INT J TUBERC LUNG DIS 13(10):12741280 2009 The Union

Tuberculosis retreatment category predicts resistance in hospitalized retreatment patients in a high HIV prevalence area
Y. S. Schreiber,* A. F. Herrera, D. Wilson, K. Wallengren, R. Draper, J. Muller, H. Dawood, S. Doucette,* D. W. Cameron,* G. G. Alvarez*
* Ottawa Health Research Institute, University of Ottawa at The Ottawa Hospital, Ottawa, Ontario, Canada; Harvard Medical School, Boston, Massachusetts, USA; University of KwaZulu Natal at Edendale Hospital and Doris Goodwin Hospital, Pietermaritzburg, KwaZulu Natal, South Africa; Harvard School of Public Health, Boston, Massachusetts, USA SUMMARY

Rates of multidrug-resistant tuberculosis (MDR-TB) are currently as high as 7.7% in retreatment cases in KwaZulu-Natal, South Africa. MDR-TB prevalence is known to be high in patients categorized as treatment failures. Recent reports have questioned the effectiveness of the World Health Organization (WHO) Category II regimen in retreatment TB cases. O B J E C T I V E : To determine whether treatment category predicts susceptibility patterns and outcomes in a hospitalized population of retreatment TB cases. D E S I G N : Retrospective cohort of 197 pulmonary retreatment cases. R E S U LT S : Retreatment cases treated with the standard retreatment regimen had a high in-hospital mortality (19.8%), or poor outcome (26.4%) and a high rate of MDR-TB (16.2%). The treatment failure category predicted resistance, with 57.1% of patients exhibiting any
SETTING:

resistance compared to other treatment categories (P = 0.02); 53.8% of patients with any resistance experienced poor outcomes, compared to 16.6% of pansusceptible cases (P = 0.02). There was a trend towards poor outcome in the treatment failure category (42.9%, P = 0.13). C O N C L U S I O N : The retreatment category treatment failure is associated with a high prevalence of resistance in an area of high human immunodeficiency virus (HIV) prevalence. The treatment failure category should be used to identify patients who may benefit from alternative regimens using directed, intensified therapy or second-line agents instead of the current standard retreatment regimen. K E Y W O R D S : retreatment; Category II regimen; multidrug-resistant tuberculosis; treatment category; outcome

THE HIGH PREVALENCE of human immunodeficiency virus (HIV) infection has fueled the rates of tuberculosis (TB) in South Africa. According to the World Health Organization (WHO) global TB 2008 report, almost half of all patients diagnosed with TB in South Africa are co-infected with HIV.1 Although HIV infection has not been shown to increase the rate of TB resistance in various studies,2,3 it is still not clear whether HIV infection has any role in the development of TB resistance. In 2006, the province of KwaZuluNatal (KZN), South Africa, registered 2806 cases with multidrug-resistant TB (MDR-TB, defined as resistance to at least rifampicin [RMP, R] and isoniazid [INH, H]), representing 2.67% of all TB cases, the highest rate of all South African provinces.4 Among the MDR-TB cases, 279 extensively drug-resistant TB (XDR-TB) cases were identified in 2006.4

In 2008, the WHO reported that in 2006, retreatment cases (defined as smear-positive cases in patients previously treated for TB) represented 20% of all notified cases in South Africa. TB retreatment cases are at higher risk than new cases of harboring resistant TB bacilli, including MDR-TB.58 The recommended treatment regimen for retreatment cases is a prolonged, reinforced 8-month regimen (Category II regimen) which adds streptomycin (SM, S) during the intensive phase and ethambutol (EMB, E) during the consolidation phase, respectively (2HRZES/1HRZE/5HRE*).9 The WHO currently recommends treatment of true treatment failures and suspected MDR cases with especially designed
* Numbers before the letters indicate the duration in months of the phase of treatment.

Correspondence to: Gonzalo G Alvarez, Division of Respirology and Infectious Diseases, University of Ottawa at The Ottawa Hospital, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada. Tel: (+1) 613 737 8899. Fax: (+1) 613 737 8537. e-mail: galvarez@ohri.ca Article submitted 11 February 2009. Final version accepted 25 May 2009.

