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Operational research: diagnostics and task-shifting

Theo Smart
Published: 29 July 2011

How best to deploy point-of-care CD4 cell testing in resource-limited settings?

Widespread introduction of point-of-care (POC) CD4 cell tests that don’t require a laboratory technician but can be performed onsite by a nurse, providing results in less than an hour – while the patient waits) is expected in the next 12 to 24 months, said Dr Steven Reid of Imperial College, London, during a session on advances in diagnostics on Monday at the International AIDS Society conference in Rome, Italy.

In fact, one such test is already being rolled out in some settings. Speakers during the session described how POC CD4 tests might improve service delivery for people living with HIV, their potential cost-effectiveness and where best to deploy them.

For instance, the availability of POC CD4 cell tests – paired with a mobile HIV counselling and testing service – significantly increased linkage to care for people testing positive for HIV, according to one study.

Dr Reid presented a modelling study suggesting that starting treatment on the basis of POC results would be more cost-effective than with traditional CD4 cell tests, and better than initiating treatment on the basis of clinical (syndromic) management of people living with HIV — potentially adding years to their lives.

However, another study, presented by Dr Ilesh V Jani of the Instituto Nacional de Saúde reported that the cost of implementing POC CD4 would depend upon the clinic and volume of tests it would perform — and that there should be “a more judicial deployment of the technology", prioritising “higher volume sites and clinics that cannot refer samples to laboratories”.

CD4 cell tests

CD4 depletion is the hallmark of acquired immune deficiency, and CD4 cell measurements are the best indication of when a person should start antiretroviral treatment — preferably before there is a seriously increased risk of opportunistic infections and tuberculosis. The World Health Organization’s 2010 antiretroviral treatment (ART) guidelines recommend that treatment begin at a CD4 count of 350 cells/mm3 — although not all countries follow this recommendation yet.

But in a number of resource-constrained settings, it is difficult to do CD4 cell measurements to start treatment — and these have instead relied on clinical staging (based upon symptoms and signs of immune deficiency). But a number of studies have shown that clinical staging is inadequate since it misses large numbers of people with very low CD4 cell counts, who are at great risk of catastrophic illnesses.

The gold standard for CD4 measurement is flow cytometry (Becton Dickinson or Beckman), but this equipment is relatively complex and it requires skilled laboratory technicians to perform. Many resource-poor settings simply don’t have the infrastructure, human resources or funds to provide convenient access to CD4 cell testing in more remote or rural settings. People either have to be referred to a site that provides CD4 cell testing, or have their specimens sent to the site and return to the clinic to get their results.

Many people simply don’t bother because of time, distance or money, and are often lost to follow-up, until they either fall ill, and come in for care again, or die.  Researchers have therefore been working to make CD4 cell testing cheaper, more accessible and easier to use.

“The CD4 Initiative was established in 2005 to develop rapid, economical, point-of-care tests for CD4,” said Dr Reid. “The aim was to develop tests which require limited or no infrastructure — no electronics, simple to use, and cheap.”

Such CD4 cell results could then be introduced into the most remote rural settings to put people onto ART on the basis of CD4 counts rather than clinical staging. The new tests would also facilitate the delivery of ART in decentralised settings (including the primary health care clinic) and possibly improve retention into ART programmes, by speeding the time it takes between when a person gets tested and when he or she goes onto ART, and by reducing loss to follow-up.

The new generation of CD4 cell tests

Dr Reid listed three of the leading POC CD4 products.

Alere’s PIMA is already in use (in both the mobile clinic study and in Mozambique). It consists of a disposable CD4 cartridge containing sealed reagents and a portable analyser to produce a CD4 cell test from either a fingerstick or venous whole blood sample within 20 minutes.

A finger prick is made with a sterile lancet to collect 25μL of capillary whole blood into the cartridge, without manual sample handling or processing. The reagents (all dried and requiring no refrigeration) are sealed inside the cartridge. The cartridge is then inserted into the battery (or A/C) powered portable analyser, which automatically begins the testing process, providing a direct CD4 measurement in 20 minutes.

Daktari CD4 is another POC test, that requires no pipetting, labels or reagents. Its cartridge is then placed into an analyser that reads electrical signals, and reports the CD4 count within minutes, according to the manufacturer’s site.

The third POC test, from CD4 Initiative working with Zyomyx, Inc., is a single disposable unit that can deliver an absolute CD4 count without complex electronics and instrumentation. It is the first readerless point-of-care, that is, without an analyzer. Instead, the healthcare worker reads the CD4 cell count by a simple visual inspection of the test tube-like unit.

Modelling

Despite the promise of POC CD4 cell tests, “the impact of introduction is not obvious”, said Dr Reid. So he adapted a published model of ART initiation, to compare the impact on life-years saved (LYS) of syndromic management and the two CD4 counting strategies (flow cytometry and POC CD4 tests), adding in costs for the CD4 cell monitoring technologies. He adjusted a number of parameters in the model (based upon the POC test’s expected impact on retention), and used two different CD4 cell initiation thresholds (250 and 350 cells/mm3) and different estimates for the CD4 cell costs.

He calculated high and low costs for the CD4 cell technologies based upon costs of reagents and the test price, the staffing, personnel costs needed to perform the test, infrastructure, laboratory costs (when needed), the overhead for hospital or laboratory (if needed), referring to data on costs from Zimbabwe and Uganda. The unit costs were higher on the POC CD4 test, but reagents and other expenses made the centralised flow cytometry test more expensive overall.

In the model, initiation based upon syndromatic management clearly cost the least (almost half of POC), but has the poorest outcomes in terms of life-years saved. Initiation on the basis of flow cytometry and POC CD4 would have similar overall costs, but POC CD4 cell tests would result in more life-years saved and thus be more cost-effective.

