Requiring tuberculin skin tests before implementing IPT leads to avoidable and substantial number of TB cases

Delaying a course of isoniazid preventive therapy (IPT) to prevent active tuberculosis (TB) because a person with HIV hasn’t yet had a tuberculin skin test (TST), or received their results, leaves the individual at very high risk of developing active TB, according to results from the THRio study team, presented on Monday at the Eighteenth International AIDS Conference in Vienna.

Although those with positive TSTs had the highest risk of TB in the study, approximately 60% of the TB cases occurred in those who were TST unknowns, and the rates were also high in those who were waiting to have their TSTs read.

“It’s taking too long for people to get a TST, and among those who have a TST, even for those who have a positive result, it’s taking them a long time to get put onto IPT,” said Dr Jonathan Golub of Johns Hopkins Center for Tuberculosis and the Consortium to Respond Effectively to the AIDS Tuberculosis Epidemic (CREATE).

Background

A course of isoniazid preventive therapy (IPT) has been shown to reduce the incidence of active TB in people with HIV – especially among those who are TST-positive. A positive TST can demonstrate whether someone has a latent TB infection. If latent TB is treated with a course of isoniazid – usually for at least six months – the risk of subsequently developing active TB is more than halved in people with HIV.

In Brazil, it has long been policy that people with HIV receive an annual tuberculin skin test and, if they are positive, that they be given IPT in order to reduce the incidence of TB disease. However there has been extremely poor uptake of this recommendation – partly because of the difficulty in implementing TSTs.

The THRio study’s object was to see if widespread implementation of the policy would result in reduced prevalence of TB in the HIV-infected population in Rio de Janiero, Brazil. To find out, the study team conducted a cluster-randomised trial in 29 public HIV clinics in Rio. (ART has been freely available since 1996 to any person with HIV in Brazil once they are medically eligible for treatment.)

The clinics were randomised to the date on which IPT services would begin, over a phased implementation. Primary outcomes in the study were the TB rates before and after the intervention, measured at the clinic level among all the TST-eligible patients.

The intervention involved training the HIV clinic staff (two clinics every other month) to screen properly for active TB in their clients with HIV, and properly perform a TST and provide IPT in those without a TB history, who had not yet taken IPT or who had a prior positive skin test. A six-month course of IPT was then given to anyone with a positive TST but without active TB, and to any contact of someone with active TB.

Before the intervention, data were abstracted from clinic records including variables such as data of HIV diagnosis, ART history, CD4 and viral load. The intervention began at two clinics in September 2005, and new clinics were enrolled every two months until January 2008, with follow-up until December 2009.

Training improves TST performance, but not well enough

After the intervention, the number of TSTs performed quadrupled (from 1505 to 6125), and the number of patient with a positive skin test increased fourfold (though the proportion of those testing positive remained constant at 13.4 to 13.55%). Prior the intervention, over 60% of the patients had not received a TST over a two-year period, but after the intervention about 50% had received one in the last six months. Likewise, the time to TST and to IPT both improved after the intervention.

“However, we still believe that it is taking too long to get skin-tested and onto preventive therapy,” said Dr Golub. “So we looked at what would happen if we removed TST from the picture, if we could provide IPT to all patients regards of their TST status.”

So the study team compared TB risk by TST and IPT status. TB-free and IPT-naive patients were analysed from HIV diagnosis until TB diagnosis, death, or censoring at last follow-up, excluding those with a very short follow-up time – less than 60 days after their HIV diagnosis. Cox proportional hazards models compared TB risk across TST and IPT categories, stratified by ART.

Results

The study included around 12,000 patients with 49,169 person-years (PY) of follow-up. Over the course of follow-up, there were 1083 incident TB cases (incidence rate (IR)=2.2/100PY); 95% confidence interval (CI):2,1 to 2.3). Males had a somewhat higher incidence rate than women, 2.4/100PY (95% CI 2.2 to 2.4 vs 1.9/100PY (95% CI 1.7 to 2.1). Among those with CD4 cells below 200mm³, the incidence rate was 3.1/100PY (95% CI 2.8 to 3.4) but people with higher CD4 cell counts had lower incidence rates.

