Anneke Hesseling, MD, of the Desmond Tutu TB Centre at Stellenbosch University in South Africa, visited the U.S. to attend the National Institutes of Health (NIH) 4th Annual Science of Dissemination and Implementation conference last week. While in town, she visited legislators on Capitol Hill to discuss the importance of global health funding, and gave a presentation to physician-scientists and advocates at the United Nations Foundation entitled “TB in Children: A Global Crisis and a South African Perspective.” Science Speaks had the opportunity to speak with her after the presentation regarding integrating TB and HIV testing and services, the potential impact of the Gene Xpert rapid TB test on children, and hot other topics. The video and text of the conversation are below.
What role do you think prevention of mother-to-child transmission (PMTCT) and pediatric antiretroviral therapy (ART) clinics should be playing in screening for and treating infants and children with TB? Do you think they are doing a good job at preventing and treating TB in HIV-infected children? I think PMTCT is firstly a wonderful opportunity to screen mothers for TB. And there are several studies from India and South Africa showing that using very simple approaches like asking mothers what are their TB symptoms can lead to very high yield of active case finding for TB amongst pregnant women – HIV-positive and HIV-negative –because remember PMTCT should also benefit HIV-negative women to stay HIV negative. So first is to detect TB among pregnant women – HIV positive and HIV negative – and putting them onto treatment, and putting the children onto isoniazid preventive therapy (IPT) once they’re born. The other very big opportunity is to put HIV-positive pregnant women on IPT – to prevent them from getting TB.
So I think systems like PMTCT that work and have worked quite well in many settings are a fantastic opportunity to be asking simple questions about, “Is there a TB contact? Have you been coughing?,” and doing TB screening. That’s within the antenatal period.
In the post-partum period, when babies come to do PMTCT follow up once or twice a month at the clinic that is again an opportunity to ask the mom, apart from whether she’s well and whether she’s had a CD4 count, “Are you coughing? Is someone in the house coughing?” A lot of TB in pregnant women occurs in the post-partum period. Then we can screen that baby for TB. If a baby comes into the healthcare system, if there’s a TB contact or the baby is sick, asking the mom and the baby, seeing them together. So we are emphasizing the mother antenatally and then both the mom and the baby postnatally.
In ART clinics, in my experience these are excellent opportunities to prevent and treat TB disease. Before we start ART, we want to exclude active tuberculosis and disease and we will go start therapy anyway. Children who are HIV positive and on ART have access to health care systems: once a month when they come for their drugs and their check-ups, one could ask, “Do you have a TB contact? Have you been coughing?” and screen for TB.
In our experience, even in the community level ARV treatment centers in Khayelitsha, South Africa, where I work, ARV doctors and HIV doctors are very aware of TB and IPT. This is a wonderful opportunity to deliver preventive therapy in a more structured way. Because there is an awareness of the need for education and interaction with parents and families around taking ARVs and being on treatment and taking other medications to prevent opportunistic infections, like Bactrim. So to add something else to prevent TB, the uptake there we find is usually very good. And there’s a lot of cultural education and interaction among parents and their families around the need for prevention and care. And so there paradoxically we often find the uptake to be far better than in HIV-negative children who are recent household contacts.
Reversing it, on the TB control-side, are infants and children who are diagnosed with TB routinely tested for HIV infection in South Africa?
The current guidelines – World Health Organization (WHO) guidelines or most national guidelines – state that any child suspected of having TB should be tested for HIV, and any child that’s HIV-positive should also be tested for TB. What we normally find as we prepare to implement it is people diagnosed with TB are also tested for HIV. So as somebody goes onto TB treatment, in a TB treatment register’s health care records they’re supposed to check off whether they’ve been tested for HIV and had a CD4 count, [and test children as well]. Uptake for children has been much lower than adults because guidelines often say “people” and often healthcare workers forget that children are also people.
But this question really pertains to HIV-positive individuals and screening them for TB and that implementation isn’t always as regularly monitored or not as well as it could be. But the TB/HIV integration focus has become much stronger in adults and there is a real need to move that forward in children as well. So I think that’s a real gap and opportunity for operational research in health systems strengthening.
Frequently, in discussions about global health programs and funding, discussions about maternal and child health are totally separate from discussions of infectious diseases like HIV and TB. What do you think we can do to make plain to funders and governments, especially in sub-Saharan Africa, that tuberculosis and HIV need to be an integral part of the child health discussions?
In countries like those in sub-Saharan Africa, one out of four or one out of three pregnant women are going to be HIV positive. That prevalence is going to be lower in some settings, but overall it’s really high. So HIV in pregnant women is a reality, and obviously cannot be ignored and HIV needs to be an essential part of a maternal and child health focus.
TB on the other hand has been somewhat less obvious. And what has been very, very ignored is the fact that TB is one of the leading causes of mortality among HIV-positive and HIV-negative pregnant women. Realizing that we are apparently not on track to achieve the Millennium Development Goals, if we think of child and maternal health and infectious diseases [separately], by focusing on pregnant women and their children for general health but also for malaria and TB and HIV together, it’s probably the smartest strategy we could implement to achieve these goals. There are relatively well established health care infrastructures that could be used to include infectious diseases which could have a massive, massive impact on morbidity and mortality for pregnant women, their children and their families. One should build upon the well-established health care structures that have been developed, but they should speak to each other and they should be integrated. So, I think integration of child and maternal health care, and a specific focus of including TB and HIV, is going to be very strategic. And these are relatively low-hanging fruit so we can have a massive impact on child and maternal health and it will probably be very highly cost effective. Because these women and children are already accessing services, we are just integrating opportunities to deliver more effective packages of care.
