Review: Multidrug‐resistant tuberculosis: public health challenges
2004; Wiley; Volume: 9; Issue: 1 Linguagem: Inglês
10.1046/j.1365-3156.2003.01156.x
ISSN1365-3156
Autores Tópico(s)Parasites and Host Interactions
ResumoThe history of communicable diseases, and in particular tuberculosis, and efforts to control them have long focused policy-makers' attention, provoked media alarm, and caused public anxiety (Rosenkrantz 1994; Rothman 1995; Coker 2000). Communicable disease control experts frequently tread a fine line. They sometimes have to balance the costs and benefits of provoking anxiety amongst the populace when they highlight public health concerns and counterbalance this with encouraging policy-makers to focus attention on issues they feel may demand urgent attention. Over the past decade or so the challenges and uncertainties associated with the spectre of multidrug-resistant tuberculosis (MDRTB) has concerned those charged with protecting public health at the highest national and international policy-making tables. In the early 1990s the World Health Organization (WHO) drew public attention to the inadequacies of global tuberculosis control efforts when it described the situation as an 'emergency'. Also through the 1990s attention started to focus on the challenge posed by strains of tuberculosis resistant to conventional treatment with first-line drugs. In the early 1990s New York City witnessed a substantial and highly publicized epidemic of MDRTB and from 1993 considerable skill, effort and resources were involved in beginning to control it. In 1998, three international organisations, Doctors without Borders (MSF), Medical Emergency Relief International (MERLIN), and the Public Health Research Institute (PHRI) invoked the name of another feared pathogen when they described the spread of multidrug-resistant tuberculosis (MDRTB) in Russia: 'Ebola with wings' (Voelker 1998). This captured an image that was also taken up by the World Health Organization (Coghlan 2001), and subsequently built upon in a 1999 report that highlighted both the global nature of the epidemic and the potential for international spread (Open Society Institute 1999). With approximately 2 million people crossing international borders every day and mass movements of people occurring because of economic woes or conflict transnational movements of diseases, including MDRTB may, it is argued, threaten us all (Brundtland 2000). MDRTB, that is tuberculosis resulting from organisms that are resistant to at least isoniazid and rifampicin, develops through selection pressures. The bacterial population in cavitary pulmonary disease may be between 107 and 109 organisms, and spontaneous mutations leading to drug resistance occur with a frequency of one in 106 to 108 replications depending on the drug (Vareldzis et al. 1994). In any cavitary population there are likely to be, therefore, a few organisms resistant to single anti-tuberculosis drugs. Thus, exposure to one drug only lends a small number of organisms a selective advantage. However, subsequent exposure to a second drug after a period of single drug use will, again, selectively advantage those organisms resistant to the first drug and now also the second drug – hence the development of MDRTB. Acquired drug resistance, i.e. resistance developing in a patient who has received or is receiving treatment, suggests contemporary programme weaknesses. Primary drug resistance occurs when a patient who has previously not received treatment develops disease with an organism that is already resistant, an indication of past programmatic frailties. Recently the traditional terms 'acquired drug resistance' and 'primary drug resistance' have been superseded by the terms 'drug resistance among new cases' as a proxy of primary resistance, and 'drug resistance among previously treated cases' as a proxy of acquired resistance (WHO 2000). The reason for this is that patients may not disclose prior treatment for tuberculosis (which would have led to the term 'primary drug resistance' being erroneously used). Alternatively, patients may fail treatment because their strain was resistant from the start and not because it acquired resistance as a consequence of treatment (which would have led to the term 'acquired drug resistance' being applied inappropriately). The purpose of this paper is to describe some of the public health challenges, many of which are formidable, facing those involved in countering the threat posed by MDRTB. Much of our understanding of the global epidemiology of MDRTB is based upon data collated from surveys and national surveillance programmes that have been analysed by WHO and IUATLD in collaboration (WHO 2000). Whilst the prevalence of MDRTB in most Western European countries is low, in the order of 1% of all cases of tuberculosis, in some countries, notably in Central and Eastern Europe, high levels have been described. The global picture of MDRTB remains somewhat opaque, however, because of the paucity of data on MDRTB from