The provision of IPT reduced the incidence rate of TB from 2.3/100PY (95% CI 2.2 to 2.4) down to 1.5/100PY (95% CI 1.2 to 1.9) – a drop of 35%. ART also reduced the risk from an incidence rate of 3.4/100PY (95% CI 3.1 to 3.7) among those not on ART to 1.7/100PY (95% CI 1.6 to 1.8) on ART – a drop of 50%.

Results were then stratified for all the patient by TST status. The background incidence rate remains the same at 2.2/100PY, but the incidence rate for those who were TST-positive who did not go onto IPT was extremely high at 14.9/100PY (95% CI 12.8 to 17.5). However, when those TST-positive people were given IPT, there was a reduction of around 90%, with an incidence rate of 1.6/100PY (95% CI 1.3 to 2.1).

Among TST negatives, there were low rates of TB whether given IPT or not (consistent with last year’s findings from the BOTUSA trial).

However, the group that the study team was most interested in were the TST unknowns (who were never tested). Among this population, IPT achieved a 50% reduction in TB incidence, going from an incidence rate of 2.5/100PY (95% CI 2.3 to 2.7) for those not on IPT down to 1.2/100PY (95% CI 0.7 to 20). (It should be noted that far fewer in this group got IPT, however).

Then the researchers stratified this group of ‘unknowns’ based upon whether they were on ART. Giving IPT to people who were taking ART reduced the incidence of TB by about 35% (from 1.7/100PY (95% CI 1.6 to 2.0) to 1.1/100PY (95% CI 0.6 to 2.0, although these confidence intervals overlap). Among the ‘unknowns’ not on ART, there was an approximately 60% reduction in those who received IPT from 3.8/100PY (95% CI 3.4 to 4.3) to 1.4/100PY (95% CI 0.4 to 4.3) – although again these confidence intervals overlap, probably because few people not on ART had been put on IPT.

But what would happen if the TST were not performed (or at least didn’t need to be performed for a person to get IPT)?

The researchers looked at the data on at all the people who were eligible for a TST from the time the intervention began at the clinic, and followed them until they received IPT, received a TB diagnosis, died, or the follow-up ended. What they found was a rate of 1.5/100PY (95% CI 1.3 to 1.7) for the group overall. The rates were higher for those who were on follow-up for 6 months or 12 months.

“What this means is that if we had given IPT to these patients instead of making them wait to get a TST and act upon that result into for their TST, we could have prevented a large amount of TB at an earlier time,” said Dr Golub.

Theresearchers then looked at people who were eligible for a TST, and followed them until one was performed (and a result was received). Among those who were categorised as 'unknown' and then tested positive, the incidence rate was extremely high, at 22.0/100PY (95% CI 17.3 to 27.6). The incidence was very low among those who tested TST-negative but was twice as high among those who remained unknown, at 1.9/100PY (95% CI 1.6 to 2.3). These results again underscore that TB cases could be prevented by earlier IPT among TST unknowns.

Policy implications

This hasn’t been the first time that a study has shown that requiring TSTs acts as a barrier to IPT implementation. WHO’s new guidelines on IPT, a new version of which will be released in a couple of months, do not require that TSTs are performed, because they are technically difficult in many settings. But even in a middle-income country like Brazil, which should have the capacity to perform TSTs, this study shows that the requirement still impedes IPT implementation. According to Golub, there are a number of policy implications.

“We could eliminate TST and give IPT to all HIV-infected patients. This would save a lot of money, it would be much more convenient, much easier to conduct at the clinics.” He said that although this might mean over-treating TST-negatives, IPT has low toxicity.

Another option would be to improve the provision of TST, but that is after all what this study had been trying to do, with some limited success. However, a final option might offer a compromise, which is to give IPT to all people with HIV until a TST can be performed and read. In settings with lower burdens of TB, it may then be possible to discontinue IPT in someone who is TST-negative. However, the wisdom of doing this in a setting with a higher burden of TB, such as South Africa, and where people may be exposed to TB in clinic settings, is uncertain.

Further information

Jonathan E Golub's abstract is available on the official conference website.