Patient referral hampered as most HCWs were unaware of the national guidelines.42

Testing rates were transiently responsive to changes in clinical guidelines and with increased awareness47

Implementingan expanded algorithm signficantly increased DST use and rates of diagnosis51

Xpert and chest X-ray were unevenly distributed.44

Few districts had laboratory capacity29

Non-functional Xpert machines reported, varying by region67

The GxAlert notification system sending short texts messages to TB coordinators when a MDR-TB case was detected. The coordinators also communicated this info with the respective district coordinators31

Lack of necessary infrastructure and tools28 45

HCW blamed for lack of equipment and delays45

“… they take it out on the health workers because, they are the people they see. If there is any form of dissatisfaction with service, if … power outage, …they take it out on you and its very painful… ”45

Unreliable equipment maintenance and electrical fluctuations67

Pre-treatment delays persist after Xpert implementation due to centralisation of clinical requirements like X-ray, liver function tests, and audiometry19

significantly increased treatment rates.35

Decentralisation and Xpert implementation reduced TTI and improved patient outcomes.36

Decentralisation and treatment availability improved treatment rates30

Decentralised Xpert reduced LTAT and improved rates of diagnosis.37

Decentralisation reduced TTI;38

A lack in integration resulted in shortage of materials28 “Our programme is vertical, …there is a shortage of [supplies]; they should integrate so that some of these things could also be budgeted for…”28

Available, decentralised DR-TB treatment a facilitator to early care32

Reasons for DST not done were contamination, failure to grow /loss of viability27

Laboratory operational issues resulted in only half of DST results, even though sputum was collected, and most of the samples reached the NRL. Only very few results got back to requesting facilities.30

Only 32.4% of samples were received at the NRL in 3 years; 58% and 97% of culture and DST had LTAT longer than recommended28

25% of submitted specimens did not have results communicated back to the clinic 67

Only 32.3% of newly diagnosed patients were treated, due to incomplete records on the GxAlert database and miscommunication31

Mean diagnostic delay of 8.1 weeks29

Difficulty in packaging, contamination, batching and transporting samples resulting in prolonged delays in diagnosis.28 “In a parcel of specimens, you could find one specimen … 15 days old and another 3 days old…. I think they [recieve] but they don’t send it on time. Instead they wait for them to be many before sending28

Specimens received at late hours or not in sufficient numbers affect laboratory operations67

An initial negative test result delayed diagnostic process32

Prolonged delay in receiving results from the laboratory32

The use of the Expedited Mail Services for sample transportation helpful if sustained28

High rates (76%) of loss to follow-up led to non-referrals 42

Referrals as per guidelines were not implemented due to not having contact information for treatment facility42

Inadequate tracking of patients and unavailable results for follow-up appointments at hampered access32

"…The clinic phoned me [but] did not say why. I only went [two weeks later] and was informed…that I have MDR-TB. … I was very disturbed that the clinic (had) not told me [earlier]…of this very contagious disease…I think this was very irresponsible of the clinic…”. Delays in communicating results of up to 3 months.32

A lack of specimen referral mechanism noted as a challenge by 43% of HCWs 67

Long waiting times in public factilities,32 45 resulting in patients seeking care in the private sector where TB care options were often not as efficient45 .

Patients referred from a hospital were 8 times more likely not to initiate treatment than clinic referrals50

Patients accessing care in higher level facilities had slightly lower odds of getting tested compared with those in lower levels44

The treatment rate was highest in TB hospitals, with PHC rates higher than for secondary or tertiary hospitals.43

Accessibility of care at a PHC facilitated treatment access. Most adolescents started treatment at a PHC compared with other levels36

In-patients were more likely than outpatients to experience timely treatment33

Variable testing rates between clinics and hospitalsfor all three comparisons47

Patients in private sector had significantly lower odds of getting tested compared with those in public sector44

Private sector as entry-point,32 poor perception of public sector care,32 and low index of suspicion at private facilities29 as barriers to care.

