The intervention that worked
So what was the primary take-home message of this complex study, the one that policy makers and funders need to take to heart?
Sending out counsellors to repeatedly make home visits for TB contact tracing (coupled with TB screening, home HIV counselling and testing (HCT) with effective linkages to care) reduced the prevalence of TB in a community with a high burden of TB and HIV by 22%. It also markedly reduced the risk of children in the home becoming latently infected, though this finding did not reach statistical significance (perhaps difficult given the relatively small number of communities in this study).
As implemented in this study, the enhanced case-finding intervention did not reduce the prevalence of TB in the communities (see below).
But contact tracing? Old news. Doing it well with HCT and making sure all TB/HIV cases get into care? Common sense really. It needs to be done.
Even so Professor Beyers recommended caution in generalising the results of the study to other settings.
“I think we have to point out that what we presented – especially from South Africa, were communities in the Western Cape province– and we need to be careful extrapolating, throughout our country,” she said. “We still need interventions to reduce TB and HIV – especially in my country.”
But while it’s true that the Western Cape has a very high prevalence of TB, and a very high rate of TB transmission in the peri-urban communities around Cape Town (and also fairly good cure rates), it would be ludicrous if after all the time and money spent, the study's positive findings could not be used to inform policy in the region. We can’t run a study like this asking the same question in every province.
As Dr Haileyesus Getahun of the World Health Organization’s Stop TB department, who co-chaired the session, pointed out that “what we see in the southern part of the continent is different.” He said that national TB prevalence surveys run by WHO and being presented concurrently in another symposium, show incidence dropping in parts of the world, including Ethiopia. “Something different is going on in southern Africa, which is the epicentre of the TB and HIV epidemic,” he said.
Additional interventions are desperately needed targetting communities with a high burden of TB and HIV. Zamstar’s data demonstrating that the intensified home counselling intervention has such a substantial impact must be used to force programmes and donors to really put these programmes in place.
“We had a discussion two weeks ago with the Global Fund directors and UNAIDS about reprogramming things that are working — and TB/HIV is the low-hanging fruit. But how can we push countries to implement TB/HIV activities that are having an impact?” asked Dr Lucica Ditiu, the Executive Secretary of the Stop TB Partnership. “We have to use these data, it should become routine in how we work.”
Some audience members asked about the cost effectiveness of the intervention, and whether it could be taken to scale outside of a clinical trial.
“How scale-able is it?” said Professor Helen Ayles, another one of the study’s principal investigators. “In Zambia, after the intervention finished in 2009, this was taken up by the communities and we’ve now trained several hundred household counsellors who are home-based carers, community-based organisations, so they are continuing household counselling — and it can be done with lay counsellors, so it can be done at scale.”
“People keep saying that Zamstar was a huge study and an expensive study. The expense is in the measurement, in the rigorous evaluation,” said Principal Investigator Professor Peter Godfrey-Faussett of the London School of Hygiene & Tropical Medicine. “This is four household counsellors per community, and these are people who aren’t paid anything like as much as me, I’m afraid. These are local people, lay counsellors, recruited to work in the community, from the community in which they work. These are not massive interventions.”
Indeed, according to Dr Yogan Pillay, the deputy director general of HIV/AIDS, TB in maternal, child and women health in the South African Department of Health, the intensified household intervention is very close to what is already being rolled out in South Africa.
“One of the implications for South Africa is that we have a high TB burden, together with a high HIV burden. So we need to do something dramatic about it. And I’m pleased to say that we have already started.We didn’t wait for the results of the study. I’m particularly glad that Zamstar found some effect, otherwise all of our interventions are going to be inefficient and cost-ineffective.”
The South African programme started in February of this year, just before World TB Day, with intensified case-finding at home level. Between February 2011 and March 2012, the goal is to visit 200,000 households of index cases, to screen all the household members for TB and offer them HIV counselling and testing (HCT). The teams will also look to see if there are children in the household that are not fully immunised, or pregnant women who are not enrolled in antenatal classes. Dr Pillay said the country was well on the way to reaching this number, having visited over 100,000 households to date.
“We are following the example, in practice, and we are hoping to go to scale,” he said, and emphasised that this was being done within the context of primary healthcare re-engineering.
