World Health Organization and experts call for $95 million in emergency funding to combat XDR-TB

XDR-TB

XDR-TB is multidrug-resistant TB (MDR-TB) that has not only developed resistance to the two most important first-line TB drugs, isoniazid and rifampicin, but which has also developed resistance to at least two of the most potent second-line TB drug classes, including a fluoroquinolone and one of the injectable antibiotics such amikacin or capreomycin.

Since it takes a combination of several drugs to cure a case of active TB, resistance to these key drugs makes it extremely difficult to put together a safe and effective treatment regimen. The danger of under treating such a case of TB, from an epidemiological viewpoint, could be the development of resistance to the remaining drugs, while for the person with XDR-TB, there is a serious risk of rapid treatment failure and death — especially if they are HIV-infected.

The phenomenon was first described in the medical literature in May of this year after anecdotal reports prompted experts to conduct a global survey which observed that the phenomenon has occurred in TB programmes all over the world, but more recent news of what appears to be a widespread outbreak in South Africa — and its extremely high mortality rate in people with HIV — has got the TB world scrambling to determine the scale of the problem, limit its spread and to find ways to diagnose and manage the disease in peo-ple who contract it.

The World Health Organization (WHO), TB and HIV experts have called on national governments and funding agencies to come up with at least $95 million in 2007 to fund an emergency response to the threat of extensively drug-resistant tuberculosis (XDR-TB).

The evolution and framework of emergency response were outlined at the 37th World Conference on Lung Health, held last week in Paris, by Dr Ken Castro of the US Centers for Disease Control (CDC) and by Dr Paul Nunn, coordinator of the TB/HIV and Drug Resistance unit of WHO’s Stop TB Department, who added that $5 million is needed “by the end of this year in order to keep existing efforts rolling.”

Response timeline so far

TB experts heard the first reports of the detection of XDR-TB among failing patients at a hospital in Tugela Ferry, KwaZulu Natal, South Africa during a meeting hosted by the “Partnership Against Resistant Tuberculosis: A Network for Equity and Resource Strengthening” (PARTNERS) where the MDR-TB working group of the STOP TB Partnership was also meeting this past May in Atlanta.

In June, WHO’s strategic and technical advisory group began discussing how to mount a response to the issue. Once the outbreak in Tugela Ferry got the attention of the press, after it was publicly presented at the World AIDS Conference in Toronto in August, the South African Medical Research Council called for an expert consultation with WHO and the CDC in Johannesburg on September 7th and 8th. By this point, a survey of KwaZulu Natal had made it clear that the outbreak was province-wide — at least 10% of all TB culture positive cases were XDR-TB.

Dr. Ken Castro presented a seven point action plan to combat XDR-TB that was developed at that meeting:

 

• To conduct rapid surveys of XDR-TB (to determine the burden of disease)
• To enhance laboratory capacity, with an emphasis on rapid drug sensitivity testing (DST) to detect XDR-TB
• To improve the technical capacity of clinical and public health practitioners to effectively respond to XDR TB outbreaks and manage people with the infection
• To implement infection control precautions (to limit the transmission of the infection) with a focus on protecting people living with HIV
• To increase research support for anti-TB drug development
• To increase research support for rapid diagnostic test development
• To promote universal access to antiretroviral drugs under joint TB/HIV activities

 

More detail on this action plan can be found here.

According to Dr Nunn, a week later, WHO gave the go-ahead to form a Global XDR-TB Task Force, which quickly put basic information on XDR-TB onto the Stop TB and WHO websites and began fundraising.

The task force held its first meeting October 9th-10th to better define the key issues and identify what actions had to be undertaken globally as well as within countries, including determining who was going to do what. The full recommendations from that meeting can be found here.

Then on October 17th and 18th, the South African Department of Health hosted a consultation with the Global XDR-TB Task Force, WHO and the representatives from seven other countries (Lesotho, Malawi, Mauritius, Mozambique, Namibia, Swaziland and Zimbabwe) of the Southern African Development Community (SADC).

The framework of the global response

Dr Nunn described a framework for the global response to XDR-TB that was developed during these meetings.

“The first and most important priority… is the immediate strengthening of the essentials of TB and HIV prevention, care and control in countries,” said Dr Nunn.