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standardized regimens.10 However, in resource-poor settings with poor TB program performance and limited access to second-line drugs, the reinforced 8-month regimen is still recommended.9 In this setting, it is thought that most MDR-TB suspects are treatment defaulters, and likely do not exhibit true bacteriological failure. Several studies have demonstrated that this regimen is inadequate for retreatment cases due to the high level of resistance among this group. Patients with a prior TB treatment history are more likely to harbor resistant TB compared to new cases.5,7,8 In a retrospective case series in Vietnam, the cure rate of the Category II regimen in patients categorized as treatment failures or relapses who were later found to have MDR-TB was very poor (33% cure), and comparable to historical studies when no chemotherapy was available.11 It has been suggested that such inadequate regimens may result in further resistance or amplification of resistance, leading to the development of MDR-TB.6,7,12 Evidence suggesting that MDR-TB prevalence is high in patients categorized as treatment failures in an area of low HIV prevalence has been documented.6,13 In a recent ecological study,14 data collected from more than 100 countries showed that the rate of failure following retreatment with the Category II regimen was significantly increased as the prevalence of MDR reached a tipping point of 3%. Once the prevalence of MDR exceeded 3%, the rate of failure in retreatment cases doubled, from 5% to 10.6% (P < 0.0001). The MDR rate among all cases of TB in KZN, South Africa, is 2.7%.1 Furthermore, South Africa uses the same standardized retreatment regimen used by other countries.14 This is in contrast with a study performed in a low HIV and MDR-TB prevalence country15 which demonstrated that the Category II regimen had a low rate of failure among retreatment cases. The present study examines the epidemiology of retreatment cases in a chronic care TB referral hospital in an area with high HIV and high MDR-TB prevalence.

and TB data for each patient were extracted from the hospital register and the TB case register. TB culture and susceptibility results were tracked through the provincial laboratory system. Due to the lack of a single unique patient identifier, cultures were matched to patients using the patients full name and age, allowing for 1 year discrepancy, and the DGH identification number assigned to patients on admission. HIV status was not recorded in the national TB registers and therefore was not available. TB smears and cultures are prepared using the Mycobacteria Growth Indicator Tube (MGIT) 960 liquid system (BD Diagnostics, Sparks, MD, USA) followed by drug susceptibility testing (DST) on solid Middelbrook 7H10 mini-plates in the reference laboratory. Resistance to ciprofloxacin, EMB, INH, kanamycin (KM), RMP and SM is routinely tested. When multiple cultures with different DST results were found for a patient, the culture with the highest resistance profile obtained within the 6-month period pre- and post-treatment start date was included. Inclusion criteria All pulmonary TB cases categorized as retreatment cases using the WHO case definition, on the standard WHO retreatment regimen in accordance with the South African national guidelines,16 admitted to DGH and with a positive TB culture and DST results available for analysis, were included. Exclusion criteria All cases with new or extra-pulmonary TB or nontuberculous mycobacteria (NTM) were excluded. If cultures were negative, failed to grow, were contaminated or data were missing, the patients were excluded, as TB disease could not be confirmed. Denitions DGH retreatment cases are defined and treated according to South African national guidelines,16 which follow WHO guidelines. Polyresistance is defined as resistance to more than one drug but not INH and RMP together. XDR-TB is defined as MDR-TB plus resistance to fluoroquinolones and to at least one of the following injectable drugs: capreomycin, KM and amikacin.17 Ethics The study protocol was approved by the Edendale Hospital Ethics Research Committee. Statistical analysis In the description of subjects, categorical data were expressed by percentages and continuous variables as mean and standard deviation. All proportions were compared using the 2 test statistic and Fishers exact

STUDY POPULATION AND METHODS

Study population Doris Goodwin Hospital (DGH) in Pietermaritzburg, South Africa, is a 126-bed chronic care facility that serves exclusively as the regional referral hospital for TB retreatment cases. DGH receives patient referrals from over 50 community clinics and hospitals in the region. Pulmonary TB cases with dyspnea, hemoptysis, fever (>38C), severe emaciation, persistent cough, significant comorbidities or complications from TB, or cases living too far from a community treatment center that provides SM injections, are admitted to this facility. All patients admitted to DGH from 1 January 2006 to 29 June 2007 were included. Demographic

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test, where appropriate. All analyses were performed using SAS version 9 (SAS, Cary, NC, USA).