“We have already started with implementing a ward-based primary healthcare outreach team approach, which will focus really on three things: HIV; TB; and maternal and child health — in the first two years. To help facilitate this, we are retraining 5,000 community healthcare workers and deploying them in specific geographic areas, with an emphasis on TB/HIV and maternal child health,” said Dr Pillay.
This part of the programme began in October and Dr Pillay said that they hope to have data on how it is doing within the year. In addition health services in the school system are to be improved and dedicated specialists will be appointed– specifically paediatricians and obstetricians; and neonatal and paediatric nurses and midwives in each of the 48 health districts.
Dr Pillay said he had taken home some key lessons from the success of the household intervention:
“What the study pointed out to me is that we need to pay specific attention to:
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The link between households and communities and clinics, and how to strengthen the referral systems.
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How to ensure that the outreach teams perform to the necessary quality standards;
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How do we better link the lab system with the outreach teams?;
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How to ensure that the impact of what we do can be measured.
A point that was raised by several of the experts in the audience was that a large part of the benefit in the household intervention was related to the early HIV diagnosis and subsequent linkages into care. Dr Godfrey-Faussett sees the household intervention as complementing a number of developments in HIV care and management
“As for where all of this is going, if you think about integration between TB and HIV services: getting out into the households, and [so] moving more towards test and treat strategies. There’s no doubt, at the individual level, that the risk of TB is lowered when people take ARVs but there hasn't been a controlled study showing that ARVs lower the risk of TB at the community level. But here's something, a TB intervention that does have an effect at the community level that we can now tie in with better HIV integration [with these test and treat strategies in the household]. Hopefully that’s something that the next study we will do at the Zamstar sites can look at,” Dr Godfrey-Faussett told HATIP.
The intervention that didn’t work
As already noted, the more novel enhanced case-finding (ECF) strategy didn’t have any impact at all on TB prevalence. Enhanced case-finding scaled up community-wide efforts to identify TB cases. with activities to increase access to a timely diagnosis for smear-positive TB, and a host of interventions to get people to seek out an early diagnosis so that they would get on treatment earlier and consequently would be less likely to spread TB. In fact, the communities randomised to that intervention did a little worse, though it wasn’t a statistically significant finding.
"I’m sure the team will spend many hours trying to figure out why the community-based interventions did not work; and why the incidence really didn’t come down as much as I think we would all have liked to see it come down,” said Dr Pillay.
“They’re not exactly the results that we’d hoped for,” Prof. Peter Godfrey-Faussett of the London School Hygiene & Tropical Medicine, told HATIP. “We’d all hoped that ECF would show an effect. And yet we are very proud that our study has shown that an intervention, intensified household counselling, can reduce the prevalence of TB at the community level, the first RCT to do this in the era of HIV.”
But what had attracted most people’s attention about the ZAMSTAR study was its testing of an enhanced case-finding model that promised to involve communities. It was colourful and exciting: there was the innovation of sputum collection posts being installed in rural communities and informal settlements, the creativity in the social mobilisation campaigns with drama, radio and other media. And there were projects in elementary schools in which children were trained to look out for symptoms of TB in their family members, and then haul, push or pull their loved one to the sputum collection post if necessary.
But perhaps what was most engaging was the sense that ECF was empowering communities to take charge of their own health. So in some ways, the failure of ECF was a bit of a moral defeat. It also raises the stakes for other studies to demonstrate that increasing case detection will have an impact on the TB epidemic.
“I’m gutted,” Dr Liz Corbett of the London School Hygiene & Tropical Medicine told HATIP, when asked how she felt about the results. “I’m so disappointed that the enhanced case finding in such a major study didn’t show an effect.”
Dr Corbett was hopeful that Zamstar would support the case for scaling up more aggressive case finding interventions that she believes are needed to reduce the burden of TB in communities.
