An assessment of nucleic acid amplification testing for active mycobacterial infection



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Study
Country


Number of patients

Median time to TB diagnosis, NAAT (IQR)

Median time to TB diagnosis, comparator (IQR)

Boehme et al. (2010)

Peru, South Africa, Uganda, Philippines



N=6648

Xpert: 0 days (0–1)

AFB microscopy: 1 day (0–1)

Solid culture: 30 days (23–43)

Liquid culture: 16 days (13–21)


Sohn et al. (2014)

Canada


N=502

Xpert: 25 hours (3–39)

AFB microscopy: 26 hours (25–51)

Culture: 516 hours, 22 days (336–720)



Van Rie et al. (2013b)

South Africa



N=344

Xpert: 1 day (1–1)

AFB microscopy: 8 days (5–10)

Culture: 29 days (24–35)



Fan et al. (2014)

China


N=280

NAAT (in-house): 0.5 day

Liquid culture: 28.2 days (15–50)

(p<0.001)



Yoon et al. (2012)

Uganda


Baseline N=157
Implementation (Xpert) N=105

Xpert: 0 days (0–1), range 0–55

AFB and/or microscopy: 1 day (0–26)

AFB = acid-fast bacilli; NAAT = nucleic acid amplification test; Xpert = GeneXpert MTB/RIF assay

Table Median time to therapy using GeneXpert versus comparator



Study

Number of patients

Median time in days to therapy, NAAT (IQR)

Median time in days to therapy, comparator (IQR)

p-value

Boehme et al. (2010)

Peru, South Africa, Uganda, Philippines



N=6648

Xpert in AFB-negative, culture-positive TB: 5 (2–8)

AFB-negative, culture-positive TB (other methods): 56 (39–81)

-

Hanrahan et al. (2013)

South Africa



Xpert positive N=50
Empiric TB N=25
X-ray positive N=19
Culture positive N=20

Those positive on Xpert: 0

Empiric TB: 14 (5–35)

Suggestive chest X-ray: 14 (7–29)

Culture positive (Xpert negative): 144 (28–180)


-

Kwak et al. (2013)

Korea


Xpert N=43
No Xpert N=86

Xpert: 7 (4–9)

No Xpert (culture and/or AFB): 21 (7–33.5)

<0.001

Omrani et al. (2014)

Saudi Arabia



Xpert N=76
Comparator N=64

Xpert: 0

AFB microscopy: 0

Culture: 22



>0.999

<0.001

Theron et al. (2014)

South Africa



Microscopy N=758
Xpert N=744

Xpert: 0 (0–3)

AFB microscopy: 1 (0–4)

0.0004

Van Rie et al. (2013b)

South Africa



N=344

Xpert: 1 (1–1)

N=162


Other methods a: 8 (1–42)




Van Rie et al. (2013a)

South Africa



N=160

Xpert: 0 (0–0)

Other methods: 13 (10–20)

<0.001

Yoon et al. (2012)

Uganda


Baseline N=157
Implementation (Xpert) N=105

Xpert: 0 (0–2)

AFB microscopy: 1 (0–5)

0.06

a Xpert-negative, culture-positive participants (N=10); six patients started treatment before the culture result was available.

AFB = acid-fast bacilli; IQR = interquartile range; MDR = multi-drug resistant; NAAT = nucleic acid amplification test; Xpert = GeneXpert MTB/RIF assay.

The RCT by Theron et al. (2014) also reported the proportion of patients initiating TB treatment and the reasons for treatment initiations, as shown in Table and Figure . The proportion of patients receiving treatment (regardless of reason of initiation) was higher in the Xpert group than in the AFB microscopy group during days 1–9. Furthermore, there were more culture-positive patients on treatment in the Xpert group, compared with the AFB microscopy group, until day 56.

Table Proportion of patients initiating treatment based on AFB microscopy or NAAT results, by day



By day:

Positive AFB microscopy (%)

Positive NAAT (%)

1

67/758 (9%)

130/744 (17%)

2

99/758 (13%)

170/744 (23%)

3

105/758 (14%)

172/744 (23%)

14

105/758 (14%)

181/744 (24%)

28

111/758 (15%)

181/744 (24%)

56

111/758 (15%)

182/744 (24%)

AFB = acid-fast bacilli; NAAT = nucleic acid amplification test

Source: Theron et al. (2014)



Figure Percentage of patients initiating treatment based on smear (AFB microscopy) or NAAT results, by day

Source: Theron et al. (2014)

Regarding antibiotic resistance detection, Boehme et al. (2010) reported that the median time for rifampicin resistance results was 1 day (IQR 0–1) for the Xpert NAAT, compared with 20 days (IQR 10–26) for line probe assay and 106 days (IQR 30–124) for phenotypic susceptibility testing.

Time-related management results other than median time to diagnosis/treatment after Xpert NAAT were reported in three studies (Lacroix et al. 2008; Marks et al. 2013; Taegtmeyer et al. 2008), all in low-prevalence countries The poor-quality retrospective cohort study by Lacroix et al. (2008) showed that the average delay in TB diagnosis in a public health department in Quebec was decreased by the use of PCR (n=77) compared with no use of PCR (n=38), with a mean of 89.3 days (95%CI 76.4, 102.2) compared with 97.9 days (95%CI 74.2, 121.6; p=0.498), respectively. NAAT (MTD, Gen-Probe, San Diego, California) also significantly decreased the average time to final TB determination for all patients except for those with AFB-negative NAAT-positive culture-negative specimens versus patients with AFB-negative culture-negative (no NAAT) specimens in an unadjusted analysis by Marks et al. (2013). Furthermore, this medium-quality retrospective cohort study, conducted in the USA, reported a multivariable analysis of time to determination of AFB-positive culture-positive patients, and found that a NAAT result reduced the time to TB diagnosis (adjusted hazard ratio = 2.3; 95%CI 1.4, 3.7). A different medium-quality retrospective cohort study (UK) used a INNO-LiPA RIF TB assay (Immunogenetics, Zwijndrecht, Belgium) and compared the mean time to identification of MTB and rifampicin resistance with AFB microscopy and/or mycobacterial culture (Taegtmeyer et al. 2008). The mean time to detection of mycobacteria and rifampicin resistance was 8.8 ± 5.9 days with NAAT compared with 26.0 ± 10.9 days to identification (p=0.001) using culture (without NAAT). In this study, for all the AFB-positive samples, NAAT identified 86% of the samples within 2 weeks, compared with only 7% of samples using culture.

Thus, all studies were in agreement that the use of NAAT resulted in a quicker diagnosis of patients with TB, especially in those who were AFB-negative. Predictably, this also resulted in earlier treatment in NAAT-positive patients.



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