Poor progress means multidrug-resistant tuberculosis

continues to spread and cost lives

Efforts to revamp international response to MDR-TB not enough!

Press Release New York/Geneva 7 July, 2011 – The global response to help countries scale up treatment of multidrug-resistant tuberculosis (MDR-TB) is underfunded and ineffective, according to a new report released today by three medical and medical advocacy organisations. A 20-month effort to reform the Green Light Committee Initiative, a World Health Organization (WHO)-hosted programme designed to help countries gain technical support for scale up of MDR-TB and access to quality-assured MDR-TB drugs, needs to be closely monitored to see if the reforms will address many key bottlenecks.

The report – issued by Médecins Sans Frontières (Doctors Without Borders, or MSF), Partners In Health (PIH) and Treatment Action Group (TAG) –identifies why efforts and progress to scale-up treatment for MDR-TB have been so sluggish. Over the past ten years, an estimated five million new cases of MDR-TB have occurred, with one and a half million lives lost. 

“We found that a lack of urgency and commitment from governments is a major stumbling block”, said Javid Syed, TB/HIV Project Director at TAG. “Many affected governments appear to be in no hurry to address the serious treatment needs of this devastating disease, and this is impeding efforts to identify new MDR-TB cases. Donors are not making TB overall a priorityand almost all of the major donors we contacted were unable to tell us how much of their funding was directed at DR-TB diagnosis and treatment. Besides funding, many countries will need global and regional support to build their capacity to diagnose and treat MDR-TB.”

Unpredictable and expensive drug supplies also contributed to the poor scale-up of treatment. The report – which looked at the MDR-TB treatment programmes of India, Russia and South Africa – also found that countries were prone to drug shortages and stock-outs, at both a national and international level – with serious consequences for patients. The price of certain key second-line anti-TB drugs – most off-patent and many more than 50 years old – has increased over the last ten years.  

“There are just too many barriers to scale-up at the country level, such as the high price of second-line drugs”, said KJ Seung, Clinical Manager of PIH-Lesotho. “Countries know they need to address MDR-TB, but with the high price of medications and lack of laboratory capacity they are often unable to scale up programmes. International support mechanisms need to be more efficient and effective at helping address these barriers.”

But the report states that the guidance and support given by such international support mechanisms falls far short of what is needed. It highlights three support mechanisms: the Green Light Committee (GLC) which monitors and assesses the progress of country MDR-TB treatment programmes; the Global Drug Facility (GDF) which supplies drugs to programmes approved by the GLC; and the Global Laboratory Initiative (GLI) which supports countries in setting up new diagnostic services for TB. All of these mechanisms are hosted by the WHO. 

The report findings show that countries, the GLC and GDF were not able to complement national efforts appropriately; barely 0.6% of the five million new MDR-TB patients over the last decade were treated through GLC-supported programmes. It also concluded that the GLI, though driven by laudable goals, was not transparent about what it had accomplished and was unable to provide data, making it impossible to evaluate its performance.

“The old GLC mechanism was no longer suited to help countries scale up treatment programmes”, said Dr Tido von Schoen-Angerer, Executive Director for MSF’s Campaign for Access to Essential Medicines. “The recent effort to reform the GLC has resulted in creating more committees, which I doubt will help countries and certainly do not address many of the bottlenecks that countries are facing.”

For further information, please contact:

Joanna Keenan, MSF +41 79 203 13 02

Kria Sakakeeny, PIH +1 617 998 6541

Javid Syed, TAG +1 646 373 8801

The report An Evaluation of Drug-Resistant TB Treatment Scale-Up can be accessed here and summarises progress and challenges in MDR-TB scale-up in India, Russia and South Africa, provides an evaluation of the effectiveness of global initiatives to support scale-up, and summarises the available data on donor commitments to scale up. 

Médecins Sans Frontières (MSF) is an international emergency medical relief organization that provides direct medical assistance in over 70 countries world-wide. In 2010, MSF supported the treatment of over 25,000 TB patients across 28 countries.

