HIV and TB in Practice: Moving towards combination TB prevention

Prevention highlights from the 3rd South African TB Conference and AIDS 2012

"What we really need is combination TB prevention," Dr Allison Grant of the London School of Hygiene and Tropical Medicine said on the final day of the 19th International AIDS Conference (AIDS 2012) in Washington DC. "Not just antiretroviral therapy (ART), not just ART plus IPT [isoniazid preventive therapy], but other things as well, and if we do all of these things — and all of these things are achievable now — we could really start to make a big difference in terms of TB prevention."

She suggested that the TB world should borrow the 'know your epidemic' message from the HIV field — meaning that the prevention strategy should suit the setting. In settings where TB transmission risks are low, it may be fine to focus primarily on preventing latent TB infection from becoming active TB disease — with short-course curative TB regimens — but in settings where the risk of being reinfected with TB is high, more drastic measures to prevent reinfection with TB may also be needed.

However, there is some controversy over whether some of these measures, such as continuous, lifelong IPT, are entirely necessary in the context of ART, especially for people without evidence of exposure to TB (as measured by a tuberculin skin test or TST), but widespread agreement that business as usual cannot be the response in high TB- and HIV-burdened settings.

"Therefore we have to intervene to break the cycle," said Dr Grant, "first, by preventing people who already have latent TB infection developing active disease, and secondly by reducing transmission to prevent new infections."

But a combination prevention approach will be needed to do it all. This point emerged very clearly in the 'Thibela TB' study for which Dr Grant was a principal investigator.

Further data from the largest trial of IPT ever: Thibela TB

The 'Thibela TB' study was the largest IPT intervention study ever to be conducted. As previously reported by aidsmap, the Thibela TB study showed that giving a nine-month course of isoniazid preventive therapy (IPT) to everyone working at randomly selected South African gold mines had no effect on TB incidence, TB prevalence or all-cause mortality in the population, when compared to a cluster of gold mines randomised to standard TB programme management. However, a post-hoc analysis found that IPT did have an effect at the individual level — reducing TB while people were taking it — but this effect was lost very quickly once IPT was stopped. This finding suggests that levels of TB transmission in the mining communities may be higher than realised — and that a longer, potentially continuous course may be necessary to better control TB.

Further modelling analysis, presented at the South African TB conference in Durban in June, shed some light on why the intervention studied may have been insufficient, and what more may be needed to minimise TB incidence.

Six months of IPT has very little effect on TB incidence

"Why did we get no detectable impact in Thibela?" asked Dr Emilia Vynnycky of the Aurum Institute, during a symposium at the conference in Durban. To find out, the researchers created a model describing the epidemiology of TB in each intervention cluster, incorporating both directly measured data and some key assumptions:

• 30% HIV prevalence
• 20% average annual risk of M. tuberculosis infection
• TB disease occurs either through reactivation or following reinfection at estimated rates
• Increased risk of disease if HIV+ and/or silicotic
• IPT protection against disease through reactivation/after reinfection, whilst on IPT — 63%: HIV- or HIV+, not on ART; 80%: HIV+ and on ART; No protection once stop IPT
• Six months of IPT cures an estimated fraction of latent infections.

"We assume there is no protection once people stop IPT — and we didn't really know what proportion of infections are cured by six months of IPT," she said.

So there were several unknown parameters in the model including the risk for developing disease — from reactivation, or following reinfection — and most importantly, the proportion of latent infections that are cured by six months of IPT is unknown. But the model had to reproduce what went on in the mines, and so they fitted models with the prevalence and incidence data until the models were able to produce the impact observed.

"It turned out that in order to match the low impact observed, the model really needed to assume that six months of IPT had a low impact," she said. "In fact, the best fitting model was one in which we assumed that 6 months of IPT does not cure any latent infections."

And once this was assumed, the model predicted that even optimal implementation of Thibela TB would have led to a modest additional impact of under 20%.

"If you’d actually improved the IPT retention to the best possible level, the overall additional impact would have been roughly 12% in addition to what we saw. And varying additional factors i.e. screening, treatment, migration, community contact ... additional reduction in TB incidence would have been up to 20%," she said.

What would it take to control TB in the mines? Combination prevention AND better prevention regimens

The Aurum Institute researchers then presented a further analysis to show what would have worked to control TB in the mines. On a Kaplan Meier plot, they added intervention after intervention, each showing the modest impact of interventions that included decreasing the delay before starting TB treatment, improving rates of diagnosis, then increasing IPT coverage to highest levels seen in the most successful round of this study. The last intervention, IPT, would have had a profound initial impact — cutting TB incidence by almost half during the course of treatment. But the effect doesn’t last once IPT stops.

They showed that if IPT did not stop, and they could get around half of people in the community to take continuous community-wide IPT, the effect would be somewhat more durable.

Notably, they also presented the impact of using a three-month regimen that cured latent infection. This had the most profound impact of all, knocking TB incidence down by almost three-quarters. Here too, the effect was lost, but importantly, it took about three years for the TB incidence to rise to the level that would be seen with optimal IPT implementation and 50% of the community on continuous IPT.

