A TAG-sponsored forum in South Africa brought together scientists, policy makers, and community activists to discuss multidrug resistant and extensively drug resistant TB and HIV and to identify steps to address the growing crisis.
"Now that we know that multiple drug resistant tuberculosis [MDR-TB] exists and is a problem in our countries, what are we going to do about it?" asked Olayide Akanni, of Journalists Against AIDS, an advocacy organization based in Nigeria, at the close of a workshop held before the World Lung Health Conference in Cape Town, South Africa, and organized by the Treatment Action Group (TAG) and Stop TB Partnership (STP). The meeting brought together scientists, policy makers, and community activists to review recent data on MDR- and extensively drug resistant- (XDR) TB, to discuss critical issues, and identify steps to address those issues.
The day was organized into three panels: Emergence and Prevention of MDR- and XDR-TB, Scaling up M/XDR Diagnostics and Treatment: Addressing the Bottlenecks, and TB Research and Development: Strategies to Move Forward.
MDR-TB is TB resistant to at least the two cornerstone TB drugs, isoniazid and rifampicin. These difficult-to-treat infections have traditionally been regarded as a problem in the countries of the former Soviet Bloc, in Peru, and in parts of Asia. XDR-TB is resistant to not only isoniazid and rifampicin (MDR-TB), but also to any fluoroquinolone drug (such as ofloxacin, ciprofloxacin) and to at least one of a group of injectable antibiotics. Without any of these key drugs, it is very difficult to cure TB, and especially so when delayed diagnosis delays appropriate treatment.
The emergence of XDR-TB in Tugela Ferry, South Africa, last year demonstrated what a threat TB drug resistance becomes when combined with HIV, as fatality rates among people with HIV and XDR-TB approached 100%. This outbreak, plus new research documenting the worldwide emergence of XDR-TB released in March 2007, caused TB experts and policy makers to state that targets for treating people with MDR-TB should be doubled.
The revised Global Plan to Stop TB: 2006-2015 now targets treating close to 1.6 million people with MDR-TB by 2015 -- at an estimated cost of US $14.4 billion. But getting from targets to implementation will require a massive and well-orchestrated effort to mobilize sufficient human, laboratory, organizational, and financial resources. With only 30,000 people put onto second-line TB treatment so far, "we are a long way from achieving the targets," noted Akanni.
The Growing Threat of MDR in the Context of HIV
TB is the leading opportunistic infection and cause of death among people with HIV. If treated soon enough, TB is curable. But MDR- and XDR-TB are now on the increase in countries with a high burden of HIV; and when MDR- and XDR-TB occur among people living with HIV, many die quickly before they are appropriately diagnosed.
"Nearly half the people with HIV and either MDR- or XDR-TB die within the first 40 days -- the time it typically takes to receive a culture and drug susceptibility results," said Dr. Neel Gandhi, of the Albert Einstein College of Medicine and the Church of Scotland Hospital in Tugela Ferry. It's been over a year and a half since the Tugela Ferry report, and yet the number of XDR-TB cases continues to increase. XDR-TB is now more common than MDR-TB in Tugela Ferry. "Mathematical modeling projects the epidemic will continue to grow rather than dying out," Dr. Gandhi said.
XDR-TB cases have now been reported in all nine provinces of South Africa, but the country has still not conducted another systematic drug resistance survey, and few countries in Africa have a clear idea about their burden of MDR-TB.
Similarly, Dr. Carmelia Basri of the National TB Program (NTP) in Indonesia -- which has the third highest burden of TB in the world -- worries that there are many risk factors for an increase in of MDR-TB in her country. Only 40% of hospitals and under 5% of the private providers currently participate in the NTP's directly observed therapy (DOTS) program; laboratory systems aren't standardized; second-line TB drugs are readily available and misused; poor history taking results in the underdetection cases that have failed standard treatment. Furthermore, HIV incidence is increasing in some areas. Without aggressive action, Dr. Basri believes Indonesia could have a serious MDR-TB problem on its hands, and many resource-limited countries share this recipe for disaster.