Partners in Health (PIH) is an organization dedicated to providing comprehensive health care to disadvantaged populations in twelve countries around the world, including MDR-TB care in Haiti, Peru, Russia, Kazakhstan, Rwanda, Malawi and Lesotho.

The Treatment Action Group (TAG) is an independent AIDS research and policy think tank fighting for better treatment, a vaccine, and a cure for AIDS. TAG works to ensure that people with HIV receive lifesaving treatment, care, and information. TAG’s programs focus on antiretroviral treatments, HIV basic science and immunology, vaccines and prevention technologies, hepatitis, and tuberculosis. 

The group of 25 leaders—including Donna Shalala, PhD, former secretary of Health and Human Services and current president of the University of Miami; Paul Farmer, MD, PhD, chair of the Department of Global Health and Social Medicine at Harvard University Medical School; Julio Frenk, MD, PhD, MPH, dean of the School of Public Health at Harvard University; Michael Klag, MD, MPH, dean of the Johns Hopkins Bloomberg School of Public Health; and Jim Yong Kim, MD, PhD, president of Dartmouth College — signed an open letter in an advertisement in Thursday’s edition of Politico, a widely read and influential newspaper reporting on Capitol Hill.

“This is a crucial time in the battle against global AIDS,” said Jim Curran, MD, MPH, dean of the Rollins School of Public Health at Emory University in Atlanta and one of the signers of the letter.  “As leaders in public health, we felt it urgent that we reach out to the President now to ensure the continued investment in these programs that have already saved the lives of millions and have the potential to do so much more.”

The President’s leadership in setting a high bar for funding these lifesaving programs is especially important given the major political changes in the next Congress, including the many new members of the House and Senate with limited knowledge of the history and value of the U.S. global AIDS response. Leadership from the White House can help ensure the continued successes of these programs, measured in lives saved and HIV infections averted, with resources aimed at expanding access to HIV treatment and implementing evidence-based interventions to protect individuals and communities from HIV infection.

The ad sponsored by amfAR, the Center for Global Health Policy and TAG can be found with additional links here. It appeared on page 12 of the Thursday, December 16, 2010 print edition of Politico.

This public service announcement which has been airing throughout New York City for the past two weeks is ostensibly aimed at promoting condom use among gay and bisexual men by stoking fear about co-morbidities that can be associated with HIV - such as osteoporosis, dementia and anal cancer.

Advocates and community members however have not been impressed by this public service announcement (PSA)  - in fact many have been expressing their outrage and frustration and have blasted the NYC Department of Health for perpetuating stigma against people with HIV. In fact, studies have shown that similar “scare tactic” ads directed at cigarette smokers do little to educate people to make more informed decisions.  Rather, the stigmatizing effect of these types of ads reduces the sufferers to tainted, discounted vectors of disease.  As Lei Chou from TAG says, the PSA’s make a mockery of the real suffering some people with HIV face and creates a "sense that people living with AIDS are those who did it this to themselves - not me. Further, it dismisses the serious medical and social services needs older people living with AIDS have at a time when we have to call attention to them." The intentional stigmatization of people living with HIV by the NYC Department of Health is not only offensive, it also increases the risk of violence against gay and bisexual men as well as the public palatability for more coercive public health measures. 

In response to widespread criticism, Dr. Monica Sweeney, Assistant Commissioner for the Bureau of HIV/AIDS Prevention and Control of the NYC Department of Health has defended the controversial ad by saying, “not everyone is going to agree with it, but we hope they remember it - the Health Department has no intention of pulling the ad or dropping the campaign.”

Echoing the frustration of advocates, Chou suggests that “if the city really wants to lower HIV transmission, it should stop the harassment of needle exchange clients, stop cutting services, provide affordable and stable housing, stop the strangulation of city hospital funding, and treat the gay community, including people living with AIDS, with respect." 

TAG's Policy Director, Sue Perez, was recently invited by the Ghana Ministry of Health (MOH) to participate in an 8-member independent team to review its medium-term health sector development plan. The team used a new assessment tool, Joint Assessment of National Strategies (JANS), developed by the International Health Partnership and related initiatives (IHP+), a global alliance of UN agencies, funding institutions including the World Bank, the Global Fund to Fight AIDS, Tuberculosis and Malaria and GAVI, as well as donor and developing country governments. The IHP+ was launched in September 2007 and is working to put the principles of the Paris Declaration on Aid Effectiveness into practice.