However, these results are entirely dependent upon the cost calculations and assumptions about how the availability of point-of-care testing would affect retention and the timely initiation of ART.  Other reports presented at the conference were conflicting on some of these points.

Increased linkage to care

For instance, there was a poster presentation of data from Themba Lethu Clinic in Johannesburg, previously reported at the 5th South African AIDS Conference, showing that having a POC CD4 test available didn’t dramatically shorten the time between testing positive and going onto ART. The lack of impact was primarily due to the fact that 39% of the people rejected the offer of POC CD4.

However, another study from the same researchers in Johannesburg, presented by Dr Bruce Larson, reported much greater acceptance – 90% – of the Pima POC CD4 cell test when it was piloted to a few hundred people testing positive at a mobile HIV counselling and testing service.

The study involved phone interviews of people who had been offered the test versus those who had not. There was a 26% increase in referral uptake (those making their first visit to the referral site within eight weeks of testing positive).

“The increase in referral completion went from 38.5% to 64.7% (a 68% improvement),” said Dr Larson.

He said the difference in the uptake of the offer for POC CD4 between the mobile clinic and Themba Lethu clinic was puzzling, but he noted that the Pima test provided results within about 20 minutes, while the test used at Themba Lethu took much longer (closer to an hour). “Once it was explained how long it would take, many of the patients at Themba Lethu may simply not have wanted to wait around that long,” he said.

Likewise, Dr Jani mentioned similar data from a study he conducted in Mozambique, which found that nurses in primary health clinics can accurately perform CD4 counting using point-of-care devices.

Comparing percentages of patients getting and returning to the clinic at baseline to post-piloting of the POC CD4, there was a clear reduction in pre-treatment loss to follow-up. At baseline, only 55.2% got their CD4 cell results, compared to 92.9% afterwards, while only 28.4% returned to the clinic for care, versus 79.4% after the introduction of POC CD4.

Costs depend on throughput needed — deploy carefully

However, Dr Jani presented data on indicating that the cost of implementing POC CD4 could be significant, and suggested that programmes may want to consider carefully where they want to install POC CD4 cell monitoring.

The traditional CD4 test has several things going for it: a higher throughput (50 to 75 tests per day), a large installed base (>1000 instruments across Africa), already existing infrastructure in some settings, and it may be more efficient and cheaper due to economy of scale. POC CD4 however can only perform 5 to 20 tests per day, and is new technology – although it does not require significant infrastructure and can be performed by non-specialised personnel.

He developed a different costing model based upon data gathered from health facilities across 13 countries in sub-Saharan Africa, looking at reagent, control, and consumable costs, equipment and maintenance costs, lab infrastructure and overhead costs, sample transport costs, human resource salaries, and site patient volumes.

These data were used to calculate a total cost per test for a site with a known testing volume to determine if it would be less costly to refer samples to an existing CD4 laboratory or to implement POC CD4 testing on-site (with the PIMA test).

The cost of conventional CD4 cell testing actually varied significantly by site (due to reagent costs), while POC CD4 costs were more stable. At sites with average throughput, the costs of testing were similar: $10.50 for the conventional CD4 and $11.78 for the POC CD4.

However, for increasing volume, the cost per test for POC CD4 drops dramatically (though it will increase again if more than 5000 tests are performed a year — because a second analyser would be needed).

The cost of POC CD4 versus conventional CD4 is about equal if ~2,900 tests per year are performed by a site.

“Sites above 2900 tests per year comprise more than 90% of CD4 test demand, but it is more intuitive that POC would belong at small, remote sites,” said Dr. Jani.

But even though it may be less costly to put the POC CD4 tests at a number of higher volume sites, Dr Jani stressed site selection should depend on other factors than simply cost, including universal access, equity, distance to laboratories, patient loss-to-follow-up, size of catchment area, ART coverage, HIV prevalence, and PMTCT services.

References

Jani IV et al. Cost comparison of point-of-care and laboratory CD4 testing in resource-limited settings. Sixth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Rome, abstract MOAD0101, 2011. 

Larson B et al. Rapid point-of-care CD4 testing at mobile HIV testing sites to increase linkage to care: an evaluation of a pilot program in South Africa. Sixth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Rome, abstract MOAD0103, 2011. 

Grundy CL Point-of-care CD4 tests can increase life-years saved with reduced costs compared to flow cytometric CD4 counting. Sixth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Rome, abstract MOAD0105, 2011.

Hallett TB et al.  The impact of monitoring HIV patients prior to treatment in resource-poor settings: insights from mathematical modelling. PLoS Med 5(3): e53.

Despite challenges, South Africa successfully scaling up GeneXpert TB test — but concerns about the cost of rapid full implementation

South Africa has quickly and successfully scaled up the first phase of implementation of the new diagnostic test for tuberculosis, the GeneXpert MTB/RIF assay, as the first-line TB test in 25 sites, achieving two to threefold higher rates of TB and drug-resistant TB diagnoses in many of the facilities, according to a late breaker presentation at IAS2011 in Rome. However, switching over from relying on smear microscopy-based diagnoses to using the new test presents a host of challenges.

“It changes everything we do,” said Professor Wendy Stevens of the University of Witwatersrand and the National Health Laboratory Service, who added that, despite the expected substantial increase in people put on earlier treatment, the cost of rapid full implementation has the programme quite “anxious.”

“Our initial algorithm is an expensive one, which may well have to be modified as confidence in technology and data emerges,” she said.

TB in South Africa

The rates of TB, HIV-related TB and MDR-TB in South Africa are among the highest in the world — with case detection and cure rates that are below WHO targets. This failure to diagnose and effectively treat TB leads to the alarming overall rate of TB, around 980 cases per 100,000, much of which is fuelled by the HIV epidemic. 70%-80% of the country’s TB suspects are infected with HIV, generating one-fifth of world’s reported HIV-associated TB cases.

