An assessment of nucleic acid amplification testing for active mycobacterial infection

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Bu səhifədəki naviqasiya:

• Interventional regimen Comparator Adverse reaction Cases (N)
• Interventional regimen Comparator Adverse reaction
• Drug-resistance pattern Appropriate treatment regimen
• Type of TB Definition
• Study reference Country Treatment appropriate based on DST Non-MDR-TB patients treated (n)
• Study reference Country Inappropriate treatment N events (total)

Drug Adverse reaction	Drug regimen	Frequency (N participants)
Studies providing evidence (K)
Isoniazide Hepatic reactions Severe hepatitis, hepatic failure Transaminase elevation, subclinical Jaundice Discontinuation of therapy due to hepatoxicity Neurologic reactions Vitamin B6 deficiency Clinical pyridoxine deficiency	< 10 mg/kg Chemoprophylaxis (early months) Chemoprophylaxis (9 months) Chemoprophylaxis (3–4 months) Chemoprophylaxis 10 mg/kg Chemoprophylaxis 10 mg/kg Chemoprophylaxis 10–20 mg/kg Daily unspecified dose Daily unspecified dose Daily 3–15 mg/kg	Occasional (NR) 5–10% 6% 1.2% 1 case (1,451) 2 cases (1,451) 0 (> 6,000) 13% 0 0	2 5 1 1 4 4 3 1 1 2
Rifampicin Hepatic reactions Hepatoxicity Discontinuation due to transaminase elevation	Chemoprophylaxis Chemoprophylaxis 10 mg/kg	0 cases (25) 1 case (157)	1 1
Ethambutol Ocular reactions Possible ocular toxicity	15–30 mg/kg	2 cases (3,811)	2

NR = not reported

Source: Frydenberg & Graham (2009)

Table AEs reported in treatment trials for TB in children

Interventional regimen	Comparator	Adverse reaction	Cases (N)	Country (N participants)
Daily: RIF 10 mg/kg INH 10 mg/kg PZA 25 mg/kg	Twice weekly: RIF 15 mg/kg INH 15 mg/kg PZA 55 mg/kg	Significant side effect	0	South Africa (206)
Twice weekly: RIF 10–15 mg/kg INH 20–30 mg/kg PZA 50–60 mg/kg	Daily: RIF 10–15mg/kg INH 10–15 mg/kg PZA 20–30 mg/kg	Requiring modification of treatment Initial vomiting Mild joint pains	0 6 2	India (76)
Daily for 9 months: RIF 12 mg/kg INH 6 mg/kg	Intermittent for 6 months: RIF 12 mg/kg INH 15 mg/kg PZA 45 mg/kg	AEs	0	India (NR)
RIF 10–15 mg/kg INH 15 mg/kg	Various, all including: RIF 10–15 mg/kg INH 15 mg/kg	Transient hepatitis Vomiting Skin rash	4 1 1	India (83)
RIF 10–12 mg/kg INH 10–12 mg/kg PZA 30–35 mg/kg	NA	Serious adverse effects Temporary asymptomatic hyperuricaemia or transient elevation of transaminases	0 11	Greece (36)
Twice weekly for 6 months: RIF 10–20 mg/kg INH 20–40 mg/kg PZA 50–70 mg/kg	NA	Significant events interrupting treatment (vomiting, skin rash) Events not requiring interruption of treatment (vomiting or abdominal pain) Hepatitis, peripheral neuritis, joint pain	2 9 0	USA (175)
Daily for 2 months: RIF 10–15 mg/kg INH 10–20 mg/kg PZA 25–35 mg/kg Then twice weekly for 4 months: RIF 10–15 mg/kg INH 10–20 mg/kg	NA	Rash Jaundice Deafness Temporary allergy (desensitised by increasing doses)	12 2 1 4	Papua New Guinea (639)

INH = isoniazid; NA = not applicable, non-comparative study; PZA = pyrazinamide; RIF = rifampicin; SM = streptomycin