The JANS tool is one of several IHP+ products that have begun to be rolled out in countries and is still evolving based on its used in different countries. In Ghana, the team used the tool to identify strengths and weaknesses of the draft plan and to make recommendations for its improvement. For civil society, ideally the JANS process would result in a more inclusive process of consultation in plan development and ultimately a better, bolder and fully funded plan. In addition, JANS aims to build the confidence of key funders to provide technical and financial support to the plan and to reduce the costs associated with multiple assessments, country visits and reports by funders.

Sue’s participation focused on assessing the level and quality of consultation and input by various stakeholders in the process to develop the plan. Sue also assessed the level of political commitment to the plan, the role of regulatory bodies, capacity of regulatory systems and linkages with national disease-specific strategies. An assessment report has been shared with the Ghanaian MOH and country partners working in the health sector, including civil society. The report is being used to inform MOH efforts to improve and finalize the plan in order to launch serious discussions with funders to fill identified financing gaps. The report is also being used to make progress in ensuring meaningful consultation processes in the future.

Today, Secretary of State Hillary Rodham Clinton hosted a State Department town hall meeting to discuss the release of the long awaited Quadrennial Diplomacy and Development Review (QDDR)  -  the first ever strategic blueprint for modernizing the diplomatic and development arms of U.S. foreign assistance. The release of the QDDR wraps up a 17-month internal review of the U.S. Department of State (State)  and the United States Agency for International Development's (USAID) capacity and capability to lead the formulation and execution of a new vision of U.S. foreign policy. The QDDR is designed to complement the Pentagon’s Quadrennial Defense Review - which is the Defense Department's congressionally mandated, once every four year master review of U.S. defense policy and strategic initiatives. 

According to Secretary of State Hilary Clinton, the QDDR will set the stage for organizational reforms of both State and USAID in four broad stroke areas  which include adapting both State & USAID to the diplomatic landscape of the 21^st century by implementing a new "global civilian operations overseas by empowering and holding accountable chief of missions as CEOs of a multi-agency effort," and integrating a focus on women and girls throughout every level of State and USAID work.  Secondarily, the QDDR proposes to elevate and modernize development by building "partnerships with host nations, investing in innovation, and strengthening monitoring and evaluation." Thirdly the QDDR outlines how "conflict prevention and response will become a core element"  of State and USAID's civil service missions. Finally, the QDDR calls for State and USAID to  “work smarter” by investing in internal technical expertise capacity, building "better management of contracting and procurement activities" through transparency mechanisms,  and "reevaluating planning and budgeting activities for impact." Implementation of the QDDR will likely be carried out by USAID head Rajiv Shah and Jack Lew’s replacement – former  House aide and COO of Morgan Stanley, Thomas Nides who will now be the deputy Secretary of State for management and resources. 

As expected, State will transition the leadership and management of the Administration's $63 billion dollar Global Health Initiative to USAID by September 2012 provided certain unelaborated benchmarks are met.  However, whether or not PEPFAR  will remain under State control is still an unanswered question. The impact of the QDDR on the Administration's global HIV and TB health funding and programming  could be significant depending on whether Clinton, Shah and Nides can effectively garner congressional support for the foreign policy reforms laid out in the QDDR. Responding to recent threats by new leadership in congress to drastically cut State and foreign aid budgets, Secretary Clinton made a point of announcing during the town hall meeting that she would fight hard to try to win back the appropriation authority State and USAID has lost over the last couple of years, "we have to win back from congress the authority and power that we need to lead.”

3.5 Years After CCR5-Negative Stem Cell Transplant, Berlin Man Remains Free of Detectable HIV

 Reposted from the Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog by Richard Jefferys, originally posted on Thursday, December 9th.  