much of the world including much of Europe and Asia. In Russia, for example, data from only two of 89 regions (or oblasts) informed understanding in this global survey (Figure 1). There remain sizeable gaps in our understanding of the distribution of cases globally, detailed systematic determinations of temporal trends remain patchy, and our comprehension of the magnitude of the global burden of disease because of MDRTB is uncertain. These gaps notwithstanding, estimates of the global burden have been made. One estimate based on data from 64 countries was that the annual incidence of MDRTB was 273 000 cases – a fraction of the estimates of the 8 million annual cases of tuberculosis worldwide (Dye et al. 1999). Projections of future incidence using mathematical modelling suggest that current annual incidence rates may climb and that concerted efforts to control MDRTB will be required and make take years if not decades if rates are to decline (Dye et al. 2002). Prevalence of MDRTB among new tuberculosis cases in countries and regions surveyed between 1994 and 1999 (Source: WHO 2000). Challenges to prevention of MDRTB include problems faced in preventing the development of MDRTB in patients with fully drug-sensitive disease and prevention of transmission of established MDRTB disease to others who then go on to develop MDRTB. Fundamentally, MDRTB is a man-made problem and results principally from clinical mismanagement and programme frailties. Factors in the genesis of MDRTB include inadequate initial treatment regimens, adding single drugs to failing regimens, poor treatment adherence and lack of or intermittent supply of standardized short-course chemotherapy. The prevalence of MDRTB increases 10-fold after unsuccessful treatment of new tuberculosis cases (Pablos-Mendez et al. 1998). A central tenet of tuberculosis control is that treatment is prevention (Crofton 1962). MDRTB is best prevented through robust programmes of tuberculosis control that ensure appropriate treatment with first-line drugs with drug supplies that are assured and of high quality (Crofton 1987). Evidence that short-course chemotherapy with first-line drugs as part of a good control strategy effectively prevents the emergence of drug resistance is suggested by data from the Global Project on Anti-tuberculosis Drug Resistance Surveillance (Raviglione 2000; WHO 2000). This survey compared levels of MDRTB in countries with 'better' tuberculosis control achieved by the WHO Directly Observed Treatment, Short-course strategy (DOTS) with results from countries that had 'poorer' control programmes. In countries with 'better' programmes, the acquired MDRTB index (or, more accurately, the MDRTB index in previously treated cases, i.e. the number MDRTB cases in previously treated cases divided by total number of tuberculosis cases) was significantly lower than in those countries with 'poorer' programmes (0.6%vs. 1.8% respectively). For drug resistance among new cases, the picture from this study was slightly more confusing (Raviglione 2000; WHO 2000).The prevalence of MDRTB among new cases was similar in the two groups of countries. But when MDRTB among new cases was correlated with countries' rates of treatment success there was a significant association. That is, countries with high levels of treatment success tended to have low MDRTB rates among new cases. Given that MDRTB among new cases is an indicator of historically weak tuberculosis control programmes, the most likely explanation is that robust tuberculosis programmes prevent, in the short term, acquired drug resistance, but that preventing drug resistance among new cases demands sustained efforts. Moreover, whilst the programmatic approaches to MDRTB usually focus upon outcomes that are individualized and short term (such as cure rates and survival) from a population perspective the critical issue is transmission and which approaches (standardized or individualized second-line regimens, for example) most favourably impact upon transmission dynamics. In some countries, such as the US and Peru, sustained commitment to addressing MDRTB now seems to be resulting in public health benefits. Prevention of spread of MDRTB, particularly in institutions such as prisons, homeless shelters, and hospitals has been well documented and is a particular concern when many highly vulnerable individuals, for example those infected with human immunodeficiency virus (HIV), congregate (Coronado et al. 1993). Prevention of nosocomial spread can be achieved through a combination of interventions including ensuring adequate ventilation, ultraviolet germicidal irradiation, and masks, respirators and filtration devices. The relative contribution of these interventions or combinations of interventions remains somewhat uncertain however. Moreover, in settings such as the former Soviet Union, where MDRTB rates are high (Farmer et al. 1998; Drobniewski et al. 2002a), care is institutionalized in hospitals and prisons (Coker et al. in press), and as an explosive HIV