“MDR/XDR-TB and HIV are converging on an increasing scale and posing huge challenges; but there is a great paucity of evidence in the understanding and magnitude of this convergence,” said Dr Getahun during the satellite session.
“Research results to address and ease the bottlenecks — either involving patients or healthcare delivery systems — for the diagnosis and treatment of MDR/XDR-TB, among people living with HIV, are a priority and crucially needed.”
Multidrug resistant TB (MDR-TB) is TB that is resistant to at least isoniazid and rifampicin, while extensively drug resistant TB (XDR-TB) is MDR-TB that is also resistant to the fluoroquinolones and at least one of the three injectable second-line drugs (amikacin, kanamycin and capreomycin).
The burden of drug-resistant TB
The most recent data suggest that the global burden of MDR-TB was around 510,000 with 150,000 deaths in 2007; while there were an estimated 50,000 XDR-TB cases leading to approximately 30,000 deaths. Dr Paul Nunn of WHO’s STOP TB Department underscored the fact that we do not know how many of the M/XDR-TB cases are in people with HIV, and participants at the research meeting felt that this was unacceptable.
“I don’t want to see TB statistics without HIV information,” said Dr Ken Castro of the US Centers for Disease Control.
Data from country surveys suggest that the greatest burden of TB drug resistance is in the countries of the former Soviet Union, China and a handful of other countries, but there were few survey and surveillance data from sub-Saharan African countries. Meanwhile, by April 2009, fifty-five countries worldwide had reported at least one case of XDR-TB. Most sub-Saharan African countries reported no cases, but this may be because there are no laboratories in Africa, other than the supranational laboratory in South Africa, that are able to do second-line drug susceptibility testing. According to Dr Getahun, this raises the question of whether there are any other possible clinical indicators or clinical parameters that could help assess the magnitude of XDR-TB in the absence of surveillance data. Also, what is the best way to strengthening the laboratory capacity to perform drug susceptibility testing for second-line TB drugs?
Data are also needed to better understand the mortality associated with MDR and XDR-TB. Early data from the Tugela Ferry outbreak in South Africa suggested rates of mortality above 85% and a very short median survival time (29 days) in people with HIV and XDR-TB. The same researchers concluded that survival with MDR was similar, with a median survival of around two months. But more data are needed on the pattern of mortality in people without HIV. Developing a clearer understanding of the dynamics and reasons for the high rate of mortality will be an important matter for research.
Diagnosis
Some of the excess mortality could be due to delayed diagnosis, because the existing ways to diagnose drug-resistant TB take time, space, and are labour-intensive. Liquid culture and DST may speed diagnosis in the few settings that can do it.
Some countries are also attempting to roll out line probe assays (LPA), a PCR-based technique that can reduce the turnaround time for detecting MDR-TB to two to four days.
These technologies are best suited for large referral laboratories — and the operational usefulness will depend upon getting healthcare staff to routinely send specimens in for testing and follow-up on the results.
However, according to Dr Giorgio Roscignio, the CEO of the Foundation for Innovative and New Diagnostics (FIND), the goal is to develop diagnostic tests that can be progressively rolled out to more decentralised levels of care.
After LPA, the next stage will be an automated desktop system, Cepheid’s Xpert MTB integrated nucleic acid amplification test, which can be used in district hospitals or microscopy centres (with electricity). It uses a common platform to diagnose TB and rifampicin resistance (which would probably indicate MDR-TB); TB that is resistant to fluoroquinolones (which could flag potential XDR-TB); and could potentially perform HIV viral load tests. Results are provided in less than 2 hours, and since it is a closed system there is no risk of contamination or need for a safety cabinet.
Dr Roscignio shared exciting results from using this platform in at least five sites (including two sites in South Africa with high HIV prevalence and two sites with high MDR prevalence) with over 1500 TB suspects, in which they found greater than 90% sensitivity (95% confidence interval 84.9 – 93.8) in smear- negative /culture-positive cases and even higher sensitivity in smear-positive/culture-positive cases. Specificity was 98.1% (95% CI 96.6-98.9). In other words, the test could also dramatically increase the diagnosis of smear-negative TB. In addition, sensitivity and specificity for rifampicin resistance were also above 90% in both smear-negative and smear-positive cases. However, one drawback is that, so far, the machine only uses sputum and hence will miss cases from people with extrapulmonary TB and children who do not produce sputum.
