IPT for adults: Should the Mantoux test have been removed from WHO guidelines?
Nathan Geffen, TBonline
The 2011 edition of the World Health Organisation’s Guidelines for Intensified Tuberculosis Case-finding and Isoniazid Preventive Therapy for People Living with HIV in Resource-Constrained Settings has 12 recommendations. 
The fourth recommendation says that adults and adolescents living with HIV who have an unknown or positive tuberculin-skin-test (TST) status and who are unlikely to have active TB should receive at least 36 months of Isoniazid Preventative Therapy (IPT). Furthermore, IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to those on ART, those who have previously been treated for TB and pregnant women. The WHO says this is a strong recommendation with moderate quality of evidence to support it. The third recommendation is identical except that six months instead of 36 months of IPT is recommended and this is ranked as a strong recommendation with high quality of evidence.
The Guidelines for Tuberculosis Preventative Therapy Among HIV Infected Individuals in South Africa, published in 2010, are consistent with recommendation three. They further state, “Clinical trials have shown that the benefit of TB preventive therapy is greatest in HIV-infected persons with a positive tuberculin skin test. Where tuberculin tests are feasible and can be performed, IPT should only be offered to those who are TST positive. However, the practicalities and logistics of doing a tuberculin skin test are often an obstacle for provision of TB preventive therapy. Therefore the tuberculin skin test is no longer required to identify HIV infected people eligible for IPT.” 
This article deals solely with adults who are not pregnant, who are not health-workers with HIV and not in special high-risk settings such as mines or prisons. The removal of the necessity of the Mantoux test to determine TST status from IPT guidelines is concerning, as the data summarised here demonstrates.
Cochrane Review of IPT trials
A Cochrane Review of short-course chemotherapy trials (6 to 12 months) to prevent TB was published in 2010. 
Twelve trials met the strict criteria for inclusion in this meta-analysis. In all, 4811 participants were TST positive, 2030 were TST negative. Of these, 1,640 were known to be unable to mount an immune response to the Mantoux test (ie they were anergic). The TST status in 1737 participants was unknown. No differences were found in trials that compared effectiveness of different combinations of drugs, but all regimens significantly reduced the risk of TB as shown in Table 1.
|Drug combination||Relative Risk||95% CI||n|
Using INH alone reduced the incidence of confirmed, probable or possible TB by 32% (RR: 0.67 95%CI: 0.51-0.87, n=4136).
However, when analysed by TST status, the effect was only significant for TST positive participants as table 2 shows.
|Mantoux test result||Relative Risk||95% CI||n|
IPT showed no mortality benefit (RR: 0.95; 95%CI 0.85-1.06). When analysed by TST status, the benefit only just reached significance in TST positive participants (RR: 0.74; 95%CI 0.55-1.00) and there was no benefit to TST negative (RR: 1.02; 95%CI: 0.90-1.16) or TST status unknown participants (RR: 0.81; 95%CI: 0.52-1.27).
The Botusa trial has previously been reported in HTB South. 
Since then it has been published in the New England Journal of Medicine. The results of the trial, contrary to the way it has been reported, are not a resounding success for long-term IPT; on the contrary the trial raises difficult questions. 
In this double-blind randomised controlled trial in Botswana, 989 HIV-positive participants were randomised to receive six months of isoniazid and 1,006 were randomised to receive 36 months of isoniazid. All participants received open-label isoniazid for the first six months, after participants either took placebo or isoniazid for 30 months. Only 2% of participants were on ART at the start of the trial. At the end of the open-label phase, 821 participants continued in the placebo group and 834 in the isoniazid arm.
TB incidence between the two groups diverged at 200 days after the open-label phase, indicating not unexpectedly that the benefits of short-course IPT were transient.
The protocol defined definite, probable and possible TB as follows:
- Definite: one or more culture was positive M tuberculosis or if two or more sputum smears were positive for acid-fast bacilli
- Probable: one sputum smear or one biopsy specimen was positive for acid-fast bacilli
- Possible: if smears and cultures were negative or not done. A death defined as possibly related to tuberculosis was one that had clinical or verbal autopsy evidence consistent with tuberculosis as the proximate cause of death.
In an analysis of participants that actually remained on the study after the open-label phase ended, the only statistically significant result in favour of long-term IPT was the reduced incidence of definite, probable and possible TB, and here the confidence interval was wide (25 on placebo versus 12 on isoniazid; HR: 0.47; 95%CI: 0.24-0.94). No significant difference between the arms could be found when only definite and probable cases were counted (18 versus 10; HR: 0.55; 95%CI: 0.25-1.18). Nor was there significant difference if TB (definite, probable and possible) and deaths were combined (41 versus 37; HR 0.89: 95%CI: 0.57-1.39). However there were more deaths in the long-course arm, although this was not significant (16 versus 25; HR 1.54; 95%CI: 0.82-2.88).
When analysed by TST status, TST positive participants benefited from 36 months IPT. There were 11 cases versus only 1 case of definite, probable and possible TB (HR: 0.08; 95%CI 0.01-0.61). There were 10 cases versus only 1 case of definite and probable TB (HR:0.09; 95%CI 0.01-0.67). TB (definite, probable and possible) and all deaths were also significantly better (20 versus 4; HR: 0.17; 95%CI: 0.06-0.50). When just deaths were looked at, the 36 month arm did better though this was not significant (9 versus 3; HR: 0.28; 95%CI: 0.08-1.03).
However, the results for TST negative participants were surprising and worrying. There were no significant differences or even trends with respect to TB. But there were 21 deaths on the 36 month arm versus 7 on the short-course arm and this was significant (HR: 2.99; 95%CI: 1.27-7.04).
The reasons for this are unclear. Only one death, due to hepatic encephalopathy, appeared to be due to a known isoniazid side-effect. The adverse event rates between the arms were almost identical (1% versus 1.3%). Nevertheless, this was a double-blinded RCT and the significantly higher deaths in TST negative people in the 36 month arm should not be ignored.
The findings of the Cochrane Review and the Botusa trial show that TST status is relevant. There is no evidence that TST negative people benefit from any form of IPT prophylaxis.
In the case of long-term prophylaxis, which is now recommended by WHO guidelines and likely where other guidelines are heading, TST negative people could be put at risk of harm unnecessarily.
Guideline writers appear to be focusing on reduced TB incidence demonstrated by IPT studies. But mortality is surely a more important measure from the perspective of patients than TB incidence.
Overall, the short-course IPT studies show no significant mortality benefit when TST status is not taken into account. And in the one major long-course IPT trial there is unequivocally no mortality benefit if TST status is not taken into account. The Mantoux test should therefore not be removed from guidelines.
There is a concern that implementing the Mantoux test is too burdensome for many health facilities. If that is the case, then we need to ask if such facilities should be implementing IPT, especially long-course IPT.
- WHO. 2011. Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource-constrained settings.
- South African Department of Health. 2010. Guidelines for tuberculosis preventative therapy among HIV infected individuals in South Africa.
- Akolo C et al. 2010. Treatment of latent tuberculosis infection in HIV infected persons.
- Geffen N. Botswana IPT trial: Continuous isoniazid superior to 6 months short course. HTB South, April 2010.
- Samandari T et al. 6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial. Lancet 2011 May 7; 377(9777):1588-98.