Services on Demand
- Cited by SciELO
- Access statistics
Print version ISSN 0042-9686
Bull World Health Organ vol.79 n.1 Genebra Jan. 2001
There is considerable exigency to take all necessary steps to cure tuberculosis cases and prevent further emergence of drug-resistant tuberculosis. The most important of these steps is to ensure that the treatment, particularly of sputum smear-positive cases, is adequate and that patients adhere to their treatment by supervised, direct observation of drug-taking according to the standardized regimens.
Use of fixed-dose combinations (FDCs) of tablets against tuberculosis is now being recommended by WHO and the International Union Against Tuberculosis and Lung Disease (IUATLD) as an additional step to ensuring proper treatment. FDCs simplify the prescription of drugs and the management of drug supply, and may also limit the risk of drug-resistant tuberculosis arising as a result of inappropriate drug selection and monotherapy.
Only FDCs of proven quality and proven rifampicin bioavailability should be purchased and used. In most situations, blood levels of the drugs are inadequate because of poor drug quality rather than poor absorption. This is true irrespective of the human immunodeficiency virus (HIV) infection status of the tuberculosis patients (other than those 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 tuberculosis programmes. 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. Standardization of FDC drug formulations has been proposed, which limits rifampicin-containing preparations to nine (including a four-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, pharmacokinetics.
Mots clés: tuberculose pulmonaire, chimiothérapie; tuberculose résistante à la polychimiothérapie, chimiothérapie; polychimiothérapie; résistance aux médicaments; antituberculeux, administration et posologie; antituberculeux, normes; rifampicine, pharmacocinétique.
Palabras clave: tuberculosis pulmonar, quimioterapia; tuberculosis resistente a multidrogas, quimioterapia; quimioterapia combinada; resistencia a las drogas; agentes antituberculosos, administración y dosificación; agentes antituberculosos, normas; rifampin, farmacocinética.
Tuberculosis has been a scourge of mankind for thousands of years (1) and remains one of the largest health problems in the world today, with an estimated 8 million new cases and at least 2 million deaths every year (2). This burden is increased by human immunodeficiency virus (HIV) infection, which impairs the immune system and allows large numbers of people already infected with tuberculosis to progress to active disease. In many African countries, where more than 60% of those infected with HIV reside, this has led to an exponential increase in tuberculosis cases over recent years (39). The emergence of multidrug-resistant cases of tuberculosis also poses a major challenge to control of the disease worldwide (10) and tuberculosis experts and health policy-makers have urged a global response (11).
Effective treatment of tuberculosis patients with short-course multidrug chemotherapy is the cornerstone of the modern approach to the control of the disease. To emphasize this principle, WHO and the International Union Against Tuberculosis and Lung Disease (IUATLD), together with their partners, recommend the use of fixed-dose combination (FDC) formulations of the essential antituberculosis drugs as one further step to ensure adequate treatment of patients (12, 13).
This article presents the justification for the change in treatment policy from single-drug formulations to FDCs and discusses the major challenges and possible solutions in this process.
Treatment options for tuberculosis
FDCs versus single drug formulations
Multidrug therapy is necessary to cure tuberculosis patients and to prevent the selection of drug-resistant mutants, which may arise during the course of treatment. The major advantages of using FDCs to treat tuberculosis are simplified treatment and drug management, and the reduced probability of monotherapy (1216). By preventing monotherapy, it is expected that FDCs can limit the risk of emergence of drug-resistant tuberculosis, although this contention remains to be validated.