Task teams are being been formed to provide technical assistance to countries on how to improve patient adherence to treatment and to reduce the number of patients who default on treatment, transfer out of care or die.

This will take increased international and national TB staff. South Africa has specifically requested assistance with human resource issues, and with how to manage cross-border migration of XDR TB cases, particularly for when those working in the mines (a setting where TB transmission commonly occurs) begin returning home, possibly to foreign countries for the holiday season.

Additionally, according to Dr Nunn, there is an urgent need to train TB staff both in basic TB management and drug resistance management. Continuing education courses are being organised and the Global Plan to Stop TB is being revised to incorporate XDR-TB, increase the budget, and increase the speed of the Plan’s scale up.

Introduce new rapid diagnostic tests

New diagnostic tests (to be described in a separate article) are being developed that could speed the detection of both TB and drug-resistant TB. The most rapid are PCR-based and should at least be able to distinguish drug susceptible TB from MDR-TB.

Strengthen both case management (for the individual patient) and programmatic management (within countries) of MDR- and XDR-TB

Guidelines for the management of drug-resistant TB that came out in May are being updated to incorporate XDR-TB. Furthermore, the algorithm for identification and management of suspected cases is being revised and will shortly be disseminated by the WHO and CDC.

Intensify efforts to build laboratory capacity

However, even the most basic laboratory capacity is missing in most of the high disease burden countries. For example, according to Dr Nunn, excluding South Africa, there are just 13 laboratories in all of Africa, serving a population of nearly 400 million, that are capable of doing culture (the gold standard for diagnosing TB), and only eleven of these laboratories can do DST. South Africa, with a population of 47 million, exceeds the African laboratory capacity on its own with 16 labs capable of performing culture and fourteen capable of doing DST.

The supranational reference laboratory system must also be strengthened to perform regional resistance surveillance (particularly in settings that where in-country laboratory capacity cannot be scaled up quickly enough to perform DST).

Overall, laboratory services must be improved at all levels to provide rapid diagnosis of TB in all patients.

“There is an urgent need for an enlarged budget plan for lab capacity — buildings, hardware, software and all the components — of course, treatment of the necessary personnel — and a strong public statement on the need for this strengthening,” said Dr Castro. “It is a shame that we are here convening in Paris in 2006 and still relying predominantly on the AFB smear as the basis for diagnosis of tuberculosis.”

The challenges of scaling up TB lab capacity in these settings will be discussed at greater length in a subsequent article.

Make high-quality second-line drugs available

Although XDR-TB is exceedingly difficult to treat, it may not be impossible if the condition is diagnosed in time and second-line drugs are at hand (thus far, they have not been in South Africa).

The WHO Green Light Committee, which oversees the procurement and distribution of second-line drugs in low-income countries, will be enlarged to provide access to more second-line drugs. The Global Fund for AIDS, TB and Malaria has agreed to support the Green Light Committee’s expansion.

Part of the Green Light Committee role is to make sure that the drugs are put to best use.

“The Green Light Committee is going to be crucial to make sure that as we make the second-line drugs that are needed available, we don’t immediately lose them because we throw them in a setting that is producing resistance,” said Dr Castro.

UNITAID, the new French effort to tax airline tickets to provide funding for com-bating AIDS, TB and malaria, has agreed to support the procurement of second line drugs for XDR-TB. They’ve also made an agreement with the WHO Essential Drugs Program to accelerate the prequalification process for manufacturers to assure that the second line drugs are of high quality.

Surveillance and monitoring of MDR and XDR-TB

The geographical distribution and size of the XDR-TB outbreak in Southern Africa must quickly be determined. The use of rapid DST could help facilitate this.

“We have a generic protocol ready, which will also link this XDR work with HIV, which is fundamentally important,” said Dr Nunn. “But, we need also to look at the detailed epidemiology of a number of cases to determine more precisely how these cases arise.”

Improve infection control to prevent the spread of XDR-TB, and protect health care workers, especially in high HIV settings

According to Dr Anthony Moll, one of the investigators who discovered the cases of XDR-TB in Tugela Ferry, one thing that all the people in the KwaZulu Natal XDR-TB outbreak had in common was that they had attended the same district hospital — which suggests that the infection was probably spread within that hospital setting.