Even if case detection were at recommended levels, the currently used first line diagnostic tests are notoriously outdated and insensitive, especially for detecting TB in smear-negative individuals, and for detecting extrapulmonary TB. Both smear negative and extrapulmonary TB are much more common in people living with HIV.

Patients seeking a diagnosis for TB and treatment have to make multiple clinic before they are finally diagnosed and access treatment. Culture takes weeks or months and cannot be not performed on all suspects. While a WHO-recommended algorithm exists to empirically manage suspected smear-negative TB, it relies on cough as a gatekeeper symptom, and thus may not be sensitive enough to capture many people living with HIV, and requires a return clinic visit before an empirical diagnosis can be made.

New diagnostic techniques have been under review over the last few years. The GeneXpert MTB/RIF assay has seemed one of the most promising technologies — a self-contained TB diagnosis system that automates sample processing on sputum and provides real time PCR results within about two hours.

The test also screens for the presence of resistance to rifampicin, which is used as a surrogate for MDR-TB, and should therefore speed the time to diagnosing drug-resistant TB as well. As previously reported, the test requires minimal specimen handling and could be theoretically be performed by trained nurses.

Recently, after a review of the new test, the WHO gave it strong recommendation: “The new automated DNA test for TB [GeneXpert] should be used as the initial diagnostic test in individuals suspected of MDR-TB or HIV/TB.”

South Africa already has a well resourced  TB diagnostic infrastructure, according to Prof. Stevens. It has 244 microscopy centres that last year performed over 4 million smears, and 16 culture labs that did 1 million cultures and thousands of line probe assays.

“Despite this we are not making the diagnosis adequately in most of our patients. Our smear sensitivity rates in HIV are about 35-40%, and delay in the results from culture frequently lead to loss to follow-up,” she said.

Scaling up Gene Xpert

South Africa began to implement a pilot roll-out of Gene Xpert in March 2011, after Health Minister Aaron Motsoaledi ordered a radical change in the country’s policy on TB diagnosis. He instructed the NHLS to get the first pilot sites up and running within six weeks.

The selection of the pilot sites was based upon burden, with 30 instruments installed at 25 of the highest burden districts in each province. The initial rollout was at microscopy centres, which generally provide about 11% of national coverage for TB diagnosis based upon smears.

“The decision at the time was to replace smears with one GeneXpert test for diagnosis. What has happened subsequently is that a lot of work has gone into the development of an algorithm,” said Prof. Stevens. The plan for the near future is that all patients will get the GeneXpert test up front. If the test fails (due to an error, such as lack of an adequate specimen), the test is repeated. If the TB result is positive, they are diagnosed with TB. If the test shows rifampicin resistance as well, the results must be confirmed by TB culture and drug sensitivity testing (DST).

One of the problems with this algorithm  is that requiring only one GeneXpert test could miss a high percentage of people living with HIV who have smear-negative TB. The GeneXpert test is able to detect TB in many — though not all — smear-negative people living with HIV, but more can be detected by performing a second or a third test — which of course, increases the cost of diagnosis.

NHLS had  a very limited time to perform the activities needed to support the rollout. Site assessments had be done at all 25 sites, with a checklist developed to looking for network points, power, space, air conditioning, and adequate human resources. Standard operating procedures had to be developed and 80 laboratory technologists had to be trained (54 were trained by World TB Day) with an intensive two day centralised training — so far, these have largely been microscopists who had previously been doing first line diagnosis.

All instruments have been interfaced with the laboratory information management system (LMIS). A Lab-Track LIS interface was developed to automatically report the lab number, instrument, cartridge number whether or not TB was detected, and whether RIF resistance was detected or not.

“This is so we can automatically collect data in real time,” said Prof Stevens. . “We have also developed an external quality assurance programme using dried culture spots. We quantitated TB bacteria by flow, placed it on a dried culture spot, and every module that gets placed in the field is tested in this way.”

The next steps were the development of the further implementation plan, the budget plan and a national TB Costing Model (NTCM).

Results

All the sites were launched by World TB day, and most were operating at  full capacity by April. Cumulatively, between March and June, 50,093 people were screened with the test — yielding a TB diagnosis in 8591 cases. 

 “We have identified a positivity rate of 17.15%, which is huge,” said Prof. Stevens. The test failure rate was 4.02% (these tests must be re-run). “For rifampicin resistance, in the same population, we have picked up 7.3% (n=630), which is literally triple what has been identified in the population previously,” she said.

Indeed, if these rates are accurate it would suggest that around 30,000 to 40,000 cases of the 400-500,000 notified TB cases in South Africa are MDR-TB — which would have profound implications for South Africa’s TB programme. However, she added that the test is known to produce false positives for rifampicin resistance, so those findings should be seen as preliminary.

Indeed, in a newly published study by Lawn et al, Gene Xpert correctly identified rifampicin resistance in four cases of multidrug-resistant TB but incorrectly identified resistance in three other patients whose disease was subsequently confirmed to be drug sensitive by gene sequencing. This means that the test is highly sensitive, but has a specificity of 94.1%; and a positive predictive value of 57%. Even at that predictive value however, the burden of MDR-TB in South Africa could be substantially greater than previously thought.

There was significant geographical variation in rates of M.TB positivity, and the rates of rifampicin resistance to a lesser extent. Excluding the Western Cape (which does not seem to have reported many test results), KwaZulu Natal has the highest rate of TB diagnoses (20.51%) ranging down to 10.91% in Limpopo; while the Northwest Province reported the highest rate of rifampicin resistance (9.3%).

Focusing just on the eThekwini District (Durban), the GeneXpert more than doubled TB diagnoses to 19.71%, compared to 8-9% for the same period in 2010.

