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Tuberculosis (2007) 87, S5–S9
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REVIEW
MDR-TB—Its characteristics and control in Asia-Pacificrim symposium in USJCMSP 10th internationalconference on emerging infectious diseases in thePacific rim
Toru Mori
Leprosy Research Center, National Institute of Infectious Diseases, 4-2-1, Aobacho, Higashimurayama-shi, Tokyo 189-0002,Japan
KEYWORDSTuberculosis;Drug resistance;MDR;DOTS-Plus
nt matter & 2007007.05.007
SummaryThe strategy of directly observed treatment, short course (DOTS) is achieving substantialprogress in coverage and quality improvements worldwide. However, the problem of multi-drug-resistant tuberculosis (MDR-TB) has emerged as a new challenge to TB control in bothdeveloping and industrialized countries. The effort of various countries of the Pacific Rimto fight this problem, one of the negative progenies from the 20th century, was a majortheme of the conference. Asia, WHO’s Southwest Asia and Western Pacific Regions,combined, account globally for almost 60% of the newly occurring MDR-TB cases. However,the problem has likely been overlooked, as it was masked by taking averages for countriesor wider regions. In this way, we may have lost sight of ‘‘hot zones’’ with extremely highprevalence of MDR-TB in smaller areas or in population segments. The problem wasbasically a result of the low-quality treatment program, but recently it may be amplified insome areas by the HIV epidemic that is another new challenge to TB strategies. So far,developing countries have not been taking active measures to manage this problem.However, some countries, such as the Philippines and Peru, have undertaken aggressiveefforts, supported technically and financially by the new international mechanisms, suchas the Stop TB Partnership and the Global Fund to fight AIDS, TB and Malaria. These effortswould be more effective if there were further technical innovation in diagnosis andtreatment, supported by a strong political commitment.& 2007 Published by Elsevier Ltd.
Published by Elsevier Ltd.
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Contents
Addendum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S8References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S8
The challenge of multi-drug-resistant tuberculosis (MDR-TB)emerged in the mid-1990s from two corners of the world.After the initial successful achievement of DOTS in severaldeveloping countries, the staffs of National TuberculosisPrograms (NTP) encountered the problem of failure, andchronic cases that they had neglected so far on the groundsof priority of treatment. The Philippines and Peru presenttypical models of the earliest challenges to this issue asshown in this conference. Another thrust came from adifferent side—the United States and some eastern Eur-opean countries. During the late 1980s through the early1990s, the USA experienced a resurgence of TB complicatedwith HIV-co-infection and drug resistance. Almost simulta-neously, TB flared up in many countries in the formersocialist bloc, accompanied by a formidable type of disease,MDR-TB. Confronting these thrusts from both sides, theWorld Health Organization (WHO) established the WorkingGroup on DOTS-Plus for MDR-TB in 1999 (www.stoptb.org/wg/dots_plus/) in order to make its commitment to theproblem of MDR clearer.
MDR-TB had been recognized as a serious issue for a longtime. However, it had been given low priority in developingcountries for two reasons: technical difficulties and funding.For these reasons, it was a very relevant first step forwardfor WHO and the International Union against Tuberculosisand Lung Disease in 1994 to set up the global network ofdrug resistance surveillance with a system of supranationalreference laboratories as a mechanism to address thetechnical aspect of the approach to this issue.1 From thattime onward, the problem of MDR has gradually come to beknown in its extent and severity. Another issue, the fundingfor treatment, has become a target of the DOTS-Plusstrategy of the Green Light Committee (GLC) that supportscountries’ efforts to combat the problem by more system-atically providing a drug supply and technology based onfunding.
