Tuberculosis preventive treatment among individuals with inactive tuberculosis suggested by untreated radiographic abnormalities: a community-based randomized controlled trial

Figures & data

Figure 1. Flowchart of the participant enrolment. ALT, alanine aminotransferase; AST, aspartate aminotransferase; DR, digital radiography; HCV, hepatitis C virus; QFT, QuantiFERON-TB Gold In-Tube; RCT, randomized controlled trial; TB, tuberculosis; ULN, upper limit of normal; WBC, white blood cell. Of the 44,500 recruited rural residents, 43,670 participants aged 18–75 years had complete results of chest radiography and questionnaire, 40,682 were excluded because of normal chest radiographic findings (n = 40,451), suspect TB (n = 119) and other pulmonary diseases (n = 112). The rest 2,988 participants were identified with radiographically inactive TB lesions. Among them, 855 individuals were identified to be QFT-positive and 830 signed the informed consent form for the RCT. Finally, 677 eligible participants were included in the RCT and were randomly classified into two groups: 345 in the preventive treatment group and 332 in the control group without treatment.

Table 1. Characteristics of the study participants included in the intention-to-treat analysis.

Characteristic	Preventive treatment group (N = 345)	Untreated control group (N = 332)	P for χ^2 test
Male	199 (57.68)	194 (58.43)	.843
Age (years)
Median (Q25–Q75)	63 (54–68)	64 (55–69)	.309
<50	45 (13.04)	40 (12.05)	.924
50–59	90 (26.09)	85 (25.60)
60–69	140 (40.58)	133 (40.06)
70–75	70 (20.29)	74 (22.29)
Body mass index (BMI, kg m^−2)
<18.5	14 (4.06)	10 (3.01)	.855
18.5–<24.0	133 (38.55)	124 (37.35)
24.0–<28.0	134 (50.38)	132 (39.76)
≥28.0	64 (18.55)	66 (19.88)
Completed primary school	133 (38.55)	116 (34.94)	.330
Married	309 (89.57)	301 (90.66)	.633
Household per capita income > RMB 2500 yuan	153 (44.35)	157 (47.29)	.443
Ever-smoker	114 (33.04)	103 (31.02)	.574
Current alcohol drinker	86 (24.93)	96 (28.92)	.242
Close contact with a patient with active TB	9 (2.61)	7 (2.11)	.669
History of type II diabetes*	19 (.51)	19 (5.72)	.903
HBsAg positive	7 (2.03)	4 (1.20)	.397^§
Self-reported history of silicosis	0 (0)	1 (0.30)	.490^§
Inactive lesions identified by chest radiograph^#
With fibrotic lesions	129 (19.05)	114 (16.84)	.459
With nodules	25 (3.69)	23 (3.40)	.872
With calcification	195 (28.80)	187 (27.62)	.959
With pleural incrassation	25 (3.69)	34 (9.94)	.167
Size of the largest fibrosis lesion (mm)^†
<20	98 (75.97)	82 (71.93)	.473
≥20	31 (24.03)	32 (28.07)
Concomitant drugs during treatment^‡
Yes	84 (24.35)	–	–
No	261 (75.65)	–	–

Data are presented as n (%). Abbreviation: Q25, quartile 25; Q75, quartile 75; TB, tuberculosis. ^‡Data on taking concomitant drugs were monitored and collected during clinic visits for study drug treatment; therefore, related information on concomitant drug use in untreated control group were not collected. ^#Every type of radiographically inactive lesions could include only a single lesion or one accompanied with other radiographically inactive lesions. Therefore, the sum of the sample sizes for inactive lesions identified by chest radiographic findings might not be equal to the total of 677. *History of self-reported type II diabetes or fasting blood glucose ≥7 mmol L⁻¹. ^†Classified by Q75 value. ^§Fisher’s exact test.

Table 2. Completion of the treatment regimens and attributions for treatment discontinuation.

Variables	n (%)
Number of completed doses
11–12 doses (completed)*	276 (80.00)
<11 doses (uncompleted)	69 (20.00)
Attribution for treatment discontinuation
Unreachable	5 (7.25)
Adverse drug effect	10 (14.49)
Refusal to continue	22 (31.88)
Hospitalization due to underlying disease^†	11 (15.94)
Management required for underlying disease but without hospitalization^†	19 (27.54)
Other reasons including right arm trauma and traffic accident	2 (2.90)

*Defined as completed ≥90% doses (i.e. ≥11 doses) of drug therapy. ^†Underlying disease management included management of hypertension and high fasting blood glucose.

Table 3. Incidence of active tuberculosis in the study groups.

