Treatment delay and associated factors among adults with drug resistant tuberculosis at treatment initiating centers in the Amhara regional state, Ethiopia

Drug resistant tuberculosis (DR-TB) has been one of the leading public health problems globally [1]. There were an estimated 580,000 new cases and 230,000 deaths from multi-drug resistant tuberculosis (MDR-TB) according to the 2018 global TB report [2]. Thirty high drug resistant tuberculosis burden countries shared more than 85% of the global DR-TB prevalence [1]. About 20% of previously treated and 4.1% of the new patients had drug resistant tuberculosis [1, 3, 4]. Ethiopia is one of the highest drug resistant TB burden countries with an estimated 2100 MDR-TB cases annually [5]. Drug resistant TB treatment is long, extending from 18 to 24 months on toxic drugs. Successful treatment outcomes of DR-TB patients remain around 50% [4, 6].

Effective TB prevention and control was achieved through early case detection and prompt treatment initiation [7]. Different evidences show that timely initiations of drug resistant tuberculosis treatments are of paramount importance for increasing favorable outcomes and halting person to person transmissions [8]. In Ethiopia however TB case detection rate which was characterized by delayed treatment commencement after diagnosis was 64% [9‐11]. Treatment delay has been one of the major factors imposing a challenge to TB prevention and control [12]. Delayed treatment initiation leads to increased morbidity, mortality, and the progression of the disease to severe and complicated forms [13‐15]. Besides, patients with cavitary lesions and high bacilli loads are associated with an increased primary form of drug resistant TB and rapid person-person transmissions [16].

Treatment delays which were studied in both high and low income countries significantly varied from 9 days in China [8] to 19 days in India [17], and from 10 days in South Africa [18] to 18 days in Zimbabwe [19]. Patient related factors such as health seeking behavior and distance from health facilities from residences [18] as well as the history of anti-TB treatment [8, 15] and diagnostic modalities [6, 20, 21] were significantly associated with delayed treatment initiations. In addition, health facility factors were contributing to treatment delays due to inadequate treatment initiating centers (TICs) with limited beds [22].

The World Health Organization (WHO) has conditionally recommended the ambulatory model of care for a timely initiation of drug resistant TB treatment [23]. The Ethiopia Federal Ministry of Health has been expanding ambulatory DR-TB treatment centers. Though some studies have been conducted in other high burden countries, evidence of treatment delays of DR-TB patients is still scarce.

Therefore, this study aimed to determine treatment delays and its associated factors in the Amhara Regional State. The study could provide insight about treatment delays to clinicians and other stakeholders.

This study showed the median time to initiate drug resistant tuberculosis treatment after a confirmed diagnosis was 8 days. Previous history of injectable drug use and diagnostic modalities were independent predictors of delays. The median time to initiate DR-TB treatment in this study was shorter than those of studies conducted in Bangladesh (median of 10 days) [22], Gauteng, South Africa (median of 10 days) [24], and Harare, Zimbabwe (median of 18 days) [19]. This might be due to differences in sample sizes, drug resistant tuberculosis diagnostic modalities, health care systems, and distance from reference laboratory which affects result turnaround time.

Treatment initiations among DR-TB patients mainly depended on baseline laboratory investigations [6], PMDT panel team decisions, the availability of drugs, and the DST result of patients [25]. Accordingly, Fig. 1 shows that the median time to initiate drug resistant tuberculosis treatment significantly decreased from a median of 27.5 and 88 days in 2010 and 2011 to 5 days in 2017. The possible explanation might be the introduction of new diagnostic methods, like Gene Xpert, which decreased laboratory result turnaround time from national reference laboratories. Gene Xpert provides worthy advantages for both mycobacterium case detection and Rifampicin resistance pattern identification within a short period of time [26]. Furthermore, the DR-TB treatment policy revision from hospital based to ambulatory model of care in health facilities helps in the reduction of waiting time for admission and commencement of treatment. Though improvements had been made to reduce treatment delay overtime, still greater efforts are needed to reduce delay to below 8 days.