The Asia-Pacific countries’ picture of this problem reflectsthe global situation, and their efforts to cope with it havebeen good illustrations for the global fight as presented atthe conference by the four speakers detailed below. Dr. S.W.Jiang gave an overview of the problem in Asia, includingCentral and Middle-east Asia.2 Asia shares 63% of the globalburden of TB with levels of prevalence of all forms of TB, aswell as MDR-TB, varying from one country to another acrossthe regions. The prevalence of MDR-TB is 1.1% (median)among new cases and 7.0% (median) among previouslytreated cases worldwide, based on the reports during theperiod 1997–2002. The figures for the Western Pacific Region(WPR) were 0.9% and 15.5%, and for the South-east AsianRegion (SEAR) 1.3% and 20.4%.3 According to an estimatecovering areas without reports but based on the multipleregression model,4 the picture is generally more serious; theglobal prevalence of MDR among new cases is 3.2%, that forWPR 4.5% and that for SEAR 2.5%. Asia’s share is estimatedto be 59% of the global total (273,000).5 Moreover, as
pointed out by Dr. Jiang, the problem is likely to be maskedby the average. In Asia there are areas with anextraordinarily high prevalence of MDR, such as 14.2%in Kazakhstan and Israel, 13.2% in Karakalpakstan(Uzbekistan), 10.4% in Liaoning Province (China), and 7.8%in Henan Province (China). At the same time, thereare countries and settings enjoying a favorably lowprevalence of MDR-TB in spite of the high incidence rateof TB, e.g., Cambodia (0.0%), Mongolia (1.0%) and Thailand(1.0%).
The basic cause of the high prevalence of MDR-TB in those‘‘hot zones’’, as described for the case of China by Dr. Jiang,is the slow expansion of DOTS that allowed a poor quality ofchemotherapy leading to drug resistance that in turn wasamplified to MDR-TB and then transmitted within thepopulation. To be more theoretical, other factors can alsopotentially produce ‘‘hot zones,’’ such as the low prevalenceof sensitive organisms, the ‘‘fitness’’ of the MDR strains incomparison with pan-sensitive ones, and the amplificationprobability from mono-resistance to MDR, all reciprocallyand delicately balanced.6
Some of the factors influencing this balance are the HIVepidemics of the community as discussed by Dr. Cegielski.7
He started the discussion from the nosocomial outbreaks ofMDR TB concomitant with the widespread HIV infectionsamong victims in the USA during 1980–1990, with thesuspicion that those two were in epidemiological associa-tion.8 No clear association in the general population hasbeen observed, as in several developing countries in SouthAfrica.9 There is, however, a report from an HIV epidemicarea of Thailand showing a positive association betweenan HIV infection and MDR-TB. In this case, the authorssuggested the possibility of nosocomial infection of TBin a big hospital where many of the HIV-infected personshad been admitted. Thus, there seems to be no straightfor-ward relationship between HIV and MDR-TB in their inter-actions determined by the level of epidemics of MDR-TB.However, there are several interactions between these two,such as is seen in the acquisition of resistance withrifapentine treatment in HIV-infected TB patients,10 drug–
drug interactions between the medications for the twodiseases, and a problem of malabsorption possibly leading toa lower blood concentration of anti-TB drugs. The coopera-tion between TB control and HIV programs should bestrengthened in order to keep the balance of related TB/HIV factors in a direction favorable to the control of co-morbidity.
The HIV epidemic of Asia is still at a moderate levelcompared with that of the African region.11 The 2003estimate of the prevalence rate of HIV for adults (15–49years) is 0.1% in WPR and 0.7% in SEAR, and 7.6% in AFR.However, with its large population, the absolute number ofinfected persons is considerable, and there are distinctepicenters scattered across Asia having extraordinarily highrates. With its high level of TB endemicity, the combination
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MDR-TB—Its characteristics and control in Asia-Pacific rim S7
of these two infections can be a time bomb in this regionunless they are addressed properly now, as Dr. Cegielski haswarned.
Another important insight was presented by Dr. Ho MinhLy12 from Vietnam, one of the countries with successfulDOTS implementation that had already achieved the globaltarget of the DOTS strategy by 1997. She introduced a seriesof molecular epidemiological studies of TB in Vietnam,focusing on the potential relationship with MDR-TB. TheIS6110 fingerprinting of Mycobacterium tuberculosis strainsisolated from Vietnamese TB patients demonstrated that53–55% of these strains were of the Beijing type having 413copies. The MDR strains had high heterogeneity, 72–84%. Itwas found that the Beijing genotype was strongly associatedwith younger age (not significant) and resistance tostreptomycin or isoniazid (significant).13 Also, the Beijinggenotype of Vietnam TB was shown to be a significant riskfactor for treatment failure and relapse with an odds ratioof 2.8.14 Moreover, the Beijing genotype’s associations withdrug resistance were assessed by summarizing data on429,000 patients from 49 studies in 35 countries.15 It wasconfirmed that the Beijing genotype was frequently asso-ciated with drug resistance. This reminds us that an MDR-TBoutbreak in the USA caused by the W strain was a part of theemergence of this family.8 A similar conclusion was alsodrawn from a systematic review of the global literature onthe Beijing strains.16
Dr. Ly also cited a recent multicenter study on MDR strains(2002–2003)17 collected from African countries, Russia andVietnam. It was found that 52% of the MDR strains fromRussia and 53% of the strains from Vietnam were Beijingstrains which were rare in African countries. The highestpercentage of clustered MDR strains was obtained in Africancountries reflecting the potential cross-border circulation ofMDR strains, and it was lowest in Vietnam (31%).
