Tuberculosis (TB) remains a major global health problem. Worldwide, there are an estimated 2 billion people infected with Mycobacterium tuberculosis from whom 9.6 million develop TB each year. A staggering 1.5 million people die from TB annually including over 400,000 with HIV infection. The emergence of drug-resistant strains of M. tuberculosis threatens to undermine TB control programs worldwide. Multidrug-resistant TB (MDR-TB) strains that are resistant to at least isoniazid and rifampin, and extensively drug-resistant TB (XDR-TB), MDR-TB strains that are also resistant to a fluoroquinolone and second-line injectable drugs, are more difficult to diagnosis and treat than other forms of TB.
The World Health Organization estimates that there are 480,000 cases of MDR-TB annually resulting in 190,000 deaths. Approximately 3% of new (untreated) TB cases and 20% of previously treated cases have MDR-TB. The estimated proportion of MDR-TB among new and retreated cases varies across the WHO regions with the highest proportion in the European region where approximately 50% of retreated cases have MDR-TB. By the end of 2014, XDR-TB was reported from 105 countries and accounted for an estimated 9.7% of MDR-TB cases. Given the significant morbidity and mortality associated with drug-resistant TB, it is imperative that we understand the barriers and gaps in the global control of MDR-TB.
Gaps in MDR-TB control
By the end of 2014, there were an estimated 480,000 patients with MDR-TB globally, which includes cases that have been notified, those that have been diagnosed but not notified and those that have yet to be diagnosed. Among already notified cases, there are estimated to be 300,000 (63% of estimated) patients with MDR-TB. The large gap between the estimated and notified cases is due in large part to lack of reporting and case detection. Unfortunately, only 123,000 patients (25% of the estimated) were actually notified to have MDR-TB: this gap between the notified TB cases and notified MDR-TB represents a lack of access to antimicrobial susceptibility testing. Among those identified as having MDR-TB, only 111,000 were enrolled into treatment, for whom outcome data are available on approximately 50%. Treatment success was reported in 48% of patients with almost a quarter being lost to follow-up. In order to scale up the programmatic management of MDR-TB, we must identify specific gaps in TB control and introduce targeted interventions to close the gaps.
The diagnosis gap – where are the missing cases?
Only 25% of patients estimated to have MDR-TB and 41% of notified TB cases are identified to have MDR-TB. These 350,000 “missing cases” result from a number of factors including poor access to and awareness of diagnostic facilities, low case detection, poor recording and reporting, as well as lack of appropriate infrastructure and human resources. Availability of antimicrobial susceptibility testing is greatly limited and culture-based methods lack standardization and reproducibility for many second-line drugs. Globally, only 12% of new cases and 58% of previously treated cases were tested for MDR-TB and only 24% of notified and confirmed MDR-TB cases had antimicrobial susceptibility testing performed for both fluoroquinolones and second-line injectable drugs. These figures fall short of the WHO End TB Strategy that calls for universal antimicrobial susceptibility testing.
Fortunately, antimicrobial susceptibility testing availability is increasing globally at a rapid pace in large part due to the availability of new molecular assays that offer the potential to identify genetic mutations that confer resistance in a fraction of the time that it takes phenotypic methods. Molecular methods have considerable advantages for scaling up programmatic management of MDR-TB and surveillance of drug-resistant TB because they offer speed of diagnosis, standardized testing, potential high through-put, and fewer requirements for laboratory biosafety.
Much of the scale-up activities related to antimicrobial susceptibility testing can be credited to the Global Laboratory Initiative that was established in 2008 as a Working Group of the Stop TB Partnership. The Global Laboratory Initiative, which consists of over 100 international partners, serves as an independent, technical expert advisory group to WHO, development and funding agencies, and countries. In collaboration with the WHO Supranational Reference Laboratory Network established in 1994, the Global Laboratory Initiative has helped to strengthen laboratory capacity and infrastructure in resource-limited areas, supported the global scale-up of rapid diagnostics, and improved quality of individual laboratories and laboratory networks.
The diagnosis-treatment gap
The number of MDR-TB cases started on second-line treatment increased from 30,492 in 2009 to 111,000 in 2014. However, this represents only 90% of the notified cases of MDR-TB and an abysmal 23% of all estimated MDR-TB cases. And unfortunately, the capacity to treat MDR-TB is lagging behind the capacity to diagnose MDR-TB so that “waiting lists” are growing. There are many reasons for the diagnostic-treatment gap including a critical shortage of human resources, lack of availability of second line drugs, inadequate facilities for treatment and monitoring and ineffective TB control programs. Scale-up of treatment is further complicated by the prolonged duration of therapy (approximately 20 months) with regimens that are associated with many drug-related adverse events and poor treatment outcomes: the proportion of MDR-TB cases that were treated successfully was only 48% and this has not changed since at least 2007.
There is great optimism that treatment results will soon be improving with the introduction of new drugs and shorter regimens. Hoping to parallel the success of the Global Laboratory Initiative, the Global Drug Resistant TB Initiative, another working group of the Stop TB Partnership, was established approximately three years ago. The GDI evolved from The Green Light Committee Initiative that was established in 2000 as a subgroup of the MDR-TB Working Group within the Stop TB Partnership. The aim of the Green Light Committee Initiative was to help countries access quality-assured second-line anti-TB drug therapy for treatment of patients with MDR-TB. Between 2000 and 2010, the Green Light Committee approved the treatment of over 100,000 patients from 133 projects in 83 countries and conducted over 300 technical assistance missions. However, only approximately 30,000 patients were actually treated over this time frame.
Although enrollment into treatment was increasing, almost doubling between 2008 and 2009, the rate of enrollment was too slow. Therefore, a new framework was created that involved establishment of regional Green Light Committees and a global Green Light Committee. Over two years, each of the regional Green Light Committees was established and all are now up and running. In 2013, the MDR-TB Working Group and global Green Light Committee merged to become the Global Drug Resistant TB Initiative. This group works closely with the Stop TB Partnership, WHO, and regional Green Light Committees to continue the scale-up of programmatic management of MDR-TB worldwide, focusing on the high MDR-TB burden countries and working with the Global Laboratory Initiative and Global Drug Facility to link diagnosis with appropriate and effective treatment.
The concerted efforts of partners in the fight against MDR-TB will hopefully speed up access to antimicrobial susceptibility testing among TB patients and provide quality assured medications and effective regimens to all patients with MDR and XDR-TB.
Charles L. Daley, MD, Chief, Division of Mycobacterial and Respiratory Infections, National Jewish Health, Denver, CO & Chair, Global Drug Resistant TB Initiative, Stop TB Partnership, Geneva, Switzerland
- 1. World Health Organization. Global Tuberculosis Report 2015. http://www.who.int/tb/publications/global_report/en/index.html
- 2. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. 2011 Update. http://www.who.int/tb/challenges/mdr/programmatic_guidelines_for_mdrtb/en/index.html