HIV and ART programme
What is the true burden of TB in the HIV and ART programme and what are the best screening algorithms and diagnostic techniques to detect it?
How does ART affect TB control at the population level? Would earlier ART in people with HIV have a different impact on the burden of TB in the community?
What adjunctive interventions are needed to further reduce TB (such as IPT)? There are indications from one open label study that IPT further reduces TB rates in patients on ART, but this needs to be validated by controlled clinical trials.
Questions remain about how to optimally combine rifampicin-containing TB regimens and ART, especially second-line ART regimens. Rifabutin could be an alternative to rifampicin for people on protease inhibitor regimens, and there are moves to get the drug onto the Essential Drugs list in order to make the drug more widely available. But is it as effective in TB regimens as rifampicin?
How should TB immune reconstitution syndrome (IRIS) be diagnosed and managed?
How can ART programmes form tighter linkages with TB services and make TB diagnostic and treatment services more convenient for people with HIV and possibly TB?
The TB programme
As Dr Gunneberg pointed out, the true burden of HIV in people with TB in many programmes is still unknown.
Studies are obviously needed to improve the diagnosis of smear-negative and extrapulmonary TB and more rapidly detect MDR-disease, and to evaluate new diagnostic technologies.
Is the relapse rate among people with HIV on TB treatment truly greater or are most cases due to reinfection? How best can relapse be prevented? Is ART adequate or is longer TB treatment necessary? Would secondary IPT work? How best should retreatment cases be managed? What is the best retreatment regimen?
What is the best time to begin ART for people on TB treatment? Recent data have suggested that survival is improved in patients who start ART before completing TB treatment but more information is needed about the exact time to start ART. A number of studies with differing designs are now underway (click here for details).
“I am leading one study of "when to start" ART in TB patients in the AIDS Clinical Trial Group and also working with the HIV Prevention Trials Network to see if early ART (>350) reduces TB burden,” Professor Diane Havlir of the University of San Francisco (and also Chairperson of the TB/HIV Working Group of the Stop TB Partnership) told HATIP.
Although TB programmes have demonstrated that they can scale up HIV testing, and offer cotrimoxazole to subjects who test positive, there has been less success getting people with HIV-related TB onto ART. Operational research is needed to develop optimal models for linking TB services to ART programmes to make sure that people aren’t lost to follow-up.
Paediatrics
As our clinical review series on childhood tuberculosis demonstrated, paediatric TB is a neglected field, and much of what we know about the disease is based on research before HIV treatment became available. (See HATIP’s recent three-part Clinical Review on childhood TB: part one, Epidemiology, part two Presentation and diagnosis, part three Treatment and prevention).3, 4, 5
“Most of the questions we’ve been answering over the past two, three years in adults, still need to be asked in children,” said Dr Lawn. Dr Mark Cotton of Tygerberg Hospital also gave a presentation at the Sydney IAS meeting on the HIV TB research agenda in children (download a slide set in pdf form here).
What is the true burden of TB in children in the community, and what is the burden of HIV-related TB in children? Diagnostic tools are desperately needed which don’t rely on sputum, which young children have difficulty producing.
What are the optimum treatment regimens for both drug-sensitive and drug-resistant TB in children, and how can this be combined with ART? Pharmacokinetic studies are desperately needed to determine the optimal doses for TB drugs for children of different ages and sizes, especially for second-line drugs and new drugs in development.6
The BCG vaccine is not recommended in HIV-infected children but can it be safely given later after initiation of ART? Because of the difficulty excluding children with HIV when the vaccine is given (at birth) many children with HIV or who become HIV-infected post-natally will be vaccinated anyway. Some may develop life-threatening systemic BCG infections and BCG IRIS. How best should these conditions be managed?
How should programmes provide routine screening for TB contacts in children with HIV to make certain that TB-exposed children receive timely preventive therapy? How should the child contacts of MDR/XDR-TB patients be managed?
Large scale community interventions
The final theme in Dr Lawn’s table is a call for the expansion of operational research beyond the confines of programmatic settings to find new ways to control TB.
“We shouldn’t be small in our thinking. We know that DOTS is necessary but insufficient and we need more epidemiological data to understand why DOTS doesn’t work and what is needed,” he said.
He argued that researchers should consider “mass interventions.” For instance, would it be possible, or advisable, to provide mass TB treatment to ALL people with HIV with symptoms of TB (simply foregoing the laboratory-based diagnostic process) and then give mass IPT to everyone else? This could require working with partners outside of the health system — an idea that CREATE has piloted in its ZAMSTAR study (which is looking at intensified and enhanced case-finding within the community.
And what would be the effect on TB of putting everyone with HIV onto ART — as one notable paper has recently suggested? (see HATIP 123, November 2008).
“Granich’s et al’s model in The Lancet of annual universal HIV testing and immediate ART has the chance to considerably reduce the TB epidemic and this needs to be tested out (and in fact plans are being made to do so),” Prof Harries told HATIP.
Again, Dr Lawn stressed that urgent and extraordinary actions are needed to control HIV-related TB.