Patients who had history of injectable anti-TB drugs from previous tuberculosis treatment courses were two times more likely to have treatment delays than patients had no prior history of injectable anti-TB drug use. This study was supported by a previous report from India [14]. The majority of the patients in this study had tuberculosis treatment experience on category-II streptomycin containing regimen resulting from poor implementations of DST among presumptive DR-TB patients. Patients experiencing injectable anti-TB drug from previous treatment courses had complaints of injection site pain and abscess. In addition, such patients frequently developed serious side effects, especially hearing impairment and renal function deterioration [27, 28]. Hence, PMDT team follow up renal function tests and hearing assessments before the initiation of treatment, frequently. Second line anti-TB drugs are highly toxic with severe and life-threatening adverse effects which result in reducing dosing intervals or suspending temporally the second line injectable anti-TB drug until patients recover. This may lead to late initiation of treatment compared to patients who had not previous injectable anti-TB drugs. This finding suggests that further improvement be made in the treatment initiation through adequate counselling and close follow ups early after diagnosis before the patient status declines as a result of fatigue from previous injectable anti-TB drugs. Currently the WHO approved short regimen reduced treatment duration to 9–12 months and the incidence of adverse drug effects [29]. Unfortunately, no patient was on Bedaquiline and Delanamide containing short regimen during our data collection period.

Drug resistant tuberculosis diagnostic modalities were significantly associated with treatment delay among DR-TB patients. Thus, patients diagnosed by conventional culture and Line probe assay (LPA) experienced treatment delays. A similar finding was observed in studies done in Europe [15, 20, 30], Asia [7, 21, 31], and Africa [19, 32‐34]. This may be so because participants were diagnosed by Gene Xpert done directly from sputum with no need for prior smear examination and facilitated the simultaneous detection of MTB and Rifampicin resistance. It provides results within two hours instead of several days and weeks unlike LPA and culture, respectively. LPA may also take several weeks in smear negative patients since culture is still needed prior to LPA examination such patients [28]. In addition, Gene Xpert takes less time to send results back to clinicians because the test is done onsite from TICs by themselves while culture and LPA are performed in reference laboratories located some distance from the TICs [21]. Some evidence from Sub-Saharan Africa also showed that the use of the Gene Xpert diagnostic modality resulted in the rapid initiation of tuberculosis treatment within same day as the diagnosis along with timely information about the presence or absence of Rifampicin-resistance [16, 35]. Therefore, this suggests that the need to scale up simple and rapid molecular diagnostic tests, like Gene Xpert that can be used at the lowest health care facilities. The finding supports the strategy to scale up this test at service delivery points to achieve early initiation of treatments.

In contrast to our finding, previous studies indicated that time from diagnosis to treatment initiation did not differ significantly among the three diagnostic modalities [12, 36, 37]. Several other studies showed that different socio-demographic factors [4, 22] and clinical characteristics [6, 8, 15] were associated with treatment delays. In however our study socio-demographic characteristics of patients (sex, age, education, occupation, residence, /rural or urban), and clinical characteristics, like baseline BMI, HIV/AIDS, and extra pulmonary TB or pulmonary TB were not associated with delays.

Firstly, since we have used secondary data, we could not address all potential variables like average monthly income, distance from TICs, and time took to reach the centers. Secondly, the fact that no WHO of national cut off point available to determine the impact of delays DR-TB patients made the comparison of main findings of the work difficult. Thirdly, differences in the diagnosis modalities relating to conforming treatment history by clinicians and biases due to missing and outcome variables might have resulted in an overall misclassification.

Treatment delay was long, especially among patients diagnosed by Culture or LPA and those who had prior history of injectable anti-TB drug. This suggests the need for universal accesses of rapid molecular diagnostic tests, such as Gene Xpert, and the PMDT teams need to decide promptly to minimize unnecessary delays.