Study Design and Population

The pilot studies combined innovative methods and tools with proven effectiveness, as evaluated in the first phase of the program, with health sector changes. These changes are being implemented by the Chinese National Health and Family Planning Commission. In addition to sputum culture and LPA-based resistance testing of culture isolates for smear-negative pulmonary TB, this second program phase introduced several other components. To reduce financial barriers to access to treatment, efforts were made to use health insurance reimbursement and other forms of social protection payment to reduce out-of-pocket costs for treatment of TB to 30% and for treatment of rifampin-resistant TB to 10%. As TB diagnosis and treatment tasks were being shifted from local CDCs to designated hospitals, a case-based payment mechanism was designed, which aimed for cost containment and standardized good clinical practice in care for patients with TB or rifampin-resistant TB (12,13).

We quantified the effect of implementation of the second phase of the program on the diagnosis of bacteriologically confirmed smear-negative pulmonary TB and rifampin-resistant TB in a before–after design. The program was designed to select 1 prefecture, respectively, from the eastern and middle regions of China as pilot study sites. Zhenjiang City (Jiangsu Province) and Yichang City (Hubei Province) were also selected based on good performance of features of the National TB Program in China (i.e., funding, laboratory capacity, and case detection). Prefectures consisted of the main municipality (city) and surrounding counties. The total population size in this pilot study was 6.9 million in 15 counties. Details of these prefectures have been described elsewhere (14). We assessed changes in numbers of patients given a diagnosis and compared a 1-year intervention period after implementation of the program (April 2014–March 2015) to a baseline period (January–December 2012). Both pilot study sites introduced all health sector changes.

Diagnosis and Treatment

During the baseline period, presumptive TB patients (i.e., patients who had TB symptoms) underwent a chest radiograph and smear examination by Ziehl–Neelsen staining according to usual clinical routine. Clinical management was based on judgment of the clinician and national guidelines: clinical smear-negative TB diagnosis requires TB symptoms, chest radiograph abnormalities indicative of TB, and 3 negative sputum smear examinations. Both prefectures had experience with diagnosis and treatment of multidrug-resistant TB (MDR TB), which was defined as resistance to rifampin and isoniazid, through an earlier project supported by the Global Fund to Fight AIDS, Tuberculosis, and Malaria (GFATM) that included drug-resistance screening of patients at high risk for MDR TB by using sputum culture and phenotypic drug susceptibility testing (DST). However, after the GFATM project ended, the degree of implementation varied among sites.

During the intervention period, patients with presumptive pulmonary TB had a chest radiograph and smear examination. In addition, culture (1 sputum specimen in Löwenstein-Jensen medium) was used in county-level laboratories for smear-negative patients. Smear-positive samples and culture isolates were tested in city-level laboratories with Genechip or GenoType MTBDRplus assays. The Genechip test, a domestically developed diagnostic test, has a sensitivity of 87.6% and a specificity of 98.0% for rifampin resistance in this setting and a sensitivity of 80.3% and a specificity of 95.8% for isoniazid resistance (15). A systematic review of the GenoType assay showed a pooled sensitivity of 94.6% and a specificity of 98.2% for rifampin resistance, and a sensitivity of 83.4% and a specificity of 99.6% for isoniazid resistance (9). We compiled additional details of the diagnostic algorithm (Table 1).

Data Collection and Analysis

We extracted data for the baseline and the intervention periods from the routine electronic recording and reporting system for notification and management of TB patients (TBIMS) (16). This system contains data about demographic characteristics of patients, laboratory test results, TB diagnosis, treatment provided, and treatment outcomes. Patient data were entered at the clinic where the patient was registered for treatment. The system is maintained by the national-level CDC, which also provides supervision and data quality checks. Data collection and data capture format was similar for the 2 periods except for results of molecular tests, which were captured only for the intervention period. TBIMS data for diagnosis and treatment for patients with TB or rifampin-resistant TB were exported and merged by using unique identification numbers.

Pulmonary TB was defined as a diagnosis of pulmonary TB in the TBIMS. Bacteriologic confirmation was defined as TB confirmed by smear examination or culture. Rifampin resistance was determined by LPA or phenotypic DST on Löwenstein-Jensen medium.

We performed analyses by using Stata version 13 (https://www.stata.com). We compared numbers and proportions of patients given a diagnosis of any type of pulmonary TB, bacteriologically confirmed pulmonary TB, and rifampin-resistant TB between the baseline and intervention periods. We calculated reporting rates by dividing the number of observed cases by the population size, available by age and sex on district level, in 2012 for the baseline period and in 2014 for the intervention period. We used MDR TB patients in the baseline period as the comparison group for rifampin-resistant TB patients in the intervention period because rifampin-resistant TB patients and MDR TB patients were treated and managed the same way in the intervention period. Patients with TB resistant to isoniazid but not rifampin received the standard first-line treatment.