Table 1 Patient demographics (n = 197)

Variables Age, years, mean [SD] Sex Male Female Retreatment category After completion After cure Treatment failure Treatment after interruption Outcome Discharged from DGH Died Transferred Absconded Unknown Length of stay, days, median [range]
SD = standard deviation; DGH = Doris Goodwin Hospital.

n (%) 36.2 [10.1] 124 (62.9) 73 (36.5) 82 (41.6) 40 (20.3) 14 (7.1) 61 (31.0) 139 (70.6) 39 (19.8) 12 (6.1) 4 (2.0) 3 (1.5) 83 [57.5107]

RESULTS
Of 612 patients admitted to DGH during the study period, 197 were eligible for inclusion. The most common reason for exclusion was the inability to confirm TB (culture result missing or negative, n = 332). Non-pulmonary TB, absence of DST results and inability to confirm a patient as a retreatment case were other reasons for exclusion (Figure). Demographics The majority of the patients were male (62.9%), and the mean age was 36.2 years. Most (41.6%) retreatment patients admitted to DGH were in the treatment completion category, which meant that they had previously completed treatment but did not have proof of cure (no smears available on at least two occasions prior to the completion of treatment). The median length of hospitalization was 83 days, reflecting the approximate length of the intensive phase of the standard retreatment regimen, which requires SM injections (Table 1).

TB cultures and drug susceptibility patterns DST results were available for 197 of 612 retreatment cases (32.2%): 145 (73.6%) were susceptible to all first-line drugs, 29 (14.7%) were MDR and 3 (1.5%) were XDR (Table 2). Among the three XDR-TB cases identified, two died and one had absconded; the patient was eventually found through community tracers, and was referred to an MDR-TB hospital for further follow-up and treatment. Of the 197 patients, 52 (26.4%) exhibited resistance to one or more drugs. The proportion of patients with any resistance was higher in the treatment failure category (57.1%) compared to after interruption, after completion and after cure (25.9%, 19.5% and 35.0%, respectively). This difference was significant (P = 0.02; Table 2). Outcomes In-hospital deaths occurred in 39/197 patients (19.8%). A poor outcome, as defined by death or transfer from the chronic care hospital (DGH) to the acute care hospital, was observed in 52/197 patients (26.4%). Patients with any resistance were more likely to experience a poor outcome than patients who were susceptible to all first-line drugs (any resistance 28/52 [53.9%] vs. fully susceptible 24/145 [16.6%]; P < 0.0001). MDR- and XDR-TB cases were more likely to have a poor outcome (MDR and XDR, 24/32 [75%] vs. all other patients in retreatment cohort, 28/165 [17.0%]; P < 0.0001). There appears to be a stepwise increase in poor outcome with increasing resistance (Table 3): 42.9% of the patients in the treatment failure category suffered a poor outcome, compared to 26.8% after completion, 25.0% after cure, and 22.9% after interruption (P = 0.13; Table 4).

DISCUSSION
Figure Patients included in analysis who had conrmed pulmonary TB with culture and DST results. TB = tuberculosis; DST = drug susceptibility testing.

In this retrospective cohort of pulmonary retreatment TB cases on Category II retreatment from an area of

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Table 2

Susceptibility patterns related to retreatment category

After completion (n = 82) n (%) After cure (n = 40) n (%) 26 (65.0) 14 (35.0) 3 (7.5) 0 11 (27.5) 0 Treatment failure (n = 14) n (%) 6 (42.9) 8 (57.1) 3 (21.4) 0 5 (35.7) 0 Treatment after interruption (n = 61) n (%) 47 (77.0) 14 (25.9) 6 (9.8) 0 6 (9.8) 2 (3.3)

Total (N = 197) 145 52* 19 1 29 3

Pansusceptible Any resistance Monoresistant Polyresistant MDR XDR

66 (80.5) 16 (19.5) 7 (8.5) 1 (1.2) 7 (8.5) 1 (1.2)

* P = 0.02. MDR = multidrug-resistant; XDR = extensively drug-resistant.