One of the constraints in the conventional treatment of tuberculosis is that patients have to take a large number of tablets, usually 916 per day for 2 months (initial phase of treatment), followed by 39 tablets daily for 46 months (continuation phase). Using FDCs, the number of tablets to be taken can be reduced to as few as three or four per day for the whole course of the treatment (Table 1). Having fewer pills to swallow makes treatment easier, and minimizes the probability of splitting the doses or of taking only some of the drugs in the regimen. In a study conducted in Hong Kong (17), only 1% of 312 patients who received FDCs complained about the quantity of drugs to be ingested or about difficulty with swallowing, compared with 5% of 308 patients receiving the single drug preparations. Complaints relating to adverse effects were similar in the two groups. Use of FDCs may therefore improve the patients compliance with treatment and limit prescription mistakes by simplifying the calculation of dosages. Where national guidelines are not readily available, and the treatment of tuberculosis is largely left in the hands of the private sector, the use of inadequate regimens may be more commonplace (18). In such a situation, FDCs might be a better option than use of single-drug formulations.
For each of the drugs needed in the treatment of tuberculosis, there is a well-defined recommended dose per kg body weight (Table 2). In FDCs, these dose-to-body-weight relationships are carefully balanced between all the drugs in the combination, in order to ensure adequate dose delivery of all drugs at all times. With single drugs, problems of nonavailability occur for three main reasons: no buffer stock, delays in receipt of orders, and no replacements in hand on reaching the expiry date. Moreover, the four single drugs involved (rifampicin, isoniazid, pyrazinamide and ethambutol) must frequently be ordered from different manufacturers. Thus any delay in the delivery of any one drug has consequences for the distribution of the complete treatment package to the peripheral health services. This issue has also to be considered when the four drugs are put together in blister-packs. With FDCs, however, there are fewer drug formulations, thus making it easier to calculate the drug needs. Because of fewer drug formulation orders, shipments and distribution involved, the efficiency of the tuberculosis drug supply system is improved.
FDCs and prevention of drug resistance
Besides tuberculosis, several other common infectious diseases can be treated successfully with rifampicin. Thus, thefts and black-market sales of this drug are not uncommon in countries where antibiotics for other common conditions (e.g. respiratory infections and sexually transmitted infections) are not readily available. Use of rifampicin on a wide scale for conditions other than tuberculosis may therefore lead to it being given as monotherapy to patients who unsuspectedly may also suffer from tuberculosis. Treating a tuberculosis patient with a monotherapy of rifampicin rapidly leads to resistance to the drug even if it is given for short periods only. In combination drugs, the presence of isoniazid reduces the probability for the survival of rifampicin-resistant mutants.
Multidrug-resistant tuberculosis (MDR-TB) refers to resistance to at least the two key first-line antituberculosis drugs, rifampicin and isoniazid, and represents a condition that is very difficult and expensive to treat (19). Weyer et al. in South Africa found that one weeks MDR-TB treatment, including cycloserine, cost the same as the full 6-month regimen for a new patient on the first-line regimen (20).
In view of the enormous costs and difficulties in treating drug-resistant tuberculosis, the highest priority must be given to preventing the emergence of drug resistance in the first place. The most important step in preventing drug resistance is to ensure adequate treatment of all tuberculosis patients, particularly the sputum smear-positive cases. Acquired resistance most commonly follows erratic drug taking, i.e. interrupting treatment frequently and for long enough to allow re-growth of bacteria which might favour resistant mutants, and/or treating with a single drug which leads to the same effect. Multiple interruptions of treatment have been shown to be the predominant cause of drug resistance (21, 22). When using single-drug formulations, patients are more prone to continue their treatment with one drug while interrupting the others, thereby creating a risk of monotherapy and selection of drug-resistant mutants. Furthermore, situations such as expiry date having been surpassed or drugs being out-of-stock in treatment facilities, which might lead to some drugs being continued while waiting for new stocks of the others, represent another potential source of monotherapy. Such problems are prevented more easily if FDCs are used.
Some indirect evidence exists for the effect of FDCs on drug resistance patterns in high prevalence countries. Relatively low prevalences of MDR-TB have been recorded in Brazil and South Africa where good quality FDCs have been used for decades (10, 23). In Brazil, 0.9% of culture-positive tuberculosis cases in 199596 showed initial multidrug resistance (newly infected with MDR), and 5.4% showed acquired multidrug resistance because of previously incomplete treatment. In South Africa, the respective proportions were 1.1% and 4.0%.