Source: Frydenberg & Graham (2009)

Table AEs reported for treatment regimens for children with severe TB disease or TB meningitis

Interventional regimen	Comparator	Adverse reaction	Frequency—Intervention	Frequency—comparator	Country (N participants)
Daily in intensive phase of more severe disease: RIF, INH, PZA, EMB	Daily for less severe disease: RIF, INH, PZA	Hepatoxicity	2%	1%	India (323)
Children with TBM: INH 20 mg/kg	Children with TBM: INH 12 mg/kg	Jaundice	39%	12%	India (NR)

EMB = ethambutol; INH = isoniazid; PZA = pyrazinamide; RIF = rifampicin; TBM = tuberculous meningitis

Source: Frydenberg & Graham (2009)

Multidrug resistance after inappropriate TB treatment

An SR and meta-analysis by van der Werf et al. (2012) assessed the risk of acquiring MDR-TB after taking inappropriate TB medication. A literature search for studies down to cohort level that assessed TB regimens as a risk factor for multidrug resistance identified no relevant articles, so the authors widened the selection criteria. Studies were included in which treatment was provided to non-MDR patients if drug resistance and genotype of the isolated TB bacilli were documented before treatment started. The definitions used by the authors for an appropriate treatment regimen and for MDR-TB are tabulated in Table and Table , respectively. Four cohort studies were identified and included in the SR.

Table Appropriate treatment regimens for TB patients with strains that have certain drug-resistance patterns

Drug-resistance pattern	Appropriate treatment regimen
Pan susceptible	H-R and two other drugs in intensive phase and H-R in the continuation phase
H	H-R and two other drugs in intensive phase and H-R-E in the continuations phase a
Non-MDR-TB, R-susceptible	At least three drugs to which the strain is sensitive in the intensive and continuation phase b
Non-MDR-TB, R-resistant	At least four drugs to which the strain is sensitive in the intensive and continuation phase b

^a Based on World Health Organization guidelines (WHO 2010)

^b Based on World Health Organization guidelines (WHO 2008)

H = isoniazid; MDR = multidrug resistance; R = rifampicin; E = ethambutol; TB = tuberculosis

Source: van der Werf et al. (2012)

Table Definitions of MDR-TB, acquired MDR-TB, recurrence, relapse and reinfection

Type of TB	Definition
MDR-TB	TB resistant to at least isoniazid and rifampicin
Acquired MDR-TB	A case with an initial strain susceptible to at least isoniazid or rifampicin that developed MDR-TB and has a genotyping pattern identical to the strain at diagnosis
Recurrence	A second episode of TB occurring after a first episode has been considered cured
Relapse	A second episode of TB occurring after a first episode has been considered cured with the same MTB strain as the first episode

MDR = multidrug resistance; MTB = Mycobacterium tuberculosis; TB = tuberculosis

Source: van der Werf et al. (2012)

The populations of the four included studies were diagnosed with TB proven either by culture, new AFB-positive sputum (two AFB-positive sputum smears or one AFB-positive smear and an abnormal chest radiograph consistent with TB), AFB-positive sputum (at least one sputum sample reading > 10 bacilli/100 fields by direct microscopy), or by both sputum AFB microscopy and culture. Results from two of the four cohort studies were used in a fixed-effects model meta-analysis as they included patients in exposed (i.e. those who received an inappropriate treatment) and unexposed (i.e. those who received appropriate treatment) groups. As the exposed and unexposed groups were drawn from the same population, the studies potentially minimised population selection bias, although baseline differences were not assessed. In one study all patients were considered to have undergone inappropriate treatment as the continuation phase consisted of isoniazid and ethambutol and not isoniazid and rifampicin. In another cohort there were no events (i.e. the strain of TB at recurrence was different to the strain at initial infection), so neither of these latter two studies could be included in the meta-analysis. The applicability of the study cohorts to an Australian setting was low, as the studies were conducted either in areas where there is moderate to high prevalence of drug-resistant TB or in patients who had experienced a previous TB infection.

