Well-resourced countries and countries with a heavy burden of DR TB (more on this below) may want to routinely screen for drug resistance in everyone with TB, but countries with limited DST capacity and resources have to prioritise case detection efforts and first investigate those at greatest risk of drug resistance.43
This section primarily deals with people who present with TB or are already in care — though one can make the case that the best outcomes are likely to be achieved by finding cases earlier through more aggressive case finding strategies and contact tracing.
But there may be many drug resistant cases in care, right under the clinician’s nose, and managing infection control risks in health facilities should be a consideration in where to look first. As Dr Krista Dong of Edendale Hospital and others have previously reported, there are many undiagnosed cases of TB in hospital wards — and unrecognised M/XDR TB cases in the wards could transmit the infection to other patients and staff, as was the case in Tugela Ferry.
Another aspect of case detection is that categorisation of the risk of having drug resistant TB (and whether DST capacity is rapid versus conventional) is an important determinant in whether an individual should be put on an empiric second line regimen while waiting for DST results.44 Indeed, avoiding the expense and hassle of having someone on unnecessary second line TB treatment is one of the best reasons to develop laboratory capacity for rapid DST.
“The current WHO recommendation is that patients considered to be at risk (based on the groups listed in the Guidelines For The Programmatic Management Of Drug-Resistant Tuberculosis) be targeted first for universal access [to DST],” WHO’s Dr Karin Weyer told HATIP. “But identifying these risk groups is a country/regional responsibility, given the huge geographical variation in TB, MDR-TB and HIV epidemiology, which guides the laboratory services required.”
The DR TB Guidelines are currently being revised, however the following risk groups were highlighted in the 2008 edition, and amended somewhat in 2010’s Treatment of Tuberculosis Guidelines.
Previously treated cases: Whether an in or out patient, once a new TB case has been diagnosed, it is extremely important to identify those who have been previously treated — especially those who have failed treatment — because they have a much higher risk of MDR-TB. (Likewise those who have failed an MDR-TB treatment regimen are more likely to have XDR-TB). The 2010 TB treatment guidelines strongly recommend that specimens should be obtained for culture and DST from all previously treated patients, defined as those who have received 1 month or more of anti-TB drugs in the past, and then further classified depending upon their outcome on their most recent course of treatment — treatment failure, default or relapse).45
The prevalence of MDR-TB varies across these treatment outcomes according to a study presented at the 40th World Union Conference on Lung Health last year.46
In this study, researchers analysed drug resistance survey data from 12 settings in 10 countries and found MDR-TB in 49% of 206 cases of treatment failure, in 32% of 208 treatment defaulters, and in 32% among 283 cases of treatment relapse.
As DST isn’t widely available everywhere yet, (even though it is one of the goals of the Global Plan to Stop TB that all previously treated patients have access to DST by 2015), classifying previously treated individuals into these patient registration groups can be helpful in settings with limited DST capacity, with the caveat that local drug resistance surveys should also be conducted to guide screening decisions since the prevalence of resistance within previously treated individuals varies by setting.
It is worth noting that the highest rate of MDR-TB — exceeding 80% in some settings — has been reported among those who have failed what was previously referred to as the category II regimen (a slightly beefed up and lengthier version of the first-line TB regimen), that was widely recommended for people failing or relapsing after their first course of TB treatment.47 Although WHO’s guidelines suggest this retreatment regimen may still be used for people who have relapsed or defaulted first-line treatment in settings without DST capacity (provided that local surveys suggest drug resistance is not very common in these subcategories), the regimen is unnecessary for cases with drug susceptible TB and ineffective against cases of MDR-TB.
In fact, using this regimen in people with MDR-TB may just lead to the evolution and onward transmission of more resistant strains of TB. Consequently, WHO intends to phase out the regimen once DST becomes widely available.48
Other aspects of the individual’s treatment history (such as a known pattern of poor treatment adherence, or a history of relapsing or defaulting more than once) as well as where he or she was treated could indicate that a person is more likely to have drug resistance. For instance, receiving TB treatment in the private sector in many settings, or from a poorly operated TB programme (where for instance, there have been frequent drug stock-outs), or where the anti-TB drugs have been found to be of poorer quality have all been associated with the development of MDR-TB.49
People with active TB failing their current regimens also have a higher risk of drug resistant TB — though failure could also be due to simply not taking their treatment in settings with inadequate treatment support. In new or retreatment cases, WHO recommends that if a specimen obtained at the end of month three is smear-positive (which, in new patients, is generally only collected if the specimen at the end of month two was positive), sputum culture and drug susceptibility testing (DST) should be performed.
The guidelines do not recommend sending out for DST if the sputum is smear-positive at the end of month two because “available evidence showed that smear status at the end of the intensive phase is a poor predictor of relapse, failure and pretreatment isoniazid resistance.” (One reason for this is that people can continue to produce non-viable bacilli which will show up on microscopy, but which cannot be cultured.)
However, local policy varies — for instance, in the Western Cape of South Africa, the policy is to send out for DST when cases are still smear-positive at the end of month two. Again, the time it takes to get DST results back and the risk of M/XDR-TB transmission in the community are important considerations since the person may be failing the first line regimen because they had M/XDR-TB to start with.