Further demonstration projects of the Xpert system are ongoing at microscopy centres and district hospitals in seven countries, and FIND expects to submit the findings to the WHO in 2010. Development of the platform for XDR-TB will take longer (probably until 2013), although an adaptation of LPA that will screen for XDR-TB may become available sooner.
In the meantime, what are the best diagnostic algorithms to diagnose MDR/XDR-TB in people living with HIV? In addition, do we have the best case finding/screening model for MDR/XDR-TB among people living with HIV?
Treatment
The number of people with drug-resistant TB who actually receive appropriate treatment is shockingly low: only 30,000, or about 6% of the nearly 510,000 estimated MDR-TB cases in 2007. Clearly there are treatment issues that need to be researched. One is, where is the best place to treat these individuals, in the hospitals or in the community? What are the barriers for patients accessing not only second-line TB drugs but also ART and newly developed drugs?
A case in point was a recent study of the new TB drug TMC207, which included 47 cases, only six of whom were HIV-positive. The key barrier to enrolling more people with HIV was the lack of data on potential drug interactions with antiretroviral drugs. But such barriers must be addressed as soon as possible, because it is essential to know the safety and effectiveness of such second-line TB drugs in people taking ART.
According to Dr Neel Ghandi, treatment of MDR-TB should be thought of in a different paradigm than the centralised treatment programmes that currently exist. Care should be decentralised to provide shorter times to referral and treatment initiation. In addition, antiretroviral therapy should be integrated into MDR and XDR-TB treatment programmes; it needs to be as much a part of their treatment as their second-line TB drugs, because these two diseases are working together to compromise the health of these patients.
Transmission and prevention
There is substantial evidence, particularly from the outbreak in Tugela Ferry, of nosocomial transmission of XDR-TB, including subjects who have been infected by multiple strains. However, Dr Paul van Helden of the Centre of Excellence for Biomedical Tuberculosis (TB) Research in South Africa, and Stellenbosch University presented data at the research meeting suggesting that most XDR-TB is actually being generated in people who have MDR-TB.
Notably, during the course of moving from susceptible TB to MDR-TB to XDR-TB, the percentage of cases acquired through transmission reduces as the disease progresses (thus acquired XDR-TB may be less infectious than contracted XDR-TB). Thus, prevention research needs to look both at how to reduce the generation of drug resistance and its transmission.
Research questions include: How and where are MDR and XDR being created? Does poor drug quality play a role? There are some signs of this in Eastern Europe, and there is currently a multi-country study trying to identify the reasons for poor drug quality. What is the contribution and nature of healthcare delivery failures or problems on the part of the patient?
Are there any preventive treatments, like IPT, that could be used to treat someone who has been exposed to XDR or MDR-TB? What are the best methods of separating infectious cases from susceptible contacts? How much impact do different infection control measures have? Do surgical masks on patients work? Do respirators really protect staff and visitors? What indicators do we use to monitor their effectiveness?
Human costs of neglecting TB research
With all the figures, and all the data, it is easy to forget the real purpose of TB research - getting the answers that will make a difference in the lives of people with HIV. But Dr Getahun concluded his report during the satellite session by reminding the audience that there are human costs attached to not prioritising TB/HIV research.
“Thembi Ngubane died a couple of weeks ago,” he said. “She was a person living with HIV who served as a reporter for a radio programme, documenting her diaries of living with HIV to teach others about HIV based on her personal experience. She inspired millions of young people and met both former President Clinton and President Obama. Thembi was serving as a UNICEF ambassador and she had a young child. But despite living with HIV for several years on ART, she died in a hospital, of MDR-TB.”
Just 24 years old, the loss of Thembi is yet another example of how tuberculosis (TB), especially drug-resistant TB, can steal away even champions in the fight against HIV, and cheat HIV prevention and treatment services of their hard-fought gains. These things should not have been allowed to happen.
Of course, there is a lot that can be done to put what we know in practice and the implementation of a number of relatively simple interventions could significantly improve outcomes of people with or at risk of TB/HIV. But sometimes these interventions are only partial solutions and stop-gap measures. Even for the best-operating programmes, it can be difficult to prevent, diagnose and treat TB/HIV cases in time using tools and technologies that are decades, if not more than a century old, and that were never meant to be used in such difficult clinical settings in people with a coinfection such as HIV that changes all the rules.
The time has come for research that will transform the field, even if for some, that time has come too late.