Challenges and lessons learned

“We’ve learned that the algorithm development is complex and time is needed to get consensus,” said Prof. Stevens. Switching over to diagnostic platforms meant sweeping changes had to be made to the TB guidelines, request forms, training and resistance reporting.

“Training needs to focus on items like sample preparation and good laboratory practice. We’re also running into regulatory issues such as who can do the test, when scope of work is well-defined in South Africa,” she said.

The error rate of about 3-4% is a cause for concern because it adds to the cost of implementation and delays diagnosis. Some of these errors are well characterised, such as one resulting from putting an insufficient volume of sputum into the cartridge. But the most common error code being seen appears to be unique to South Africa and is being investigated at the current time. “Electricity is also critical for the good running of the instrument,” said Prof. Stevens. “As is good temperature control.”

Pace of implementation, cost modelling and anticipated impact

But the biggest challenge could be the cost, which could clearly affect the pace to full implementation.

There are two timelines for phased implementation on the table, a fast-scale up scenario, with full coverage with GeneXpert by December 2012 and a slower scale-up scenario, with full coverage by September 2013.

“The minister would prefer the first one,” said Prof. Stevens.

The first phase of implementation is already completed. The second phase will be to fully capacitate the high burden districts. Phase 3a/3b will be part of a Gates funded, cluster-based randomised trial to analyse cost effectiveness and impact on patient outcome.

But the capital expenditures for the equipment alone with be significant, at around (US) $21 million for 238 machines (65 G4, 169 G16 and 4 G48s)..

“This is a huge capital outlay, and we are looking at this with great anxiety,” said Prof. Stevens.

This costing model adjusts for a 10% increase in TB suspects coming in for screening — but this estimate may be low given the intensified case finding campaign and routine TB screening of people coming through the HIV counselling and testing campaign.

The cost of each test itself, or rather the cartridge, is currently 161.45 Rand, but there are a number of hidden costs including staff costs, the cost of calibrating the equipment, consumables, waste disposal (the cartridges are bulky), transport and logistics, training and quality assurance and overhead. Costs will also vary dependent on implementation rate, exchange rates, global volumes, negotiations, and freight costs.

When hidden costs are included, the model projects that the actual cost of performing a test will be R 216.30 (around US $36) between 2011 to 2014, decreasing to 189.85 Rand ($26) per test from 2014 to 2017.

The NHLH has also developed a National TB Cost Model to estimate the incremental costs to the national health service of switching to the new diagnostic platform, under routine care conditions and at costs incurred by the government.

“We think that the programme costs per suspect will increase by about 53%, and that the cost per case, for diagnosis alone will increase by 17%. Having said that, we will probably identify 30% more cases, 76% more MDR-TB and by 2013, if everything goes to plan, initiate 39% more people on treatment,” said Prof Stevens.

The increase in initiation of treatment is only one of the benefits however. According to a study by Boehme et al, the test will lead to dramatic reductions in the time to initiating treatment from 56 days (39–81) currently to 5 days (2–8). Currently, only 46% of patients are diagnosed by their second visit to the clinic, and another 40% only by the third visit. In contrast, at full GeneXpert coverage, 83% of patients will be diagnosed by their second visit and 89% by visit three.

Meanwhile, there should be reductions in the use of other TB diagnostics. AFB microscopy — a time-consuming task — will still be necessary for monitoring treatment response, but the number of smears from 4.1 million per year currently to 1.5 million per year. Use of culture should also decrease by about 30%.

A leap into the well-modelled

Although switching to use of GeneXpert for first-line diagnosis is a radical step, so far it has gone well, and one cannot fault the South African National Health Laboratory Services for lack of preparation.

“Significant changes to the national TB programme are envisaged,” she said. “What we have already identified is that it is beginning to facilitate [TB/HIV] integration at both the laboratory, clinic and programmatic level because people are being forced to analyse their budgets and look at putting clinics together.”

“I think it is a brave bold step, and we are hoping that by the end of full Xpert implementation, the bulk of our patients will be diagnosed by Xpert, and the bulk of our patients will be diagnosed before 5 days. We are completely aware of the implications this will have on our treatment programme.”

However, it should be pointed out that the current algorithm is relatively conservative. Other presentations at the conference (and in a series of articles just published in PLoS Medicine) argue for much broader use of GeneXpert, with repeated testing to diagnose more smear negative TB in people living with HIV. However, this would increase financial outlays significantly — and not everyone is convinced that the expenditures are the best use of limited programme funds.

References

Stevens W. Taking the first steps: Xpert MTB/RIF Implementation in public sector in South Africa: lessons learned. International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Rome, 2011.

Scott L et al. Dried culture spots for Xpert MTB/RIF external quality assessment. International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention,, Rome, 2011 Abstract MOPE147.

Lawn SD et al.  Screening for HIV-associated tuberculosis and rifampicin resistance before antiretroviral therapy using the Xpert MTB/RIF assay: a prospective study. PLoS Med 8(7): e1001067. doi:10.1371/journal.pmed.1001067.

Boehme CC et al. Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study. The Lancet, 377(9776): 1495 - 1505, 2011.

Should the GeneXpert test be performed on all people living with HIV before initiating ART?

Symptom screening and smear microscopy should be replaced by Gene Xpert in patients initiating ART in South Africa,” said Dr Jason Andrews of Massachusetts General Hospital, who presented findings at the International AIDS Society conference in Rome of a cost-effectiveness analysis comparing different TB screening strategies in people with more advanced HIV.