All studies performed DST before the start of treatment, as per the selection criteria of the review. The quality of the included studies was assessed to be moderate to high by van der Werf et al. (2012); a summary of the data is presented in Table .

Table Patients who acquired MDR-TB following appropriate or inappropriate TB treatment

Study reference Country	Treatment appropriate based on DST	Non-MDR-TB patients treated (n)	Patients that failed treatment and acquired MDR-TB (n)	Patients with recurrence with acquired MDR-TB (n)
Sonnenberg et al. (2001) South Africa	Yes No	294 29	− −	0 0
Quy et al. (2003) Vietnam	Yes No	0 2,551	0 38	0 10
Cox et al. (2007) Uzbekistan	Yes No	240 74	1 9	− −
Matthys et al. (2009) Russian Federation	Yes No	127 62	0 5	− −

DST = drug susceptibility testing; MDR = multidrug resistance; TB = tuberculosis

Patients for whom it was unknown whether they acquired MDR-TB are not included as acquired MDR-TB

Source: van der Werf et al. (2012)

Patients included in the meta-analysis were shown to have a 27-fold increased risk of drug resistance if they received an inappropriate treatment regimen (RR=26.7, 95%CI 5.0, 141.7). When two patients for whom the strain of re-infection was not clear were excluded from the analysis, the risk was lower (RR=17.7, 95%CI 4.1, 77.6). Results are shown in Table . Heterogeneity was measured at 0.02 (df=1, p=0.88, I²=0%) using a Chi-squared analysis.

Table Meta-analysis of two studies showing the risk ratio of inappropriate treatment and risk of developing multidrug-resistant TB

Study reference Country	Inappropriate treatment N events (total)	Appropriate treatment N events (total)	Weight	Fixed RR IV (95%CI)
Cox et al. (2007)	9 (74)	1 (240)	66.4	29.19 (3.76, 226.62)
Matthys et al. (2009)	5 (62)	0 (127)	43.6	22.35 (1.26, 397.86)
Total (95%CI)	14 (136)	1 (367)	100.0	26.68 (5.02, 141.70)

RR = risk ratio

Source: van der Werf et al. (2012)

In summary, there are AEs and morbidity associated with anti-TB treatment. Patients who carry a resistant strain that can be identified by NAAT will possibly benefit from its early identification, followed by appropriate treatment. It should be noted that a patient receiving appropriate treatment for a resistant or non-resistant strain will still be at risk of adverse health events associated with that drug or regimen.

Data providing the evidence on AEs was non-comparative and came primarily from countries with high or medium incidence of TB, and therefore there is limited relevance in an Australian setting. Heterogeneity of reporting, dosing regimens and definitions of AEs (e.g. hepatitis) in studies makes it difficult to conduct a serious analysis of the data.

An important finding by van der Werf et al. (2012) was that patients were found to be at higher risk of developing MDR-TB if they received inappropriate compared with appropriate treatment (RR=26.7, 95%CI 5.0, 141.7). Appropriate treatment was as defined according to WHO treatment guidelines for MDR-TB (WHO 2008). Thus, from a public health perspective, earlier identification of drug resistant strains via NAAT could be beneficial in preventing inappropriate treatment and the further spread of MDR-TB.

The Tuberculosis notifications in Australia, 2010 Annual Report¹⁵ found that 12% of culture isolates with available DST results showed resistance to at least one of the standard first-line anti-TB agents. Resistance to isoniazid (no rifampicin resistance) was shown in 4.7% of isolates. Resistance to at least isoniazid and rifampicin (MDR-TB by definition) was reported in 3.5% of cases but half of these were from the Papua New Guinea – Torres Strait Islands cross-border region and the remainder from recent immigrants. Thus, drug resistance is currently not a serious problem in Australia. Appropriate treatment regimens would enable physicians to continue to contain or even reduce the spread of drug-resistant TB cases in Australia.

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