	Preventive treatment group		Untreated control group		Difference in cumulative rate^‡	P-value for difference in cumulative rate^¶	Protective rate* % (95% CI)	Protective rate^† % (95% CI)
	Cumulative incidence, n/N (%, 95% CI)	Incidence rate per 100 person-years (95% CI)	Cumulative incidence, n/N (%, 95% CI)	Incidence rate per 100 person-years (95% CI)
ITT analysis
Microbiologically confirmed and clinically diagnosed cases among total population	8/345 (2.32, 0.73–3.91)	8/650 (1.23, 0.62–2.41)	7/332 (2.11, 0.56–3.65)	7/620 (1.13, 0.55–2.31)	0.21	.531	–	–
Microbiologically confirmed among total population	4/345 (1.16, 0.03––2.29)	4/650 (0.62, 0.24–1.58)	5/332 (1.51, 0.20–2.82)	5/620 (0.81, 0.35–1.88)	−0.35	.485	23.18 (1.83–83.04)	23.46 (1.07–89.69)
Microbiologically confirmed cases among individuals with fibrosis	1/129 (0.78, 0.02–4.24)	1/243 (0.41, 0.07–2.29)	2/114 (1.75, 0.21–6.19)	2/218 (0.92, 0.25–3.29)	−0.97	.454	55.42 (10.33–93.07)	55.43 (6.19–95.91)
Microbiologically confirmed cases among individuals with fibrosis size ≥ 20 mm	0/31 (0)	0/59 (0)	1/32 (3.13, 0.08–9.15)	2/62 (3.23, 0.89–11.03)	−3.13	.508	100.00 (0–55.10)	100.00 (0–54.32)
Microbiologically confirmed cases among individuals aged ≥ 60 years	1/210 (0.48, 0.01–2.62)	1/397 (0.25, 0.04–1.41)	5/207 (2.42, 0.32–4.51)	5/388 (1.29, 0.55–2.98)	−1.94	.104	80.17 (25.36–97.96)	80.62 (16.53–98.87)
PP analysis
Microbiologically confirmed and clinically diagnosed cases among total population	6/276 (2.17, 0.45–3.89)	6/524 (1.15, 0.53–2.48)	7/332 (2.11, 0.56–3.65)	7/620 (1.13, 0.55–2.31)	0.06	.586	–	–
Microbiologically confirmed among total population	3/276 (1.09, 0.22–3.14)	3/524 (0.57, 0.19–1.67)	5/332 (1.51, 0.20–2.82)	5/620 (0.81, 0.35–1.88)	−0.42	.467	27.81 (2.57–84.91)	29.63 (1.68–91.23)
Microbiologically confirmed cases among individuals with fibrosis	1/108 (0.93, 0.02–5.05)	1/206 (0.49, 0.03–3.10)	2/114 (1.75, 0.21–6.19)	2/218 (0.92, 0.25–3.29)	−0.82	.520	46.86 (7.60–90.43)	46.74 (4.48–94.26)
Microbiologically confirmed cases among individuals with fibrosis size ≥ 20 mm	0/27 (0)	0/52 (0)	1/32 (3.13, 0.08–9.15)	2/62 (3.23, 0.89–11.03)	−3.13	.542	100.00 (0–55.10)	100.00 (0–54.32)
Microbiologically confirmed cases among individuals aged ≥ 60 years	1/165 (0.61, 0.02–3.33)	1/316 (0.32, 0.06–1.78)	5/207 (2.42, 0.32–4.51)	5/388 (1.29, 0.55–2.98)	−1.81	.170	74.79 (22.33–96.84)	75.19 (14.48–98.19)

Abbreviation: CI, confidence interval; ITT, intention-to-treat analysis; PP, per-protocol analysis. *Protective rate was calculated by using cumulative incidence. ^†Protective rate was calculated by using incidence rate per 100 person-years. ^‡The difference was the rate in the preventive treatment group minus the rate in the untreated control group. ^¶One-sided p-value for Chi-squared test or Fisher’s exact test.

Table 4. Characteristics of the participants with adverse events and study drug side-effects.

Variables	n (%)
Participants	345
Adverse events
Participants with any of the adverse events	74 (21.45)
Death	0 (0)
Occurrence of serious adverse events
Yes	10 (2.37)
No	64 (18.55)
Frequency per person
1 event	53 (15.36)
>1 event	21 (6.07)
Attributed to drug
Yes	41 (11.88)
No	33 (9.57)
Classified by event severity grade
Grade 1	56 (16.23)
Grade 2	15 (4.35)
Grade 3	2 (0.58)
Grade 4	1 (0.29)
Side-effects
Participants with any of the side-effects	41 (11.88)
Specific side-effect
Gastrointestinal reaction	22 (6.38)
Hyposensitivity or allergy	6 (1.74)
Influenza-like symptoms	5 (1.45)
Neurological symptoms	10 (2.90)
Hepatotoxicity	2 (0.58)
Other drug reactions	3 (0.87)
Categories occurring per person
1	34 (9.86)
2	5 (1.45)
3	2 (0.58)
Hospitalization due to side-effects	1 (0.29)

Data availability statement

This study is registered at www.chictr.org.cn with identifier ChiCTR-1800018224. The corresponding author can provide, upon request, individual participant data that underlie the results reported in this article after applying necessary measures to guarantee that no individual is identified or identifiable.