Review: Multidrug‐resistant tuberculosis: public health challenges (2004)

The 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 and short term as rates and from a population the is transmission and which approaches or regimens, for most upon transmission In some countries, as the and sustained to MDRTB now to be resulting in public health of spread of MDRTB, in as and has been and is a particular when many highly for those with et al. of spread be achieved through a of including and and The of or of remains somewhat Moreover, in as the MDRTB rates are high et al. et al. is in and et al. in and as an epidemic the challenges faced in spread are both and demand urgent attention 2002). is MDRTB a feared to treatment of MDRTB with first-line drug have been poor et al. et al. 2000; et al. 2000; et al. of with short-course treatment from to et al. 2000; et al. In a study from a in for example, treatment was in only of patients with MDRTB and treatment in all patients was associated as the of the of drug resistance of at the of the initial treatment cavitary and poor treatment et al. 1999). A study as the that approximately in the of treatment was as the number of drugs to which the strains were resistant et al. 2000). This study a of treatment and of and in patients with MDRTB compared with patients with drug-sensitive suggests that treatment with first-line drugs for to who are from disease from a of cases in that this results to outcomes when chemotherapy for tuberculosis was et al. With treatment success in MDRTB from to of patients (or et al. et al. et al. rates from to in of and up to in et al. et al. 1998). not were in those with but this also suggests that the of MDRTB disease in may not be for years – a that is from drug-sensitive tuberculosis treated with first-line drug and in many of are short (or however, and the of treatment for and the public health of remain somewhat uncertain. Moreover, many of were using a of and have outcomes that are in between on in MDRTB using drugs in countries have few in and from countries there have been et al. et al. et al. et al. 2000; et al. however, approaches to treatment using drugs in countries, notably have been et al. et al. approaches to treatment were taken in two with The uncertainties that in our understanding of the of treatment of MDRTB have an when 2002). Moreover, because clinical have to the most clinical approaches to of MDRTB, treatment are upon and upon from and of suggest that poor clinical prior to treatment and resistance to a number of drugs are associated with poor outcomes et al. et al. in those patients in is not may be poor et al. Moreover, it that more treatment that include a may et al. 2000; et al. et al. One of the challenges therefore, is to the most drug for any two approaches a of have been and in upon and resources et al. 1999). One is based on an of the prevalence of drug resistance and an that patients are likely to have strains of similar the that of resistance are in all regions of the (WHO treatment that second drugs are usually for a period of to 2 The of this using a of and et al. 2002). of this that treatment based upon determinations of drug is the of countries, is to on may and that standardized treatment is the only if patients are to be standardized treatment the that those failing short-course are to have MDRTB. treatment or who are then a that drugs (Crofton et al. et al. et al. of this is to those who have a first treatment with them the WHO of first-line drugs. who fail this are then standardized treatment with drugs. The reason this is that few of treatment may have MDRTB in some as is not part of the treatment in the in a for compared with most in the (Crofton 2000). one may be to estimate the of MDRTB in an and without costs and whilst and drug in this is that is the first treatment, much more with MDRTB et al. 2000). In their study of treatment patients et al. that had MDRTB. be informed by the prior use first-line treatment have been using standardized treatment approaches for MDRTB, but those that have outcomes that are than for most using treatment in – but results for than treatment or treatment with first-line drugs et al. 2002). is to the of standardized compared with The and one more usually in is to use treatment based upon an of the likely on the of and from patient This whilst a in the potential to resistance and may be more than a standardized 1). for patient depending upon clinical history and of in the of 2 with traditional that the of may be et al. A between standardized and treatment may be from results of two approaches in et al. et al. In the study an few were a period of patients This upon considerable for drugs and drug was by a in the The standardized by in significantly rates but a treatment using an that is effectively upon the of with in this and disease to be the most But are that and resources are and be upon in a sustained are an be and many international experts this is then many that standardized approaches be The is which and which drugs with have been in the to MDRTB is up of drugs many decades – many of which had because of their poor and the use of the few that have has also been a substantial and one than has not been The use of in for example, that their as anti-tuberculosis may already be being et al. et al. 2002). the most of of MDRTB