Challenges in Africa
"In Africa, less than 40% of countries include MDR-TB treatment as part of their routine program activities," said Dr. Haileyesus Getahun of the World Health Organization's (WHO's) Stop TB Department. "Only 4% of those patients who were estimated to have MDR-TB are able to be detected and get services from national programs."
Confronting the dual epidemic of TB and HIV is difficult in resource-limited settings, according to Dr. Rhehab Chimzizi of Malawi's National TB Program. Despite being a very poor country with a high HIV burden, Malawi has been a model for the region, with a relatively strong TB program with one of the highest TB treatment success rates (between 70 and 80%). Although within four years HIV testing increased among TB patients from 8% to 64%, Dr. Chimzizi worries that "we're only detecting 46% of all TB cases in the country." They are having trouble getting those who need antiretroviral therapy (ART) on treatment and there is also a high rate of attrition among health care workers in the country -- with 44% of the attrition due to death. Added Dr. Chimzizi, "We will not have the staff to deal with all the issues."
Trouble Accessing Second-Line Medications
Dr. Chimizizi said the country would like to address MDR-TB, but with only one laboratory that can perform culture and drug sensitivity testing (DST) for 12.8 million people, developing adequate laboratory infrastructure capacity is difficult. The lack of laboratory infrastructure has caused problems for Malawi and other countries trying to access treatment for MDR-TB, since building a strong laboratory is key to getting Green Light Committee (GLC) approval to access high-quality second-line drugs (which are not widely available).
The GLC is a technical review panel that makes certain that countries needing second-line anti-TB drugs get them from the Global Drug Facility, the Stop TB procurement mechanism, and use the treatments effectively and safely. There is no third-line regimen to cure TB, so it is critical to use drug sensitivity testing (DST) to identify the best drugs for each TB case; establish good infection control practices to stop TB transmission; provide adherence support through strong community-based care programs; and develop guidelines, training programs, and good supervision in partnership with the national TB program. Due to political pressure in Malawi to begin treating people with MDR-TB the drugs were procured directly from other suppliers and people were started people on MDR-TB treatment. But it's expensive: "The prices of second-line drugs range anywhere from US$1,500 to $4,000 for a course of treatment," said Dr. Robert Matiru, manager of the Global Drug Facility. And the drug quality is suspect: "We may even be complicating the issue -- increasing the number of XDR cases," said Dr. Chimzizi.
Indeed, the GLC could fail in its mandate to limit the development of more XDR-TB if countries (or individual patients) find it easier to get the drugs themselves. At present in Africa, the GLC is only making drugs available to small projects in Burkino Faso, the Democratic Republic of Congo, Uganda, and Lesotho.
"So, can the GLC respond quickly enough and at the scale that's being demanded?" Mark Harrington, executive director of TAG, asked Dr. Salmaan Keshavjee of Harvard Medical School, who acts as chair of the GLC, and Dr. Ernesto Jaramillo, of the MDR working group at the WHO. "Because you've been doing pilot projects for 5 or 10 years and now suddenly it's going to be going to scale involving 1.6 million people. Do the times demand a change in structure?"
"One of the solutions is to improve the way that we're providing technical assistance to countries," said Dr. Keshavjee. As a technical review panel, this is not the GLC's role. "Where there's a gap -- and this is something we all have to work on -- is in getting the projects to the stage that they can implement DOTS Plus projects or MDR-TB projects appropriately without putting patients at danger and without actually risking having an increase in XDR-TB."
It's the WHO's job (and that of other partners) to provide that technical assistance. Dr. Jaramillo agreed that better coordination of efforts and identification of potential partners are needed. "We need to work collaboratively to seriously expand advocacy, coordinate all efforts, to approach all possible supporters, and identify and address all bottlenecks," he said, adding that there has been progress at recent meetings on how to tackle some of these bottlenecks.
