A major public health challenge
Stigma, isolation and a high risk of death: these are the challenges facing most drug-resistant TB patients. This article explains drug-resistance and what is fueling it.
These drugs are used to treat people with multi-drug resistance TB. They do not work as well as the first-line drugs and have worse side-effects. Nevertheless, MDR TB can be cured.
Regrettably drug-resistant TB is a much bigger problem than it should be because of inadequate and poor management of healthcare programs.
Extensively drug-resistant (XDR) and multi-drug resistant (MDR) TB are immense public health challenges. Debates are unsettled about how to treat patients with these conditions, whether patients should be quarantined or treated in their communities [^1] and what measures need to be taken to reduce the incidence of drug-resistance.
The Global Plan to Stop TB predicts that from 2010 till 2015, 1.3 million MDR TB cases will need to be treated in 27 countries with the highest incidence of drug resistant TB, including South Africa, at a price tag of US$16.2 billion. [^2]
Regrettably drug-resistant TB is a much bigger problem than it should be because of inadequate and poor management of healthcare programs. Although drug development for MDR and XDR TB is currently in progress, for now treatment outcomes are often poor and can vary quite extensively from area to area. For example in South Africa, 6-month mortality amongst MDR and XDR TB patients is much lower than in the Western Cape province than in Kwazulu-Natal. The reasons for this are not understood, but might be due to different strains of drug-resistant TB.
The prevalence of MDR and XDR TB pose a serious public health concern that stresses the need for rapid drug development and a joint effort amongst governments and supranational organizations to provide additional measures.
There are several types of resistance to anti-TB drugs. Monoresistance and polyresistance are defined as resistance to one and two anti-TB drugs, respectively. When a patient is polyresistant to the two most potent first-line anti-TB drugs, isoniazid (INH) and rifampicin (RIF), the condition is termed MDR TB.
Less frequent but even more serious is XDR TB. Patients with XDR TB show resistance to INH and RIF. But they are also resistant to at least one of the three following injectable anti-TB drugs – capreomycin, kanamycin and amikacin. [^3] These antibiotics are more toxic and not recommended for pregnant women. Side effects include seizure, peripheral neuropathy, hearing loss, psychosis, depression, nausea/vomiting, hepatitis and optic neuritis.[^4]
Patients who show drug resistance fall into two categories – patients with “primary” or “initial” drug resistance who have not had previous treatment for TB and patients with “secondary” or “acquired” drug resistance who have had previous treatment for TB. [^3] While most cases of drug resistance fall under the second category, there have been incidences of nosocomial (originating in health facilities) infection where predominantly HIV-positive patients who never had TB had acquired drug-resistant TB.
According to WHO’s latest surveillance report, in 2008 there were an estimated 440,000 cases of MDR TB worldwide. [^2] Compared to the 511,000 new episodes of MDR TB WHO reported in 2007, the overall trend seems to be decreasing. [^2] Cases of MDR-TB account for less than 5% of TB incidence globally. Approximately 5% of MDR TB cases progress into XDR TB. An important note to consider is that due to severe under-reporting of MDR and XDR TB cases, the numbers above are only projected figures. In fact, less than 10% of all cases are actually diagnosed.
So far, 58 countries, predominantly in the Eastern European and Central Asian region, have reported at least one case of XDR TB. [^2]
Since the first outbreak of MDR TB was reported in America in the early 90’s, only 59% of all countries globally have investigated drug resistance on a national or sub-national level. [^2] [^3] Out of these countries merely 42 countries routinely test their TB patients as part of their surveillance programs. [^2] Some countries, such as Tajikistan, have only started surveying MDR TB just this year (2011 at the time of writing).
More than half of all MDR TB episodes globally occur in three countries. In the 27 high-burden countries, the number of primary and secondary MDR TB cases for China, India and the Russian Federation constitute 30%, 20% and 10% of all cases, respectively. [^2]
There are several factors that explain how a patient might develop MDR or XDR TB, if he or she is not inherently resistant. First, regardless of exposure to anti-TB drugs, any population of TB bacilli will produce mutations resistant to a single drug. Therefore, a prolonged use of anti-TB drugs will eliminate all drug-susceptible bacilli but ultimately select mutants that eventually become the dominant population.