is the of et al. outcomes may be poor in this This was highlighted in in the early 1990s in the which were associated with high rates with from disease to from to et al. et al. et al. In the et al. that if anti-tuberculosis drugs to which the organism was to be were in MDRTB associated with then 2 rates were likely to however, a was that organisms were likely to be to then at was in the order of et al. et al. that in the with MDRTB are more likely to than patients who are not the that early of appropriate treatment may if are et al. 1995; et al. et al. in at in some to benefits in patients with and MDRTB. is our of the of treatment on MDRTB and the history of tuberculosis the of (or with their in results from treatment may not be so through example, Coker 2002). when current efforts in MDRTB it is upon by two decades that of patients with disease with on their be in when are that an drug a patient with bacterial there is a between some the history of tuberculosis in the and a contemporary associated with MDRTB in a from the a with a of MDRTB with treatment (Figure Institute et al. contemporary some et al. et al. describe short benefits are usually for example, and patients or those treated with treatment compared with those not et al. 1995; et al. et al. at years may be in the of only in the of in some a not from that in et al. et al. trends in and those treated for MDRTB et al. Institute of appropriate treatment is an of more patients early treatment that the organism be to then treatment is more likely to be et al. 1995; et al. et al. a number of challenges those MDRTB in the The first is using to resistance a for early after are an clinical that treatment for be more using drugs and outcomes A challenge is to the an in public health will upon efforts to control the public health threat that is MDRTB by the potential for transmission by the to of appropriate treatment and of of drug resistance of disease would be a in to treatment in the disease and and of and public health to drug in the developing also surveillance of drug for as the and the are based on the of in media et al. et al. Whilst and of results usually take and this is of treatment may in of and results at the Whilst the of the and for drug has been a significant et al. this remains the of most tuberculosis control programmes and is by the to of of 1999). Moreover, whilst is significantly than conventional it may be in the order of et al. efforts have the development of drug many of at to countries or because of their and 2000). Moreover, the of approaches to treatment through of drug remains that their in of treatment of MDRTB remains uncertain. approaches two and et al. et al. et al. have from the of drug resistance and the of new demand and of in the for and are and resources and that are usually in most regions rates of MDRTB are A of approaches at is that not all of drug resistance are potential advantage is that there is for of the organism and drug results be in than Moreover, suggests that they be highly 2000). the most encouraging development is the of to et al. 2000; et al. 2002). have been and the high with approaches suggests that they may be in the of appropriate of patients with MDRTB 2002). to drug that or early of The most and of is the which in the or of drug et al. with of drug resistance be in than but is by approaches that to in developing countries because of their low are but of approaches are et al. 1995; et al. 1999). substantial in and in years significant challenges the most of is approaches and highly that to will and to ensure levels of and and of if are to of to drugs remains a substantial Whilst high and for isoniazid and resistance only in years has the for to through the Global of (WHO 2000). Moreover, for drug results remain et al. 2002). For an understanding of clinical through an understanding of or and quality are in their not in international programmes. experts have that treatment of MDRTB in countries be an use of resources (Crofton et al. et al. 2002). of MDRTB is more than drug-sensitive et al. has suggested that the global burden MDRTB may as much as all the drug-sensitive cases. there has been much countries, much of the burden of MDRTB to cases et al. Coker et al. the to the epidemic of MDRTB in New York was up as an of the potential costs that be to MDRTB in some of the to tuberculosis control efforts in the early 1990s in that have that many have the of MDRTB the resources of lower whilst at the the success of this programme a of the et al. The that this was on an of issues including a of New control programme is et al. In more estimates of the of a patient with MDRTB are in the of the of drug-sensitive disease 2000). In of the for in and for drugs that treatment costs which include drugs may be a of a treatment programme in of patients with MDRTB by that cases be effectively treated a standardized treatment for as as approximately a of – a not from the World has suggested be as an in countries et al. 2002). This study also that an be in some However, as with rates of remain the of a standardized treatment which drugs. Moreover, it may not be a to the and and in this and be is an to be from One in the of treatment to MDRTB has been the of the This has been charged with lower for drugs to MDRTB and to drugs at for programmes that are to to control have