The recommended strengths of FDCs
A 1998 WHO survey of the global market for FDCs showed that there is a significant number of such combinations available in the market, but with very little consistency in dose formulation. In fact, most of these preparations do not conform to theWHO dose specifications (24). Two- and three-drug FDCs already appear in the WHO Model List of Essential Drugs (25). In August 1998, the Technical Research and Advisory Committee (TRAC) to WHOs former Global Tuberculosis Programme recommended that a four-drug FDC for adults, as well as three paediatric FDCs be added to theWHO Model List of Essential Drugs (26). Table 3 provides an overview of the recommended strengths of FDCs in daily doses and intermittent (3 times a week) doses. These recommendations are based on the WHO dosage schedule given in Table 1.
For any drug there is a therapeutic range within which it is effective and not toxic. Table 4 and Table 5 show the dosage schedules for adults and children, respectively, demonstrating that for the anti-tuberculosis drugs included in FDC tablets, the simplified schedule according to body weight ensures that the doses remain within the therapeutic margins. In many tuberculosis control programme settings where FDCs are being used, a body weight cut-off of 50 kg is usually set as the weight at which an increase in the number of tablets is indicated. Below 50 kg, a patient would receive, for example, four tablets, and from 50 kg upwards, five tablets. This is done to ensure sufficient amounts of the drug to satisfy the mg/kg dose requirement in heavier patients; in other settings, different criteria are used, with an upper cutoff of 55 kg. In such a case, FDCs formulated specifically for a 50-kg body weight will be inapplicable. Current WHO-recommended FDCs, however, have been formulated in such a way that it satisfies both situations. Fig. 1 and Fig. 2 show that irrespective of whether the cut-off weight for changing from three tablets to four in the proposed four-drug FDC is at 50 kg or 55 kg, therapeutic efficacy is maintained because the mg/kg doses would be kept between the maximum and minimum recommended limits at all times; thus, for the vast majority of adults the number of tablets for both the initial phase and the continuation phase would be the same. For individuals weighing below 50 kg or 55 kg (depending on the decision of local national tuberculosis programmes) the dose would be three tablets, while for those over 55 kg it would be four tablets. For children weighing >10 kg, the dose would be one dispersible tablet per 5 kg body weight. For lower body weights, the tablet dose would be halved and administered per 2.5 kg increments as appropriate.
FDCs and adverse effects
Adverse reactions to drugs are not more common if FDCs are used (17, 27). Nevertheless, whenever side-effects to one of the components in a FDC are suspected there will be a need for single-drug formulations. Adverse drug reactions, severe enough to warrant withdrawal of drugs, generally occur in only 36% of patients on tuberculosis treatment (28 32). These reactions may be more common in areas where the prevalence of HIV is high. Therefore, limited stocks of single-drug tablets should be available in higher level referral centres where patients with severe adverse reactions to drugs could be managed under supervision.
The price of FDCs
A disadvantage of the three- and four-drug FDCs is that they are currently more expensive than the sum of the costs of the individual single-drug tablets. However, prices are expected to drop as competition and volumes of production increase. Indeed, some suppliers now sell the two-drug FDC with rifampicin and isoniazid at a lower price than the individual single-drug tablets of rifampicin and isoniazid (33). In addition, use of FDCs decreases the cost of managing drug supply, and may therefore further reduce the overall costs of delivering treatment to patients and preventing shortages of individual drugs.
FDCs and the DOT strategy
Although it simplifies both prescribing and drug taking, the use of FDCs does not eliminate the need for direct observation of treatment (DOT). Whether FDCs or single-drug tablets are used, the other components of the WHO/IUATLD recommended strategy for tuberculosis control remain vital for successful tuberculosis control. Particularly, the information system used in modern tuberculosis control programmes should be maintained so that the effects of a change in treatment policy to use FDCs can be properly monitored. Thus, FDCs are promoted as an integrated part of good service delivery, helping to ensure that the treatment given is of good quality.