This proposal is based on data demonstrating GeneXpert is more sensitive than smear microscopy, and the premise that symptom screening might miss a substantial proportion of active TB cases — as suggested by another study presented at the conference by Dr Tolu Oni of Imperial College, London, and the University of Cape Town. That study found ‘subclinical TB’ (M. TB that could be cultured from induced sputum even though there were no symptoms of TB) in 8.5% of HIV-positive people at a site in Khayelitsha.

Similar data were published in PLoS Medicine this week, from a study by Lawn et al on the use of GeneXpert, notably conducted in the same setting. When including ‘asymptomatic culture-confirmed TB” Lawn et al concluded that the GeneXpert was 73.3% sensitive for TB in people living with HIV. The sensitivity for smear-negative disease was lower than previously reported: 43.3% versus 72.5% using one sputum sample; 63.3% versus 85.1% using two samples). Dr Andrew’s cost analysis was at least partially based on Lawn’s data.

However, the conclusions of each of these reports are somewhat controversial because there is no clear consensus on the meaning of culture-positive TB without symptoms, which could result from primary TB infection or re-infection (that would be common in this community with one of the highest rates of TB transmission in the world). Although finding such cases is certainly an important observation from a natural history and epidemiological perspective — the clinical implications of primary infection are different (see below).

Furthermore, the cost analysis doesn’t really consider the diagnostic strategy currently being proposed in South Africa’s new first-line TB diagnostic algorithm or the costs of implementing and performing GeneXpert at a scale significantly beyond the already ambitious targets set by South Africa’s Department of Health for switching over from smear microscopy to GeneXpert-based diagnosis.  Notably, Professor Wendy Stevens of South Africa’s National Health Laboratory Services presented significantly different costing data during a late breaker session of the conference.

Analysing all the real costs versus the full potential downstream benefit of implementing a new diagnostic strategy is complex, however. As Dowdy et al wrote in another article in PLoS Medicine this week, “standard cost-effectiveness analyses may give misleading results when applied blindly to the scale-up of TB diagnostics. Challenges in economic analysis of TB diagnostic tests include: underestimating the cost of false-positive diagnoses, overlooking operational and clinical impact of diagnostics, and utilizing unrealistic cost-effectiveness thresholds.”

Screening for and diagnosing TB

Stopping the spread of TB is dependent upon rapidly detecting and treating active TB, reducing new TB infections (through measures such as TB infection control), and preventing activation of latent TB infections.

The inability to rapidly detect TB has been a major impediment to this strategy. It is widely acknowledged that smear microscopy is an outdated, insensitive and appallingly inadequate way to diagnose TB, particularly in people living with HIV, who are far more likely to present with smear-negative disease.

Culture is considered the gold standard for detecting the presence of replicating TB bacilli in a specimen, but is a more expensive, technically complex, and time-consuming process. Even with automated liquid culture equipment, culturing can take two to three weeks to make a diagnosis. Culture-based drug susceptibility testing (to detect drug resistant TB) takes even longer.

Consequently, the development of new, simple inexpensive point of care diagnostic test for TB (and drug-resistant TB) has been a major focus of research in the last five or six years. Unfortunately, a handheld dipstick-like test (like a rapid HIV test) that could be deployed anywhere people present for care is still a long way off.

However, as described elsewhere, the GeneXpert MTB Rif test is a dramatic step forward in diagnostic technology, with much greater sensitivity and specificity for smear-positive TB, and to a somewhat lesser extent, smear-negative TB. It could be performed by a trained nurse and deliver results within two hours.

It has been recommended by WHO as the initial diagnostic test in individuals suspected of MDR-TB or HIV/TB.

However, the equipment and test requires electricity and temperature control, and is too expensive for the equipment to be deployed at the primary care level in most countries.

South Africa, however, has taken the ambitious step of implementing the technology at all smear microscopy sites. As it is being implemented, the test won’t really be point-of-care, but it should generate a more rapid diagnosis in more people.

But the first challenge to rapidly detecting TB is the failure to look for it in the first place — which is particularly egregious in people living with HIV who are at much greater risk of developing and dying from TB.

For this reason, WHO recommends intensified case finding in people living with HIV, using a simple symptom screen. People with symptoms should be effectively referred to the TB diagnostic process, while those without symptoms should be given isoniazid preventive therapy (IPT), a low cost intervention, to prevent the re-activation (and perhaps acquisition) of TB disease. It is well recognised that there may be breakthrough TB cases that are missed and which develop despite IPT — thus, people should be rescreened for TB symptoms each month when they pick up their month’s supply of IPT. South Africa has adopted this policy — though not all provinces are implementing it equally.

In addition, WHO recommends earlier antiretroviral therapy — when people’s CD4 cell counts fall below 350 — partly because ART reduces the risk of TB as well. Aside from people who already have TB, and pregnant women, South Africa has not yet adopted this policy.

It is within this context that these reports (of asymptomatic TB in people living with HIV and the recommendation to use GeneXpert to screen all South Africans living with HIV before starting ART) must be considered.

Questions regarding TB ‘without symptoms’

The study presented by Dr Oni evaluated the prevalence and outcome of ‘subclinical TB disease’ in people not eligible for ART in Khayelitsha. It included 274 asymptomatic persons from pre-ART wellness clinic or from the HIV counseling and testing site (who were compared to 162 symptomatic TB cases). Participants were screened for TB symptoms, given a tuberculin skin test (TST) and a chest X-ray if their TST was above 4mm. Culture positive cases were spoligotyped to exclude cross-contamination.

As already noted, there was an 8.5% (95% C.I. 5.1-13.0%) prevalence of asymptomatic TB disease. 71% of those with TST ≥ 5mm (which, it should be noted, is an indication of TB infection, but not active TB) had normal chest X-rays.

Similarly, Lawn et al reported that the WHO TB symptom screen only detected 85% of the cases of ‘culture confirmed TB” in that cohort, which included people with more advanced HIV disease qualifying for ART. In other words, 15% had no symptoms of TB when they were screened.