been achieved for a of drugs and the past of years costs for an of treatment have from approximately from to et al. Whilst the has been a to and ensure drug quality for programmes to the of drugs in some countries that be but quality may not be Moreover, it be that the success of for MDRTB treatment programmes has some as those in the to by MDRTB treatment programmes not after developing robust programmes as by but by upon already programmes in a In regions the is a a that is sometimes and the of drug costs is only a small part of the costs in MDRTB treatment programmes. which may be for example, in regions of the world and are informed by clinical and health approaches to for the as much as the epidemiology of MDRTB. In New York and for example, costs for are considerable et al. 1995; 2000). In Russia, costs are much the of for is more and may benefits as as costs in MDRTB 2000). Moreover, whilst the costs of MDRTB to the of cases, rates are high as in the there may be because that a programme of control be In rates are but likely to be as in then the magnitude of the problem has the potential to This problem likely to be when both rates and are likely to be as in to and the of resources to MDRTB is an understanding of the transmission of MDRTB. of MDRTB are if treatment are not may to resources to and public health that on their (Dye et al. 2002). The and which are are 2002). One of the most significant challenges facing those to MDRTB is understanding more the of resistant strains of tuberculosis compared with drug-sensitive strains and using understanding to control more that MDRTB strains are as or more from a of of MDRTB, in some to than drug-sensitive strains et al. 2000; et al. 2002). to in some suggested a to for strains et al. 1999). In this isoniazid resistant strains were likely to that some strains are likely to cases. including however, suggested rates with MDRTB et al. et al. 1994; et al. et al. et al. The one that remains is strains are as to as In in the and suggested that strains resistant to isoniazid and were and than strains et al. et al. In this by that some strains and some strains have also been to et al. the that resistant strains be is the of and that resistance, at least to some strains with mutations and isoniazid resistance, may not et al. et al. 1999). in from or of the or in in of resistant strains remain to be some for which is frequently associated with drug resistance and and may be an from a selective advantage is a that et al. The challenges posed by MDRTB are They start with considerable the magnitude of the and the potential of another that of in of the world high prevalence rates of MDRTB. and most is the situation in some of the with and many countries of the have health and that have or are and are to to new With borders with the of the European international borders with and of mass it that of the remain focused on efforts to MDRTB if not for then of this be focused remains The of the some would that programmes be upon the to This that the upon which programmes may may not be as robust as some the that to demands now than the is more that if the approaches that have not been to robust from a public health then programmes may in the of this challenge is considerable the transmission of MDRTB strains and the of the and upon has on the and of the strategy in regions with prevalence rates of MDRTB. is that robust programmes will the emergence of strains if rates of MDRTB are The is be MDRTB is already 1998). have that MDRTB strains may be and with a robust programme strains of MDRTB would because of rates and transmission without focused attention on MDRTB (Dye et al. 2002). the of an with MDRTB, however, programmes that to a strategy using first-line drugs to the history of tuberculosis in the et al. et al. et al. there may be a in single drug resistance is that use of may selection that the emergence of MDRTB – the et al. 1998). One challenge is, therefore, to the of in a of to ensure control of and the emergence of MDRTB whilst those that have MDRTB effectively in order to ensure their and the public from transmission of of challenge MDRTB Evidence in of is a challenge that will as the of MDRTB and in of the highly drugs for tuberculosis remain whilst the potential benefits by some drugs with as the are because more in more in the and because of use in the developing world 2002). challenges not in this paper include the and of patients who decline treatment or are but threaten public health treatment for some with MDRTB remains patients a disease that disease in the of cases remain and be to with The which to the epidemic of MDRTB in some countries, be to ensure in are not to 1999). Whilst transmission of MDRTB is most an consequence of the threat of spread in the remains a for tuberculosis are the as in the more the challenge of MDRTB challenges associated with and A challenge for public health will be to that effectively to the challenge of MDRTB. that the and which make up the of programmes charged with MDRTB are so that be and applied in a and appropriate et al. in The public health challenges by the spectre of MDRTB are They from the to the from the economic to the and from the to the In facing challenges and on the that tuberculosis is of our 1998). That MDRTB, a man-made only to the of to the who on an of this paper and