The rationale for recommending fixed-dose …

1 The rationale for recommending fixed-dosecombination tablets for treatment of tuberculosisBj rn Blomberg,1 Sergio Spinaci,2 Bernard Fourie,3& Richard Laing4 There is considerable exigency to take all necessary steps to cure tuberculosis cases and prevent further emergenceof drug-resistant tuberculosis . The most important of these steps is to ensure that the treatment, particularly ofsputum smear-positive cases, is adequate and that patients adhere to their treatment by supervised, directobservation of drug-taking according to the standardized of fixed-dose combinations (FDCs) of tablets against tuberculosis is now being recommended by WHOand the International Union Against tuberculosis and Lung Disease (IUATLD) as an additional step to ensuringproper treatment.

2 FDCs simplify the prescription of drugs and the management of drug supply, and may also limitthe risk of drug-resistant tuberculosis arising as a result of inappropriate drug selection and FDCs of proven quality and proven rifampicin bioavailability should be purchased and used. In mostsituations, blood levels of the drugs are inadequate because of poor drug quality rather than poor absorption. This istrue irrespective of the human immunodeficiency virus (HIV) infection status of the tuberculosis patients (other thanthose with overt acquired immunodeficiency syndrome, with CD4 counts <200 cells/mm3). Currently, WHO,IUATLD and their partners are developing strategies for ensuring that only quality FDCs are used in tuberculosisprogrammes.

3 A simplified and effective protocol for assessment of rifampicin bioavailability has been developed,and laboratories are being recruited to form a supranational network for quality assurance of FDCs. Standardizationof FDC drug formulations has been proposed, which limits rifampicin-containing preparations to nine (including afour-drug FDC and three paediatric FDCs).Keywords: tuberculosis , pulmonary, drug therapy; tuberculosis , multidrug-resistant, drug therapy; drug therapy,combination; drug resistance; antitubercular agents, administration and dosage; antitubercular agents, standards;rifampin, cle s:tuberculose pulmonaire, chimiothe rapie; tuberculose re sistante a` la polychimiothe rapie,chimiothe rapie; polychimiothe rapie; re sistance aux me dicaments; antituberculeux, administration et posologie;antituberculeux, normes; rifampicine, pharmacocine clave: tuberculosis pulmonar, quimioterapia; tuberculosis resistente a multidrogas, quimioterapia.

4 Quimioterapia combinada; resistencia a las drogas; agentes antituberculosos, administracio n y dosificacio n;agentes antituberculosos, normas; rifampin, farmacocine of the World Health Organization, 2001,79: 61 page 66 le re sume en franc ais. En la pa gina 67 figura un resumen en espan has been a scourge of mankind forthousands of years (1) and remains one of the largesthealth problems in the world today, with an estimated8 million new cases and at least 2 million deaths everyyear (2). This burden is increased by humanimmunodeficiency virus (HIV) infection, which im-pairs the immune system and allows large numbers ofpeople already infected with tuberculosis to progressto active disease.

5 In many African countries, wheremorethan60%ofthoseinfectedwithHIVre side,thishasledtoanexponentialincreasein tuberculosiscasesover recent years (3 9). The emergence of multidrug-resistant cases of tuberculosis also poses a majorchallenge to control of the disease worldwide (10) andtuberculosis experts and health policy-makers haveurged a global response (11).Effective treatment of tuberculosis patientswith short-course multidrug chemotherapy is thecornerstone of the modern approach to the controlof the disease. To emphasize this principle, WHOand the International Union Against Tuberculosis1 Research Fellow, Centre for International Health, Universityof Bergen, Bergen, Secretary of the Commission on Macroeconomics andHealth, Evidence and Information for Policy, World Health Organiza-tion, 1211 Geneva 27, Switzerland.

6 Correspondence should beaddressed to this , National tuberculosis Research Programme, MedicalResearch Council, Pretoria, South Professor, Department of International Health,Boston University, Boston, of the World Health Organization, 2001,79(1)#World Health Organization 2001and Lung Disease (IUATLD), together with theirpartners, recommend the use of fixed-dose combi-nation (FDC) formulations of the essential anti- tuberculosis drugs as one further step to ensureadequate treatment of patients (12,13).This article presents the justification for thechange in treatment policy from single-drug for-mulations to FDCs and discusses the majorchallenges and possible solutions in this options for tuberculosisFDCs versus single drug formulationsMultidrug therapy is necessary to cure tuberculosispatientsandtopreventtheselec tionofdrug-resistantmutants, which may arise during the course oftreatment.

7 The major advantages of using FDCs totreat tuberculosis are simplified treatment and drugmanagement, and the reduced probability of mono-therapy (12 16). By preventing monotherapy, it isexpected that FDCs can limit the risk of emergenceof drug-resistant tuberculosis , although this conten-tion remains to be treatmentOne of the constraints in the conventional treatmentof tuberculosis is that patients have to take a largenumber oftablets,usually 9 16 per dayfor 2months(initial phase of treatment), followed by 3 9 tabletsdaily for 4 6 months (continuation phase). UsingFDCs, the number of tablets to be taken can bereduced to as few as three or four per day for thewhole course of the treatment (Table 1).

8 Havingfewer pills to swallow makes treatment easier, andminimizes the probability of splitting the doses or oftaking only some of the drugs in the regimen. In astudy conducted in Hong Kong (17), only 1% of312 patients who received FDCs complained aboutthe quantity of drugs to be ingested or aboutdifficulty with swallowing, compared with 5% of308 patients receiving the single drug toadverse effects were similar patient s compliance with treatment and limitprescription mistakes by simplifying the calculationof dosages. Where national guidelines are not readilyavailable, and the treatment of tuberculosis is largelyleft in the hands of the private sector, the use ofinadequate regimens may be more commonplace(18).

9 In such a situation, FDCs might be a betteroption than use of single-drug each of the drugs needed in the treatmentoftuberculosis,thereisawell-def inedrecommendeddose per kg body weight (Table 2). In FDCs, thesedose-to-body-weight relationships are carefully ba-lanced between all the drugs in the combination, inorder to ensure adequate dose delivery of all drugs atall times. With single drugs, problems of non-availability occur for three main reasons: no bufferstock, delays in receipt of orders, and no ,the four single drugs involved (rifampicin, isoniazid,pyrazinamide and ethambutol) must frequently beordered from different manufacturers.

10 Thus anydelay in the delivery of any one drug has con-sequences for the distribution of the completetreatment package to the peripheral health issue has also to be considered when the fourdrugs are put together in blister-packs. With FDCs,however, there are fewer drug formulations, thusmaking it easier to calculate the drug needs. Becauseof fewer drug formulation orders, shipments anddistribution involved, the efficiency of the tubercu-losis drug supply system is and prevention of drug resistanceBesidestuberculosis,severaloth ercommoninfectiousdiseases can be treated successfully with ,theftsandblack-marketsalesofthisdrugare notuncommon in countries where antibiotics for othercommon conditions ( respiratory infections andsexually transmitted infections) are not readily avail-able.