epidemic unfolds, the challenges faced in combating nosocomial spread are both daunting and demand urgent attention (UNAIDS 2002). Why is MDRTB a feared scourge? Clinical responses to treatment of MDRTB with standard first-line drug regimens have been poor (Table 1) (Coninx et al. 1999; Ivanovo Oblast 1999; Espinal et al. 2000; Garcia-Garcia et al. 2000; Drobniewski et al. 2002b). Rates of cure with standard short-course treatment range from 5% to 60% (Ivanovo Oblast 1999; Espinal et al. 2000; Lan et al. 2001). In a study from a prison in Baku, Azerbaijan, for example, treatment was successful in only 27% of patients with MDRTB and treatment failure in all patients was associated factors such as the breadth of the spectrum of drug resistance of isolates, positive sputum microscopy at the end of the initial treatment period, cavitary disease, and poor treatment compliance (Coninx et al. 1999). A multi-site study showed, as did the Baku study, that 'an approximately linear increase in the likelihood of treatment failures was observed as the number of drugs to which the strains were resistant increased' (Espinal et al. 2000). This later study reported a relative risk of treatment failure and death of 15.4 and 3.73, respectively, in patients with MDRTB compared with patients with drug-sensitive strains. Overall, research suggests that treatment with first-line drugs for MDRB offers little benefit to individuals who are suffering from disease from these strains. Indeed, a retrospective review of cases in Vietnam concluded that this approach produces results 'similar to historic outcomes when no chemotherapy for tuberculosis was given' (Lan et al. 2001). With second-line drugs, treatment success in MDRTB varies from 48% to >80% of patients cured (or probably cured) (Park et al. 1998; Kim et al. 2001; Mitnick et al. 2003). Death rates vary from 0% to 37% in studies of HIV-seronegative individuals, and up to 89% in HIV-seropositive populations (Goble et al. 1993; Park et al. 1996, 1998). Higher death rates, not surprisingly, were recorded in those studies with longer follow-up periods, but this also suggests that the effect of MDRTB disease in individuals may not be seen for years – a scenario that is very different from drug-sensitive tuberculosis treated with standard first-line drug regimens. Follow-up duration and survival analyses in many of these studies are relatively short (or unclear), however, and the long-term implications of treatment for individuals and the public health impact of these interventions remain somewhat uncertain. Moreover, many of these studies were conducted using a variety of methodologies and have outcomes (of cure, success, failure) that are defined in different ways making comparisons between studies difficult. Reports on experience in treating MDRTB using second-line drugs in middle-income countries have been, until very recently, few in number, and from low-income countries there have been none (Hadiarto et al. 1996; Suo et al. 1996; Park et al. 1998; Yew et al. 2000; Tahaoglu et al. 2001). More recently, however, successful approaches to treatment using second-line drugs in low-income countries, notably Peru, have been reported (Suarez et al. 2002; Mitnick et al. 2003). Different approaches to treatment were taken in these two studies with markedly different outcomes. The uncertainties that persist in our understanding of the long-term impact of treatment of MDRTB have an important resonance when we contemplate resource allocations (Coker 2002). Moreover, because robustly designed prospectively conducted clinical trials have yet to determine the most effective clinical approaches to management of MDRTB, treatment strategies are still largely dependent upon professional experience and upon drawing inferences from retrospective case series and cohort studies. Several of these reports suggest that poor clinical condition prior to treatment initiation and resistance to a large number of drugs are associated with poor outcomes (Suarez et al. 2002; Mitnick et al. 2003). Furthermore, in those patients in whom sputum sterilization is not achieved, survival may be poor (Goble et al. 1993). Moreover, it appears that more recent treatment strategies that include a quinolone may offer advantages (Yew et al. 2000; Tahaoglu et al. 2001; Mitnick et al. 2003). One of the challenges clinicians face, therefore, is to decide the most effective drug regimen for any given patient. Broadly, two approaches under a rubric of DOTS-plus have been proposed and these are, in essence, dependent upon local laboratory capacity and resources (Farmer et al. 1999). One is based on an assessment of the background prevalence of second-line drug resistance and an assumption that chronic patients are likely to have strains of similar pattern (despite the fact that patterns of second-line resistance are largely unknown in almost all regions of the world) (WHO 1997b). Standardized treatment that includes second line drugs are offered, usually for a period of 18 