Dr Corbett was not involved in ZAMSTAR, but has been very involved in researching different approaches to case finding and TB prevention in the community. At the Union Conference two years ago, she reported the results of DetecTB, which evaluated two periodic case finding interventions (a week every six months), providing TB diagnostic services with either a mobile van visiting the neighbourhood, or via door-to-door screening. The mobile van appeared to find a higher yield of TB cases, but together both interventions diagnosed about 41% of the TB cases in the community during the study period, presumably earlier than the cases would have been diagnosed otherwise. Consequently, this was followed by a substantial reduction in the prevalence of TB at the population level within a few years — with a more marked reduction seen in the HIV-negative than HIV-positive members of the community.
Dr Corbett did wonder whether there weren’t too many differences between the urban sites in the Western Cape with exceptionally high burdens of TB and Zambia’s sites, noting that “one size does not fit all when it comes to case finding”. Differences between community structure and local transport could serve as more of a barrier to health services in one setting than another.
In addition, ECF couldn’t really be standardised across the communities, as Dr Beyers noted during the Zamstar symposia.
“ECF was done locally by the local community, and while everything was carefully documented, it was heterogeneous. It was easier to standardise the household intervention,” she said.
But it is also possible, that for one reason or another, the Zamstar ECF intervention may not have been aggressive enough, only contributing to about a quarter of the smear positive diagnoses in the community. There is little information, as yet, about how well the enhanced case-finding intervention succeeded in getting people diagnosed and onto treatment earlier.
It is also worth pointing out that ECF relied on smear microscopy aiming for a 48-hour diagnosis, and smear microscopy misses a lot of cases, especially among people living with HIV who are far more likely to have smear-negative TB. The prevalence survey at the end of the study screened for culture-positive TB, which would include smear-negative cases that might have been more likely to go undiagnosed in the ECF arm.
One member of the audience drew attention to the fact that communities randomised to ECF actually had a higher TB prevalence than those without it. Had any of the investigators considered whether the intervention had a harmful effect?
Prof. Godfrey-Faussett pointed out that the confidence interval on that observation crosses 1, so this could well have been chance. But he also said that they had thought about it, and hadn’t yet come up with any plausible way for the ECF intervention to do harm. However, they had only had the results for about a week at the time, and with more time to look at the data (it would be interesting to see a comparison of each arm of the study for instance), and analyses, someone may come up with at least a partial possible explanation.
It might be useful to consider exactly who was using those sputum collection centres in the ECF communities. Some of those cases were indeed the people investigators were hoping for, with highly infectious smear-positive TB presenting earlier, and being put on treatment sooner than they would otherwise. If that was all that was happening in the community, one would certainly think it should reduce the burden of TB, with the magnitude of the effect depending on how much earlier and how many more of the cases in the community they were picking up.
But that wasn’t the only thing going on in these communities. Most of the people leaving specimens at the sputum collection centre didn’t have smear-positive TB, yet they were leaving their specimens anyway, which must have increased the workload for the smear microscopist. That would have meant processing more specimens and more time looking at slides through the microscope, which could have delayed timely diagnosis, and the turnaround of results of cases likely to be positive. Studies have found that the efficiency and accuracy of smear microscopists falls with larger volumes of slides (their eyes get tired reading slide after slide after slide, day in, day out). But the microscopists in the communities without ECF may have had a lighter workload. So laboratory-related delays in diagnosis are one potential problem that could reduce the impact of ECF.
In addition to possibly flooding the lab with specimens, what else was going on with these other people who left their specimens at the drop off centre? What was their story? Obviously, they must have had a cough or some symptoms, or they wouldn’t have done it.
Many of them could in fact have had smear-negative TB, especially if they were HIV-positive. (In fact, it seems likely that the household intervention with its prolonged contact and linkage to health services may have resulted in smear-negative cases being diagnosed sooner). Many of the TB suspects could have had some other respiratory infection, or condition, and again might be HIV-positive. Some of them could have been quite ill with other HIV-related complications.
So what would have happened to these people? If everything goes according to protocol, they should know in a few days that they don’t have TB. In practice, Prof Ayles noted that they had trouble turning around results that quickly, succeeding only 50% of the time in Zambia, and only 25% of the time in the Western Cape.
But once sick people know that they don’t have TB, what do they do? One would hope that they would eventually present to the clinic and receive diagnosis and care. But believing that they don’t have TB, will going to the clinic to get a diagnosis seem to be as pressing, or will they try to self-medicate, or visit their sangoma instead? Could getting that negative TB result actually reduce further health-seeking behaviour, and delay diagnosis?
