The impact of drug resistance on the global tuberculosis epidemic

Transcription

1 INT J TUBERC LUNG DIS 4(2):S71 S IUATLD The impact of drug resistance on the global tuberculosis epidemic N. W. Schluger The Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA SCOPE OF THE PROBLEM DRUG-RESISTANT MYCOBACTERIA were identified shortly after the introduction of streptomycin as the first effective chemotherapy for tuberculosis in the late 1940s. 1 Resistance to isoniazid was also noted soon after the introduction of that drug. The realization that prolonged exposure to a single drug would select for drug-resistant strains of Mycobacterium tuberculosis led to the development of the principle of multi-agent chemotherapy for tuberculosis. 2 The success of such an approach was widely demonstrated in a number of clinical trials which showed that drug resistance in treatment failures and/or relapsed cases of tuberculosis was uncommon if a multi-agent regimen was administered with good adherence during treatment of drug-susceptible cases. In addition, isolated resistance to rifampin, which has never been used as a single agent to treat tuberculosis, has been exceedingly rare, although a number of cases of rifampin-monoresistant tuberculosis, almost always in patients with the human immunodeficiency virus (HIV) infection, have been reported recently. 3 5 Although several published studies clearly suggested that drug resistance was a potential problem in developing countries, 6,7 it was the emergence of drug resistance in the United States that attracted the most attention in the early 1990s. 8 Many outbreaks of multidrug-resistant tuberculosis (MDR-TB, defined as cases of tuberculosis with strains of M. tuberculosis resistant to isoniazid and rifampin) were described in patients with HIV infection, and restriction fragment length polymorphism (RFLP) analysis demonstrated that many of these cases had apparently arisen as a result of direct transmission among persons in hospitals, prisons, jails, and homeless shelters. 9,10 With the ease of travel around the country being what it is, it is not surprising to note that RFLP analysis has demonstrated the spread of MDR clones around the US. 11 Unquestionably, the epicenter of these outbreaks of multidrug-resistant tuberculosis was New York City, which reported 450 such cases in Reports of the morbidity and mortality related to MDR-TB indicate the seriousness of this problem for individual patients. 12,13 Both HIV-negative and HIVpositive persons with MDR-TB have considerably poorer survival from MDR-TB than if they developed disease due to drug-susceptible strains. Median survival in AIDS patients has been reported to be about 14 months, and overall survival in immunocompetent patients with MDR-TB is in the range of 60 90%. However, it has been clearly shown that aggressive therapy with tailored regimens which may include surgery for localized disease can result in improved survival, although the commitment of time, personnel, and money both for drugs and drug susceptibility testing to achieve these results is high. 13,14 This latter point has important implications for the global rise of MDR-TB. Although AIDS and poor infection control procedures in hospitals and other congregate settings undoubtedly contributed mightily to the rapid spread of MDR-TB, it is useful to remember that many cases of drug resistance arise as the result of physician error. Mahmoudi and Iseman reviewed 35 consecutive cases of MDR-TB referred to the National Jewish Hospital in Denver, and found that serious errors had been made in 28/35 of them, with an average of 3.93 errors per patient. 15 These errors typically included adding a single drug to a failing regimen, failing to obtain a complete history of prior tuberculosis treatment and drug susceptibility patterns, and failure to develop a plan to monitor and ensure completion of therapy. In the past 5 to 6 years, cases of MDR-TB in New York City have fallen sharply. 16 This has occurred as a result of much improved institutional infection control, active case management and tailoring of drug regimens for patients with drug-resistant tuberculosis, and strenuous efforts to ensure completion of therapy. The precise contribution of each of these Correspondence to: Neil W Schluger, MD, Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, VC , 630 West 168th Street, New York, NY USA. Tel: ( 212) Fax: ( 212) ns311@columbia.edu