high HIV prevalence, high in-hospital mortality and a high rate of MDR-TB were observed. The retreatment category treatment failure was associated with a high prevalence of resistance compared to other treatment categories. A trend towards a higher rate of poor outcomes compared to other retreatment categories was noted in the treatment failure category. Retreatment cases had a high rate of in-hospital mortality (19.8%) and poor outcome (26.4%), as defined by death or escalation of care (i.e., transferred to an acute care facility). Poor outcomes were observed
Table 3

in 53.8% of patients with any resistance, compared to 16.6% of pansusceptible cases (P < 0.0001). A stepwise increase in poor outcome with increasing resistance (Table 3) was observed. A higher proportion (42.9%) of patients in the treatment failure category suffered a poor outcome compared to the other categories. Although this result was limited by sample size and did not reach statistical significance, a trend suggesting an association between the retreatment category treatment failure and poor outcome was noted (Table 4). Mortality may have been higher in our

Outcomes related to Mycobacterium tuberculosis drug susceptibility patterns

Pansusceptible (n = 145) n (%) 116 (80) 24 (16.6) 23 (15.9) 1 (0.7) 2 (1.4) 3 (2.1) Monoresistant (n = 19) n (%) 15 (78.9) 4 (21.1) 2 (10.5) 2 (10.5) 0 0 MDR (n = 29) n (%) 7 (24.1) 21 (72.4) 12 (41.4) 9 (31.0) 1 (3.4) 0 XDR (n = 3) n (%) 0 3 (100) 2 (66.7) 1 (33.3) 0 0 Total (N = 197) 139 52 39 13 3 3

Outcome* Discharged Poor outcome Died Transferred Absconded Unknown

* Outcomes are mutually exclusive: discharged = from DGH to the community after completion of intensive phase treatment; poor outcome = died or transferred to an acute care hospital; patient died = death occurring at DGH during admission; transferred = escalation of care by transfer to an acute care facility from DGH; absconded = without continuation of treatment; unknown = no information was recorded in the registers. P < 0.0001. Patient initially absconded, but was later referred to an MDR-TB treatment hospital. MDR = multidrug-resistant; XDR = extensively drug-resistant; DGH = Doris Goodwin Hospital; TB = tuberculosis.

Table 4

Outcomes related to retreatment category

After completion (n = 82) n (%) 57 (69.5) 22 (26.8) 19 (23.1) 3 (3.7) 2 (2.4) 1 (1.2) After cure (n = 40) n (%) 29 (72.5) 10 (25.0) 6 (15.0) 4 (10.0) 0 1 (2.5) Treatment failure (n = 14) n (%) 8 (57.1) 6 (42.9) 3 (21.4) 3 (21.4) 0 0 Treatment after interruption (n = 61) n (%) 45 (73.8) 14 (22.9) 11 (18.0) 3 (4.9) 1 (1.6) 1 (1.6)

Outcome* Discharged Poor outcome Died Transferred Absconded Unknown

Total (N = 197) 139 52 39 13 3 3

* Outcomes are mutually exclusive: discharged = from DGH to the community after completion of intensive phase treatment; poor outcome = died or transferred to an acute care hospital; patient died = death occurring at DGH during admission; transferred = escalation of care by transfer to an acute care facility from DGH; absconded = without continuation of treatment; unknown = no information was recorded in the registers. P = 0.13. DGH = Doris Goodwin Hospital.

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cohort compared to the national data on retreatment cases due to the increased severity of TB disease in patients admitted to this chronic care TB facility. However, a comparable Malawian study18 demonstrated similar mortality rates, of approximately 25%, among retreatment cases. Information on HIV status was not available from the national TB registers; the contribution of HIV disease to all-cause mortality in this study is therefore not known. However, as previously mentioned, the rate of TB patients co-infected with HIV is 53%.1 The rate of MDR-TB was high, at 16.2%, more than double the observed South African national rate of 7.7% of retreatment cases collected in 2001. The rate of resistance among retreatment cases in the present study is higher than in other TB retreatment studies conducted in Malawi (4%) and Benin (11.1%), which have comparable HIV prevalence rates and programmatic challenges.18,19 This difference may have been related to the increased severity of TB disease in the patients admitted to this chronic care TB facility compared to national data, which would include the healthier out-patient population. It could also have been a result of an amplified resistance effect secondary to using Category II in retreatment cases where there is a high MDR prevalence rate. The retreatment category treatment failure predicted resistance, with 57.1% of patients in this category exhibiting any drug resistance compared to after completion, after cure and after interruption (19.5%, 35%, and 25.9%, respectively; Table 2). In a prospective cohort study,6 treatment failure cases among new smear-positive patients in Vietnam had a higher rate of MDR-TB compared to relapse or after cure patients in a region of low HIV prevalence. The study also demonstrated that the acquisition of MDR-TB was more common in patients with primary resistance to more than one drug than among fully susceptible and monoresistant cases.6 Furthermore, a case series in Vietnam11 showed acquisition of additional resistance in MDR-TB patients on Category II, underscoring the effect of resistance amplification in the absence of effective treatment. The amplifier effect has been described by several groups,20,21 and its contribution to an outbreak of MDR-TB in Peru is well documented.12 It has been suggested that Category II retreatment of treatment failure cases promotes longer infectiousness, increased drug resistance, repeated failure and increased mortality.22 Some have therefore advocated for treatment failure cases to receive a standard retreatment regimen that includes second-line drugs, or an individualized regimen if direct DST is available.23 A Peruvian study demonstrated higher cure rates with an expanded retreatment regimen that included empiric second-line agents, followed by susceptibility guided therapy, compared to standard Category II treatment.24 Alternatively, an effective empiric retreat-

