Operational research on tuberculosis control in Malawi - 9. A unified treatment regimen for new cases of tuberculosis in resource-poor countries: a study in a rural district in Malawi.

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Operational research on tuberculosis control in Malawi

Banerjee, A.

Publication date

2003

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Citation for published version (APA):

Banerjee, A. (2003). Operational research on tuberculosis control in Malawi.

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9.. A unified treatment regimen for new cases of tuberculosis in

resource-poorr countries: a study in a rural district in Malawi.

AA Banerjee

, AD Harries

, N Mphasa

, J Veen

, T Ringdal

, J Van Gorkom

,

FMLL Salaniponi

11

_{National Tuberculosis Control Programme, Community Health Science}

Unit, ,

Lilongwe,, Malawi

The Royal Netherlands Tuberculosis Association, KNCV,

Thee Hague, The Netherlands

33

Norwegian Health Association (Council of Tuberculosis),

Voss,, Norway

Publishedd in:

Thee International Journal of Tuberculosis and Lung Disease 2001; Vol. 5: pp.

376-379 9

SUMMARY Y

Ann oral ambulatory unified treatment regimen was introduced in Ntcheu District, Malawi,, between April 1996 and June 1997 for all new patients (600) with tuberculosiss (TB). There was no change in the case finding pattern compared with thee previous five years; 65% of new smear-positive pulmonary tuberculosis (PTB) patientss completed treatment, not significantly different compared with the previous threee years. Treatment completion was significantly lower in patients with smear-negativee PTB and extra-pulmonary tuberculosis, due mainly to high mortality rates (40%% and 4 1 % respectively). In a rural district with high human immunodeficiency viruss sero-prevalence rates in TB patients, case finding and end of treatment outcomee of the oral unified regimen were comparable to those of previous regimens.

INTRODUCTION N

Inn industrialised countries where considerations of cost of anti - tuberculosis treatmentt are a minor factor, six months of short-course chemotherapy consisting off isoniazid and rifampicin with an initial supplement of two months pyrazinamide (withh or without ethambutol or streptomycin, depending on local rates of primary drugg resistance) is widely used for all newly diagnosed tuberculosis cases. In developingg countries, current recommendations from the World Health Organization (WHO)) [1], endorsed by the International Union Against Tuberculosis and Lung Diseasee (IUATLD) [2], are that TB patients be categorised according to priority for treatment.. In general, patients with new smear-positive pulmonary tuberculosis (PTB)) and other clinically serious forms of extra-pulmonary TB (EPTB) are accorded highestt priority and are treated with short-course chemotherapy for six or eight months.. Patients with smear-negative PTB and less serious forms of EPTB are givenn different regimens, and in many countries in sub-Saharan Africa "standard" treatmentt consists of 12 months of isoniazid and thiacetazone.

Thee multiple regimens in use for different categories of TBB may cause confusion and leadd to mistakes in implementation, particularly amongst health staff who are not activelyy involved in TB control programmes. Several analyses have shown that short coursee chemotherapy for smear-positive PTB cases is cheaper than standard chemotherapyy per case cured and per death averted [3,4], as vit has a higher cure

rate.. It is likely that this will be valid for smear-negative PTB cases as well, although theree have to our knowledge been no published cost-effectiveness studies to examinee this question. One of the reasons for using "standard" treatment in smear-negativee PTB patients was the high cost of rifampicin and pyrazinamide. However,

sincee 1992 the prices of anti-TB drugs have fallen considerably on the international markett [5], and some of the short-course regimens are now less costly than a 12-monthh regimen consisting of streptomycin, isoniazid and ethambutol. There is now aa rationale in developing countries for using a unified treatment regimen in new patientss with all types of TB, and such alternative approaches to TB control have beenn strongly advocated by some international experts [6]. However, there is concernn that using the same regimen for all types of TB might reduce the perceived needd for sputum smear microscopy as the first diagnostic investigation. This might leadd to an increased incidence of "smear-not-examined" TB cases associated with ann increase in costs due to more chest X-Rays and undetected smear-positive failuress due to misclassification as smear-negative PTB or EPTB.

Inn 1996, the Malawi National Tuberculosis Control Programme introduced a unified treatmentt regimen into one rural district of the country which was maintained for 15 months.. We report on our observations and compare the results with case-finding patternss and treatment outcomes recorded when the previous established treatment regimenss were in place.

METHODS S

Thee unified treatment regimen was introduced in Ntcheu District, in Malawi, which servess a population of approximately 500,000 with a well-run district TB control programmee operating at the district hospital and 32 health centres throughout the district. .