FDCs of good quality facilitate accurate dose delivery, and ensure cure when given as directly observed treatment (14). However, inadequate doses, especially of rifampicin, may also lead to treatment failure and drug resistance. Thus, if FDCs are given unsupervised, patients can interrupt treatment repeatedly, and this may lead to emergence of drug resistance (21). The risk is best avoided by giving FDCs as directly observed treatment, at least during the initial phase of treatment.
Quality of FDCs
Using tuberculosis drugs of good quality is fundamental, since treatment with poor quality drugs will create drug resistance and fail to cure patients. While drug quality is important for all anti-tuberculosis drugs, there are particular concerns regarding the bioavailability of rifampicin in FDCs. Some studies have shown that while it is perfectly possible to obtain satisfactory bioavailability of rifampicin in FDCs, other studies have demonstrated inadequate bioavailability of rifampicin in some cases (3441). Adequate results in dissolution tests are no guarantee that rifampicin will have acceptable bioavailability when FDCs are given to healthy adults (34). It appears that the bioavailability of rifampicin in FDCs is easily compromised if strict manufacturing procedures are not followed or poor quality raw materials are used.
If the bioavailability of rifampicin is inadequate, as might be the case in substandard FDCs, treatment failures and emergence of drug-resistant tuberculosis could follow. Thus, it is an absolute requirement to purchase and use only FDCs that have been proved to have full rifampicin bioavailability. Procurement and regulatory bodies in individual countries should be strongly encouraged to insist on obtaining data proving the bioavailability of rifampicin, in addition to other quality assurance data when purchasing and distributing FDCs.
Giving FDCs with poor rifampicin bioavailability means giving inadequate therapy, without even being aware of it. Because of a narrow therapeutic margin (21), the rifampicin dose is crucial. Consequently, using FDCs of poor rifampicin bioavailability could lead directly to a poor treatment outcome and may create, not prevent, drug resistance. Good quality and proven rifampicin bioavailability are absolute requirements for successful tuberculosis control in programmes utilizing FDC based regimens. WHO, IUATLD and partners are currently establishing strategies for quality assurance of FDCs. A simplified protocol for testing of rifampicin bioavailability has been developed (42, 43), and laboratories are being recruited to form an international network for quality assurance and rifampicin bioavailability testing for FDCs. A global mechanism for pre-qualification of FDCs has been proposed to ensure that only quality FDCs will be purchased and used (44).
A further point of concern lies with the potential for poor absorption of drugs in tuberculosis patients co-infected with HIV. If this possibility turns out to be correct, it may have disastrous consequences for tuberculosis control efforts in countries with high HIV prevalence. Current indications are that poor absorption predominantly occurs in patients with symptoms of AIDS and with CD4 counts <200 cells/mm3. In all other cases, there is no difference between HIV-positive and HIV-negative patients in the pharmacokinetics of any of the first-line tuberculosis drugs, whether administered as single drugs or as FDCs (45, 46).
Registration of FDCs
Pharmaceutical products of good and poor quality circulate in international trade (47). The registration process and the institutions responsible for registration of drugs are fundamental elements to ensure that only drugs of good quality are purchased and used in any country. Registration of pharmaceutical products should ensure not only that the product itself is of good quality, but also that the manufacturer adheres to recognized good manufacturing practices (GMP) and that proper quality control is in place. Only in this way is it possible to ensure reliable supplies and long-term availability of quality FDCs.
WHO and its partners are working to develop and strengthen mechanisms for registration of FDCs. Among other issues, the feasibility of establishing a global mechanism for pre-qualification of FDC manufacturers is being evaluated. A fast-track process for registration of four-drug FDCs and reduction of registration fees and import taxes has been proposed to help making registration of FDCs swifter (48). There must be strong emphasis on the quality of FDCs in the registration process, with proven rifampicin bioavailability being an absolute requirement for registration and procurement.