Dr Oni’s findings suggested that these patients were clearly at a much earlier stage of disease.

“The findings suggest the asymptomatic cases had a lower bacterial burden compared to symptomatic TB cases,” said Dr Oni. “These patients had higher CD4 counts, a higher proportion were smear-negative but culture-positive with longer days to culture positivity.” Culture positivity occurred within a median of 17 days (interquartile range 12-39) in the asymptomatic compared to symptomatic TB patients (7 days; IQR 6-12).

She suggested that culture should be performed after testing positive for TB in settings with a high burden of HIV/TB, especially in people with TST ≥5mm (OR 4.96; p=0.064), lower CD4 counts (OR 0.996; p=0.06), and longer histories of HIV (OR 1.006; p=0.056).

“However, there are logistic difficulties in performing culture. It is labour intensive and there is the need for laboratory infrastructure, so these findings highlight the need for new rapid and affordable point-of-care diagnostic tests to identify persons with clinical and subclinical TB disease,” she concluded.

She reported that treatment was started earlier than if these patients had waited for symptoms to develop — and that all of these patients had completed TB treatment and remained in care 6-12 months later.

However, some experts are not convinced that all of these culture confirmed cases are truly ‘active TB.” Despite the general assumption that culture-confirmed TB is re-activation TB (full-blown TB), it could be also be primary TB or perhaps TB re-infection. TB transmission is ongoing in high burden settings.

There are many cases in the literature of culture confirmed primary infection in children. For instance, back in 1999 van Rie et al reported a significant number of TB cases were due to exogenous re-infection. A study in 1996 reported clustering of spoligotypes in 24 out of 34 homeless patients with culture-confirmed TB in Los Angeles — documenting that these were cases of primary infection TB (or just post-primary TB). Culture positive primary infection TB has also be documented in individuals on immunosuppressant therapy.

Such cases may not present with some TB symptoms, but might not quickly progress to active disease and could even be suppressible with IPT.

Professor Ben Marais of Stellenbosch University recently wrote a letter on the issue to the Editor of the American Journal of Respiratory and Critical Care Medicine.

 “Transient M. tuberculosis excretion has been well documented in children following recent primary infection and there is no reason to expect that this phenomenon is restricted to children. A survey conducted among randomly selected adults in South Africa identified a significant number of "asymptomatic" individuals, both with and without HIV, from whom M. tuberculosis was isolated. This presents a clinical dilemma and it would be important to differentiate transient organism excretion, after primary infection or reinfection, from active disease.

The likelihood of M. tuberculosis infection depends on the level of ongoing transmission in a particular setting, which is difficult to quantify. The annual rate of TB infection (ARTI) has been used as a surrogate, but the age restriction applied introduces severe selection bias and probably underestimates the infection pressure experienced by adults within the same community.

It can be argued that the risk posed to a patient who is infected with HIV and immune-compromised is self evident, which obviates the need to distinguish transient organism excretion from active TB. However, it remains an open question if a completely asymptomatic person with sputum smear-negative "culture-confirmed TB," who has no clinical or radiological signs suggestive of active disease, represents a true case of TB. With poor epidemic control, M. tuberculosis infection (both primary infection and reinfection) events are common. In these settings, careful reappraisal of TB case definitions seems warranted, especially among those without significant immune compromise.”

Dr Oni reported that 56% of the asymptomatic did progress clinically (a median of 28 days later), however, it remains an open question whether this would have occurred if WHO policy (IPT and ART) had been followed in these patients.

Gene Xpert for all people with HIV?

The current South African TB diagnostic algorithm using the GeneXpert test (at least once) should pick up many more cases of TB among symptomatic people living with HIV and those who are household contacts of active TB cases. But it will not pick them all up.

Lawn's et al's study found that 'compared to the strategy of doing an Xpert assay on one sputum sample from patients with a positive symptom screen, a strategy of doing two Xpert tests on all patients was associated with 22.9% higher sensitivity for TB and the fewest missed cases. Although the latter strategy would require a large absolute number of tests, at a TB prevalence of 20%, one extra TB case would be diagnosed for every additional 6.3 tests done.

Dr Andrews and colleagues established a costing model based on Lawn et al's data, the costs of performing different screening strategies (including performing one GeneXpert test versus two, in symptomatic or everyone with HIV) to determine whether this was cost effective as defined by incremental cost-effectiveness ratio (ICER), which divides the cost by the additional benefit.

According to his calculations, the incremental cost per year of life saved for performing two GeneXperts on everyone qualifying for ART (the CD4 count in Lawn's study was 177) would be $5,200 , more cost effective than the other options - except for just using smear microscopy - which was still more cost effective at $4000 if just performed in symptomatic patients and $4200 if performed in all people living with HIV about to start ART.

Because of the decreased sensitivity of the GeneXpert to detect smear negative TB cases (once these asymptomatic cases are included), Dr Andrew’s study concluded that performing two GeneXpert tests on every person with HIV about to start ART in South Africa would be cost effective — partly because it was assumed that these cases would otherwise lead to active disease. It is not clear that this would be the case.

The cost analysis was also only based upon the cost of the GeneXpert cartridge, estimating a test cost of only $22 — and doesn’t include the hidden costs mentioned in Prof. Steven’s presentation or the cost of scaling up the capacity to perform these tests more widely. Further costing analysis studies on the South African programme will be presented at the Union World Conference on Lung Health in October.

From a patient perspective, anyone who presents to care with low CD4 cell counts should get the best diagnostic services that can be made available in order to avoid a life-threatening case of TB — as long as scaling up these services does not put other aspects of their care in jeopardy — which is a concern in the current economic clinic

From a public health perspective, implementing existing policies to prevent TB may have greater impact on a larger number of people. As Dr Carlton A. Evans, of Imperial College, London,  wrote in an opinion piece commenting on the recent series of articles:

“This new test must not divert resources from preventive efforts and well-established TB diagnostic and treatment systems that already have the potential to have considerable impact upon TB morbidity and mortality.”