ment regimen could be chosen based on regional susceptibilities to simplify the approach. However, this approach may be limited by increased side effects among patients who are labeled retreatment cases but are susceptible to all first-line drugs. Our study demonstrated that almost 75% of all retreatment patients were susceptible to all first-line drugs. These patients could have been treated by the Category I regimen and did not need to be on Category II, which put them at higher risk of side effects. The programmatic difficulties and cost of treating patients with second-line drugs provide formidable challenges. Focusing our efforts on the treatment failures where the highest concentration of MDR-TB is found amongst the different retreatment categories may allow rapid MDR-TB diagnostic technologies and empiric regimens to be tailored to the local resistance patterns. However, the Category II retreatment regimen has been shown to be a satisfactory approach in some settings such as Nicaragua, where the MDR-TB rate is low.15 Identification of patients harboring a resistant strain, especially those with MDR- and XDR-TB, is of paramount importance for the isolation, management and treatment of TB patients. Using epidemiologic categories as tools to identify patients at risk for resistance and poor outcomes has limitations; however, they are inexpensive and easily implementable in developing countries. These categories can also set the stage for improved yield in new TB diagnostics by increasing the pre-test probability of having TB disease. Training health care staff to accurately categorize patients is essential for maximal impact. There are several limitations to this study. First, of 612 consecutive admissions to a TB retreatment care hospital, only about half (46%) had culture confirmed TB (Figure). Those retreatment patients who were culture-negative (22%) may have had the wrong diagnosis (not TB), inadequate sample collection (not enough volume or saliva), and problems in sample transport (heat, prolonged time from collection to processing, leakage) or a problem in sample processing (overly harsh decontamination, bacterial overgrowth). A third of the patients (32%) did not have their sputum sent for analysis, likely due to patients not being able to produce adequate sputum samples and lack of induced sputum facilities. Our study may have underestimated mortality, as patients may have died prior to referral or after discharge from DGH. Lastly, the findings represent a TB chronic care referral hospital in an area of high HIV and MDR prevalence, and may not be generalizable to other regions.

CONCLUSION
Category II retreatment of patients in the treatment failure group may not portend a good outcome in regions where the prevalence of HIV and MDR-TB are

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high. The treatment failure category should be used to identify patients who may benefit from a retreatment regimen using second-line agents instead of current standard retreatment therapy. More studies are needed to evaluate a targeted treatment approach for retreatment TB cases in resource-limited settings. Acknowledgements
The authors thank Matron VanDenBroek, Sister Lungile, Bongani and the staff at DGH for their help in data acquisition, and Y Su for assistance in statistical analysis. They appreciate the support of the KZN Department of Health.

