Management of Drug Resistant Tuberculosis Patients, Egypt experience

1. Management of Drug Resistant Tuberculosis Patients,Egypt experience

2. Study Objective • To evaluate the so far effect of treatment on the first treatment cohort of MDR-TB patients and analysing some factors that might affect the interim outcome.

3. Materials & Methods • The pilot program had the initial approval of the GLC/WHO to treat 75 patients in the first DR-TB centre in Abbassia chest hospital for inpatient care of patients with MDR-TB. • One floor of 12 rooms was chosen and modified to apply the necessary infection control procedures. • Mission from the GLC in early 2003 before approval of the program was issued. • This centre was assigned for the inpatients treatment while ambulatory treatment was conducted in TB units after the working staff in these units received 3 days training on management of those patients before they are discharged for ambulatory treatment.

4. Materials & Methods • The national reference laboratory was chosen to do the initial culture and drug susceptibility testing (DST) to determine the resistance pattern of the patient before starting treatment. • The first cohort of patients to be enrolled in the pilot project consisted of chronic patients found in the TBMUs and DSTs were done to all of them to confirm infection with MDR-TB. • The frequency of patient enrolment was determined by the hospital capacity and availability of the drugs. Patients were eligible for treatment if they were proved to be MDR-TB with no absolute exclusion criteria.

5. Materials & Methods • Patient with concomitant diseases or with poor general condition were considered high risk group for close supervision and frequent evaluation. • A formal written consent was taken from every patient before starting treatment. • The proved MDR-TB patients were put on a treatment regimen based on the resistance profile of patients to first line anti-TB treatment and would be modified according to treatment history of the patient. • If the patient gave any history of previous use of the second line anti-TB drugs, which are not available in the market in Egypt, except for Amikacin and Flouroquinolones, the regimen would have been adjusted accordingly. • DST for second line drugs was made for patients who gave history of previous use of the previously mentioned second line anti-TB drugs or showed potential failure to prepare the retreatment regimen. Accordingly, the regimen used can be considered, more or less an individualized one.

6. Treatment regimens • MDR-TB patients were started on a regimen consisting Kanamycin, Ofloxacin, Ethionamide, p-aminosalicylic acid (PAS), Cycloserine. • Patient received the injectable drug for nine months, the first three months on daily basis, and then every other day. The treatment duration was 21 months for patients who were enrolled and completed treatment before the emergency update of the programmatic management of DR-TB guidelines were issued with recommendation of at least 18 months treatment after sputum culture conversion. • The duration of hospitalization was about 9 months, during the use of an injectable drug and the clinical condition of the patient and tolerability of the drugs. Patients were tested for HIV at the start of treatment.

7. Treatment regimens • Sputum smear and culture were conducted monthly, and, when culture positive • Chest radiographs were performed at enrolment, and every 6 months thereafter • Adverse events were managed rapidly and aggressively with the ancillary drugs and with the help of specialists like a psychiatrist, without permanent removal of a drug from the treatment regimen for any patient of the study cohort. • All treatment doses of drugs were directly observed during the hospitalization period, and three times a week after discharge during the ambulatory treatment period. • Resection surgery was undertaken for one of the patients who declared failed and he is now on retreatment as after failure of second-line anti-TB treatment and not included in this analysis after surgery

8. Laboratory testing • Sputum smear microscopy, culture and were conducted according to international standards in Abbassia chest hospital laboratory but DST was conducted only in the national reference laboratory. Smears were assessed using direct microscopy and culture using Lowenstein-Jensen media. • DST was conducted for 4 first-line drugs (isoniazid, rifampicin, ethambutol, streptomycin) and second-line drugs (Capreomycin, Kanamyin, Ofloxacin)

9. Data collection and analysis • A computerized medical record system, Excel based, was instituted from the start of the pilot program. • This system was designed to record significantly more information than that routinely collected in the DOT program, where patient data from the entire treatment course were recorded on a single, two-sided treatment card. • Analyses were performed using SPSS (SPSS version 16.0)

10. Results - Description of the studied group: - • Among the multi-drug resistant (MDR) patients (n=168) admitted to Abbassia Chest Hospital till 30/6/2009 only 65 patients completed their treatment course. •  Their age ranges from 17 to 76 years with the mean = 37.8 ± 12.4 years. Male to female ratio is 46 (70.8 %) to 19 (29.2 %). No statistically significant difference between males and females as regards their mean age (t-test = 1.2, p > 0.05) •  All of the patients were pulmonary tuberculosis except for 1 extra-pulmonary (cervical Pott's); 3 (4.6 %) were new cases and 62 (95.4 %) retreated cases.