Careful preparation will be necessary when FDCs are introduced into a national tuberculosis programme. Operational research will need to be undertaken to assess the effect of using these drugs on patients adherence and attitudes to the new large tablets, and a system to monitor for adverse effects. As always, cohort analysis should be used to assess the effect of the introduction of these tablets to assess outcomes. In larger countries, it may be useful to phase in the introduction of these new tablets to allow some provinces to serve as controls for other provinces where the intervention is being applied.
Les raisons de recommander les associations fixes en comprimés pour le traitement de la tuberculose
Il est indispensable de prendre toutes les mesures qui simposent pour parvenir à la guérison des cas de tuberculose et empêcher toute nouvelle émergence de la tuberculose multirésistante. La plus importante de ces mesures consiste à assurer que le traitement, notamment celui des cas à frottis positif, est adapté et que les patients sy conforment grâce à lobservation directe de la prise des médicaments selon la posologie standard.
Lutilisation dassociations fixes dantituberculeux en comprimés est maintenant recommandée par lOMS et lUnion Internationale contre la Tuberculose et les Maladies Respiratoires (UICTMR) en tant que mesure supplémentaire visant à assurer un traitement correct. Ces comprimés simplifient à la fois la prescription des médicaments et la gestion des approvisionnements et peuvent aussi limiter le risque dapparition dune tuberculose multirésistante à la suite dun choix thérapeutique inapproprié et comme conséquence de la monothérapie.
Seuls les comprimés dassociations fixes de qualité avérée et dont la biodisponibilité de la rifampicine a été démontrée devront être achetés et utilisés. Dans la plupart des cas, les taux sanguins de médicaments sont insuffisants en raison dun défaut de qualité du médicament plutôt que dune mauvaise résorption, et cela quel que soit le statut des malades vis-à-vis de linfection par le virus de limmunodéficience humaine (VIH) (à lexception de ceux qui présentent un syndrome dimmunodéficience acquise avéré , avec une numération des CD4 inférieure à 200/mm3). Actuellement, lOMS, lUICTMR et leurs partenaires mettent au point des stratégies permettant dassurer que seuls des comprimés dassociations fixes de qualité sont utilisés dans les programmes de lutte contre la tuberculose. Un protocole simplifiéet efficace dévaluation de la biodisponibilité de la rifampicine a été établi, et un réseau supranational de laboratoires est en cours de constitution pour lassurance de la qualité de ces comprimés. Il a été proposé de normaliser la formulation des associations fixes afin de limiter à neuf le nombre de préparations contenant de la rifampicine (dont un comprimé contenant une association de quatre médicaments et trois comprimés à usage pédiatrique).
Razones para recomendar las combinaciones de dosis fija como tratamiento de la tuberculosis
Urge tomar todas las medidas necesarias para curar los casos de tuberculosis y evitar que siga propagándose la variante farmacorresistente de esa enfermedad. La más importante de esas medidas consiste en asegurar que el tratamiento sea el adecuado, en particular en los casos con esputo positivo, comprobando el seguimiento de la medicación mediante la observación directa y supervisada de la toma de los fármacos por el paciente de acuerdo con lo previsto en los regímenes normalizados.
La OMS y la Unión Internacional contra la Tuberculosis y las Enfermedades Pulmonares (IUATLD) recomiendan hoy el uso de combinaciones de dosis fija (CDF) contra la tuberculosis como medida adicional para garantizar un tratamiento idóneo. Las CDF simplifican la prescripción de los medicamentos y la gestión del suministro de fármacos, y además pueden limitar el riesgo de tuberculosis farmacorresistente que resulta de una selección inadecuada de medicamentos y de la monoterapia. No obstante, con las CDF sigue siendo necesaria la observación directa de los pacientes para confirmar que se tomen los medicamentos.
