHO, 2012). Funding for tuberculosis research has risen greatly in the last several years, reaching $400-500 million per year globally. Much of this is due to the increase in the number of public-private philanthropic partnerships, with the US NIH and the European Commission leading the public sector, and the Bill & Melinda Gates Foundation and Wellcome Trust leading the private sector (Kaufmann, 2010). All in all, mismanagement of tuberculosis treatment at several levels, including the government and private sector (with India being a prime example but just one of many) and the past stagnation of tuberculosis drug research and development have led to the present crisis of drug resistant tuberculosis that threatens to undermine global efforts to beat back the disease that has killed countless millions. The last several years have seen remarkable improvements over the last decades of the 1900s: governments are becoming more conscious about regulating private sector tuberculosis care, funding for research and development of much needed drugs has risen greatly (though not quite the estimated $2 billion needed every year to adequately fund vaccine research), and international treatment protocols are becoming uniform under the WHO (Kaufmann, 2010). Still, high burden nations like India, China, and Brazil continue to feel the social and economic impact of tuberculosis. The HIV epidemic and new strains of total drug resistant strains of tuberculosis are proving to be stiff opposition to the global efforts to stop tuberculosis. Regardless, the war against this pestilence that has plagued human-kind for millenia must go on, and the future has hope for success with the international effort learning from past errors.

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Works Cited Andre, Maria do Rosario, et al. Tuberculosis Infection in the 21st Century: Can We Win? Clinical Care Reports 2.10 (2012): 1-3. Cole, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393 (1998): 537-544. Daniel, Thomas M. The history of tuberculosis. Respiratory Medicine 100.11 (2006): 1862-1870. Dasgupta, Rajib, et al. Connecting the DOTS: Spectre of a Public Health Iatrogenesis? Indian Journal of Community Medicine 37.1 (2012): 13-15. Gupta, Rishi. Trips Compliance: Dealing with the Consequences of Drug Patents in India. Houston Journal of International Law 26.3 (2004): 599-645. Havlir, Diane V., et al. Opportunities and Challenges for HIV Care in Overlapping HIV and TB Epidemics. JAMA 300(4) (2008): 423-430. Kaufmann, Stefan H. E. et al. New vaccines for tuberculosis. The Lancet 375 (2010):2110-2119. Lnnroth, Knut, et al. Drivers of tuberculosis epidemics: The role of risk factors and social determinants. Social Science and Medicine 68 (2009):2240-2246. Lucchini, Stphane, et al. Decrease in Prices of Antiretroviral Drugs for Developing Countries: from Political Philanthropy to Regulated Markets? In Economics of AIDS and Access to HIV/AIDS Care in Developing Countries: Issues and Challenge. Paris: ANRS, 2003. Maartens, Gary, et al. Effectiveness and safety of antiretrovirals with rifampicin: crucial issues for high-burden countries. Antiviral Therapy 14 (2009): 1039-1043. 11

Mueller, Janice M., et al. Taking TRIPS to IndiaNovartis, Patent Law, and Access to Medicines. New England Journal of Medicine 356 (2007): 541-543. OBrien, Richard J., et al. The Need for New Drugs against Tuberculosis. American Journal of Respiratory and Critical Care Medicine 163 (2001): 1055-1058. Trouiller, Patrice, et al. Drug development for neglected diseases: a deficient market and a public-health policy failure. The Lancet 359 (2002): 2188-2194. Udwadia, Zarir F. MDR, XDR, TDR tuberculosis: ominous progression. Thorax 67.4 (2012): 286-288. Udwadia, Zarir F., et al. Tuberculosis Management by Private Practitioners in Mumbai, India: Has Anything Changed in Two Decades? PLoS ONE 5.8 (2010). Wells, W. A., et al. Size and Usage Patterns of Private TB Drug Markets in the High Burden Countries. PLoS ONE 15.6 (2011): 746-753. Williams, B. G., et al. The impact of HIV/AIDS on the control of tuberculosis in India. PNAS 102.27 (2005): 9619-9624. WHO. A brief history of tuberculosis control in India. 2010. WHO. Global Tuberculosis Report 2012.

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