But one of the biggest TB prevention stories
from AIDS 2012 was the suggestion — from Dr Molebogeng Rangaka's presentation of the randomised trial
of ART with (or without) IPT — that the preventive benefits of one year of
IPT appear more durable on ART. This suggests that, while the effect may wear off
eventually, it might be possible to take IPT intermittently while on ART — so if IPT doesn’t
need to be taken continuously, perhaps TSTs aren’t so critical either.
At least, that was what was being discussed in
the impromptu celebration among many of the South Africans involved the study,
right after the late-breaker presentation. It was pointed out that the rate of
TB in the first year after IPT doesn’t increase much (unlike what was seen in
BOTUSA). For instance, the hazard ratios for TB for the study overall (both ART
plus IPT and placebo while on ART) was HR 0.52 (95% CI: 0-27-1.01)
and only marginally higher 0.61 (0.3-1.21) in the following year.
Dr Rangaka and Dr Grant both showed a graph demonstrating the cumulative TB incidence in
which the incidence lines began to converge towards the third year, but less
than one-third of the participants have had three years of follow-up yet.
RCT of IPT plus ART
of study in years
# at risk
ART + placebo
ART + IPT
It is possible that the longer duration of IPT
— when given with ART — effectively clears up more of the TB that occurs shortly
after going on ART. This is a particularly critical period, Dr Graeme Meintjes
of GF Jooste Hospital in Cape Town told HATIP. After that, any TB reinfection that occurs may
still progress to active TB disease — but it takes longer than in more immune-suppressed subjects not yet on ART.
Note, the median CD4 cell count at baseline in
this study was around 214 to 218 — and TB rates might be expected to be even lower
when ART and IPT are started together at higher CD4 cell counts. With further follow-up, it may be determined
that 'continuous IPT' in combination with ART may only be necessary in a small
subset of patients with lower CD4 counts or positive TSTs and that patients
doing better on ART may be able to get by with an intermittent course of IPT.
This is likely to go down better with patients.
As much as TB experts like to say in one breath that IPT is well tolerated —
and indeed, there have been very few serious side-effects reported in these
studies in people with HIV — with the next breath, they will say
how difficult it is to get people to take IPT for twelve or nine or even six
For instance, earlier in her talk, when
speaking about prevention regimens in low TB burden/transmission areas, Dr
Grant said: "They have to take IPT for six to nine months
— that's a long time and retention in a long care programme like that is
typically quite difficult and completion rates are poor, so shorter regimens
would be preferable if they were safe and effective."
Indeed. But if that’s the case, if six to nine
months is too long, what sort of uptake do we really expect to get with
continuous IPT? According to the Thibela TB modelling study, the continuous IPT
combination approach would cut the rate of TB in the mines in half — clearly a
But TB would still be occurring at outrageously
high levels: ~1500 to 2000 cases per 100,000 people.
If TB in the mines — and TB in southern Africa
— is an emergency, why just cut rates in half? Why not use more effective
preventive therapy regimens, if there are any? The Thibela TB study clearly
suggested that a more effective or curative regimen would do better.
Of course, a curative regimen could not be
given continuously — but when taken with ART, we may only be talking about
intermittent therapy anyway. If
something like that could be given every other year, then perhaps it would be
possible to begin to eliminate TB in
the mines and in people living with HIV in southern Africa.
Perhaps the real problem is that IPT just isn’t
"Another potential contributor
could be that IPT just isn't using the right drug. Isoniazid is not very good at
curing latent infection," Dr Grant said in her talk, noting
that this appears to be the case in mouse models where even six months of isoniazid
is not enough to prevent relapse. "On the other hand, some of the newer
regimens and in particular, the new drug TMC207 [bedaquilline], seem to have
much more activity against latent infection," she said.
So of course, those new drugs
aren’t available yet, but what about other potentially curative TB regimens
that are on the market or close to the market? What about the short-course
regimens that have been tested for TB prevention in the United States, where Americans
are considered to have too much trouble adhering to six months of IPT?
"In settings where transmission
is rare we've got rifapentine and isoniazid looking very promising as a simpler
and shorter regimen," said Dr Grant. She reviewed the results of
the PREVENT TB trial, released last year which tested the novel TB preventive
therapy regimen of rifapentine plus isoniazid given weekly, directly observed,
for three months.7
The short-course was non-inferior to the standard of care of nine months of
isoniazid in the low TB burden setting where it was tested. There were not many
people living with HIV in that study, so enrolment was continued to boost the
numbers of HIV-positive people in the study.
Dr Tim Sterling presented the safety data in 393 people with HIV who
were randomised to IPT versus the short-course regimen in the PREVENT TB study at
AIDS 2012.8 Rifapentine may interact with some antiretroviral therapies, particularly with
protease inhibitors, so people entering the study could not be taking
antiretrovirals and so had relatively high median CD4 cell counts (~500).
Significantly, more people finished the short course regimen (89%), and only
11% discontinued it for any reason (compared to 35% who quit IPT over the nine-month
period). About 4% of the participants discontinued IPT due to an adverse
event in either arm.
Similarly, there are other, shorter preventive therapy regimens
currently under investigation, including: another ultra-short-course regimen of
rifapentine plus isoniazid given daily for one month; and a regimen of four
months of rifampicin
monotherapy versus nine months of IPT (in adults who
are TST or gamma-interferon test positive for TB exposure, excluding people
living with HIV if they are on incompatible ART). Both of
those studies are underway.
have been barriers to using rifampicin-like drugs for prevention — one has been
the concern that the drugs are too important for treatment, and if over-used
without direct observed therapy, resistance could be an issue — however, with
new TB drugs with fewer side-effects and drug interactions approaching the
market, it appears as though these concerns are not so pressing.
other issue has been the difficulty in using the class of drugs with ARVs.
However, AIDS 2012 attendees heard that not only were rifampicin’s drug
interactions with efavirenz less serious than once thought, there are also data
to suggest that a newer class of ARVs (integrase inhibitors) may also be used in
combination without serious drug-drug interactions — at least with rifampicin.
data from these studies on preventing TB in people living with HIV won’t be available for
over a year — data from the PREVENT TB study in people living with HIV aren’t due until the end
of 2013 — and even then it will take a while to introduce a new preventive
regimen into the market.
Either way, despite the recommendations or the controversy, it doesn’t
look like IPT will ever really need to be "continuous" — more effective
regimens appear to be on the way to take over.
Using IPT for now, in combination with widespread earlier ART, better
diagnosis and less delay in getting onto effective treatment, could put us on
the path to cutting the incidence of TB in half over the next couple of years.
Then if the researchers, drug approval, drug purchasing agencies and health
systems can start delivering better curative
regimens, TB preventive therapy may truly begin to turn the tide turn on TB and