Sólo deben comprarse y emplearse CDF de calidad demostrada que garanticen una adecuada biodisponibilidad de la rifampicina. En la mayoría de las situaciones, los niveles sanguíneos de los medicamentos son insuficientes, de resultas no tanto de una mala absorción como de su mala calidad. Ello es así con independencia de la serología VIH de los enfermos de tuberculosis (exceptuando los casos de SIDA declarado, con recuentos de CD4 < 200 células/mm3). Actualmente, la OMS, la IUATLD y otros asociados están desarrollando estrategias para garantizar que en los programas contra la tuberculosis sólo se empleen CDF de alta calidad. Se ha desarrollado un protocolo simplificado y eficaz para evaluar la biodisponibilidad de la rifampicina, y se está reclutando a diversos laboratorios para constituir una red supranacional de garantía de la calidad de las CDF. Se ha propuesto una normalización de los preparados de CDF, que limita a nueve los que contienen rifampicina (entre ellos una CDF de cuatro medicamentos y tres CDF de uso pediátrico).
1. Bloom BR, Murray CJ. Tuberculosis: commentary on a re-emergent killer. Science, 1992, 257: 10551064. [ Links ]
2. Dye C et al. Global burden of tuberculosis: estimated incidence, prevalence and mortality by country in 1997. Journal of the American Medical Association, 1999, 282: 677686. [ Links ]
3. UNAIDS/WHO. AIDS epidemic update: December 1998. Geneva, Joint United Nations Programme on HIV/AIDS (UNAIDS), World Health Organization, 1998 (unpublished document UNAIDS/ 98.35). [ Links ]
4. Narain JP, Raviglione MC, Kochi A. HIV-associated tuberculosis in developing countries: epidemiology and strategies for prevention. Tuberculosis and Lung Disease, 1992, 73: 311321. [ Links ]
5. Van den Broek J et al. HIV-1 infection as a risk factor for the development of tuberculosis: a case-control study in Tanzania. International Journal of Epidemiology, 1993, 22: 11591165. [ Links ]
6. De Cock KM et al. Tuberculosis and HIV infection in sub-Saharan Africa. Journal of the American Medical Association, 1992, 268: 15811587. [ Links ]
7. McLeod DT et al. Pulmonary diseases in patients infected with the human immunodeficiency virus in Zimbabwe, Central Africa. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1989, 83: 694697. [ Links ]
8. Mbaga JM et al. Survival time of patients with acquired immune deficiency syndrome: experience with 274 patients in Dar-es-Salaam. East African Medical Journal, 1990, 67: 9599. [ Links ]
9. Lucas SB et al. The mortality and pathology of HIV infection in a west African city. AIDS, 1993, 7: 15691579. [ Links ]
10. Pablos-Mendez A et al. Global surveillance for antituberculosis-drug resistance, 19941997. World Health Organization International Union against Tuberculosis and Lung Disease Working Group on Anti-Tuberculosis Drug Resistance Surveillance. New England Journal of Medicine, 1998, 338: 16411649. [ Links ]
11. Kochi A. The global tuberculosis situation and the new control strategy of the World Health Organization. Tubercle, 1991, 72: 16. [ Links ]
12. The promise and the reality of fixed-dose combinations with rifampicin. A joint statement of the International Union Against Tuberculosis and Lung Diseases and the Tuberculosis Programme of the World Health Organization. International Journal of Tuberculosis and Lung Disease, 1994, 75: 180181. [ Links ]
13. Maher D et al. Treatment of tuberculosis. Guidelines for National Programmes. Geneva, World Health Organization, 1997 (unpublished document WHO/TB/97/220). [ Links ]
14. Moulding T, Dutt AK, Reichman LB. Fixed-dose combinations of antituberculous medications to prevent drug resistance. Annals of Internal Medicine, 1995, 122: 951954. [ Links ]
15. Sbarbaro JA. Reality versus the academic milieu. American Review of Respiratory Disease, 1986, 134: 1109. [ Links ]
16. Sbarbaro JA. A challenge to our practices and to our principles. Tubercle and Lung Disease, 1996, 77: 23. [ Links ]