Thus it is crucial that health facilities and programmes institute adequate infection control practices to contain the spread of drug resistance.

According to Dr Nunn, infection control guidelines prepared in 1999 are being updated to address the issues of infection control in high HIV settings and will be disseminated shortly

“These infection control measures need to be put into place immediately in health care settings and other risk areas, including prisons,” said Dr Nunn. Accordingly, resource-constrained countries may need support to implement these precautions.

Research and development of new tools (diagnostics and drugs) must be accelerated

An emergency meeting on the research implications of XDR-TB on new tools (including drugs and diagnostics) will be held in early 2007, probably in Cape Town.

“Are we to sit here and wait for the usual 20 years to get these drugs evaluated for efficacy and out there?” said Dr Castro. “That is one of the challenges that we’re going to need to face. So the best laid-out plans are being overtaken by the more recent events that we’ve seen.”

Advocacy, communication, social mobilisation (ACSM) is fundamental

“An ACSM task force has been established... addressing the priorities the strat-egy and the funding for increasing capacity and strengthening communications at all levels,” said Dr Nunn.

Funding will be sought to strengthen the communication channels and to mobilise existing supportive networks such as the HIV community.

Urgent financial resource mobilisation

“In order to pay for all this, we need urgent resource mobilisation,” Dr Nunn said.

An estimated $95 million will be needed primarily for the southern African countries. Most of the emergency funds ($80 million) will go to in-country costs with $35 million going to strengthening TB control activities and infrastructure devel-opment including infection control and laboratory capacity building as described above.

This funding is actually long overdue, since it has been a lack of infrastructure that contributed to the development of the problem in the first place — particularly in countries where the healthcare system has been stretched thin by the co-epidemics of TB and HIV.

About $40 million will be used to pay for the second-line anti-TB drugs in southern Africa for around 6,000 MDR and XDR-TB patients. UNITAID has committed to provide these funds over the coming year.

$5 million will be needed to purchase rapid diagnostic tests to screen an estimated 154,000 people for suspected MDR and XDR-TB.

WHO and its international partners will need about 15 million to provide the re-quired technical assistance.

However, these figures are just a crude estimate — each affected country still must perform a needs assessment to calculate their individual needs. The seven SADC countries that participated in the consultation in South Africa have agreed to provide national level plans with costing by the middle of November.

Aside from the funding promised by UNITAID for the medications, it is not entirely clear where the funding will come from. The Global Fund has reported that it is open to reprogramming of existing grants to incorporate XDR-TB ac-tivities, which can also be part of the 7th round of funding applications that should occur next year (provided that the Global Fund is itself adequately re-funded).

Without a new additional “emergency” response, the President’s Emergency Plan for AIDS Relief (PEPFAR) has already designated how funds will be spent in the coming year in most countries. However, there may still be some flexibility in some countries.

“We’re trying to influence those plans to include the ability to do some of these rapid surveys within those existing resources that are there,” said Dr Castro.

In the meantime, the Tuberculosis Control Assistance Program (TB CAP), a USAID funding mechanism to provide countries with technical assistance in TB control through a coalition of technical agencies including WHO, the International Union against Tuberculosis and Lung Diseases (IUATLD), the KNCV Tuberculosis Foundation and other partners may be used to support XDR-TB activities if countries request it.

Next steps: global coordination

A few meetings are slated for the middle of November, including a meeting between WHO and the South African Department of Health.

On November 16th, 2006, the Foundation for New Innovative Diagnostics (FIND) (a public private partnership focusing on the development of TB diagnostics and the South African Medical Research Council will have a workshop to establish demonstration sites on rapid culture and DST in Pretoria on November 16.

The following day, there will be a SADC Health Ministers meeting in Namibia to discuss country needs and regional coordination.

The coordinating board of the of the STOP TB Partnership will also be meeting in Jakarta later in November to consider how to strengthen links between the MDR-TB working group and other relevant working groups in order to de-velop the response to XDR-TB and revise the Global Plan.

“We would anticipate that country level implementation should be underway in the worst affected Southern African countries by December of this year," said Dr Nunn. “[But] countries need to request that support.”