Lesotho -- a very remote and poor country -- was presented as the model for how to successfully apply to the GLC. Despite its limitations, Lesotho got help, according to a presentation by Dr. Hind E. Satti of Partners in Health (PIH). The process began when Lesotho identified its MDR-TB problem and asked the WHO for technical assistance. PIH helped to devise a plan and prepare the GLC application.
In addition, the Foundation for Innovative New Diagnostics (FIND) set up a national reference lab (NRL) capable of performing culture and DST on solid media, training local staff. The NRL is now introducing the Mycobacteria Growth Indicator Tube (MGIT) automated liquid culture system to perform more rapid DST and culture.
The Open Society Institute helped upgrade TB facilities, complete with a state-of-the-art ventilation system (for infection control).
Dr. Keshavjee said, "It's not just a matter of putting in the right technical assistance and getting the systems in place on a global level -- there have to be a lot of resources for health systems development. In Lesotho, we had to build the infrastructure that makes the system capable to deliver this type of care."
The country submitted its application to the GLC in November 2006 and the drugs arrived in July 2007. Within two months, the country had put its first year's target of 40 patients on second-line drugs. Lesotho did things the right way, according to Dr. Jaramillo: "You don't want to have second-line drugs available where conditions are not ready, but to start piloting treating patients in those areas where patients can receive the best treatment and where the health care worker can develop the skills and the managerial capacity to replicate that treatment, that capacity, to the rest of the country."
These partners deserve praise; however, it is unfair to suggest that every country in Africa can easily duplicate this success. "The amazing progress in Lesotho is not because the GLC was nice," said Harrington.
"It was because PIH, the Open Society Institute, and all these donors were there helping to set it up. But there aren't cadres of Partners in Health who are able to go all around the world and treat 1.6 million cases of MDR-TB." So additional partners must be identified and resources leveraged for other countries.
"We hear from the Global Fund that TB programs aren't asking for enough money," said Harrington. "So TB programs should ask for enough money to do the MDR scale-up that they need, to build the labs and to ensure the purchases and supply chain management of the drugs and the training of the people that will be providing the services."
"We need to be ambitious," said Dr. Alasdair Reid of UNAIDS. "The TB community has always done what it can with the resources it has. We need to say that these are the resources that we need, and without it, we will fail."
Scaling Up Laboratory Capacity
"Increasing lab capacity is essential to the management of MDR-TB, and it's also critical for improved surveillance," said Carole Mitnick of PIH. "It has become clear that the estimates suffer from a lack of data from sub-Saharan Africa."
"Less than 3 to 5% of MDR cases are currently being diagnosed," said Dr. Abigail Wright of the WHO -- and this clearly complicates the goal of putting close to 1.6 million cases of MDR-TB on treatment by 2015. "We can't put patients on treatment until we can find them," she said. "Right now, we don't even have the ability to find these patients in most countries. So as far as I'm concerned, until we start seriously dealing with labs, the targets are kind of a joke."
Another development that could increase the capacity to perform cultures and diagnose drug-resistant TB is the rollout of MGIT 960 systems in several countries. FIND has negotiated a new cost structure with the manufacturer, Becton, Dickinson and Company, for low-income countries that reduces costs to under US$3 per test -- comparable to solid culture costs. Also, PEPFAR has announced a commitment to funding the rollout of MGIT systems in several countries.
This will occur in stages, based upon FIND's experience in Lesotho. In most settings, laboratories first need to renovate and upgrade their infrastructure, train technicians, and establish the basics before attempting liquid culture. Additionally, safety, transporting and rapid results reporting systems must be established. But Dr. Ruth McNerney of the London School of Hygiene and Tropical Medicine cautioned against "airlifting" such complex machinery -- which will require ongoing maintenance -- into lower-resourced settings. "We haven't yet seen any data on the impact of MGIT and the liquid culture systems on patient care," she said. "No one even knows if it's going to make an impact. Two weeks is still quite a long time to get your results. Is that going to make a difference to your patients or will you already have them on treatment? If they're not on treatment, will you ever see them again?"
