The Growing Problem of Multidrug-Resistant Tuberculosis in North Korea

Tuberculosis (TB) has long been one of the most serious public health problems in North Korea (Democratic People’s Republic of Korea). The estimated TB incidence of 345/100,000 population is higher than in some countries with generalized HIV/AIDS epidemics [1]. HIV is thought to be almost nonexistent in North Korea, but chronic malnutrition, an important risk factor for TB, has become a fact of life for much of the population since the 1990s [2]. The North Korean health care system has been devastated by the economic problems of the past two decades, making it difficult to respond to povertyand nutrition-related diseases such as TB [3]. In 1998, the Ministry of Public Health (MOPH) adopted DOTS (Directly Observed Treatment, Short-course), the World Health Organization (WHO)-recommended approach for TB control in resource-limited settings. The major components of DOTS—sputum smear microscopy for diagnosis, and standardized regimens of quality-assured drugs for treatment—had not been as strongly emphasized in North Korea previously. In 2003, North Korea began procurement of TB drugs from the Global Drug Facility (GDF), a WHO-led initiative that has supplied high-quality drugs to over 90 countries since its inception in 2001 [4]. In 2010, the Global Fund to Fight AIDS, TB and Malaria (GFATM) began a five-year, US$41.1M project to continue and expand these initiatives [5]. UNICEF, the principal recipient, and WHO, the technical lead, are responsible for implementation of this project. Little of this international aid has included treatment of drug-resistant TB. For example, in 2011, North Korea reported 85,564 new cases of TB, the vast majority of whom would have received the GDF standard treatment kit for new patients (category I), a red/white cardboard box containing two months of isoniazid, rifampicin, ethambutol, and pyrazinamide, followed by four months of isoniazid and rifampicin. There were also 13,507 patients with a past history of TB treatment who would have received the GDF standard retreatment kit (category II): two months of streptomycin injections plus isoniazid, rifampicin, ethambutol, and pyrazinamide, followed by one month of isoniazid, rifampicin, ethambutol, and pyrazinamide, followed by five months of isoniazid, rifampicin, and ethambutol. These two regimens have been shown to be highly effective for drug-susceptible TB, but are significantly less effective for drug-resistant TB [6]. There has never been any clear scientific evidence that drug-resistant TB is a serious problem in North Korea. North Korea does not have any system for drug resistance surveillance, nor has it ever performed a national or subnational drug resistance survey [7]. The GFATM focus on treatment for drug-susceptible TB would make programmatic sense if the overall proportion of North Korean TB patients with drug resistance were low. In such settings, improving the diagnosis and treatment of drug-susceptible TB can prevent the creation of drug resistance. It is much more difficult to diagnose and treat drug-resistant TB, particularly multidrug-resistant (MDR) TB, defined as resistance to isoniazid and rifampicin, the two strongest TB drugs and the backbone of standard DOTS regimens. MDR TB requires 18–24 months of treatment with expensive and poorly tolerated second-line TB drugs. In the absence of drug resistance surveillance data, the successful implementation of DOTS has suggested that drug resistance should not be a problem in North Korea. According to WHO, the outcomes for new smear-positive patients receiving category I in 2010 were 86% cured, 4% completed, 3% died, 4% failed, 2% defaulted (1% not evaluated). Outcomes of retreatment patients (category II) were 76% cured, 8% completed, 4% died, 8% failed, 3% defaulted (2% not evaluated) [1]. North Korea is one of the few countries in the world that have attained the WHO target of 90% success (cured plus completed) for new patients, a monumental achievement given the challenges faced by the MOPH. WHO programmatic indicators, however, can exaggerate cure rates because they rely on the relatively insensitive tool of smear microscopy. A patient who is sputum smear-negative after completing a standard DOTS regimen is considered to be a cure, even if there is a small amount of viable bacteria in the sputum that would be detectable by a more sensitive test like culture. This is rarely an issue in settings where almost all TB is drug-susceptible, but in settings where drug-resistant TB is more common, such as Siberia, WHO indicators can overestimate the efficacy of standard DOTS regimens [8,9]. The experience of countries such as Russia, Azerbaijan, and Uzbekistan,