“I went back again and again to the pharmacy and got different medication every time. I must have gone there five times”.32

Public sector care identified as having more DR-TB care options32

“…. There are much better options at the (public) clinic than the private doctors…lots of test which can be taken…”32

Wide regional variations in staff training, sample collection,testing capacity, rates and monitoring27 47 67

Geographic location of referral was not associated with treatment initiation time48

Facilities >250 km away from NRL took longer to receive DST results compared with facilities <50 km30

Significant regional differences in treatment rates and TTI across the nine South African provinces .43

Western Cape patients were more likely to have second-line DST results than the remaining provinces, due to the specific provincial guidelines 27

Utilisation of Xpert increased between 2016 and 2017 (88% increase), and was significantly higher in provincial than in rural hospitals.49

Facilities that were <50 km away from the NRL were more likely to have DSTs done compared with those >250 km away.30

Transportation of samples more difficult in rural areas28

“the transportation …to the NRL is not a problem…. Actually, biggest problem is referring samples from peripheral laboratory to district laboratory where post services is not available”.28

Despite complete rollout of Xpert testing, only 59% of new cases were diagnosed 43

Less than half of RR-TB patients had DST results, as recommended by the guidelines27

Poor guideline adherence was among reasons for incorrect patient screening and Xpert under-utilisation 34 44.

Guidelines not implemented due to patient follow-up perceived as difficult 42

44

Incomplete adherence to National guidelines (51% of patients had DST).30

Health providers’ failure to follow diagnostic algorithms delayed DR-TB testing and led to wrong (first-line) treatment regimens32

“When the results came back they told me I do not take my tablets. I told them ‘but I take my pills every day’. They could not understand why my results were 3-plus positive… The treatment did not help…I started to give up hope” (Xpert-6—a high-risk patient with DR-TB experienced 5-month delay due to not having a test done and initiation on first-line treatment).32

Laboratory staff shortages contributing to delays28 45

“NRL staff have been trying to perform their work but they are overloaded with many specimens from each side of the country. ”.28

Shortage of trained laboratory staff to man the Xpert machines noted as a challenge by heads of laboratories10

Poor adherence to Xpert algorithm attributed to Xpert rollout preceding training of clinicians; only half of patients tested received confirmatory results.41

HCW knowledge, application and interpretation of molecular diagnostics below expected levels. 67

Frequency of untrained laboratory staff performing Xpert was common in all regions67

Only 41.7% of initial diagnoses were correct and a patient was started empirically on a DS-TB regimen without culture, delayed diagnosis.29

Most HCWs were more comfortable and knowledgeable using Xpert than other test types and it was the most common test used (72%)67

HCW low index of suspicion for TB resulting in delayed diagnosis32

“I was at (the CHC) for 24 hours …they told me that I had infection in my lungs and gave me the drip and antibiotics…In the same month I didn’t feel so well so I went back… and they gave me the same drip and antibiotics”.32

“I just feel some of the staff at the clinic is inexperienced.”40

Poor supervision leading to demotivation28

Provider scheduling early return visits for DR-TB test results identified as a facilitator32

Support to the districts by the National programme helpful if sustained28

“there is a need to strengthen supervision, make it more fruitful not just a vehicle visiting. It needs to be supportive, get there, stay with the staff, for them to recognize and listen to their problems … then provide solution”28

Pre-treatment assessment tests were often not performed as other HCWs distanced themselves from DR-TB services45

Fear of infection leading to stigma and discrimination affecting both DR-TB HCWs and patients. Deliberate patients appointments cancellation noted45

"…some nurses and medical workers treated us like we are not fit to live. They keep a distance when they [talk] with us. If you come closer, they will shout go! go!! go!!! … I felt like the worst person on earth having MDR-TB”45

HCW blamed for lack of equipment and delays45

A lack of HCW motivation noted as a challenge to care67

HCW attitude and patient counselling expedited treatment acceptance and process32

Provider responsiveness at first contact and communicating concern about patients’ well-being facilitated early care32

"I … had mixed feelings(when I was told about MDR-TB). …. I thought it was the end of time for me, but when the treatment process was explained to me, I felt much better and looked forward to the treatment”32

Only 68% of specimens received by the laboratory had retrievable request forms34

56% of patients with confirmatory samples were untraceable within 3 months of Xpert samples,41 21% not found at all33

Data errors missing data and 21.2% of treated patients not linked to diagnostic register likely indicative of missing patients33

Incomplete records likely contributed to why most patients (67%) of patients were untreated31

Incorrectly filled laboratory requests forms leading to misplaced results28

“This is a long-standing problem laboratory request forms not filled in well, a lot of information is missing. We see forms coming with either one name or just initials and the rest of the information not filled in”.28

Unreliable patient addresses a challenge for HCWs67

Median time to treatment reduced to 0 days for Xpert-positive patients, compared with 14 days for empiric TB and suggestive chest X-ray findings, and 144 for culture-positive, Xpert-negative patients38

Use of LPA was associated with delays in diagnosis and treatment, mostly due to prolonged laboratory TAT39

LPA introduction associated with reduced TTI (76 to 50 days). Xpert associated with a further reduction to 8 days .7