At the 2008 Conference on Retroviruses & Opportunistic Infections, a piece of paper pinned to a poster board conveyed some surprising information: an HIV-infected man who had received two stem cell transplants for acute myelogenous leukemia (and the dauntingly toxic ablation regimens that go with them) had remained off antiretroviral therapy for nearly ten months since, without any evidence of the virus coming back. The finding did not rest entirely on serendipity; his doctors had intelligently sought out a stem cell donor homozygous for the CCR5 delta 32 mutation, which prevents expression of the HIV co-receptor CCR5 on the surface of cells.

Most people, including me, wandered past the poster oblivious to its potential import. But Marty Delaney, the much-missed leader of Project Inform who passed away in January 2009, was more alert. He wrote an article for the PI website describing the case, which was posted February 12, 2008. It concluded:

This is another one of the kind of “one step at a time” approaches that we hope will one day lead to an outright cure of HIV infection, a state in which people who were once actively infected can remain “HIV undetectable” without any ongoing use of therapy. We urge other researchers to replicate or build upon this impressive case study, and we salute the patient and his doctors for taking this bold approach to treating HIV disease.

Many months later, in November 2008, the story finally broke in the mainstream media when Mark Schoofs authored an article for the Wall Street Journal entitled “A Doctor, a Mutation and a Potential Cure for AIDS;” many other outlets followed his lead. The article was prompted by a September 2008 scientific workshop on the case, sponsored by amfAR, at which the man’s doctor—a cheerful German hematologist named Gero Hütter—spoke. A detailed case report followed in the February 12, 2009 issue of the New England Journal of Medicine.

Yesterday, in the first edition section of the journal Blood, the latest update on the individual in question appeared. Follow-up is now out to 3.5 years and HIV remains undetectable in blood and every tissue studied, including gut and brain. CD4 T cell counts have climbed back into the normal range (the highest they have been since the original HIV diagnosis). There are some immunological deficits reported: the numbers of naïve T cells and newly-produced T cells known as recent thymic emigrants remain lower than those of healthy individuals, but are at similar levels to those seen in stem cell transplant recipients without HIV infection. Of concern to the researchers was the fact that, before his transplant procedures, the individual showed evidence of the presence of HIV capable of entering cells via the CXCR4 receptor (X4-tropic HIV). It was initially assumed that this virus would re-emerge at some point, but that has not occurred despite the documented presence of activated, CXCR4-expressing CD4 T cells in the gut (which would be expected to be prime targets). The paper closes with this sober statement: “From these results, it is reasonable to conclude that cure of HIV infection has been achieved in this patient.”

As Marty Delaney had advocated, an expanding number of projects are aiming to build on this result. The National Institutes of Health will soon be funding a multi-researcher project named after him, theMartin Delaney Collaboratory: Towards an HIV-1 Cure. Several potentially far safer approaches to abrogating CCR5 expression via genetic modification are in—or will soon enter—human trials. In April of next year, the AIDS Policy Project, amfAR, Project Inform and TAG are sponsoring a workshop to specifically address issues related to advancing cure-related clinical research. What was once writ small in a cavernous Boston conference hall now looms large, providing hope that a cure for HIV infection is possible.

UPDATE 12/10/2010: The individual has now gone public in Stern magazine; his name is Timothy Ray Brown, a 44 year old US citizen. Click here for a rough google translation of the article, which describes the series of difficult medical challenges he faced, including a bout of leukoencephalopathy that he is still recovering from. 

Given the media attention that is likely to follow, it's important to stress the not-so-good news: the extremely risky procedures that Timothy Ray Brown underwent to treat his cancer carry a very high risk of mortality, and they cannot be used to try and cure HIV in people without acute myelogenous leukemia (AML). Even for people with HIV who have AML and need a stem cell transplant, the likelihood of finding an appropriate (HLA-matched) donor with the CCR5 delta 32 mutation is extremely low due to its rarity. 

A new rapid test for tuberculosis which was just recommended by the World Health Organization for widespread use has the potential to revolutionize the world’s fight against the disease, said the Treatment Action Group today, but there are a number of obstacles that threaten to limit its impact, including cost.