months to 2 years. The National TB Control Programme of Peru adopted this approach using a regimen consisting of kanamycin, ciprofloxacin, ethionamide, pyrazinamide, and ethambutol (Suarez et al. 2002). Advocates of this approach argue that tailored treatment based upon individual determinations of drug sensitivity patterns is beyond the budget of resource-poor countries, laboratory capacity is insufficient to deliver timely, reliable results, dependence on reference laboratories may introduce clinically important delays, and that standardized treatment is the only feasible alternative if patients are to be treated. Using standardized treatment advances the notion that those failing empiric short-course regimens are presumed to have MDRTB. Those individuals whose treatment fails or who relapse are then offered a re-treatment regimen that includes second-line drugs (Crofton et al. 1996; Suarez et al. 2002; Quy et al. 2003). An extension of this approach is to treat those who have failed a first treatment with second-line drugs, offering them the WHO re-treatment regimen of first-line drugs. Those who fail this re-treatment regimen are then offered standardized treatment with second-line drugs. The reason behind this approach is that relatively few failures of treatment may have MDRTB in some settings, such as where rifampicin is not part of the treatment regimen in the continuation phase (22% in a rural Bangladeshi population, for example) compared with most re-treatment failures (87% in the Bangladesh study) (Crofton & Van Deun 2000). Thus one may be able to estimate the probability of MDRTB in an individual and treat accordingly without incurring costs and delays whilst performing and awaiting drug susceptibility test results. Of concern in advancing this approach is that where rifampicin is used throughout the first treatment, failure correlates much more closely with MDRTB (Becerra et al. 2000). In their study of 160 consecutive treatment failure patients Becerra et al. (2000) showed that 150 (95%) had MDRTB. Clinical management should be informed by the prior use first-line treatment regimens. Few studies have been conducted using standardized treatment approaches for MDRTB, but those that have show outcomes that are worse than for most studies using individualized treatment regimens in expert hands – but better results for individuals than either no treatment or treatment with first-line drugs alone (Suarez et al. 2002). Further research is needed to determine the relative merits of standardized regimens compared with individualized approaches. The alternative strategy, and one more usually adopted in resource-rich settings, is to use individualized treatment regimens based upon an assessment of the likely sensitivity on the basis of previous regimens used and drug-susceptibility testing derived from patient specimens. This approach, whilst costly, offers a reduction in the potential to amplify resistance further, and may be more effective than a standardized approach (Table 1). Regimens therefore vary for each patient depending upon clinical history and sensitivity patterns of isolates. Delays in the determination of sensitivity patterns (usually about 2 months with traditional methods) mean that the initiation of definitive regimens may be delayed (Mitnick et al. 2003). A comparison between standardized and individualized treatment strategies may be inferred from results of research taking these two approaches in Peru (Suarez et al. 2002; Mitnick et al. 2003). In the study taking an individualized approach few failures were observed and, over a median follow-up period of 40 months, 23% patients died. This model relied upon considerable independent financial support for drugs and drug susceptibility testing was conducted by a laboratory in the US. The standardized approach resulted, by comparison, in significantly higher failure rates (32%) but fewer deaths (11%) over a shorter assessment period. Overall then, treatment using an individualized approach that is competently implemented drawing effectively upon the skills of clinicians with experience in managing this demanding and complex disease appears to be the most effective approach. But ensuring standards are maintained, that sufficient human and other resources are available and can be drawn upon in a sustained manner are real challenges. If such an approach cannot be assured, and many international experts fear this is true, then many argue that standardized approaches should be implemented. The question, still unanswered, is then, which standard regimens and under which circumstances? Few drugs with effective anti-mycobacterial properties have been developed in recent decades. Consequently the therapeutic armamentarium to combat MDRTB is largely made up of drugs developed many decades ago – many of which had become almost obsolete because of their relatively poor activity and potent toxicity profiles. Restricting the widespread use of the few newer antimicrobials that do have anti-mycobacterial