17. Hong Kong Chest Service/British Medical Research Council. Acceptability, compliance, and adverse reactions when isoniazid, rifampin, and pyrazinamide are given as a combined formulation or separately during three-times-weekly antituberculosis chemotherapy. American Review of Respiratory Disease, 1989, 140: 16181622. [ Links ]
18. Uplekar MW, Shepard DS. Treatment of tuberculosis by private general practitioners in India. Tubercle, 1991, 72: 284290. [ Links ]
19. Mahmoudi A, Iseman MD. Pitfalls in the care of patients with tuberculosis. Common errors and their association with the acquisition of drug resistance. Journal of the American Medical Association, 1993, 270: 6568. [ Links ]
20. Weyer K, Fourie PB, Nardell EA. The global impact of drug-resistant tuberculosis. Chapter 5. A noxious synergy: tuberculosis and HIV in South Africa. Boston, Harvard Medical School and Open Society Institute, 1999. [ Links ]
21. Mitchison DA. How drug resistance emerges as a result of poor compliance during short course chemotherapy for tuberculosis. International Journal of Tuberculosis and Lung Disease, 1998, 2: 1015. [ Links ]
22. Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the United Kingdom: Recommendations 1998. Thorax, 1998, 53: 536548. [ Links ]
23. Weyer K et al. Tuberculosis drug resistance in the Western Cape. South African Medical Journal, 1995, 85: 499504. [ Links ]
24. Kitler ME. The fixed-dose combination project. Geneva, World Health Organization, 1998 (unpublished WHO document, Global Tuberculosis Programme). [ Links ]
25. The use of essential drugs. Model list of essential drugs (Ninth list). Seventh report of the WHO Expert Committee. Geneva, World Health Organization, 1997 (WHO Technical Report Series, No. 867). [ Links ]
26. World Health Organization. Report and recommendations from the meeting of the Technical Research and Advisory Committee of the Global Tuberculosis Programme (TRAC), 1719 August 1998, Geneva. Geneva, World Health Organization, 1998. [ Links ]
27. Chaulet P, Boulahbal F. [Clinical trial of a combination of three drugs in fixed proportions for the treatment of tuberculosis]. Tuberculosis and Lung Disease, 1995, 76: 407412 (in French). [ Links ]
28. Snider DE et al. Supervised six-months treatment of newly diagnosed pulmonary tuberculosis using isoniazid, rifampin, and pyrazinamide with and without streptomycin. American Review of Respiratory Disease, 1984, 130: 10911094. [ Links ]
29. Girling DJ. The role of pyrazinamide in primary chemotherapy for pulmonary tuberculosis. Tubercle, 1984, 65: 14. [ Links ]
30. East African and British Medical Research Councils. Controlled clinical trial of five short-course (4-month) chemotherapy regimens in pulmonary tuberculosis. First report of 4th study. Lancet, 1978, 2: 334338. [ Links ]
31. Singapore Tuberculosis Service/British Medical Research Council. Clinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis. American Review of Respiratory Disease, 1979, 119: 579585. [ Links ]
32. British Thoracic Association. A controlled trial of six months chemotherapy in pulmonary tuberculosis. First report: results during chemotherapy. British Journal of Diseases of the Chest, 1981, 75: 141153. [ Links ]
33. Management Sciences for Health. International drug price indicator guide (19911996). Arlington, VA, Management Sciences for Health/Washington, DC, The World Bank, 19911996. [ Links ]
34. Acocella G. Human bioavailability studies (IUATLD Symposium Quality Control of Antituberculosis Drugs, Dubrovnik, 6 October 1988). Bulletin of the International Union Against Tuberculosis and Lung Disease, 1989, 64: 3840. [ Links ]
35. Acocella G et al. Pharmacokinetic studies on antituberculosis regimens in humans. I. Absorption and metabolism of the compounds used in the initial intensive phase of the short-course regimens: single administration study. American Review of Respiratory Disease, 1985, 132: 510515. [ Links ]
