Evaluation of Xpert MTB-RIF guided diagnosis and treatment of rifampicin-resistant tuberculosis in Indonesia: A retrospective cohort study

Abstract

Background: Rifampicin-resistant tuberculosis (RR-TB) is largely underdetected in Indonesia. Xpert MTB/RIF (Xpert) has recently been introduced, prioritizing patients at risk of RR-TB, followed by phenotypic drug-susceptibility (DST) if rifampicin resistance is detected.

Objective: This study investigated Xpert-based management of presumptive RR-TB cases under routine practice in West Java, Indonesia.

Methods: We examined all records of patients tested with Xpert in the referral hospital for West Java in 2015-2016. We measured loss across a limited cascade of care, time to Xpert diagnosis and the commencement of initial second-line treatment, and identified factors associated with diagnostic and treatment delay. Additionally, we analyzed the appropriateness of treatment according to DST results.

Results: Of 3415 patients with presumptive RR-TB, 3215 (94%) were tested by Xpert, of whom 339 (10.5%) were diagnosed as RR-TB. 288 (85%) of 339 RR-TB patients started initial second-line TB treatment, with 48 (14%) patients being lost between diagnosis and pre-treatment assessment. Second-line treatment was commenced at a median of 41 days (IQR 29-70) after RR-TB diagnosis. Delays in both diagnosis and treatment initiation were observed in 104 (52%) of 201 RR-TB patients with identifiable referral date. Rural residence was associated with delay to diagnosis (adjusted OR 2.7; 95%CI 1.5-5.2) and treatment initiation (adjusted OR 2.0; 1.2-3.4). Of 162 patients with available DST result, 107 (66%) had multidrug-resistant tuberculosis (MDR-TB) and 32 (20%) had either pre-extensively drug resistant (pre-XDR) or extensively drug resistant tuberculosis (XDR-TB). We estimated that with the current algorithm 41% of pre-XDR or XDR-TB patients are diagnosed, and 33% of them started on an appropriate treatment regimen.

Conclusions: Many patients with Xpert-diagnosed RR-TB either do not start MDR-TB treatment or encountered diagnostic and treatment delays under programmatic conditions in Indonesia, and most pre-XDR and XDR-TB cases remain undiagnosed. Further expansion and ongoing quality improvement of RR-TB services are urgently needed.

Fig 1. Time to diagnosis and treatment of presumptive rifampicin-resistant TB using Xpert.

Time between microscopic TB diagnosis and patient presentation for Xpert examination (a), Xpert result (b), time between Xpert result and patients visit for pre-treatment assessment (c), initiation of second line treatment (d), total time between microscopic TB diagnosis and diagnosis of RR-TB (e), and total time between RR-TB diagnosis and start of second line treatment (f). Total time between microscopic TB diagnosis and start of MDR-TB treatment (g).

Fig 2. Flow chart of study participants.

MDR-TB: Multidrug-resistant TB, PMDT: Programmatic Management of Drug-resistant TB, NTM: Non-tuberculous Mycobacteria, DST: phenotypic Drug Susceptibility Testing. *pre-XDR (n = 27) and XDR (n = 3). ** Appropriate treatment was defined as compatibility between DST result and the choice of drug-resistant treatment regimen. ***Patients with DST result not suggesting MDR continued their 2nd line treatment according to Indonesian PMDT guideline. ^aThe 200 patients were not tested due to possible reasons, which were: 1) patients didn’t present to the laboratory for Xpert testing; 2) patients weren’t able to expectorate sputum.

Fig 3. Cascade of care and time to diagnosis and treatment of Xpert rifampicin-resistant TB patients.

Values in the bars indicate number (percentages). *12 of 118 with a failed result were imputed as Xpert positive and assigned the censored time of 180 days. **Pre-treatment examination included blood & urine test, HIV test, chest X-ray, audiometry and psychiatric assessment. ***Data were only available for 201 patients. Median (IQR) times between: microscopic TB diagnosis and patient presentation for Xpert examination (a), Xpert examination and Xpert result (b), Xpert result and visit for pre-treatment assessment (c), pre-treatment assessment and initiation of second line treatment (d), microscopic TB diagnosis and diagnosis of RR-TB (e), Xpert result and initiation of second line treatment (f), microscopic TB diagnosis and initiation of second-line treatment (g).

Fig 4. Kaplan Meier curves for time between specific cascade of care steps.

These figures show Kaplan-Meier time-to-event graphs for specific cascade of care steps between registration and Xpert result (n = 351) (A), Xpert result and pre-treatment examination (n = 339) (B), and pre-treatment examination and MDR-TB treatment initiation (n = 291) (C).