Then the researchers looked at other factors such as better diagnosis with the GeneXpert test, which had an impact, but not as much as one might think; and addressing dust control/silicosis in the mines, which reduced TB incidence by only 10 to 20%. The most significant impact, which should come as no surprise, would be to put all the miners living with HIV onto ART. Alone, this intervention wouldn’t be adequate either — additional interventions would be needed (as was shown in the randomised control study of ART and IPT in Khayelitsha (see this news report).

"However, combining interventions could reduce the TB incidence by over 50%," said Dr Richard G White, in Durban. The interventions included: reducing treatment delay, screening with Xpert in annual occupational health screening, ART coverage increased to 80% by 2009, an initial 9-month course of IPT, with coverage at highest levels seen in Thibela, followed by continuous community-wide IPT with 50% coverage.

Does the Thibela TB study add weight to the case for continuous IPT?

Both in Durban and in Washington DC, Dr Grant reported the team’s conclusions about the potential ramifications of Thibela TB.

It cannot be that IPT does not work.

"We have lots of evidence to know that it works, so for example amongst people with HIV in clinical trials we know that, overall, people receiving IPT have a one-third reduction in their risk of going on to develop active TB. If they have a positive tuberculin skin test, they've got a two-thirds reduction in their risk of developing active TB, but in order to do that they have to take IPT for six to nine months," she said. "And clearly, we've got very consistent data suggesting that IPT works while you're taking it, but unfortunately it doesn't seem to have a durable effect after you stop."

She noted this poor durability of IPT was observed in a couple of other studies in high HIV prevalence settings, with high TB transmission. In the BOTUSA trial, 36 months of IPT was superior to a six-month course, and TB rates increased shortly after going off IPT even in the 36-month arm (in TST-positive subjects).^1,2 In a smaller study some patients took a short course of curative combination rifampicin and isoniazid (though this last observation was a bit more anecdotal).³

"So in high transmission settings, increasing evidence to suggest that IPT has limited durability is leading us to the thought that we need to very seriously consider continuous IPT for people with HIV," she said, adding that "more broadly than that, we need to think about a combination approach."

Taking IPT continuously is generally in agreement with WHO policy, which states: "IPT for a duration of 36 months is conditionally recommended in settings with a high transmission of TB among people living with HIV,"⁴ and incidentally, also the conclusion reached by Professors Steven Lawn and Robin Wood of the Desmond Tutu HIV Centre, and the University of Cape Town. "Growing evidence therefore suggests that if IPT is used, to do so on a long-term basis would be a more rational approach," they wrote recently in the International Journal of Tuberculosis and Lung Disease (IJTLD).

They took exception to the next component of the WHO IPT policy, which emphasises that "a tuberculin skin test (TST) is not a requirement for initiating IPT in people living with HIV. However, in some settings where it is feasible, it can help to identify those who would benefit most from IPT."

Lawn and Wood argue that, if IPT is to be given lifelong, it is wasteful to give it to those who are not TST-positive.

"A shift in policy towards long-term or even lifelong therapy, however, would provide an even stronger rationale for targeting IPT according to TST status. Indeed, targeted provision of IPT for 36 months to TST-positive individuals in Botswana has been found to be more cost-effective than providing IPT without TST assessment or providing IPT for 6 months only," Lawn and Wood wrote, citing another recent paper.⁵ Their main criticism is that the current South African IPT programme guidelines, as reported by Bristow and colleagues in IJTLD,⁶ are not being properly targeted.

"The current rapid scale-up of IPT … is not being targeted in patients who will benefit, and is being given for too short a duration that will not provide durable prevention. This policy is inefficient use of scarce health care resources. Current scientific evidence suggests that if the intervention is to be appropriately tailored to the local epidemiological situation, it should be given to patients who are confirmed to be TST-positive, and on a long-term basis," they concluded.

In her talk, Dr Grant conceded that the lack of benefit of IPT in TST-negative patients is indeed a bit of a quandary.

"I don't think we understand everything that there is to understand about the epidemiology of TB in these settings still. The results from the Botswana study, were very different amongst people who were tuberculin skin test positive and negative, and the people who were tuberculin skin test negative at the start of the study didn't benefit from continuous IPT. What I think is interesting though is, how is it that TB incidence remains so low in the placebo arm of people who are TST negative, even though their TST result was some years ago — if most TB [in these settings] is due to reinfection, it's a little bit difficult to understand that," she said.

South African activists have pointed this out too, and have also suggested that TSTs ought to be provided before anyone is put on continuous IPT (see recent HATIP blogpost on the debate over IPT in South Africa).

But Dr Grant is afraid that will take IPT programmes back to square one.

"If you can come up with another more effective way to do TSTs, maybe, the danger is that if you require TSTs, how will it be any different from the same old ‘business as usual’ which led to so many missed opportunities for TB prevention, and the failure to scale-up IPT?" she told HATIP.

Might ART make continuous IPT (and TSTs) unnecessary?

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

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 months.

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 marked improvement.

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 aggressive enough.

"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.

There 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.

The 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.

Unfortunately, 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 HIV-related TB.