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References
1 World Health Organization. Global tuberculosis control 2008: surveillance, planning, financing. WHO/HTM/TB/2008.393. Geneva, Switzerland: WHO, 2008. http://www.who.int/tb/ publications/global_report/2008/en/index.html Accessed April 2009. 2 Murray J, Sonnenberg P, Shearer S C, Godfrey-Faussett P. Human immunodeficiency virus and the outcome of treatment for new and recurrent pulmonary tuberculosis in African patients. Am J Respir Crit Care Med 1999; 159: 733740. 3 Chaisson R E, Clermont H C, Holt E A, et al. Six-month supervised intermittent tuberculosis therapy in Haitian patients with and without HIV infection. Am J Respir Crit Care Med 1996; 154: 10341038. 4 Department of Health of South Africa. Tuberculosis strategic plan for South Africa 20072011. Pretoria, South Africa: Department of Health of South Africa, 2007. http://www.info.gov. za/gazette/otherdocs/2007/tbstratplan.pdf Accessed February 2009. 5 Telzak E E, Chirgwin K D, Nelson E T, et al. Predictors for multidrug-resistant tuberculosis among HIV-infected patients and response to specific drug regimens. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) and the AIDS Clinical Trials Group (ACTG), National Institutes for Health. Int J Tuberc Lung Dis 1999; 3: 337343. 6 Quy H T, Lan N T, Borgdorff M W, et al. Drug resistance among failure and relapse cases of tuberculosis: is the standard re-treatment regimen adequate? Int J Tuberc Lung Dis 2003; 7: 631636. 7 Espinal M A, Kim S J, Suarez P G, et al. Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcomes in 6 countries. JAMA 2000; 283: 25372545. 8 Faustini A, Hall A J, Perucci C A. Risk factors for multidrug resistant tuberculosis in Europe: a systematic review. Thorax 2006; 61: 158163. 9 World Health Organization. Treatment of tuberculosis: guidelines for national programmes. 3rd ed. WHO/CDS/TB/2003. 313. Geneva, Switzerland: WHO, 2003. http://www.who.int/ tb/publications/cds_tb_2003_313/en/ Accessed February 2009. 10 World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. WHO/HTM/TB/

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2006.361. Geneva, Switzerland: WHO, 2006. http://www.who. int/tb/publications/2006/who_htm_tb_2006_361/en/index. html Accessed February 2009. Lan N T N, Lademarco M F, Binkin N J, Tung L B, Quy H T, C N V. A case series: initial outcome of persons with multij drug-resistant tuberculosis after treatment with the WHO standard retreatment regimen in Ho Chi Minh City, Vietnam. Int J Tuberc Lung Dis 2001; 5: 575578. Farmer P, Kim J Y. Community based approaches to the control of multidrug resistant tuberculosis: introducing DOTSplus. BMJ 1998; 317: 671674. Kritski A L, Rodrigues de Jesus L S, Andrade M K, et al. Retreatment tuberculosis cases. Factors associated with drug resistance and adverse outcomes. Chest 1997; 111: 11621167. Mak A, Thomas A, Del Granado M, Zaleskis R, Mouzafarova N, Menzies D. Influence of multidrug resistance on tuberculosis treatment outcomes with standardized regimens. Am J Respir Crit Care Med 2008; 178: 306312. Heldal E, Arnadottir T, Cruz J R, Tardencilla A, Chacon L. Low failure rate in standardised retreatment of tuberculosis in Nicaragua: patient category, drug resistance and survival of chronic patients. Int J Tuberc Lung Dis 2001; 5: 129136. Department of Health of South Africa. The South African Tuberculosis Control Programme: practical guidelines. Pretoria, South Africa: Department of Health of South Africa, 2004. http://www.kznhealth.gov.za/chrp/documents/Guidelines/ Guidelines%20National/Tuberculosis/SA%20TB%20Guide lines%202004.pdf Accessed February 2009. Dorman S E, Chaisson R E. From magic bullets back to the magic mountain: the rise of extensively drug-resistant tuberculosis. Nat Med 2007; 13: 295298. Salaniponi F M, Nyirenda T E, Kemp J R, Squire S B, GodfreyFaussett P, Harries A D. Characteristics, management and outcome of patients with recurrent tuberculosis under routine programme conditions in Malawi. Int J Tuberc Lung Dis 2003; 7: 948952. Affolabi D, Adjagba O A, Tanimomo-Kledjo B, Gninafon M, Anagonou S Y, Portaels F. Anti-tuberculosis drug resistance among new and previously treated pulmonary tuberculosis patients in Cotonou, Benin. Int J Tuberc Lung Dis 2007; 11: 12211224. Mitchison D A, Nunn A J. Influence of initial drug resistance on the response to short-course chemotherapy of pulmonary tuberculosis. Am Rev Respir Dis 1986; 133: 423430. Farmer P, Bayona J, Becerra M, et al. The dilemma of MDR-TB in the global era. Int J Tuberc Lung Dis 1998; 2: 869876. Espinal M A. Time to abandon the standard retreatment regimen with first-line drugs for failures of standard treatment. Int J Tuberc Lung Dis 2003; 7: 607608. Caminero J A. Management of multidrug-resistant tuberculosis and patients in retreatment. Eur Respir J 2005; 25: 928 936. Saravia J C, Appleton S C, Rich M L, Sarria M, Bayona J, Becerra M C. Retreatment management strategies when firstline tuberculosis therapy fails. Int J Tuberc Lung Dis 2005; 9: 421429.