LTAT reduced from 38 to 2 days for new patients; and to 1 day for patients diagnosed with Xpert, 43

LPA diagnosis vs liquid culture reduced laboratory TAT from 52 to 26 days, and TTI from 79 to 54 days; and from 89 to 73.5 days for smear positives and negatives, respectively51

Compared with culture, patients diagnosed with LPA were 73.3% less likely to be initiated late on treatment52

Patients diagnosed with Xpert were more likely to have an earlier TTI when compared with DST culture and were less likely to have late TTI (after 60 days)53

TTI in the Xpert-based algorithm was 17 days, with a median laboratory TAT of 1 day. There was a decrease of 25 days in median MDR-TB TTI in the Xpert-based algorithm.39

Older diagnostic tests prolonged diagnostic process28

“I would say the methods used to examine the specimens … I think it is a big challenge because we need to be able to get these results quicker, for instance, they could be examined by liquid culture and drug susceptibility testing is done using molecular methods these could give results quicker”28

* Treatment rates remained unchanged with Xpert.7 39 43

Case detection rates did not increase following the introduction of Xpert37

The proportion of RR-TB cases diagnosed by Xpert increased from 43% to 61% with increased Xpert implementation. The proportion who initiated treatment increased from 43% to 60% also.35

Unavailable diagnostic services in campus health facilities and students were referred to private or public hospitals.29

Full implementation of Xpert resulted in increased diagnosis rates (20%) and timeliness (92%), treatment referral and initiation (15%), increased treatment timeliness (49%) and decreased deaths before treatment (66.9%)35

Stock outs of Xpert cartridges and reagents reported as a challenge by HCWs67

Inadequate health financing resulted in a poor access to care or catastrophic costs for patients.29

Funding for sample transportation29

“… Who will take the specimens to the stations and …pick [them] up … and who will pay the costs for sending …? …”29

Sex not associated with having a DST done,27 30 nor with treatment initiation rates or timeliness33 43 48 54

Females less likely to have TB screening on hospital presentation with TB-related symptoms, OR=0.646

LTAT was for females was 1.09 times longer.27

The mother being the TB source case resulted in children being more likely to miss clinic appointments OR=3.7840

Being male was associated with increased odds of getting and Xpert test in all age groups.44

Females more likely to have timely diagnosis as males were 89.3% more likely to be diagnosed after 12 days compared with those diagnosed in 2 days or less, even when adjusted for the HIV status.52

Patients aged ≥ 55 years a had lower treatment rates than those 45–54 years43

Adults (aged 20–59 years) were less likely than children (aged 0–19 years) to be initiated on treatment33

TTI was longer for children aged 0–15 years compared with those aged 16–24 years43

Patients age ≤10 years were less likely to have a DST result27

Few patients aged 0–14 years (5%) and ≥15 years (12.2%) had an Xpert test done44

Age was not associated with time to diagnosis,52 nor having a DST done,30 nor with rates of treatment36 or timeliness.39

Adults aged 55 years and above were more likely to be screened for TB on hospital presentation for other reasons than those aged 18–24 years46

Middle-aged adults 35–44 years had higher case notification rates, whereas it was the lowest for children aged 5–9 years44

Being pregnant made it more difficult to access TB care, resulting in transmission to family members32

"I was coughing and having sharp pains …They said they could not help me because I am pregnant…It was a very bad pregnancy”32

Inconclusive: HIV-negative (aOR=0.6)50 or with unknown status43 patients, and in orther cases HIV positive,43 were less likely to start treatment50

HIV status was not associated with having a DST done,30 nor with treatment timeliness48 53

Odds of receiving TB diagnosis higher if HIV-positive using Xpert than for ART-naïve38

HIV-positive patients had nearly twice the odds of receiving an Xpert test.44

Fear of an HIV diagnosis delayed care-seeking32

“My mother said I must go to the clinic for a TB test. She was worried that I may have TB because my (relative) also had TB. I did not want to go …too scared that if I go for a TB test, they will also test me for HIV”32

Some HIV-infected patient had an awareness of their increased risk of TB32

“I was coughing, my bones pained and I was losing weight…I thought I had TB …I went to the ARV doctor because I had an appointment … and told him how I feel. I asked him to send me for a TB test”32

“I knew I was HIV positive, and that made me more worried when I felt sick. Even when my TB results were negative…I went again for a TB test”32

Patients with smear-negative disease were less likely to have DST results 27

Patients from the Western Cape had more forms of resistance than patients from the other provinces; leading to increased likelihood of ineffective DR-TB treatment.27

Patients with fever and any two symptom combination (cough, fever, weight loss, night sweats) were less likely to be screened for TB46