36. Acocella G et al. Comparative bioavailability of isoniazid, rifampin, and pyrazinamide administered in free combination and in a fixed triple formulation designed for daily use in antituberculosis chemotherapy. I. Single-dose study. American Review of Respiratory Disease, 1988, 138: 882885. [ Links ]
37. Acocella G et al. Comparative bioavailability of isoniazid, rifampin, and pyrazinamide administered in free combination and in a fixed triple formulation designed for daily use in antituberculosis chemotherapy. II. Two-month, daily administration study. American Review of Respiratory Disease, 1988, 138: 886890. [ Links ]
38. Acocella G et al. Bioavailability of isoniazid, rifampicin and pyrazinamide (in free combination or fixed-triple formulation) in intermittent antituberculous chemotherapy. Monaldi Archives of Chest Disease, 1993, 48: 205209. [ Links ]
39. Ellard GA, Ellard DR, Allen BW, et al. The bioavailability of isoniazid, rifampin, and pyrazinamide in two commercially available combined formulations designed for use in the short-course treatment of tuberculosis. American Review of Respiratory Disease, 1986, 133: 10761080. [ Links ]
40. Fox W. Drug combinations and the bioavailability of rifampicin. Tubercle, 1990, 71: 241245. [ Links ]
41. Schall R et al. Relative bioavailability of rifampicin, isoniazid and ethambutol from a combination tablet vs. concomitant administration of a capsule containing rifampicin and a tablet containing isoniazid and ethambutol. Arzneimittelforschung, 1995, 45: 12361239. [ Links ]
42. Ellard GA. Quality assurance: protocol for assessing the rifampicin bioavailability of combined formulations in healthy volunteers. International Journal of Tuberculosis and Lung Disease, 1999, 3 (Suppl.): S284S285. [ Links ]
43. Fourie PB et al. WHO Model Protocol. Establishing the bioequivalence of rifampicin in fixed-dose formulations containing isoniazid with or without pyrazinamide and/or ethambutol, compared to the single drug reference preparations administered in loose combination. Geneva, World Health Organization, 1999 (unpublished document WHO/CDS/TB/99.274). [ Links ]
44. Blomberg B et al. Availability of quality fixed-dose combination tablets for the treatment of tuberculosis: what can we learn from studying the World Health Organizations vaccine model? International Journal for Tuberculosis and Lung Disease, 1999, 3 (Suppl.): S371S380. [ Links ]
45. Peloquin CA et al. AIDS and TB drug absorption. International Journal for Tuberculosis and Lung Disease, 1999, 3 (12): 11431144. [ Links ]
46. Peloquin CA et al. Low antituberculosis drug concentrations in patients with AIDS. Annals of Pharmacotherapy, 1996, 30: 919925. [ Links ]
47. Pillai G et al. Recent bioequivalence studies on fixed-dose combination anti-tuberculosis drug formulations available on the global market. International Journal for Tuberculosis and Lung Disease, 1999, 3 (Suppl.): S309S316. [ Links ]
48. Laing R et al. Fixed-dose combination tablets for the treatment of tuberculosis. Report from an informal meeting held in Geneva, Tuesday, 27 April 1999. Geneva, World Health Organization, 1999 (unpublished document WHO/CDS/CPC/TB/99.267). [ Links ]
49. The use of essential drugs: ninth report of the WHO Expert Committee (including the revised Model List of Essential Drugs). Geneva, World Health Organization, 2000 (WHO Technical Report Series, No. 895). [ Links ]
1 Research Fellow, Centre for International Health, University of Bergen, Bergen, Norway.
2 Executive Secretary of the Commission on Macroeconomics and Health, Evidence and Information for Policy, World Health Organization, 1211 Geneva 27, Switzerland. Correspondence should be addressed to this author.
3 Director, National Tuberculosis Research Programme, Medical Research Council, Pretoria, South Africa.
4 Associate Professor, Department of International Health, Boston University, Boston, USA.
Ref. No. 99-0435