Where Best to Treat People with Drug-Resistant TB -- Addressing Stigma
Another important discussion topic at the meeting was how to care for people with drug-resistant TB in the context of stigma, and concerns around transmission. In Southern Africa, drug-resistant TB is usually treated in a hospital (in some cases, behind barbed wire fencing) so patients do not transmit infection to other members of the community. This has led to demonstrations by some people with MDR-TB who feel that they are "not being treated like human beings," said Dr. Eric Goemare, from the Médecins Sans Frontières (MSF) clinic in Khayelitsha.
The irony is that there aren't enough beds in the MDR-TB units for everyone with MDR-TB in South Africa, so while some are virtual prisoners in these facilities, most must wait for months for admittance and treatment (if they survive); in the meantime they are potentially transmitting drug-resistant TB within their communities.
"Hospital-based management of MDR-TB is not really the answer at this point in time," said Dr. Pheello Lethola of MSF-Lesotho. "We don't really have the resources and capacity. We have to decentralize TB treatment to the communities, to the district hospitals, and to the clinics."
"The way to treat patient is in the community -- a big relief in terms of human resources and time," said Dr. Jaime Bayona of Socios en Salud, which has pioneered community-based care of MDR-TB in Peru. "However, one of the challenges is the high default rate due to poor tolerance to many patients, stigma, lack of follow-up, and ineffective DOTS programs." In Peru, community members were invited to take part in the program to control MDR-TB and were trained to supervise treatment. A similar opportunity exists for community-based support in South Africa, according to Boniswa Seti, of the Treatment Action Campaign (TAC) in Khayelitsha.
"Directly observed therapy doesn't work in this setting because people feel that health workers are policing" them, Ms. Seti said. But a peer support system provides a "way of encouraging people and making sure that they adhere to their treatment." It worked in Peru. "Peer supporters provided the moral support and helped the doctors to identify, on time, the problems that may arise. The community health worker helps MDR-TB program managers identify and put in practice potential solutions," said Dr. Bayona. "We used the same strategy with HIV. Since community health workers were familiar with the health system, they helped identify more HIV patients and put them on ARV treatment right away."
But in Southern Africa, people with HIV are more likely to be called on to be treatment supporters -- and are at a much greater risk of contracting and dying from TB.
Dr. Goemaere worried that MDRTB is so stigmatized in South Africa that treatment advocates are afraid to work with people with MDR-TB. But even Harrington admitted that he would be concerned about that. "I don't hear enough about the support and training that's going to be necessary for these so-called treatment supporters," he said. "I mean, I'm HIV-positive, I've been doing HIV work for over 20 years, and I would be frightened to be a treatment supporter for an MDRTB patient. I would first want to know about how you do it."
"What is the real risk for a layperson with HIV in South Africa?" said Javid Syed of TAG. "We don't only need education and understanding, but also aggressive efforts for infection control and intensified case finding, detection, and appropriate treatment." Detecting and treating cases sooner is critical to prevent transmission.
Infection Control in Lesotho
Good infection control is essential to reduce the risk of TB transmission -- and to reduce stigma.
"We first started treating patients with MDR-TB in the private wards," said Dr. Lethola. "The nurses and the workers who learned that these were MDR cases did not want to have anything to do with them. No one wanted to go into the room," she said. So they performed trainings at the hospital and community clinics on MDRTB, infection control, and how to care for these patients.
Infection control measures include:
keeping the windows wide open, especially on opposite sides of the room (with heaters to keep the patient warm in cold weather)
providing respirator masks for the staff and education on how to use them
teaching cough etiquette for the patient
creating outside waiting rooms
providing triage for suspected TB carriers
"The stigma came down," added Dr. Lethola. "I cannot say that there is no stigma, but people have become more willing to work with these patients."
Dr. Bayona said that successful treatment also reduces stigma: "With the first culture-negative patient, hope began to spread to health workers and to people in the community." Cured patients now participate in their trainings.
