Patients with Previously Treated Tuberculosis No Longer Neglected
- Reprints or correspondence: Dr. Matteo Zignol, STOP TB Dept., World Health Organization, 20, Ave. Appia, CH-1211 Geneva 27 Switzerland(zignolm{at}who.int).
Abstract
Over the past decade, global and national tuberculosis (TB)—control programs, challenged with limited resources, have had to prioritize interventions to maximize impact. For this reason, patients with newly diagnosed cases of TB received more attention than did patients with a previous history of treatment. The recently launched STOP TB Strategy and Global Plan to STOP TB 2006–2015 now promote proper diagnosis and treatment of TB for all patients, without distinction of smear status, drug susceptibility, sex, or age, including all patients with a history of previous treatment. Previously treated patients are difficult to re-treat and represent an important source of disease transmission, as well as a serious threat to TB control worldwide, because of their higher rate of drug resistance.
1995, when the launch of the global strategy for tuberculosis (TB) control known as DOTS occurred, important progress has been made in the expansion of TB services and the number of patients with TB detected. The number of countries implementing DOTS increased from 73 in 1995 to 183 in 2004. During the same period, rates of detection of new smear-positive cases of TB in areas implementing DOTS increased from 11% to 53%. In 2004, the incidence of TB was growing globally at a rate of 0.6%, but the incidence, prevalence, and mortality rate associated with TB were stable or decreased in all regions except Africa [1].
In October 2005, a decade after the launch of DOTS, the World Health Organization and technical partners revised the global approach to TB control and introduced the new STOP TB Strategy, which is based on DOTS but is inclusive of measures to face emergent challenges [2]. The goal is to halt and begin to reverse the incidence of TB by 2015, to achieve the Millennium Development Goals [3], by pursuing high-quality expansion and enhancement of DOTS, as in the previous strategy, and, in addition, by addressing TB/HIV infection, multidrug-resistant TB (MDR-TB), and other challenges; contributing to strengthening the health system; engaging all care providers; empowering people with TB and communities; and enabling and promoting research [2]. This strategy should foster access for all patients with TB to the best standard of care, as stated in the International Standards for Tuberculosis Care developed by the Tuberculosis Coalition for Technical Assistance [4]. To implement the STOP TB Strategy, a global plan for TB control for the decade 2006–2015 has been developed [5]. The plan outlines the actions and the funding required to improve TB services, and it addresses the new challenges to achieving the Millennium Development Goals.
One group of patients who should benefit significantly from the implementation of the new STOP TB Strategy and the Global Plan to STOP TB 2006–2015 is the group of previously treated patients. Patients with a history of previous treatment often have the most complex cases to manage. They constitute a very heterogeneous group that is composed of patients with TB who experience relapse after receiving successful treatment, those who return after default, and those who start receiving a re-treatment regimen after having experienced previous treatment failure, as well as other patients (i.e., those who do not fit in one of the aforementioned categories), such as those who received unknown or unstandardized treatment regimens [6]. In most countries, patients with TB who experienced relapse after treatment represent the largest proportion of previously treated patients. In countries that are considered to be exceptions (e.g., countries of the former Soviet Union, such as Lithuania, the Russian Federation, and Uzbekistan), the group of other patients accounts for the total or the large majority of notified previously treated patients (figure 1) [1].
Figure 1
Proportion of patients with previously treated tuberculosis (TB), disaggregated by TB relapses, failures, defaults, and other cases. Data refer to patients with TB notified in 2004 in the 22 high-burden countries (i.e., countries estimated to account for >80% of the global TB burden) and in the sites with the highest prevalence of multidrug-resistant TB.
The World Health Organization recording and reporting system does not discriminate between true relapse (i.e., reactivation of latent TB) and reinfection (i.e., exogenous acquisition of TB), and it designates as relapse any recurrence of TB. The contribution of reinfection (vs. relapse) to the burden of TB recurrences is still debated, but more and more evidence shows that TB recurrences among HIV-positive patients in areas with a high incidence of TB are largely the result of reinfection [7, 8].
Previously treated patients with TB represent >15% of all patients with TB in large countries, such as India, China, and the Russian Federation, and in all areas with the highest MDR-TB burden ( figure 1) [1, 9]. In some areas, particularly in the former Soviet Union, where considerable proportions of TB cases are classified neither as new nor as previously treated cases, the burden of previously treated cases may even be underestimated. Among previously treated patients are those with the highest risk of harboring MDR or even extensively drug-resistant strains of Mycobacterium tuberculosis [10], those who are coinfected with HIV, those who repeatedly seek care from the unregulated private health sector, and those who remain contagious for longer periods, potentially spreading the disease to a large number of people.