“The new test, which yields results in two hours rather than the weeks to months it takes for standard TB culture to grow, has the potential to cause a paradigm shift in TB diagnosis and treatment, “said TAG Executive Director Mark Harrington. “The WHO has taken a bold step which if implemented by countries in TB and HIV programs has the potential to save millions of people from the ravages of HIV related and suspected multi-drug resistant (MDR) TB. But more actions are needed to make sure it reaches those most in need.”

Harrington noted that people with TB/HIV and MDR-TB are among those at greatest risk of death from the disease. Delayed diagnosis costs millions in undiagnosed or improperly treated TB, which sickened 20 million people and killed almost 2 million in 2009.

The test – called Xpert MTB/RIF – was developed by Cepheid of Sunnyvale, CA, with grant support from the U.S. National Institutes of Health, the Bill and Melinda Gates Foundation, the University of Medicine and Dentistry, New Jersey (UMDNJ), and the Foundation for Innovative New Diagnostics (FIND). While FIND has worked with Cepheid to reduce the cost of the test, TAG and other organizations have called for further price reductions to help ensure availability in resource-poor countries that are the most hard-hit by TB.

“We desperately need tools like the Xpert MTB/RIF test so that we can get people on life-saving treatment. With the current TB tests, many people with HIV are either not diagnosed, misdiagnosed, or dead before TB is properly diagnosed and treated,” said Nelson Tom Otwoma, a TB/HIV activist from the Network of People Living with HIV/AIDS in Kenya.  

The Xpert MTB/RIF is a cartridge based test which involves placing a small amount of sputum into a self-contained cartridge which decontaminates the sample, breaks open the cells, and copies their DNA to determine whether the Mycobacterium tuberculosis (Mtb) bacillus and mutations associated with resistance to rifampin – the anchor of first-line treatment for the disease –  are present. The test takes two hours and successfully detects between 92-98% of culture confirmed cases. The test also detects up to 73% of smear negative pulmonary TB cases, demonstrating potential to identify HIV positive TB cases and 98% of TB cases with resistance to rifampin within hours rather than the weeks to months it currently takes using standard TB culture tests.

 According to TAG’s TB/HIV Project Director, Javid Syed, “The test is a vast improvement over what is currently available. Even though it is expensive, at $19 per test and $17,000 per machine at the best current price for middle and low-income countries through the public sector, the test has major potential to reduce the burden on patients and on the health system. For the test to have a meaningful impact, we need to ensure that national TB programs and international donors such as the Global Fund to Fight AIDS, Tuberculosis and Malaria, and the U.S. government through the U.S. Agency for International Development (USAID) and the President’s Emergency Plan for AIDS Relief (PEPFAR) support urgent and accelerated roll out and implementation of the new test where it is most needed so that TB cases are detected rapidly and treated with the right course of antibiotic therapy.”

TAG expressed concern about the high cost of the test and the lack of U.S. Food and Drug Administration approval for its use in the United States. “The sponsor, Cepheid, deserves praise for working with FIND to develop a tiered pricing scheme to broaden access to the Xpert MTB/RIF test,” said Syed. “However, the test cost will need to come down further to maximize the availability and accessibility of the test where it is needed most.”

TAG’s Mark Harrington said, “Cepheid has received $3.3 million dollars in U.S. research contracts from the NIH to develop this TB test. The least it can do in return is to provide the test at an affordable price, and to submit the test for approval by the U.S. FDA so that the taxpayers who funded its development can benefit from its use. Though the numbers of TB cases are much smaller in the U.S., detecting TB is cumbersome everywhere, and FDA approval will further encourage global uptake. Only through innovations such as the Xpert MTB/RIF test will the world be able to reach the goal of eliminating TB as a public health threat by 2050.”

Blessina Kumar, a TB activist from India added, “We applaud WHO’s recommendation of Xpert MTB/RIF as a new rapid TB test, but caution that continued research is necessary to develop an accurate, rapid, and cheap ($1) point-of-care test for TB that does not need require sophisticated instruments, electricity, and can diagnose TB in HIV positive individuals and in infants and children unable to produce sputum.”