The cycle is worsened by poor management of patients, incomplete antibiotic treatments or lack of adequate health resources. Often lack of treatment literacy, absence of symptoms, or complexity of regimen worsen adherence. In resource-poor settings, clinics may run out of drugs and unintentionally interrupt therapy.
Furthermore, one of the biggest obstacles to reducing drug-resistant TB is the lack of diagnostic capacity. Diagnostic tests for drug-resistant TB require a drug susceptibility test (DST) which, until now, have been done in culture and required 6 to 16 weeks for results. A new diagnostic tool, the Gene Xpert can diagnose rifampicin resistance in two hours. But diagnostics for quick diagnosis of resistance to other drugs do not yet exist.
### Lack of surveillance
When there are too few laboratories to diagnose TB patients under-reporting and under-funding of drug-resistant TB programs are inevitable. The World Health Organisation states, “The burden of anti-TB drug resistance in the African Region remains largely unquantified”; in fact only South Africa in the region is equipped for routine drug resistance surveillance. [^5] Although there is at least one laboratory in most of the 27 high MDR TB-burden countries that can perform DST to first-line drugs, the diagnostic capacity does not meet the need. WHO states that in the 27 high MDR TB burden countries, merely 1% of new TB cases and 3% of acquired TB cases underwent DST. [^2]
### Expensive treatment
Treating patients with drug-resistant TB is costly, takes longer and has a poor prognosis. Compared to first-line drugs, those used to treat MDR TB are far more expensive. WHO highlighted this fact showing that in all the 27 high burden countries, the expenditure for MDR TB treatment surpasses their gross national income per capita. On average, a regimen for an MDR TB patient costs 50 to 200 times more than that for a drug-susceptible TB patient undergoing first-line treatment. For example, in Kenya, the government spends around US$21,000 on an MDR TB patient. This is compared to US$80 spent on a drug-susceptible TB patient. Due to its funding constraints, the Kenyan government has only managed to put 110 MDR TB patients on treatment, leaving over 400 other patients on their own. [^2] [^5]
In response, the “Narrowing The Gap” Project: Expanding And Accelerating Access to Diagnostics For Patients At Risk Of Multi-Drug Resistant Tuberculosis 2008 – 2011” (EXPAND TB) project was launched in December 2008. The project, set in 27 high burden countries, aims to “narrow the huge diagnostic gap in MDR TB control by expanding and accelerating access to new diagnostic technologies.” Its partners include WHO, the Global Laboratory Initiative, the Foundation for Innovative New Diagnostics (FIND) and the Stop TB Partnership’s Global Drug Facility and UNITAID. [^6]
[^1]: Markel H, Gostin LO, Fidler DP. Extensively drug-resistant tuberculosis: an isolation order, public health powers, and a global crisis. JAMA. 2007;298(1):83-6. Available at http://www.umdnj.edu/ntbc/downloads/QuarantineJAMA.pdf
[^2]: WHO. Multidrug and extensively drug-resistant TB (M/XDR-TB) 2010 Global Report on Surveillance and Response. Geneva: WHO, 2010 Available at http://whqlibdoc.who.int/publications/2010/9789241599191_eng.pdf
[^3]: Palomino, J.C., Leao, S.C. and Viviana Ritacco. Tuberculosis 2007: from basic science to patient care. Available at www.tuberculosistextbook.com/pdf/genprot.pdf
[^4]: TB in Our Lives. TAC
[^5]: Too Few MDR TB Cases Diagnosed. IRIN news. 19 Mar 2010. Available at http://www.irinnews.org/Report.aspx?ReportId=88489
[^6]: StopTB Partnership. Expanding and accelerating access to diagnostics for patients at risk of multi-drug resistant tuberculosis. http://www.stoptb.org/wg/gli/assets/documents/EXPAND-TB%20project%20information.pdf