Anti-tuberculosisAnti-tuberculosis treatment regimens

Untill 1 April 1996, all new patients with smear-positive PTB and serious forms of EPTBB (military TB, bilateral or extensive pleural effusion, TB pericarditis, spinal TB) weree given short-course chemotherapy with two months of daily directly observed streptomycin,, isoniazid, rifampicin and pyrazinamide followed by six months of daily self-administeredd isoniazid and thiacetazone (2SRHZ/6HT). All patients with smear-negativee PTB and less serious forms of EPTB (TB lymphadenitis, unilateral pleural effusion,, TB bone) were given standard treatment with one month of daily directly observedd SHT followed by 11 months of daily self-administered HT (1SHT/11HT). In aitt patients the intensive phase of directly observed treatment was given in hospital. Onn 1 April 1996, an oral ambulatory unified anti - tuberculosis treatment was commencedd for all new TB patients in Ntcheu district; this was continued for all new registeredd patients up to 30 June 1997. The unified regimen consisted of a one-monthh intensive phase of daily RHZE (E * ethambutol), followed by one month of

thee four drugs given three times a week under direct observation, followed by six monthss of daily self-administered HE (1RHZE/1R3H3Z3E3/6HE). Direct observation wass performed by health workers for hospitalised patients and those receiving ambulatoryy treatment from health centres. For those smear-negative PTB and EPTB patientss who were fit enough to receive the intensive phase at home, direct observationn was performed by a guardian identified by the patient [7].

CaseCase finding and treatment outcome

Thee pattern of case-finding for all TB patients and the treatment outcome of new patientss with smear-positive PTB for the previous five years was obtained from the districtt TB registers. For new patients being registered for the unified regimen, registrationn data, type and category of TB were collected each quarter from the districtt TB register. Treatment outcome at eight months in all patients was determinedd from the TB register and from the TB treatment cards. Treatment outcomess were categorised according to WHO and IUATLD guidelines [1,2].

DataData analysis

Dataa was entered into an Epi-lnfo software package (Epi-lnfo, version 6.0). Treatmentt outcomes between different groups were compared using the x "test and Fisher'ss two-tailed exact test, with differences at the 5% level being regarded as significant.. Relative risks (RR), their 95% confidence intervals (CI) and P values weree also calculated where appropriate.

RESULTS S

Duringg the 15 months from April 1996 to June 1997, 622 patients with TB were registered.. There were 600 new patients and 22 with recurrent disease. Of the 600 neww patients, 286 were men and 314 were women, with a mean age of 32 years. Theree were some variations in case pattern from year to year, but the proportion of patientss with smear-positive PTB was not significantly reduced during the period of thee unified regimen compared with previous years (Table 1).

Thee proportion of smear-positive PTB patients who completed treatment was significantlyy higher than patients with smear-negative PTB and EPTB (P < 0.05) (Tablee 2). Compared with smear-positive PTB patients, the relative risk of death and defaultt was significantly higher in patients with smear-negative PTB (RR for death 1.63,, 95% CI 1.3-2.1 and RR for default 1.93, 95% CI 1.4-2.6) and patients with EPTBB (RR for death 1.66, 95% C11.3-2.1 and RR for default 1.58, 95% C11.1-2.3).

Thee 8-month treatment outcome for new smear-positive PTB patients who were commencedd on the unified treatment regimen was compared with results for patients inn the previous five years. Although the proportion of smear-positive patients on the unifiedd regimen who completed treatment was similar to the previous three years, thee proportions who failed to submit sputum smears at eight months and who defaultedd and transferred out were significantly higher (P < 0.05).

Tablee 1 Case finding in new patients with tuberculosis in Nteheu District

Period d

Oldd treatment regimen Jann 1991-December 1995 Unifiedd treatment regimen

Aprill 96-June 1997* Smear--positive e PTB B n(%) ) 9266 (46) 302(50) ) Smear--negative e PTB B n(%) n(%) 5188 (26) 150(25) ) Extra--pulmonary y TB B n(%) n(%) 5655 (28) 1488 (25) Total l 2009 9 600 0

*6000 patients over the 15-month period would come to around 480 in a year, almost 788 more than the average over the previous 5 years