Among six WHO regions, WPR was the first to surpass theglobal target of the DOTS strategy, i.e. to detect and treatwith DOTS 470% of sputum smear positive patients and cure485% of them.18 However, so far, not many countries of theregion have embarked on the aggressive fight against MDR-TB. This conference heard presentations from countries thathad pioneered DOTS-Plus in NTP in the Asia-Pacific region,sharing common principles adapted to the local conditions.
Peru experienced a dramatic expansion of the DOTS strategyin the mid-1990s that led to the demonstrable decline ofobserved trends of the notification rate.19 As presented by Dr.Bayona,20 after the early successes in DOTS by 1995, theproblem of MDR emerged in northern Lima. In 1996, Socios EnSalud and NTP started the individualized treatment regimen atthe Health District of Comas with the support from theinternational community in laboratory technology, drug supply,and patient support through a data recording system. In October1997, based on the international recommendations WHO/TB/96.210, NTP initiated a National Standardized TreatmentRegimen (3 months kanamycin–ciprofloxacin–ethionamide–pyr-azinamide–ethambutol/15 months ciprofloxacin–ethionami-de–ethambutol–pyrazinamide). In April 1998, participants at aHarvard University meeting resolved to initiate a DOTS-Plusstrategy for treatment of MDR-TB in resource-poor settings21;and Peru was selected as a project area supported byWHO. Later, in 1999, when the WHO Working Group on DOTS-Plus for MDR-TB was established, a PIH/PIDC (Partners in
Health/Program of Infectious Disease and Social Change)project, supported by NTP and WHO/PAHO, embarked on theindividualized treatment regimen program for MDR-TB failuresto replace the standardized regimen. Having started from 10cases enrolled in 1996 with the help of 10 community healthpromoters, the scale of DOTS-Plus in Peru gradually and steadilyincreased until 2005 when the number of enrolled cases reached3491 patients under the support of 700 promoters.
Comprehensive support for the DOTS-Plus was extendedfrom the MDR-TB Working Group of the WHO/Stop TBPartnership and GLC. Treatment with full patient supportthroughout was ascertained initially by private donors, laterby the Bill & Melinda Gates Foundation, and currently byGFATM. From 2006, the government of Peru will also sharethe costs with GFATM. The management of drugs andsupplies was supported by IDA. Technically, the NationalInstitute of Health reference laboratory is now capable ofperforming drug sensitivity testing for first- and second-linedrugs, and a study is currently underway to develop rapidmethods for MDR-TB diagnosis.22 For patient data handlingin DOTS-Plus, a computer network system is utilized in orderto improve the quality of information. To summarize, thefeasibility and usefulness of DOTS-Plus, studies23,24 haveshown repeatedly that the DOTS-Plus of Peru was clearlycost-effective, saving US$211 per DALY.
Another remarkable and unique model of DOTS-Plusimplementation can be seen in the presentation of Dr.Quelapio25 from the Philippines, a country that has achievedexcellent progress in DOTS expansion during the last 10years.
MDR-TB is prevalent in countries with poor NTP in thepast. The national TB prevalence survey in 1997 found thatMDR-TB was 1.4% in new cases and 14.5% in previouslytreated cases (the number of patients estimated as26,330).26 The first nationwide drug resistance survey(DRS) conducted by the Department of Health, WHO andJICA in 2004 reveals a higher MDR-TB rate, although resultsare still preliminary. In a large urban area in one province inthe Philippines,27 MDR-TB among new cases was 3.9%.