"With tiered pricing for low-income countries, each MTB/RIF test machine currently costs US$17,000–$62,000. More importantly, each disposable test-cartridge costs US$17–$120, which is comparable with the per capita annual health expenditure in the countries with the highest TB burdens... For example, it has been estimated that in India, providing the MTB/RIF test to only 15% of the suspected cases of TB would consume the annual budget for the entire TB control program."

References

 Andrews JR et al. Cost-effectiveness of routine tuberculosis screening with Xpert MTB/RIF prior to initiation of antiretroviral therapy in South Africa. Sixth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Rome, abstract MOAD0102, 2011.

Oni T et al.  High prevalence of subclinical tuberculosis in HIV-1 infected persons without advanced immunodeficiency: implications for TB screening. Sixth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention Rome, abstract WEPDB0206, 2011.

Lawn SD et al. Screening for HIV-associated tuberculosis and rifampicin resistance before antiretroviral therapy using the Xpert MTB/RIF assay: a prospective study. PLoS Med 8(7): e1001067. doi:10.1371/journal.pmed.1001067, 2011.

Dowdy DW et al. Is scale-up worth it? Challenges in economic analysis of diagnostic tests for tuberculosis. PLoS Med 8(7): e1001063. doi:10.1371/journal.pmed.1001063, 2011.

van Rie A et al. Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Engl J Med 341:1174–1179, 1999.

Barnes PF et al. Transmission of tuberculosis among the urban homeless. JAMA 275:305-307, 1996.

Arend SM et al. A patient with de novo tuberculosis during anti-tumor necrosis factor—α therapy illustrating diagnostic pitfalls and paradoxical response to treatment. Clin Infect Dis.  45 (11): 1470-1475, 2007.

Marias B. Does finding M. Tuberculosis in sputum always equal tuberculosis disease? American Journal of Respiratory and Critical Care Medicine 181: 195-196, 2010.

Evans CA. GeneXpert - A game-changer for tuberculosis control? PLoS Med 8(7): e1001064. doi:10.1371/journal.pmed.1001064, 2011.

 

Task-shifting of HIV care to nurses: successes, but problems to watch out for

“A nurse-led service can deliver ART care as effectively as a doctor-driven one, and even improves quality of care, but this pragmatic trial did not result in increased access to ART,” said Lara Fairall of the University of Cape Town. She was describing the results of the STRETCH study, a cluster-based randomised controlled study of nurse-managed and initiated antiretroviral therapy (ART) presented at the sixth International AIDS Society conference, held in Rome this week.

Another presentation in the session suggested non-physician health workers could be mobilised to respond to AIDS in prevention services – notably male circumcision.

Meanwhile, an observational cohort study presented by Dr Megan McGuire of Epicentre, a public health research unit of Médecins Sans Frontières, suggested that HIV-care provided by nurses in Malawi was superior to that provided by clinical officers. However, as McGuire herself pointed, the clinical officers primarily managed the sickest patients with the most advanced disease. This was not an entirely fair comparison.

All these reports recommended task-shifting HIV care to nurses at the primary healthcare level. But the session also highlighted the tension at the conference between those lobbying for a quick shift to task-shifting and decentralisation in order to reach goals for universal access to HIV treatment, versus those warning that task-shifting may not be an overnight solution to the crisis in human resources for health care. Rather, there are indicators suggesting programmes must be aware that there can be gaps and problems in the transition for doctor-based to task-shifted care.

Nurses can make the cut

Several large, randomised studies have reported that male circumcision significantly reduces the risk of HIV acquisition among heterosexual men, and the World Health Organization has recommended that services offering male circumcision should be incorporated into national HIV prevention activities in high-HIV-burden settings. As a result of news reports and prevention campaigns, demand for the procedure outstrips supply in some sub-Saharan African settings.

“The shortage of health professionals poses a critical challenge to the male circumcision scale-up,” according to Dr Kelly Curran of JHPIEGO in Baltimore.

However, programmes have identified a number of potential approaches to expanding the numbers of health workers who can offer the intervention.

In Kenya, procedures and policy were adapted to empower nurses to safely perform male circumcision. After two campaigns, the programme has delivered 268,000 male circumcisions within 2.5 years.

In Swaziland, a survey was performed to identify existing nurses who were under-utilised: in other words, registered but unemployed nurses (many of whom were Zimbabwean), those recently retired or recently graduated, and often working abroad (mainly in the UK). At least 259 were found who could be trained to do the procedure.

Some public critics have been concerned that HIV services for treatment – not to mention prevention interventions, such as male circumcision campaigns – might draw healthcare staff away from other critical health care services, but Dr Curran pointed out that the Swaziland approach might remedy that to an extent.

“My lesson learnt from our efforts in Swaziland is that the first place where we should go is the unemployed healthcare workers, as well as the recently retired yet still energetic. In many of the countries where we work, retirement age is as low as 55 – many of those nurses would happily still be employed. They may not want to do surgery all day on their feet but they could happily do post-operative reviews or staff recovery rooms,” said Dr Curran. “So I think the key here is really to look everywhere you can first before engaging nurses or other healthcare workers away from service provision of other critical health interventions.”

Programmatic data on nurses and clinical officer-based care in Malawi

Malawi has a severe shortage of doctors, and yet over the last several years has ramped up a massive HIV treatment and care programme with very few resources. For example, in 2010, there were roughly 14,000 HIV consultations, 700 program enrollments and 400 ART initiations.