11. Results • The number of treatment courses taken before starting second-line treatment ranged from 1 to more than 7 with the median = 3 and mode = 2 courses. •  As regards the resistance pattern: - 51 (78.5 %) patients were resistant to the four first-line drugs hence, they received the treatment regimen I (36 males and 15 females). 13 (20.0 %) patients were resistant to three of them and on treatment regimen II (9 males and 4 female). There is one (1.5 %) male patient resistant to 2 drugs (RH) and on regimen III. Resistance pattern was not significantly different between males and females (Chi-Square = 0.4, p>0.05). •  12 (18.5 %) patients (10 males and 2 female) gave positive history of receiving the second line anti-tuberculosis drugs (Ofloxacin and Amikacin in addition to one Sudanese male patient received all second line drugs) and 53 (81.5 %) patients (36 male and 17 females) denied their use. The sex difference was not statistically significant (Fisher’s Exact test, p>0.05).

12. Results • The duration of TB illness before starting treatment with the second line anti-tuberculosis drugs, it was found that the mean duration = 7.3 ± 6.1 and the median = 6 years • Co-morbidity: - 12 (18.5 %) patients were found to be diabetic (6 males and 6 female) and only 2 (3.1 %) male patient was HCV positive. No statistically significant sex differences were observed for both variables (Fisher’s Exact test, p > 0.05). • There were no HIV positive cases.

13. Distribution of patients according to the time taken for sputum smear to be converted negative

14. Distribution of patients according to the time taken for sputum culture to be converted negative

15. Reported side effects

16. Treatment outcome of the studied patients

17. Some factors that might affect treatment outcome were studied. Of them the following showed significant association with successful treatment: - young age of patients, - non smoking, - no past history of intake of the second-line anti-tuberculosis drugs, - the extension of lung tissue destruction on x-ray findings and - the sputum culture conversion within 3 months of treatment. more than half of the total patients and about 83% of those achieved successful outcome were converted culture negative within the first 3 months of treatment. These factors could be taken as parameters to predict a successful outcome

18. Alcoholism and smoking are among the factors that might contribute to the development of drug resistance and hence, the unsuccessful outcome. The difference in the rate of treatment success was significant with smoking but did not reach the statistical significance among the alcohol or drug users most probably because of the small number of this group of patients. • The clearly observed high mortality rate (about 17%) could be due to that 52.3 % of the cases (34 patients out of the 65) showed extensive unilateral or bilateral lung tissue destruction, and of those who died this proportion was 90.9% ,10 out of 11 patients.

19. Conclusion • About 68 % treatment success is achieved with the first group of MDR-TB cases admitted to Abbassia chest hospital. • The proportion of failures, defaulters and deaths were 9, 6, and 17% respectively. These rate that are comparable with the average treatment success rate reached within the GLC projects and with other reported literatures.

20. The high mortality rate (about 17%) highlighted the importance of continuing the ongoing efforts for the rapid diagnosis and treatment of MDR patients and the urgency of applying the direct observation throughout the whole treatment period. • The significant risk factors for successful outcome included young age of patients, non smoking, and the factors related to treatment which are the most important factors. These are negative history of intake of 2nd line anti-tuberculosis drugs, no cavity in x-ray findings and sputum culture conversion before 3 months of treatment.

21. Recommendations • Decrease the inefficient and unnecessary use of the second-line anti-TB drugs (aminoglycosides&floroquinolones). • Encouragement of the application of direct observation for MDR TB patients throughout their treatment period. • Application of rapid diagnostic techniques for prompt enrollment of patients in the correct treatment regimen. • Strong patient support and follow up system is mandatory to achieve better results especially with MDR TB patients

22. Limitations • The effect of surgical intervention on the treatment outcome of MDR TB patients was not investigated as this treatment modality was not performed widely enough with our patients to evaluate its role. • More data from high risk patients is needed for better evaluation of treatment especially those with diabetes, HCV and HIV infections.