Contacts of people known to have M/XDR-TB: After treatment failures, the risk of resistance is probably greatest among people who develop active TB after contact with a person with documented M/XDR-TB — especially close household contacts. WHO recommends that anyone who develops TB after contact with someone with M/XDR- should be treated with a regimen based on the DST of the presumed source case while awaiting DST results.
However, transmission of drug resistance cannot be taken for granted when there is a high burden of TB in the community. Again, in such cases, it is important to have rapid DST results because second line regimens are dramatically more expensive, more toxic, and less effective for people with drug susceptible TB.
Similarly, people who develop TB after exposure in institutions with MDR-TB outbreaks need DST results as soon as possible; and depending on the setting, there may also be an increased risk of drug resistance after hospitalization or incarceration (DST should also be prioritised for staff members who develop TB after working in those facilities).
This means, of course, that people diagnosed with TB need to be asked carefully about whether they have had any known contact with people with TB, or possible exposure to TB in congregate settings.
Everyone with HIV : Not only do people with HIV have an elevated risk of exposure to M/XDR-TB (because of their increased utilisation of the health system, and possibly other risk factors) they are in greatest need of rapid M/XDR-TB diagnosis because M/XDR-TB can be rapidly fatal.
“WHO recommends that NTPs undertake DST at the start of TB therapy in all HIV-positive TB patients, to avoid mortality due to unrecognised drug-resistant TB, and strongly encourages the use of rapid DST in sputum smear-positive persons living with HIV,” according to the 2010 Guidelines.
In settings where the capacity does not yet exist to provide DST for everyone with HIV-related TB, the guidelines suggest first screening people who have failed treatment, then those who relapse or have defaulted on treatment. In addition, it may also be wise to prioritise people with lower CD4 cell counts.
A word about smear negative M/XDR-TB in people with HIV . Given the poor sensitivity of molecular tests in smear-negative TB, WHO recommends that conventional DST be performed in these cases, or a rapid DST should be performed on a cultured isolate as soon as it is available.
However, smear microscopy misses huge numbers of people with HIV and TB — and one of the most effective ways to diagnose these cases, the smear-negative TB diagnostic algorithm, depends on a response to TB treatment — a response that won’t be seen in people with HIV and drug resistant smear-negative TB (although there is a chance of eventual diagnosis if a specimen was sent in for culture).
But in reality, this means that diagnosis won’t come in time in the majority of those who have the greatest risk of mortality from M/XDR-TB. This is unconscionable. It is unreasonable to not find an alternative DST solution for people with HIV and smear-negative M/XDR-TB — expecting them to wait for conventional DST simply is not acceptable. For this reason, either the GeneXpert system or MODS simply must be scaled up in settings with a high burden of HIV and DR TB, until a better (cheaper, safer, more sensitive) rapid test is found.
People with other co-morbid conditions: A number of other illnesses have also been associated with M/XDR-TB or a higher risk of mortality from it, such as malabsorption and diarrhoea and Type 2 diabetes.50
All new TB cases, in settings with a high rate of M/XDR-TB transmission
As already noted, in settings with a high burden of M/XDR-TB in new TB cases, the risk of ongoing transmission, morbidity and mortality is simply too great to not screen everyone. But what exactly this threshold should be is subject to debate. The 2008 DR TB Guidelines, and the 2010 TB Treatment Guidelines suggest that if country data (or WHO estimates) show that more than 3% of new patients have MDR, DST should be obtained at the start of therapy for all new patients.
Countries such as South Africa don’t quite meet these criteria and so new cases are only screened after they appear to be failing treatment.
But many clinicians and researchers speaking at the 2nd South African TB conference made strong cases for screening all new TB cases in that country. One was Dr Cheryl McDermid, from MSF in Khayelitsha, who described the findings of a DR-TB survey in 2008 to illustrate what the implications of the policy would be. The survey found that 5.2% rifampicin resistance was found among new cases and 11.1% in previously treated cases (rifampicin resistance was being used as a rough surrogate for MDR-TB).
“When people look at this data, they think we need to focus on previously treated TB cases because rifampicin resistance is higher in previously treated cases. However when we look at what is actually seen in Khayelitsha we find many more new cases notified - 4279 new cases notified compared to 1512 retreatment cases. And in absolute numbers, the majority of rifampicin resistance is amongst new cases.”
She estimated that about 54% of the cases were detected that year in Khayelitsha — and said that the number of cases (not simply the cases being detected) keep going up despite a good TB control programme in Khayelitsha. 61% of the cases who died of drug-resistant TB in the cohort were “new” cases and all were HIV-positive.
“Despite dramatically improved case detection in Khayelitsha, case detection is still not high enough to interrupt transmission,” she said. “So improved case detection and reduced mortality AND reduced transmission culture and DST for all TB suspects is an urgent priority.”
In the next iteration of the Guidelines for DR TB, there may be a shift away from the 3% threshold.
“One of the questions in the forthcoming guidelines will be thresholds of DR prevalence for the promotion of wider testing with rapid techniques like LPA. Apart from South Africa other countries are scaling up in the use of these diagnostics, such as Lesotho and Ethiopia,” Dr Dennis Falzon of WHO told HATIP.
“My personal feeling is that there is no ‘magical’ threshold for rapid resistance testing. The best we can do is to model the cost-effectiveness and cost-benefit of various approaches, and policy decisions would then have to be based on available resources,” said Dr Weyer.