This was achieved with a mixed model of care, shifting ART initiation and management to clinical officers and nurses.

Dr Megan McGuire presented the findings of a study comparing treatment outcomes of 10,112 adults patients receiving ART between 2007 and 2010, who were cared for either by nurses, clinical officers or both in a large HIV programme in rural Malawi.

However, nurses were only supposed to care for patients who were antiretroviral naïve and starting on first-line treatment, with WHO stage 1 or 2 disease, CD4 cell counts above 100 and BMIs over 17. In practice there were some exceptions, but in general, patients cared for by nurses had less severe HIV disease and wasting than those cared for by clinical officers.

The nurses provided the majority of care for 1901 patients and the clinical officers 3386, while 4825 patients received mixed care.

At baseline, BMI was under 18.5 in 15.4% of those cared for by nurses, 35.4% of those cared for by clinical officers, and 25.9% who received mixed care.

Similarly, median CD4 cell counts at baseline were 195, 147 and 182, respectively, for the nurse, clinical officer and mixed-care cohort. The difference in severely symptomatic disease was more pronounced, with 19.1, versus 58.9 and 33.1% with WHO stage III/IV disease for the nurse, clinical officer and mixed-care cohorts, respectively.

Follow-up was right-censored at the earliest of the following dates: death, transfer out, last visit or 24 months of follow-up. Not surprisingly, more of those receiving care from clinical officers (the sicker patients) were around 5 times likely to die (around 20% vs. less than 5% for both nurses and mixed care) within 2 years of follow-up. Similarly about 40% of the clinical officer cohort was lost to follow-up, versus around 10% for the nurses, and just over 5% for those receiving care for both.

Acknowledging that some of this may have been due to ill health at baseline, the analysis was restricted to less severely ill patients (n=3846) with BMI>18.5, WHO stage 1 or 2, and CD4>100. The aIRR (95% confidence interval) for mortality was 3.42 (2.60-4.48) for those in the clinic officer cohort and 0.63 (0.47-0.86) for those receiving mixed care (versus those getting nurse-provided care).

However, this was an analysis based upon the health of the patient at baseline – and a serious long-term illness developing after entry into care (such as TB) would have led to the patient being referred to (and having more visits) with a clinical officer. Tellingly, CD4 cell counts were somewhat poorer for the clinical officer group at 12 months, but there was not much difference at 24 months.

It is possible that nurse care was indeed better for retention and health outcomes, but this was not a randomised study and cannot be used to reach that conclusion.

STRETCH

The STRETCH study (Streamlining Tasks and Roles to Expand Treatment and Care for HIV) was randomised – but because it was performed in real-world conditions, at a time and place (the Free State Province in South Africa) where nurses were in the process of being trained up to provide ART, it may not serve as the final word for whether nurses can provide ART care just as well as doctors or other clinicians.

Thirty-one clinics were randomised: 16 operated the STRETCH protocol, alongside 15 control clinics. The study had two parts: one (n=6321 patients) was to show whether nurse-led clinics could maintain patients who had been stable on ART for at least six months as well as clinics with more doctor-based care or support – as measured by viral load. This they could do easily.

The second part of the study evaluated whether task-shifting to nurse-led clinics would reduce mortality in people on ‘waiting lists’ for treatment by improving access and initiating ART among those with CD4 cell counts below 350 (9252 patients).

This study was unable to show this. However, Fairall pointed out that the nurse-led clinics began initiating ART gradually.

The results were previously presented at the 5th South African AIDS Conference, and reported in much more detail in HATIP 179.

Discussion

Audience members asked whether it was too much to ask nurses to take on the additional burden of ART initiation and management – and whether this was reflected by STRETCH’s inability to increase access to ART during the study period.

“We did monitor [the adverse consequences of task-shifting on the nurses] during the trial. And yes, nurses are very burnt out. So one has to be very cautious about how and when one can delegate the clinical responsibility. So that really is ... a cause for consideration,” said Fairall.

“But going back to this concept of task-shifting – I think we’ve seen nurses as really having extremely broad shoulders and able to take on more and more and more. That does have consequences. The nurses in our trial didn’t seem to mind the new duties but they were well supported by our provincial co-ordinator, with whom they had a direct personal relationship,” she added.

Indeed, nurses need encouragement and support – and nurses should not be expected to handle the most complicated cases. Part of the STRETCH programme involves training nurses when to recognise the need to refer patients for doctor-based management.

The need for more specialised clinical support is recognised in Malawi as well – the goal is to be less reliant on it, however.

Dr McGuire said that they were now looking at whether it was possible to space out clinic appointments further, so that patients visit the clinic once every six months, or even once a year if they are stable.

Another important aspect of shifting more of the burden of care to nurses involves shifting some of their existing duties to less highly trained health workers, such as expert patients.

A number of other studies at IAS 2011 reported on how lay personnel can dramatically improve outcomes such as initiation of ART and retention in care. Conversely, the failure to make certain that such support services are available at the primary healthcare level could be one reason behind some of the disappointing results on the decentralisation of ART services reported during other sessions of the conference. Both these issues will be addressed in subsequent articles on www.aidsmap.com.

References

Curran K et al. Innovative and efficient approaches for meeting the human resource needs of the male circumcision scale up in southern and eastern Africa. Sixth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Rome, abstract MOPDD0103, 2011.

Fairall L et al. The effect of task-shifting antiretroviral care in South Africa: a pragmatic cluster randomised trial. Sixth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Rome, abstract MOPDD0105, 2011.

McGuire M et al. Task-shifting of HIV care and ART initiation: Three year evaluation of a mixed-care provider model for ART delivery. Sixth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Rome, abstract MOPDD0104, 2011.

HATIP #180, July 29th, 2011

This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends checking whether this is the most current information when making decisions that may affect your health.