RSUM
C O N T E X T E : Au KwaZulu-Natal, Afrique du Sud, une tuberculose germes multirsistants (TB-MDR) se trouve actuellement chez 7,7% des cas de retraitement. La prvalence de la TB-MDR savre leve chez les patients classs comme checs du traitement. Des rapports rcents ont mis en question lefficience du rgime de Catgorie II de lOrganisation mondiale de la Sant dans les cas de TB en retraitement.

Dterminer dans quelle mesure la catgorie de traitement permet de prdire les types de sensibilit et les rsultats dans une population de cas hospitaliss pour retraitement de TB. S C H M A : Cohorte rtrospective de 197 cas de retraitement pour TB pulmonaire. R S U LTAT S : Dans les cas de retraitement soumis au rgime de retraitement standard, la mortalit hospitalire
OBJECTIF :

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est leve (19,8%) ou le rsultat mdiocre (26,4%), et le taux de TB-MDR est lev (16,2%). La catgorie dchec de traitement permet de prdire la rsistance, 57,1% des patients dmontrant nimporte quel type de rsistance par comparaison avec dautres catgories de traitement (P = 0,02). Les rsultats sont mdiocres chez les 53,8% de patients chez qui nimporte quel type de rsistance existe, par comparaison 16,6% dans les cas sensibles tous les mdicaments (P = 0,02). Il y a une tendance vers les rsultats mdiocres (42,9% ; P = 0,13) dans la catgorie dchecs du traitement.

CONCLUSION :

La catgorie de retraitement chec du traitement est en association avec une prvalence leve de rsistance dans une zone de prvalence leve du VIH. La catgorie chec du traitement doit tre utilise pour identifier les patients qui pourraient bnficier de rgimes alternatifs utilisant une thrapie directe intensifie par des agents de deuxime ligne au lieu du rgime standard actuel de retraitement.

RESUMEN

La frecuencia de tuberculosis multidrogorresistente (TB-MDR) en los casos de retratamiento puede alcanzar 7,7% en KwaZulu-Natal, en Sudfrica. Se sabe que la prevalencia de TB-MDR es alta en los pacientes clasificados como fracasos teraputicos. Algunos informes recientes han cuestionado la eficacia prctica del tratamiento de Categora II de la Organizacin mundial de la Salud en los casos de retratamiento de la TB. O B J E T I V O : Determinar si la categora de tratamiento predice el tipo de sensibilidad a los medicamentos y los desenlaces teraputicos en una poblacin de pacientes hospitalizados por retratamiento de la TB. M T O D O S : Estudio retrospectivo de cohortes de 197 casos de retratamiento de TB pulmonar. R E S U LTA D O S : Los pacientes que recibieron la pauta estndar de retratamiento presentaron una alta tasa de mortalidad intrahospitalaria (19,8%) o un desenlace desfavorable (26,4%) y una alta tasa de TB-MDR (16,2%). La categora de fracaso teraputico predijo la resistenMARCO DE REFERENCIA :

cia, pues 57,1% de estos pacientes exhibieron algn tipo de resistencia en comparacin con las dems categoras de tratamiento (P = 0,02). Se observ un desenlace desfavorable en 53,8% de los pacientes que presentaron algn tipo de resistencia, en comparacin con 16,6% de los casos sensibles a todos los medicamentos (P = 0,02). Se encontr una tendencia hacia el desenlace desfavorable en la categora de fracaso teraputico (42,9% ; P = 0,13). C O N C L U S I N : Los casos de retratamiento de la categora fracaso teraputico se asocian con una alta frecuencia de resistencia en zonas donde existe una alta prevalencia de infeccin por el virus de la inmunodeficiencia humana. Se debe usar la categora de fracaso teraputico con el fin de escoger a los pacientes en quienes puede ser til otra opcin teraputica como el tratamiento intensivo o los medicamentos de segunda lnea, en lugar de la administracin de la pauta corriente estndar de retratamiento.