The DOTS-Plus program was started in 1999 by theTropical Disease Foundation through the Makati MedicalCenter (MMC) DOTS Clinic,28 a privately initiated Private–
Public Mix DOTS (PPMD) unit which evolved into a DOTS-Pluspilot project, The MMC is one of the largest private medicalcenters of the country. The project was approved in 2000 bythe Green Light Committee which continues to supervise it.In 2003, the project received a grant from the Global Fundto Fight AIDS, TB & Malaria (round 2). The DOTS-Plus projecthas expanded covering both public and private institutionsfostering partnerships since December 2003. As of Septem-ber 2005, a total of 433 MDR-TB patients have beenenrolled. Among 151 patients with outcomes, treatmentsuccess was 60%, default 15%, death 15%, and failure 10%.The 151 cases were pre-Global Fund patients availing ofhighly centralized MDR-TB services with no provision fortransportation allowance nor drugs to counter adverseeffects of second-line drugs.
The most characteristic point of DOTS-Plus in thePhilippines is that while it started in the private sector, itis now being integrated into the government’s national TBProgram. DOTS-Plus is also starting to involve other PPMDunits. PPMD is a nationwide movement led by the Philippine
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Coalition against TB (PhilCAT) in close collaboration with theNTP of the Department of Health, which was established 12years ago and now covers the whole country.29 This programhelped the NTP attain a 73% DOTS detection rate by 2004with an 88% treatment success rate for 2003 cohort.2,18
While still facing many challenges such as an insufficientpublic health infrastructure to match the demands of thecomplex MDR-TB management, including human resourcesand laboratory capacity, DOTS-Plus mainstreamed into theNTP will make it a routine component of DOTS, as stressed inthe International Standards for Tuberculosis Care.30
The experiences of two countries tell us that such publichealth efforts would be even further supported by bettertechnologies, particularly chemotherapy and laboratorytechnology. Dr. Xiao31 analyzed the treatment outcomes ofthe relapse or failure cases of the initial treatment inShanghai, China, seeking the possibilities of better ther-apeutic strategies of re-treatment. He reviewed treatmentoutcomes and drug sensitivity test results of 283 patientswho were treated for the first time after relapse or failure intheir initial treatment. The frequency of any drug resistanceas well as MDR was higher in patients who had beenpreviously treated with a standard regimen compared tothose treated with non-standard regimens. At the sametime, it was found that patients who had been treated forlonger than 12 months had a higher rate of resistance thanthose with a shorter treatment history. These findingssuggest that the current standardized re-treatment regi-mens, assuming the standard and short-term treatmenthistory, are often ineffective in the actual settings and mayamplify drug resistance.32 Therefore, the choice of the re-treatment regimen should be more flexible.33
In addition to the innovations in chemotherapy, thedevelopment of laboratory technologies for drug sensitivitytesting and the detection of M. tuberculosis in smear-negative patients that are simple and feasible enough foruse in developing countries are badly needed now. Opera-tional research by field staff will also be important to guideand sharpen the actual needs of R&D by the academe, aswas repeatedly pointed out in this conference.
In the Strategic Plan to Stop TB in the Western Pacific2006–2010, the issues of MDR-TB and TB/HIV are explicitlyaddressed18:
�
at least 90% of identified MDR-TB patients are to beprovided with second-line anti-TB drugs and � at least 90% of identified TB patients with HIV, who areeligible for antiretroviral treatment, are to be providedwith antiretroviral treatment.
Countries of the Asia-Pacific rim should share this strategyfor the control of MDR-TB and TB/HIV. Finally, it should bereiterated that the efforts toward this direction will beeffective only with clear political will and commitmentsupported by the funding.
Addendum
Recently the problem of extensively drug-resistant tubercu-losis (XDR-TB) has emerged as a serious threat to tubercu-losis control.34 XDR-TB is defined as a case of tuberculosis
resistant to isoniazid and rifampin and resistant to anyfluoroquinolone and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin).35
XDR-TB does not represent a major new discovery, but it hasan important significance as a new recognition of and anaggressive commitment to a serious negative progeny of thetuberculosis treatment in the past. The problem has notbeen recognized precisely in Asia except in Korea (15% ofMDR cases)) and in Japan (31%).36 However, we should not beoptimistic about this issue, based on the situation of MDR. Inspite of the massive efforts to treat MDR such as in the caseof Latvia,37 the prognosis seems to be poor. Current effortsseeking new anti-TB drugs and their combination regimenstogether with better drug susceptibility testing, includingthat for second line drugs should be continued in order torespond to this problem effectively.
Funding: None
Competing interest: None declared
Ethical approval: None
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