That a history of previous treatment is a risk factor for the development of drug-resistant TB is well recognized [9, 11], although the proportion of cases of MDR-TB among previously treated patients is unknown in many developing countries. Because of their higher risk of harboring drug-resistant strains, previously treated patients require more complex laboratory investigations to diagnose their disease and much longer, more expensive, and more potentially toxic regimens to be cured. Only in a few areas with good TB-control programs and a low frequency of misuse of drugs have World Health Organization—recommended regimens involving first-line drugs demonstrated acceptable treatment cure rates among previously treated patients [12]. This is likely related to a low prevalence of drug-resistant TB. In other areas, treatment failure rates have been shown to be significantly associated with MDR-TB, and, for these cases, standard re-treatment regimens have proved to be inadequate and should be replaced by stronger regimens utilizing second-line anti-TB drugs [13]. To accelerate proper diagnosis and treatment of drug-resistant TB among previously treated patients, it is necessary to develop a better understanding of the prevalence of drug-resistant TB in this group of patients, both by country and globally. In addition, screening systems for the early diagnosis of MDR-TB in high-risk subgroups of patients receiving re-treatment, such as those with treatment failure, should be established in all countries, to maximize the impact of the interventions.
The effect of HIV infection on recurrence of TB has been extensively explored. HIV-positive patients with a compromised immune system are more likely to develop reactivation of latent TB infection and acquire exogenous TB reinfection, compared with HIV-negative patients [14, 15]; however, the overall effect of HIV infection on mortality among patients with previously treated TB is still debated. Some evidence suggests that MDR-TB, which is known to occur more frequently among previously treated patients than among patients with new cases of TB, is responsible for high mortality rates among HIV-infected patients in resource-limited countries. Similar findings were documented during hospital outbreaks in industrialized countries in the early 1990s [16]. Unfortunately, these studies are not conclusive, and it is still debated whether HIV infection has greater effect on mortality among previously treated patients, compared with patients with newly diagnosed TB. Such an issue needs to be further investigated to understand the epidemiological profile of previously treated cases, clarify the role of HIV in the spread of drug-resistant TB, measure the effect of TB-control efforts, and target appropriate interventions.
In large areas of the world, particularly in Southeast Asia and in metropolitan settings, a substantial proportion of patients with TB seek care from private health providers. This phenomenon is of great concern for TB control, but its magnitude is poorly understood. Treatment regimens prescribed by private practitioners often do not meet the International Standards for Tuberculosis Care [17]. In addition, the cost of care, which is unaffordable for the large majority of patients with TB, is an important cause of infrequent adherence to therapy and treatment default, potentially leading to the development of drug resistance. Public-private collaborations have been shown to be feasible and cost-effective in developing countries [18], but they need to be quickly implemented on a large scale and should be tailored to meet the needs of patients who are following longer and more demanding treatment regimens and who have a higher risk of defaulting if managed only by private providers.
Furthermore, the role of previously treated patients in the dynamics of transmission of M. tuberculosis has not yet been adequately investigated. The fact that these patients may remain sputum smear positive for longer periods than patients with new cases of TB (because of a higher proportion of patients harboring drug-resistant strains that are more difficult to diagnose and treat) poses additional concerns for TB control, particularly in areas where re-treatment of cases occurs frequently.
Public health programs are frequently challenged with limited resources, requiring prioritization of interventions. For this reason, and because of the difficulties in the classification, diagnosis, and clinical management of previously treated cases, TB control has focused on new cases during the past decade.
However, the status quo is now being challenged by the new Global Plan to STOP TB 2006–2015, which acknowledges the contribution of previously treated cases to the overall burden of TB and MDR-TB cases and outlines explicit plans to address these cases. The Global Plan has set a target by specifying that, by 2015, all previously treated patients should have access to culture and drug susceptibility testing at the beginning of treatment to identify MDR-TB as early as possible. Countries are invited to increase access to culture and drug susceptibility testing services in a phased manner, starting with groups at higher risk for drug resistance, such as patients who have experienced treatment failure. This would allow confirmation of their disease and eventually allow access to more effective treatment regimens. Appropriate treatment with quality-assured, second-line anti-TB drugs should be provided to all patients who have MDR-TB diagnosed [5], as well as to patients infected with mono- and polyresistant strains (drug-resistant TB other than MDR-TB) [19].
These goals express a strong commitment to provide proper TB care to the patients who are most difficult to treat and to outline the direction that the international community will pursue over the next decade. Patients with previously treated TB will no longer be neglected and will receive the same type of high-quality care that is promoted for patients with newly diagnosed cases.
Acknowledgements
We thank Catharina Lambregts-van Weezenbeek for providing initial guidance in the development of this manuscript.
Financial support. World Health Organization.
Potential conflict of interest. All authors: no conflicts.
Footnotes
-
The named authors alone are responsible for the views expressed in this publication.
- Received May 30, 2006.
- Accepted August 30, 2006.
- © 2007 by the Infectious Diseases Society of America
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