Patients with any three or four symptom combination (cough, fever, weight loss, night sweats) were more likely to be screened for TB on hospital presentation46

Retreatment cases (ie, failures, relapses/recurrences, defaulters) had the highest odds of getting an Xpert44

Being underweight, especially in children aged 0–14 years doubled the odds of receiving an Xpert test.44

Half the patients had previously been treated for TB but that did not always translate to symptom recognition or timely health seeking “I did not believe it could be TB again because I completed my treatment the first time”.32

Half the patients were previously treated for TB and several recognised the symptoms as a recurrence, responding by quickly seeking help at a PHC facility “I had all the symptoms that I had the last time when I had TB. So I wanted them to check (for TB)”.32

Patients had a higher likelihood of missing clinic appointments when cigarettes were smoked in the house40

Coloured patients when compared with Xhosa were less likely to attend clinic appointments and more likely delayed diagnosis40

Patients concerned about the risk of DR-TB infection at the clinic: OR=2.45 ; and those with perception of long waiting times not attending clinic OR=2.4740

Failure to recognise TB symptoms or lack of awareness that TB can recur resulted in delayed care-seeking32

“I was having a terrible cough and I was sweating at night, but … I still thought this was just a fever and the change of season and that everything was going to be fine”32

Negative perceptions of the public sector (over-burdened; rights infringement; negative staff attitudes; lack of privacy)32 45

“I was expecting long queues and sitting for ages before getting help, but … there was no queue and I got helped within 10 min…t”32

Beliefs in superstitions 31 among patients, non-disclosure delayed proper care45 “An illness that will make doctors and nurses to run away, if you tell a non-medic, will they stay with you? . … …I cannot tell them. Not even my girlfriend”45

Earlier care-seeking was enabled by symptom recognition or an awareness of increased risk of TB among HIV patients32 “I knew I was HIV positive, and that made me more worried … Even when my TB results were negative…I went again for a TB test”.32

Perceptions of good quality service and familiarity with service32 32

Patient’s agency in specifically requesting TB screening services that were not offered facilitated early diagnosis32

Patient patience in waiting for care32

“I waited for a long time …I just told myself that… I am sick already and I need help and in order for me to get help I must be patient”.32

Health seeking delay was 3.2 weeks (0–16 weeks, SD 4.6) due to fear of missing academic teaching and clinical duties29

Family/ work/ school commitments or dissatisfaction with the service preventing a return to facilities or interruptions to the diagnostic process.29 32 40

“The day… I was told I have MDR-TB, my family phoned… that my sister passed away. Everything then went crazy. All I could think about then was the fastest way to get (home.) …not thinking about my MDR-TB treatment, maybe because my mind was very occupied with my family responsibilities …”.32

Family support enabled early care-seeking32

31.2% of patients died before treatment initiation and 46.4% lost to follow-up50

Main reason for patients’ non-referral was LFTU42

Several patients (19% vs 33% in hospital and PHC respectively) died before referral.42

Only 32% new diagnosed patients were treated; 38% were untraceable and 26% died before treatment31

Of six untreated patients, one outmigrated and one died before treatment.36

Symptoms worsening and death before treatment‘…this patient …decided to contact RTLC for help. … but the patient died before [being] taken to KIDH’.31

Patients reluctant to disclose their correct addresses due to confidentiality concerns29

More than one minibus transfer to get to clinic was associated with children missing appointments40

Patients incurred substantial healthcare costs and transport costs.29

Lack of transportation cost to keep appointments32

Participants reported substantial expenses, including specialist appointments, investigations, treatment costs29

Informal settlements, (aOR=0.4) suburb (0.3) and prison (0.1) less likely to start treatment compared with township residence50

Late DR-TB treatment Initiation (after 60 days) was less likely in patients having a town address.53

Variable treatment initiation patterns within regions and within states in the same region; and between semi-urban and urban locations.33

City/town residence was more likely to initiate treatment compared with township residence50

Patients living in semi-urban areas were more likely to experience timely initiation of treatment than those in urban areas.33

Convenience of free, accessible local services enabled early care-seeking32

Of six patients who were not placed on treatment, two were due to treatment refusals.36

Symptom minimisation or denial,resulted in delayed care-seeking32 “But at all these times I was not sick. It was just a cough, sweat at night and I felt that I was also losing weight, nothing else, not a day I ever felt like I was sick”.32

Patients opt for traditional medicine and do not return for results67

Cultural beliefs and seeking traditional healthcare32

Patients opting for traditional medicine and not returning for results noted as a challenge to care by HCWs67