 

A report released by TAG in collaboration with Global Stop TB Partnership, reveals that in 2009 the world invested just $614 million in TB research and development (R&D). While spending has risen, it still remains at less than one-third of the projected $2 billion annual investment that will be needed to eliminate TB as a public health threat by the year 2050.

TB is a disease of the poor – more than 80% of TB cases worldwide arise in the global south.  According to the World Health Organization, there were 9.4 million people newly diagnosed with TB in 2008, including 1.5 million cases among people with HIV – which coupled with the emergence of drug resistant TB - creates a deadly synergy. Despite this reality, investment in TB research has remained very low compared to the worldwide burden. 

The newly released report - Tuberculosis Research and Development: 2010 Report on Tuberculosis Research Funding Trends, 2005-2009  - tracks annual research spending on TB across six research and development areas, with a deeper analysis of the top ten funders who accounted for 81% of the global funding total in 2009. “The report provides year-on-year trends for policymakers and activists so they may identify who the major TB donors are, know where the funds are invested, and determine where to target advocacy efforts,” said Eleonora Jiménez Salazar, the author’s report. “We hope it will catalyze donors, government, industry, and civil society to work toward the $2 billion per year needed to produce new tools to prevent, diagnose, and treat TB.” 

Though the economy remained fragile in 2009, funding levels for TB drugs increased from $174 million in 2008 to $188 million says the report. Funding for basic science also grew from $99 million to $170 million. In 2009, TB diagnostics research funding fell from $50 million to $41 million, a 17% drop, and TB vaccine spending remained flat at $109 million—raising concerns about the pace of vaccine development. Jiménez notes, “without an effective vaccine against all forms of TB that is safe to administer to children and adults regardless of their HIV status, the world will be unable to stop TB.”

In the lead up to World AIDS Day (December 1st) students from Harvard University make a case against cutting back on AIDS funding and why AIDS activism is critical to the success of global health targets overall. The amazing 3 and a half minute video also features Paul Farmer of Partners in Health and the the South African national anthem as the background music theme. Check it out below!

Last week, David Bryden from the Center for Global Health Policy of the Infectious Diseases Society of America and the HIV Medicine Association reported on the Urgent Need for New TB diagnostics with a fantastic piece written while he (along with TAG staff) attended the 41st Union World Conference on Lung Health in Berlin. In his blog David highlights a recent must read article in the New Yorker titled “Letter from India: A Deadly Misdiagnosis: Is it possible to save the millions of people who die from TB?”

According to the most recent World Health Organization (WHO) data, 9 million people developed tuberculosis in 2008 while 1.8 million died. 440,000 people developed multidrug resistant (MDR) TB and of these 150,000 died. 1.5 million people living with HIV developed TB and about 500,000 of them died. After HIV, tuberculosis is the leading global killer of women of childbearing age. About 15% of the global TB burden occurs in children. Shockingly it is estimated that almost 40% of TB cases go undetected and therefore untreated.

 The Stop TB Partnership recently released its updated Global Plan to Stop TB: 2011-2015. The plan outlines global targets to bring TB rates down and to scale up high quality TB care and research to pave the way for the elimination of TB as a public health threat by the year 2050, which can only be done if new diagnostics, treatment regimens, and vaccines are developed. In addition the Global Plan recommends that $2 billion per year be invested in TB research and development. According to recent TAG report, in 2009, the world invested $614 billion in TB R&D but that is still not enough.

As David reviews on his blog one of the most exciting TB R&D related innovations is in the diagnostics field and incidentally came from  US biodefense funds through the NIH (the initial machine was made to detect anthrax spores in the mail system and it was adapted to detect tuberculosis).  The Cepheid Xpert® MTB/RIF molecular diagnostic test  can detect tuberculosis DNA sequences and drug resistance to indicate MDR-TB within 90 minutes, as compared with the four to 12 weeks it usually takes for TB and MDR-TB to be detected. Although this long overdue diagnostic test is revolutionary – at $30,000 per machine and $25 per cartridge - it may still be out of reach for those who need it. Now is the time to capitalize on the innovative TB technologies coming down the pike and spur the development of even more research and development. It is time for G8 leaders to finally get serious about TB research, control and eradication.