activity has also been a substantial challenge, and one than has not been met. The widespread use of quinolones in non-tuberculous disease, for example, means that their effectiveness as anti-tuberculosis agents may already be being diminished (Grimaldo et al. 2001; Tahaoglu et al. 2001; Reichman & Tanne 2002). An important, perhaps the most important, determinant of outcome of MDRTB is the presence of HIV co-infection (Park et al. 1996). Clinical outcomes may be very poor in this setting. This fact was highlighted in outbreaks in the early 1990s in the United States which were associated with extremely high mortality rates (72–89%) with rapid progression from disease to death within weeks (median interval from diagnosis to death, 4–16 weeks) (CDC 1991a,b, 1993; Edlin et al. 1992; Fischl et al. 1992; Pearson et al. 1992). In the mid-1990s Turett et al. (1995) showed that if anti-tuberculosis drugs to which the organism was unlikely to be sensitive were used in treating MDRTB associated with advanced HIV disease, then within 2 months mortality rates approaching 100% were likely to result. If, however, a regimen was used that organisms were likely to be sensitive to then survival at 1 year was in the order of 60% (Turett et al. 1995). More recently, Drobniewski et al. (2002b) showed that immunocompromised individuals in the United Kingdom with MDRTB are nine times more likely to die than patients who are not immunocompromised. Other studies support the notion that early institution of appropriate treatment may extend survival even if individuals are HIV positive (Turett et al. 1995; Park et al. 1996, 1998; Drobniewski et al. 2002b). Experience in management at specialized centres appears, in some studies, to confer prognostic benefits in managing patients co-infected with HIV and MDRTB. Another important issue is our limited knowledge of the impact of treatment on MDRTB above and beyond the natural history of tuberculosis outside the bounds of experienced centres (or with their support), in centres where results from treatment may not be so accessible through peer-reviewed publications (for example, Coker 2002). Indeed, when contemplating current efforts in treating MDRTB it is worth reflecting upon comments made by Grzybowski (1983) two decades ago: 'The largely forgotten fact that one-third of patients with advanced disease with positive sputum smears recover on their own, should be kept in mind when claims are made that an inappropriate drug regimen cured a patient with bacterial resistance'. Indeed, there is a remarkable symmetry between some survival curves describing the natural history of tuberculosis in the pre-antibiotic era and a contemporary survival curve associated with MDRTB in a recent analysis from the UK, a country with a tradition of treating MDRTB with individualized treatment regimens (Figure 2) (Stephens 1941; Tattersall 1947; Buhl & Nyboe 1967; National Tuberculosis Institute 1974; Drobniewski et al. 2002b). Most contemporary studies (with some notable exceptions (Park et al. 1996; Kim et al. 2001) describe survival over short periods where benefits are usually marked between, for example, immunocompromised and immunocompetent patients or those treated with 'appropriate' treatment compared with those not (Turett et al. 1995; Park et al. 1996, 1998; Drobniewski et al. 2002b). Survival at 5 years may be in the region of only 50% in the absence of HIV co-infection in some settings, a figure not too dissimilar from that noted in pre-chemotherapy studies (Goble et al. 1993; Drobniewski et al. 2002b). Survival trends in untreated individuals and those treated for MDRTB (sources: Drobniewski et al. 2002b; National Tuberculosis Institute 1974). Choice of appropriate treatment is an important determinant of more favourable outcomes. If patients receive early treatment that the organism proves be sensitive to then treatment is more likely to be successful (Turett et al. 1995; Tahaoglu et al. 2001; Drobniewski et al. 2002b). Hence a number of challenges face those managing MDRTB in the diagnostic arena. The first is whether rapid diagnostics using amplification techniques to determine rifampicin resistance (as a marker for MDRTB) early after presentation are an effective (and cost-effective) clinical tool such that treatment for individuals might be more appropriately tailored using second-line drugs and outcomes potentially improved. A further important challenge is to answer the question whether such an approach, in public health terms, will impact upon efforts to control the public health threat that is MDRTB by reducing the potential for transmission by shortening the time to initiation of appropriate treatment and duration of infectiousness. Rapid determination of drug resistance profiles of isolates causing disease would be a useful step in enabling clinicians to tailor treatment appropriately earlier in the disease course and potentially reduce morbidity, mortality, and duration of infectiousness and thereby reduce public health