PTBB pulmonary tuberculosis

DISCUSSION N

Thee introduction of a unified treatment regimen was associated with a satisfactory case-findingg pattern and acceptable end of treatment outcome. The fear that a unifiedd regimen may result in clinicians not following diagnostic guidelines was not observedd in this study. Case finding, particularly the identification of smear-positive PTBB patients, was not compromised compared with the previous five years. The proportionn of smear-positive PTB patients who completed treatment was similar to thee previous three years, although fewer patients submitted sputum specimens at thee end of treatment and there was a trend towards a higher default and transfer out rate.. The reasons for this are unclear. Cure rates were below those recommended byy the WHO [1], and are largely a result of high mortality during treatment. There wass an even higher mortality rate amongst patients with smear-negative PTB and EPTBB compared with patients who had smear-positive PTB, most likely attributable

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too the human immunodeficiency virus (HIV) [8].n HIV seroprevalence is high amongstt smear-positive PTB patients in Ntcheu [9], and is likely to be higher in thosee with smear-negative PTB and EPTB.

Becausee the introduction of the unified regimen included ambulatory treatment, it wass not possible to have a control district to compare case-finding and outcomes. Furthermore,, the briefings organised as part of the introduction of the regimen might havee led to improved management within the district. Although the comparison basedd on historical data is difficult because óf changing circumstances, motivation andd economic factors, amongst others, we feel that as the district already had a goodd programme running the data are still valid.

Wee feel that the unified treatment regimen described here could be considered for implementationn in resource-poor countries. However, due to the different dosages neededd for the daily and intermittent months of the intensive phase of treatment and duee to the potential confusion this can cause, the whole intensive phase has been changedd to two months of intermittent treatment. Further, cost remains a factor to takee into consideration. One thousand tablets of ethambutol in 1999 cost USD 19.95 (source:: International Drug Association, IDA). In pauci-bacillary TB, four drugs may nott be needed [1], and the Malawi TB Control Programme has decided to remove ethambutoll from the intensive phase for patients with smear-negative PTB and less seriouss forms of EPTB. The new regimens, which started on 1 July 1997, are as follows:: 2R3H3Z3E3/6HE for smear-positive PTB cases and serious EPTB cases, and 2R3H3Z3/6HEE for smear-negative PTB cases and less serious EPTB cases.

Thee unified regimen has therefore been abandoned for economic reasons rather thann unsatisfactory performance. These new regimens have been implemented in 166 out of 25 districts, and will cover the whole country within the next year.

Wee thank the TB Programme staff and general medical and nursing staff at Ntcheu Districtt Hospital and health centres for their assistance and support in ensuring good TBB control in the district. We thank Drs M J Boeree, W Nkhoma and D S Nyangulu forr their initial input to the study. We thank the Department for International Developmentt (DFID), UK, for financial support. The study received the support of thee TB Programme Steering Group and ethical approval from the Malawi Health Sciencee Research Committee.

References References

1.. World Health Organization. Treatment of Tuberculosis. Guidelines for national programmes.. 2nd ed., Geneva: WHO 1997.

2.. Enarson DA, Rieder HL, Amadottir T, Trebucq A. Tuberculosis guide for low income countries.. 4th ed. Paris: IUATLD, 1996.

3.. Murray CJL, Dejonghe E, Chum HJ, Nyangulu DS, Salomao A, Styblo K. Cost-effectivenesss of chemotherapy for pulmonary tuberculosis in three sub-Saharan African countries.. Lancet 1991; 338:1305 -1308.

4.. Fryatt RJ. Review of published cost-effectiveness studies on tuberculosis treatment programmes,, tnt J Tuberc Lung Dis 1997; 1:101 -109.

5.. Chaulet P. The supply of antituberculosis drugs: price evolution. Tubercle Lung Dis 1995; 76:: 261 - 263.

6.. De Cock KM, Wilkinson D. Tuberculosis control in resource-poor countries: alternative approachess in the era of HIV. Lancet 1995; 346:675 - 677.

7.. Banerjee A, Harries AD, Mphasa N, et al. Evaluation of a unified treatment regimen for all neww cases of tuberculosis using guardian-based supervision. Int J Tuberc Lung Dis 2000; 4:: 333-339

8.. Harries AD, Nyirenda TE, Banerjee A, Boeree MJ, Salaniponi FML. Treatment outcome off patients with smear-negative and smear-positive pulmonary tuberculosis in the Nationall Tuberculosis Control Programme, Malawi. Trans Roy Soc Trap Med Hyg 1999; 93:: 443 - 446.

9.. Banerjee A, Moyo S, Salaniponi F, Harries A. HIV testing and tuberculosis treatment outcomee in a rural district in Malawi. Trans R Soc Trap Med Hyg 1997; 91: 707-8