Many probably never make their way to the health services, so the sputum collection centre might have been their one effort to get diagnosed by Western medicine.
Those who do present to heath facilities may go later than they would have otherwise. For these people, sputum drop off/collection centres could have actually introduced another step before presenting for care. In settings where the drop-off centres weren’t available, it is possible that more people would have gone to the clinic for diagnosis, possibly sooner if still motivated by fear that they have TB. Given the improving standard of care, there is a good chance that, they would have also received provider-initiated testing and counselling in the clinic, and gotten their HIV diagnosed. And once the HIV diagnosis was made, they should have received a more thorough examination, and had their other conditions, potentially smear-negative TB, diagnosed as well. On top of that, a proportion of the people who test HIV positive would hopefully have been put on ART, which would in turn decrease their risk of TB over the long run.
By not providing this opportunity for HIV diagnosis, ECF and the sputum collection centres may not do as good a job of getting people living with HIV into care and reducing their TB risk, as health facilities that offered more than just a TB diagnosis. Consequently, communities randomised to ECF could have had a larger pool of the very people who are most susceptible to TB, which could have undermined TB control in that district, possibly leading to a higher prevalence of TB. Which is just what the study found (though it was not statistically significant). That’s compared to the arm that had no intervention, other than general health system and laboratory strengthening.
For the communities that had the enhanced household counselling intervention on top of standard clinical care, there would have been an even smaller pool of people at high risk of TB. One thing that the counselling intervention excelled at was finding large numbers of individuals with HIV in the index case’s household, even though it did not appear to reduce the burden of TB within the households at the time point when this was assessed. Households receiving some continuity in care could have been more likely to receive early and effective treatment, and less likely to spread TB within the broader community.
This is supposition and the evidence in fact may turn out not to support it — nevertheless, in complex systems, interventions can have unintended consequences. There could be a danger with ECF approaches that are too narrowly focused primarily on smear-positive TB as though that is the primary problem in the communities. The DOTS strategy that successfully contained TB in the rest of the world ran into the same problem — even the best performing DOTS programmes in Southern Africa failed in the context of HIV. And even with the higher case detection rates that ECF may deliver, focussing on smear- positive TB alone, without increasing HIV case detection and treatment, may not be enough in a setting with a high burden of HIV.
In fact, in a recently published paper in the South African Medical Journal by Wood et al describe how TB control policy based on passive case detection and the DOTS strategy has failed in the region, partly because of HIV.
“Passive case-finding is detection of active TB disease among symptomatic patients presenting to medical services, and is promoted in developing countries as part of the WHO-recommended DOTS strategy,” they wrote, but, “The DOTS strategy is insufficient in high HIV-burdened settings. In high transmission settings where effective contact numbers are high, lower case-finding rates and delays in diagnosis and initiation of chemotherapy result in ongoing transmission.”
Wood et al call for a new more aggressive approach to go into the worst affected communities, using new diagnostic technologies and intensified case finding. Despite the the efforts to encourage case detection using enhanced case-finding in this setting, it remains passive. A number of other studies at the conference generated more promising results to increase case finding — though none of these have looked at population level impacts as yet. These are described in a separate article.
More from Zamstar to come?
Finally, Zamstar was one of the largest, most complex studies ever performed in communities with a high burden of both TB and HIV, and simply conducting the study was transformative for many involved.
Some of the study’s benefits are ancillary. For instance, Dr Nathan Kapatha, the National TB programme manager in Zambia, said Zamstar opened his mind to a certain TB/HIV intervention.
“We learned that we can actually implement IPT. We implemented it within the Zamstar sites, and if we could do it in the Zamstar sites, why can’t we do it in our programme? It gives me strength and confidence that we can implement what we should implement,” he said.
And the data on the primary outcomes are only the tip of the iceberg. This study will be data mined for years to come.
“We still have lots more work to do,” said Dr Beyers. “Lots of analyses need to happen; and we have a very strong social science team and there’s an enormous amount of data available on risk factors for tuberculosis. So watch this space.”