threat. Greater access to drug susceptibility testing, particularly in the developing world, might also facilitate epidemiological surveillance of drug resistance. Conventional methods for determining susceptibility such as the proportion method and the absolute concentration method are based on the measurement of growth in culture media containing antibiotics (Canetti et al. 1969; Kent et al. 1985). Whilst relatively inexpensive and undemanding of sophisticated equipment, results usually take weeks and this is problematic, particularly where inappropriate choice of treatment regimen may result in death within weeks of initiation and before results arrive at the bedside. Whilst the introduction of the BACTEC® radiometric system, and its modification for drug susceptibility testing (BACTEC® TB-460), has been a significant advance (Roberts et al. 1983), this expensive technology remains beyond the reach of most tuberculosis control programmes and is hindered by the need to dispose of large volumes of radioactive materials (Heifets & Cangelosi 1999). Moreover, whilst turnaround time is significantly better than conventional methods, it may still be in the order of 3 weeks (Roberts et al. 1983). Considerable research efforts have gone into the development of novel rapid drug susceptibility tests, yet many of these remain, at present, restricted to developed countries or reference laboratories because of their expense and sophistication (Palomino 2000). Moreover, the application of these approaches to support individualized treatment through determination of second-line drug susceptibility profiles remains largely unexplored implying that their application in support of individualized treatment of MDRTB remains uncertain. Novel approaches broadly fall into two groups, genotypic methods and phenotypic methods. Genotypic techniques (including automated DNA sequencing (Pai et al. 1997), polymerase chain reaction (PCR)-single strand conformation polymorphism (Pretorius et al. 1996), PCR-heteroduplex formation (Wiliams et al. 1998) have resulted from recent insights into the molecular basis of drug resistance and the application of new molecular biology tools. All demand DNA extraction, gene amplification, and detection of mutation (for example in the rpoB gene for rifampicin resistance) and therefore are relatively expensive and sophisticated, demanding resources and skills that are usually unavailable in most regions where rates of MDRTB are high. A further limitation of these approaches at present is that not all molecular mechanisms of drug resistance are known. Their potential advantage is that there is no need for growth of the organism and drug susceptibility results can be determined in days rather than weeks. Moreover, research suggests that they can be highly reliable (Palomino 2000). Perhaps the most encouraging development is the adoption of phage technology to rapidly detect drug-resistance profiles (McNerney et al. 2000; Albert et al. 2002). Several tools have been developed and the high correlation with standard approaches suggests that they may be useful in facilitating the rapid initiation of appropriate management of patients with MDRTB (Takiff & Heiferts 2002). Novel rapid phenotypic methods to determine drug susceptibility harness technologies that can detect metabolic activity or early visualization of microcolonies. The most advanced and well validated of these is the Mycobacteria Growth Indicator Tube (MGIT) which detects oxygen consumption in the presence or absence of drug (Reisner et al. 1995). As with genotypic approaches, detection of drug resistance can be accomplished in days rather than weeks but is again constrained by cost. Alternative approaches that might lend themselves to laboratories in developing countries because of their relatively low cost are microcolony detection but further evaluation of these approaches are needed (Schaberg et al. 1995; Mejia et al. 1999). Despite substantial advances in rapid diagnostics and susceptibility testing in recent years significant challenges persist. Perhaps the most critical of these is cost. Most novel rapid diagnostic approaches developed require expensive equipment and highly trained personnel. Others that might lend themselves to resource-poor settings will require careful evaluation and field testing to ensure acceptable levels of sensitivity, specificity and reproducibility. Finally, and of greatest relevance if individualized second-line regimens are to become widely used, rapid determination of susceptibility patterns to second-line drugs remains a substantial challenge. Whilst high laboratory sensitivity and specificity measures for isoniazid and rifampicin resistance support surveillance, only in recent years has the sensitivity for ethambutol improved to above 90% through the Global Network of Supranational Reference Laboratories (WHO 2000). Moreover, for pyrazinamide, drug susceptibility results remain less reliable (Zhang e
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