The Need for TB Research and Development
Safety is also essential for lab technicians and is another reason Dr. McNerney worries about rolling out culture-based diagnoses into new areas. "We're pushing out culture facilities to people who haven't got many resources -- and these new labs are expensive to maintain. What happens when the [biosafety] filter blocks or you run out of masks? It is dangerous," she said. She believes some of other newer technologies, such as rapid molecular tests for drug resistance would be much safer for technicians. The molecular techniques -- with a turnaround time of two days or less -- would also speed the detection of drug-resistance in smear-positive infectious cases. "Molecular testing in the next couple years has the potential to make obsolete growth-based detection methods for MDR-TB," said Dr. O'Brien.
FIND is currently demonstrating one such system, the HAIN MTBDR Plus Assay, in South Africa. Even though this test must be performed in a well-equipped laboratory by very well trained technicians, it could be introduced into the laboratories that currently do HIV molecular tests. FIND is also working on a rapid rifampicin resistance test from Cepheid that could be introduced to peripheral laboratories, with some electricity, where microscopy is done.
Dr. Elsa Villarino of the Centers for Disease Control and Prevention believes such tests could be used for a much more aggressive treatment algorithm, with a positive test as a cue to starting a second-line MDR-TB regimen (culture-based DST results could be used later to optimize the regimen). "With rapid detection of drug resistance, there are improved cure rates. People get to live long enough to get treatment, if they start soon enough." A point-of-care dipstick test that could reliably detect TB without any laboratory infrastructure could have an even greater impact on speeding access to TB treatment. But Dr. O'Brien believes that such a test may still be 10 years away.
New drugs that could improve the treatment of MDR-TB also seem to be years away, according to Dr. Mel Spigelman of the TB Alliance and Dr. David McNeeley of Tibotec Pharmaceuticals. However, at least two compounds could get to market faster by first being evaluated against MDR-TB -- according to an article in the recent issue of PloS Medicine (Mitnick, et al., PLoS Med 4, 11 (2007): e292; doi: 10.1371/journal.pmed.0040292).
Yet the rather meager pipeline is evidence that the small market for secondline TB treatment and diagnosis is not incentive enough to stimulate commercial interest in research and development, said Dr. Tido von Schoen-Angerer of MSF -- and that alternate incentives are needed.
One idea: a sort of Kyoto Treaty among countries to invest in care and treatment for diseases of high public health importance. But countries are currently showing little inclination toward making such investments on their own accord.
"Some of the biggest and most powerful institutions and organizations in the world did not step up to the challenge," said Harrington. "The U.S. government's investment in TB research actually went down last year -- indeed, they gave less in the first year of the Global Plan than they gave in the year before the Global Plan!"
Strategies for Moving Forward
"We have to work with the health workers; the scientists have to be on board; community activists have a key role to play," Akanni said in her conclusion. "And one of the key ways is to speed up and scale up treatment literacy efforts."
"The community has to become more involved in research and development," said Ezio Santos Filho, an activist from Brazil. But he also stressed the need to strengthen existing health systems: "We need new drug sensitivity tests, but how can we do that when the systems are broken and the laboratories don't work? We cannot detach research and development from the health systems problems."
"Nothing is going to translate into practical changes on the ground within the next two years," said Dr. Umesh Lalloo of the Nelson Mandela School of Medicine. "In the interim, we should strengthen the current technologies and facilities we have." Activists will have to work together to get TB programs and research plans, as outlined in the Global Plan to Stop TB, 2006-2015, fully funded and supported by political leaders to ensure the prevention of drug-resistant TB.
One action already taking place is that PIH and TAG are organizing a meeting to discuss how the GLC will not be able to resolve the need for country level capacity and that activists need to advocate more with the STP to address this gap. "We really need a multidisciplinary approach and the engagement of all the aspects -- the laboratory, clinical, research, and the community are critical," said Dr. Villarino. "Because if one of the parts doesn't work, really, none of the parts work."