2 S72 The International Journal of Tuberculosis and Lung Disease components in reducing the burden of MDR-TB cases is difficult to determine, however. For example, there is certainly a temporal association between the widespread application of directly observed therapy (DOT) for tuberculosis in New York (and elsewhere) and the reduction of cases of MDR-TB, but it should be noted that cases of MDR-TB began to decline before DOT was widely available in the city. The incidence of drug-resistant tuberculosis around the world has been poorly defined until recently, when the World Health Organization and the International Union Against Tuberculosis and Lung Disease completed the WHO/IUATLD Global Surveillance Project on Drug Resistance. 17 This survey, which collected data from 35 countries on five continents, found that multidrug-resistant tuberculosis is present in every country in the survey. Two features of the survey deserve special comment. First, if anything, the survey likely underestimates the true magnitude of the extent of multidrug-resistant tuberculosis around the world. This is because a substantial number of countries neither follow WHO guidelines for tuberculosis control and treatment nor report tuberculosis statistics to the WHO. It is a reasonable assumption that most of those countries that do not accept WHO guidelines or report data to them are performing less well than the other countries in the report, and may have more drug resistance. Second, although the report noted that drug resistance occurs in every region of the world, it identified several hot spots in which MDR-TB cases have already reached alarming levels. These countries or regions include Argentina, the Dominican Republic, Côte d Ivoire, Russia, Estonia, Latvia, and Delhi (state) in India. The prevalence of MDR-TB cases in these regions reported in the survey range from 7 22%. The impact of these cases is made more striking with the realization that in many of these regions the background incidence of tuberculosis generally is extremely high; in Delhi, for example, there are roughly 450 cases of tuberculosis per population, so there are approximately 60 new cases of MDR-TB per persons. As a point of reference, this MDR- TB rate exceeds the incidence of all cases of tuberculosis reported in New York City in 1992, the apex of the recent tuberculosis epidemic in that city. A more detailed examination of the problem of drug resistance around the world provides some striking similarities between the experience of the US and less economically advanced countries. A recent report from Argentina noted a sharp increase in cases of MDR-TB occurring in patients with HIV infection in a single hospital; 18 RFLP analysis indicated that recent transmission (nosocomial spread) likely accounted for a significant number of those cases. Prisons around the world are also foci of MDR-TB. A recent report from Baku, Azerbaijan, indicated that of 35 consecutive tuberculosis treatment failures in prisoners, multidrug resistance was found in 89%. 19 In a small series of previously untreated cases of tuberculosis in persons in the same prison, 24% were MDR-TB. The significance of these findings, particularly in the countries of the former Soviet Union, is magnified by both the number of prisoners and the incidence of tuberculosis in prisons in many regions. It is estimated, for example, that in Russia there are 1 million prisoners, of whom have active tuberculosis. The nature of the problem of MDR-TB is likely to vary from country to country, and it is imperative that the WHO/IUATLD report be followed by a more detailed examination of individual countries. This will help to determine the precise epidemiologic and demographic features of MDR-TB in those countries and suggest effective strategies for control, based on local conditions. FUTURE TRENDS FOR MDR-TB AROUND THE WORLD In the short to medium term, the outlook for containing the spread of MDR-TB is decidedly mixed. In countries where the prevalence of MDR-TB is currently low, the best strategy for preventing the emergence of drug resistance probably lies in the widespread application of programs of directly observed therapy using short-course treatment regimens (DOTS). There are good reasons to think that this approach will be successful in preventing the emergence of MDR-TB. This has been the experience in Baltimore (in the US), where DOT has been in place for 20 years, and drug resistance has never emerged as a significant problem. 20 Where MDR-TB is already prevalent, however, focusing on treating drug-susceptible cases alone (by DOTS or other means) is unlikely, on either theoretical or empiric grounds, to greatly reduce the burden of drug resistance. 21 Unfortunately, in countries where MDR-TB already occurs, there are more reasons to think that the situation is about to become worse rather than better, at least in the near future. The reasons for this are described in detail in the following discussion. Lack of individualized treatment regimens As noted above, in most countries of the world cultures are not used to confirm an individual diagnosis of tuberculosis, and as a result, drug susceptibility testing results are not available for any given case of tuberculosis. In the context of a DOTS program in a country where MDR-TB cases are rare, this may not have serious consequences. However, in regions where MDR-TB is prevalent, failure to prescribe treatment based on individual drug susceptibility results may not only have dire consequences for individual patients but may also lead to the creation of greater drug resistance. For example, the current regimen recommended by WHO for treatment failures

