Determine LAM urine antigen TB test is highly cost-effective for use in hospitalised people living with HIV

The lateral-flow urine LAM test for tuberculosis – a simple inexpensive strip test for tuberculosis – is a feasible point-of-care test in hospitalised South African adults living with HIV and – if patients are then quickly put on effective treatment – would be a very cost-effective diagnostic strategy in such patients, according to a South African study presented on Wednesday afternoon at the 19^th International AIDS Conference (AIDS 2012) in Washington DC.

“It is a cost-effective diagnostic strategy, having an incremental cost-effectiveness ratio (ICER) of $1370 per disability-adjusted life-year (DALY) averted, and this is less than the per capita GDP in South Africa of over $7000,” said Dr Di Sun of Johns Hopkins Bloomberg School of Public Health, who presented the findings. “This remained robust across wide range of sensitivity and uncertainty analysis.”

Five or six years ago, TB-HIV activists began drawing attention to the shocking inadequacy of the existing TB diagnostics – smear microscopy and culturing – which were relatively unchanged in over 120 years since they had been established by Dr Robert Koch, who discovered Mycobacterium tuberculosis (M.TB). Smear microscopy fails to detect the majority of cases in people who are coinfected with HIV, resulting in delays in diagnosis and treatment, and all too often in death. Even culture fails to detect about a quarter of the TB cases that have to be diagnosed clinically.

As a field, TB diagnostics research and development was virtually non-existent.  But the activists caught the attention of the Bill & Melinda Gates Foundation and others, who invested heavily in the Foundation for Innovative Diagnostics and other concerns, setting off a flurry of activity. A product pipeline evolved, out of which GeneXpert has emerged to great fanfare, despite being too expensive and having running requirements complex to put into every primary health care facility – or for that matter even district hospitals.

“Dropping the machine with a parachute and cartridge will not do the job – you need quite a lot of logistical back-up to install this machine in lower resource settings – you need a stable electrical power supply which is very challenging in the settings we are working in, and you also need air conditioning for both the machine and the cartridges; the temperature should not rise about 30 degrees,” said Dr Steven Van Den Broucke of MSF during a TB diagnostics session almost entirely devoted to the Xpert MTB/Rif tests at the conference on Thursday.

The only exception was during the overview on TB diagnostics given by Professor Gavin Churchyard of the Aurum Institute, who mentioned a couple of other assays entering into use, including those that try to detect lipoarabinomannan (LAM), a component of MTB’s cell wall that can be detected in urine samples, when it gets released from metabolically active or degraded MTB.

Urine tests for TB are appealing for a couple of reasons, according to Dr Churchyard. “Urine is easy to obtain,” he said, particularly from patients who may have trouble producing sputum – a common problem in people living with HIV who have extrapulmonary TB. Plus it lacks infection control issues associated with handling blood or sputum.”

An earlier version of the LAM urine antigen test was ELISA-based, which would have to be used in a centralised laboratory. However, a new form of the test uses the Determine testing platform, requires no sample processing and produces results in 25 minutes.

In other words, it is a test that can be performed at the point of care, whichever medical facility the patient is in.

The test isn’t perfectly sensitive or specific. Its highest sensitivity is in people with high MTB burden, who have more detectable antigen in urine, in immunosuppressed patients, and in those with disseminated TB.

The test seems to perform much better in people living with advanced HIV, particularly those with CD4 cell counts below 100. Dr Churchyard presented a table summarising the results using the POC test thus far in people living with HIV.

Determine TB-LAM

Dr Sun noted that the lateral flow test has a few other profound advantages: it requires minimal training, and no expensive additional equipment that has to be airlifted to remote facilities in resource-limited settings.

The cost of each test is also profoundly less expensive than Xpert MTB/RIF, which was about $17 per cartridge test – though as cost-analysis studies in South Africa have shown, once shipping costs and other expenses were added in, the cost of the was closer to $32 (See HIV & AIDS Treatment in Practice's review of LAM and other diagnostic assays for further information). More recently, UNITAID and other funding partners agreed to collaborate on a ‘buy-down’, essentially paying a percentage of the cost of the cartridge so that the cost to national TB programmes in resource-limited settings would be $10 each – though again, shipping and other costs getting the cartridges into the country may not change that much.

The LAM lateral flow assays aren’t bulky, don’t weigh much and don’t require air conditioning. They cost roughly $3.50 per test.

But that still doesn’t mean it would necessarily be cost-effective to roll-out the test widely, or that it would improve upon the already available lab tests (smear microscopy, chest X-ray).

The purpose of the study presented this week was to evaluate the cost-effectiveness of lateral-flow urine LAM assay in HIV-infected South African adults and the economic conditions under which it is most likely to be preferred.

This, other studies have suggested, would be for the most ill people living with HIV, who are desperately waiting in the hospital for a diagnosis.

The cost-effectiveness analysis considered certain aspects of the diagnostic decision as being constant such as:

1. ALL patients would receive the same existing diagnostic tests regardless of whether the LAM assay was added or not (and the costs of those tests would be a constant.

2. A positive result on smear microscopy or LAM would get treatment.

3. Undiagnosed, untreated TB in these patients would lead to death.

4. A proportion of undiagnosed cases would be treated anyway based upon the clinician’s judgment.

Parameter values and unit costs were drawn from studies performed in the South African setting. The estimates (for instance, of life gained on treatment) used were conservative.

The primary outcome, was the incremental cost-effectiveness ratio that adding LAM into the diagnostic decision would yield, in terms of cost per DALY averted. Sensitivity and uncertainty analyses were performed on all parameters.

Results

By adding the LAM test, they would be able to diagnose 80 more true cases of TB, at a cost of 25 false-positive TB cases. These false positives occur because the test is only 95% specific, However, it should be noted that specificity is determined in reference to culture as the gold standard for diagnosis – and yet culture misses a substantial proportion of cases, particularly in this population.

All of this comes at an additional incremental cost of $79,000 (mostly the cost of treatment for these cases).

Cost-Effectiveness of Adding Lateral-flow LAM to Standard TB Diagnostics

The addition of urine lateral-flow LAM averted 58 DALYs at a cost of $1370 per DALY averted (95% uncertainty range: $710-3396). Even if Dr Sun and colleagues had used high values in the sensitivity analysis, the cost per DALY averted is much less than the GDP per capita of South Africa of $7275.It should be noted however, that as of yet, there are no empirical evidence from other trials that the addition of urinary LAM improves survival. In addition, the results may not be generalisable to other populations, such as the outpatient setting or in other high-burden settings settings.

However a three-way sensitivity analysis Dr Sun presented suggested that for a test with 95% specificity to be cost effective, if the resulting life expectancy gained from treatment is only 1.5 years, the TB prevalence would need to be at least 5%. If however, the life expectancy is 5 years, TB prevalence must be at least 1%. But if TB treatment prevents TB-related death, and the patient is put on effective antiretroviral therapy, life expectancy would be much greater, making the test begin to look cost effective in advanced people living with HIV even in settings with a substantially lower TB prevalence.

“This illustrates the importance of extending the life expectancy of our population of interest, which can be done by putting them on antiretroviral treatment, which will cause LAM testing to be much more cost-effective,” Dr Sun said.

“Cost-effectiveness depends most strongly on LAM specificity, life expectancy, and TB prevalence, and it is highly cost-effective with longer life expectancies,” she concluded.