You participated in a session at the NIH Conference on the Science of Dissemination and Implementation last week regarding the Gene Xpert rapid TB test. Do you believe implementation of Gene Xpert will make a significant contribution to the diagnosis of pediatric TB in resource-poor settings?
Gene Xpert is obviously very exciting – it’s wonderful to have a new tool for the first time in ages. Firstly, there are no data published in children yet. So the WHO has made recommendations about the use of Gene Xpert in some populations and they’ve extrapolated those data for children. I think as a pediatric community, we want to embrace any new diagnostic tool that could potentially help children and help diagnose them more rapidly.
One of the major challenges, however, is the fact the gold standard of diagnosis in adults with pulmonary TB, which is culture, is not a very sensitive gold standard in children. So maybe one out of every three children with pulmonary TB will be culture positive and that means that if we implement a new tool that’s almost as good – say it’s 80 percent as good as the gold standard – that means that we may be detecting 80 percent of the third of kids that could be culture positive. That could be seen as not good enough, but it could potentially contribute to making a confirmed diagnosis in a significant proportion of children – not just to give presumptive therapy and treatment, but actually to know that we are treating kids with bacteriologically confirmed TB, even if it’s only a smaller proportion. But it may encourage health care workers to get sputum samples in kids, because [Gene Xpert] can test sputum samples in kids. It will tell us about drug-resistance in children. It helps manage them appropriately, so that we don’t put them on [multidrug-resistant (MDR)] TB treatment when they don’t have MDR disease. And then I think finally getting better estimates of TB that’s bacteriologically confirmed could be useful. I think we have to realize that the test is not designed for children.
So I think in summary we will be able to confirm a diagnosis in a significant proportion of children, that will be a small proportion but a significant proportion of children. Where I think it would be interesting to do more research, and that’s obviously very much needed – both the clinical research and the operational research – is to see where having a more rapid result will actually impact on the management of children. Because if you take a sputum and you can do point-of-care Gene Xpert at a clinic, and it’s positive and you can start a child on therapy in the same day without having to come back a month later after a course of antibiotics etcetera, that may really impact on morbidity and mortality. But I think we need to see the data and we actually need to generate the data. We obviously are excited about any new tools but an important message is that the development of new diagnostic tools up front should include the needs of children, with their low yields of organisms in their cultures as well as their real struggle to produce sputum. So we do need diagnostic tests that are going to be more child-friendly and child appropriate.
What were some of the main challenges to eliminating childhood TB that were addressed at the International Childhood TB meeting in Stockholm?
Some of the major challenges… I would call control and non-elimination [laughter]. I think maybe the pediatric community is somewhat more modest but it’s called recognizing the challenges. I think some of the challenges that were highlighted are that there’s been a limited focus by WHO and national TB programs on children. There’s been systems neglect and that is being addressed, but it’s going to take time to address these needs.
There’s limited technical capacity on the ground and that’s a theme that consistently emerged, there are guidelines but how do we actually go about implementing health systems that are child-friendly. There were major gaps highlighted in research for new tools – those are drugs, vaccines and diagnostics. The other major point that was highlighted was the fact that TB in children is a global disease, and we saw data from Europe where almost 40,000 children were diagnosed with TB in the last 10 years, which is astounding. And most transmission actually occurred within Europe. And the challenges that were highlighted sounded very familiar to me, as a South African. There are major problems with pediatric TB in the U.S. that is also being neglected. Pediatric TB is really a global entity. We need to join forces as a global community.
Two of the other key messages that emerged were the need for partnerships – the need for advocacy, and a need to join forces with scientific health reporters, with health advocates, with industry, with funders, academics joining forces, the TB and HIV communities joining forces to really impact on childhood tuberculosis and collaborate as much as possible.
The final theme that hopefully emerged is that finally people are starting to realize that childhood tuberculosis is important. Now is the time to act, and it’s a major challenge to people who are in the field to now come to the table and start delivering. Yes, people are now more aware, but what are the next steps and can we actually show in five years’ time that we’ve set targets and we’ve achieved targets at program levels; that more children with TB have been detected, more have been managed; that more trials have been done for TB drugs in children; that doses that are appropriate for children or pediatric drugs have been developed and actually given; that contact tracing is happening; that we’re actually achieving some of these targets and we’re not just talking about this neglected entity. We’re showing that there’s real progress being made in the field both for research and for program implementation at a sustainable level, and that countries start taking responsibility for their children with TB.
Yes there are gaps, but there is much we can do and there is much that still needs to be done. As an international community, we need to start delivering.
Is that in essence what the Call to Action for Childhood TB that was developed at this meeting in Stockholm articulates?
Yes, absolutely. And it’s very broad and inclusive so as not to preclude anyone from signing on [laughter].