3 MDR-TB and the global epidemic S73 consists of 2 months of streptomycin, isoniazid, rifampin, pyrazinamide and ethambutol, followed by 1 month of isoniazid, rifampin, pyrazinamide and ethambutol, followed by 5 months of isoniazid, rifampin and ethambutol (2SHRZE/1HRZE/5HRE). This regimen is inadequate for cases of tuberculosis resistant to isoniazid and rifampin, and if used widely in regions where MDR-TB is common could select for increasing drug resistance, as in the face of isoniazid and rifampin resistance the final 5 months of the regimen essentially consists of ethambutol monotherapy. The failure of one such programmatic approach has recently been demonstrated in prisons in Baku, Azerbaijan. 22 Lack of availability of drugs to treat multidrug-resistant tuberculosis At present, treatment of multidrug-resistant tuberculosis in industrialised countries relies heavily on regimens containing injectable agents such as streptomycin, kanamycin, amikacin, and capreomycin with a quinolone such as ciprofloxacin, ofloxacin, or levofloxacin, in addition to two or three additional secondline drugs. Regimens of this type for the treatment of isoniazid- and rifampin-resistant tuberculosis have achieved high rates of success, although treatment must generally be prolonged. However, in poor countries, the cost of these drugs is prohibitive. A survey of drug costs done by WHO and IUATLD indicates that the cost of one month s worth of streptomycin is roughly $ For amikacin the price is $ a month, and for ofloxacin the price ranges between $87.00 and $ a month. (Of interest, cycloserine and PAS are similarly priced.) In poor countries, these costs are staggering. In many of the poor countries of the world, one month s supply of any of the drugs cited above exceeds the entire annual per capita health expenditure. Compounding the lack of available drugs for MDR-TB is the failure of drug development for tuberculosis. No new class of drugs has been specifically developed for the treatment of tuberculosis since the introduction of the rifamycins in the late 1960s and early 1970s. Pharmaceutical companies have apparently not judged tuberculosis drug development to be economically favorable, and there are no new classes of antituberculosis drugs in phase III trials anywhere in the world at present. Developments in basic science in the past few years have lead to a greater understanding of the molecular mechanisms of drug resistance in mycobacteria, and information gained from sequencing the M. tuberculosis genome also points to possible targets for novel antituberculosis compounds Perhaps this knowledge will translate into more targeted and efficient strategies for drug development, although the inescapable fact remains that tuberculosis remains a disease of poverty-stricken societies which have not traditionally been the focus of drug manufacturers attention or largesse. The global AIDS epidemic HIV infection is a powerful accelerant for tuberculosis epidemics, as disease develops and spreads rapidly through communities in which HIV infection is common. As tuberculosis may already be the most common pulmonary complication of AIDS in some areas of the world, 27 so might MDR-TB spread rapidly. In addition it is possible that HIV infection in and of itself might lead to the generation of drug-resistant tuberculosis. Several recent studies have described the relatively unusual phenomenon of rifampin-monoresistant tuberculosis and have noted that this pattern of drug resistance occurs almost exclusively in patients with HIV infection. 3 5,28 Peloquin has demonstrated that patients with HIV infection may have altered absorption of rifampin even in the absence of clinically apparent malabsorption. 29 Interestingly, the majority of patients in the reports of rifampinmonoresistant tuberculosis had neither evidence of clinical malabsorption nor concurrent administration of protease inhibitors. Poorly functioning and poorly funded tuberculosis control programs As noted above, over 80 countries around the world do not follow WHO recommendations for tuberculosis control and/or reporting of tuberculosis statistics to the WHO. It is difficult to imagine that most of these countries have exemplary programs. In some countries, such as Russia, tuberculosis control efforts in recent years can only be described as chaotic. Adoption of DOTS has not been universal, both for reasons of funding and of philosophical objections to the utility of this strategy as a method to reduce cases of tuberculosis. Indeed, there has unfortunately been a recent backlash against DOT as a component of tuberculosis control programs, based on a few studies that did not show an increase in treatment completion with the DOTS approach. 30 However, these studies demonstrate only that poorly functioning DOT programs do not work, in contrast to the large published experience demonstrating the utility of DOT when well-designed programs are employed. 31 In fact, tailored DOT, or DOT which encompasses the treatment of MDR-TB cases (so-called DOTS-plus ), is probably essential to the solution to the global MDR-TB problem. 32 Other approaches to tuberculosis control, such as active case finding, provision of therapy for latent infection, and novel approaches to vaccination (such as vaccination of persons already infected with M. tuberculosis), have theoretical benefit, although it is not clear how they fit into current tuberculosis control programs. In addition to reflecting the stark fact of poverty, to a certain degree the lack of funding of tuberculosis

4 S74 The International Journal of Tuberculosis and Lung Disease control programs globally may also represent a failure of advocacy and leadership in wealthy countries which may be capable of providing more financial support for worldwide tuberculosis control than they now do. In addition, within poor countries it is possible that the small amount of money spent by governments for health-related expenditures (often less than 5% of GNP) could be increased by enlightened leadership. Highly mobile populations Mobility of populations also increases the pressure favoring spread of MDR-TB. As noted above, clones of MDR-TB strains first seen in New York City later appeared in many different parts of the US, 11 and undoubtedly this will occur in other parts of the world as well. Poor people are frequently forced to move to seek economic opportunity, or because of natural disasters. In addition, political instability, regional conflicts, and wars also create mobile populations. These factors make treatment of MDR-TB even more problematic, as it is difficult for persons who are forced to move every few months for any of a variety of reasons to complete 18 to 24 months of therapy. CONCLUSIONS As the above discussion indicates, it is difficult to be optimistic about controlling the spread of multidrugresistant tuberculosis in many countries around the world where this is now a problem. In countries which currently have a low prevalence of MDR-TB, aggressive treatment through widespread use of DOT is probably the best strategy to prevent the emergence of drug resistance. In countries where MDR-TB is already a significant problem, the best approach to the situation might be to adopt the comprehensive measures used with great success in places such as New York City, but this is an obviously unrealistic strategy because of the costs involved. On the other hand, dismissing individuals with MDR-TB as simply untreatable seems both morally indefensible on an individual basis (since the disease is in fact treatable) and counter-productive on a programmatic basis, as failure to provide treatment will lead only to the spread of drug resistance through populations. Physicians engaged in tuberculosis control in both wealthy and poor countries must become strong advocates to obtain the resources needed to address this problem. References 1 Harris H. Chemotherapy of tuberculosis: the beginning. In: Rom W, Garay S, eds. Tuberculosis. Boston: Little, Brown, 1996: Schluger N, Harkin T, Rom W. Principles of therapy of tuberculosis. In: Rom WN, Garay S, eds. Tuberculosis. Boston: Little Brown, Ridzon R, Whitney C G, McKenna M T, et al. Risk factors for rifampin mono-resistant tuberculosis. Am J Respir Crit Care Med 1998; 157: Munsiff S S, Joseph S, Ebrahimzadeh A, Frieden T R. 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