We tested distributions for categorical data by using 2-sided Fisher exact tests and for numerical data by using the nonparametric Wilcoxon rank test. We used logistic regression to determine patient characteristics associated with culture positivity for smear-negative pulmonary TB patients given a diagnosis during the intervention period, and characteristics associated with rifampin resistance for all bacteriologically confirmed pulmonary TB patients during the intervention period. Potential characteristics available and included in univariable and multivariable regression were age, sex, treatment history, disease severity, and migrant status. All statistical testing used 0.05 as the significance level.

Culture Confirmation

During the baseline period 0.5% (12/2,258) of smear-negative patients were culture-confirmed in Yichang and 1.6% (19/1,156) in Zhenjiang. These proportions increased to 17.4% (358/2,055) in Yichang and 6.5% (52/800) in Zhenjiang, or 14.4% overall (95% CI 13.0%–15.7%), during the intervention period (p<0.001 for both prefectures) (Table 2). In Yichang, 5% of results were indeterminate, compared with 12% in Zhenjiang. The analysis of determinants of culture positivity among smear-negative patients showed strong effect modification by prefecture. Therefore, analysis was performed separately for each prefecture. In Yichang, the proportion culture-positive was independently associated with a history of previous TB treatment (adjusted odds ratio [aOR] 7.7, 95% CI 4.2–14.1), more severe disease (aOR 2.1, 95% CI 1.5–2.9), and being an internal migrant (aOR 3.1, 95% CI 2.2–4.1). In Zhenjiang, none of these determinants showed a significant association with culture positivity (Table 3).

Drug Resistance Testing

The proportion of smear-positive patients tested for drug resistance increased from 42.3% (899/2,126) to 83.0% (988/1,191; p<0.001) overall between the baseline and intervention periods, from 3.1% to 90.9% (p<0.001) for Yichang, and from 74.5% to 92.5% (p<0.001) for Zhenjiang (Table 2). In contrast, for smear-negative patients, the proportion tested for drug resistance increased between the baseline and intervention periods from 0.7% (23/3,414) to only 14.2% (405/2,855) (p<0.01); overall, from <0.1% (1/2,258) to 17.1% (352/2,055) (p<0.001) in Yichang and from 1.9% (22/1,156) to 6.6% (53/800) (p<0.001) in Zhenjiang.

Drug Resistance Results

For smear-positive patients during the intervention period, rifampin resistance was detected in 7.1% (67/949; 95% CI 5.5–8.9) in Yichang and 5.4% (30/560; 95% CI 3.6–7.6) in Zhenjiang (Table 2). Overall, the number of smear-positive patients with rifampin resistance more than tripled from 30 during the baseline period to 97 during the intervention period.

For smear-negative patients during the intervention period, a drug resistance result was available for 16.1% of smear-negative patients in Yichang and for 5.9% of smear-negative patients in Zhenjiang. Rifampin resistance was detected in 13 patients with a smear-negative, culture-positive result: 3.5% of those tested with results, and 0.5% of all smear-negative patients. Two additional smear-negative patients who were culture negative showed rifampin resistance by LPA directly on sputum; thus, the physicians ordered the LPA directly on sputum, contrary to the guideline, to have the result as quickly as possible, because the patients had been considered at high risk for MDR TB.

The proportion of patients that showed rifampin resistance among those tested was significantly higher for smear-positive patients (97/1,381, 7.0%) than for smear-negative patients (13/405, 3.2%) (p = 0.005). Overall, the addition of culture and rapid resistance testing during the intervention period yielded 10.9% (13/119; 95% CI 5.9%–18.0%) additional diagnoses of rifampin-resistant TB and no significant difference between prefectures (p = 0.180). For isoniazid-monoresistant TB, the additional increase was 20.8% (22/106; 95% CI 13.5%–29.7%). A total of 13/2,591 patients were determined to have rifampin-resistant TB, and 22/2,591 were determined to have isoniazid-monoresistant TB.

Second-Line Treatment

Of the 110 (including 13 smear-negative) rifampin-resistant patients with MDR TB given a diagnosis during the intervention period, 94 (85.5%) started second-line treatment, compared with 20 (60.6%) of 33 during the baseline period (p<0.001) (Table 4). The proportion that started treatment during the intervention period was 100% (13/13) for smear-negative patients and 83.5% (81/97) for smear-positive patients (p = 0.243).

For smear-positive patients, the median delay between presentation for diagnosis and initiation of second-line drug treatment decreased from 16 weeks during the baseline period to 16 days during the intervention period. For smear-negative patients, the median delay decreased from 21 weeks to 7 weeks. Among patients given second-line treatment, 12 (60.0%) of 20 patients during the baseline period and 47 (50.0%) of 94 patients during the intervention period had treatment success (cure or completion) as the outcome (p = 0.572). The proportion with treatment failure or death did not differ significantly between the intervention (16 patients, 17.0%) and baseline (5 patients, 25.0%) periods (p = 0.603). During the intervention period, 6 patients did not return for follow-up appointments and 8 stopped treatment because of side effects (total 14.9%), whereas neither finding was reported during the baseline period (p = 0.143). Three (9.1%) eligible patients during the baseline period and 16 (14.5%) patients during the intervention period were known not to have started second-line treatment (Table 4).