Posts Tagged ‘drug-resistant TB’

Last week, the Global Center released a new issue brief on drug-resistant TB to mark World TB Day. Included in the brief was this interview with Dr. Sarita Shah, who recently presented new research showing that strains of extensively drug-resistant TB (XDR-TB) in Tugela Ferry, South Africa, are becoming more resistant.

Tugela Ferry is ground zero for XDR, where doctors first described this deadly bug in 2005. Soon, 53 patients were diagnosed with XDR-TB; 52 of those patients died within an average of 16 days after they sought medical care. Since those first cases emerged, over 500 patients in Tugela Ferry have been diagnosed with XDR-TB, and cases of this deadly infection have been reported in 58 countries. And because of inadequate treatment, XDR-TB strains have developed resistance to an even greater number of drugs than before. In this Q&A, Dr. Shah, an assistant professor of medicine and of epidemiology and population health at Albert Einstein College of Medicine, describes a global health system that essentially guarantees the continued spread of multidrug-resistant TB (MDR-TB) and XDR-TB and talks about innovative efforts to transform the treatment of drug-resistant TB.

Q: You presented new research at the Union World Conference on Lung Health in 2009 showing that XDR has become more resistant. Why and how is this happening?

A: In July 2005, most of the XDR we analyzed in Tugela Ferry was resistant to four to five drugs. By 2009, 100% of patients in our study had XDR that was resistant to at least 6 drugs—and most to 8 drugs. This is a very worrying trend. But it’s not a surprise that drug resistance is going to increase if we have weak TB programs, not enough support, and not enough attention to this critical issue. This is happening because in many places, MDR is being treated in a completely unsupported, chaotic way. That treatment fails, and then we get XDR. And it’s not surprising that if we don’t treat XDR properly, it’s going to get ever more resistant. We will run out of letters soon, and we’ll be at the end of the road, with no more medicines available.

Q: Can you talk about the lineage of XDR and how it was initially passed along?

A: XDR has been around for a very long time. It was present in South Africa as early as 2001. Now that people are looking for it, we’re finding it everywhere. It isn’t a person spreading it around. It’s the conditions that create XDR, and those are everywhere—weak public health infrastructure and inadequate patient support for completing treatment, plus HIV/AIDS.

Q: Can you describe what’s happening on the ground now in KwaZulu-Natal Province, where you and your colleagues do much of your work on drug-resistant TB?

A: What happens in South Africa—and in many other countries around the world—is there’s a centralized, specialty hospital that treats all patients with MDR-TB, because the drugs used for treatment are complicated, expensive and specialized. So, it is felt that treatment should be by specialists who can use the drugs correctly and monitor for side effects appropriately. In KwaZulu-Natal, this hospital used to be able to admit all MDR patients for six months, during which patients are assured to take their medicines every single day. And then for the remaining year and a half of MDR treatment, the patients are supposed to come back every month for a check-up and more medicines. You can probably imagine that not everyone comes back. They live far away. They’re probably feeling better. They can’t afford to miss a day of work. So what happens? In South Africa, we had an MDR default rate of 15–20% percent, so you’re at XDR.

Starting about four years ago, that referral hospital became completely overwhelmed. They have 160 beds, and we diagnose over 2,500 MDR cases in our province alone per year, so you can see how that math doesn’t work. Since the central hospital couldn’t admit everyone anymore, there were long waiting lists to get into the hospital, which is the only way to get the MDR medicines. Half of the diagnosed cases might die before being admitted. The same thing happens in other places as well—or worse, no MDR treatment is available in the country at all—so it’s important to realize South Africa isn’t unique in this sense. The issue of getting MDR patients access to good drugs in a timely way is a major global effort led by the Green Light Committee.

But let’s say a patient manages to get in to the MDR hospital. The doctors would try to give him or her medicines, but they might discharge the patient after 3 or 4 months because they have to face the daily reality of the long waiting lists of patients who are, literally, dying while waiting to get access to the medicines. So, patients are discharged early—with all the best intentions of trying to get more people into care—but, this is the way you get more resistance and also transmit disease to others.

Q: What’s the fix for this kind of situation that guarantees failed treatment, more transmission, and greater resistance?     (more…)

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Tomorrow is World TB Day—and the halfway point for the Global Plan to Stop TB. What better time to learn about the latest TB research and the most innovative approaches to combating combat this ancient deadly epidemic?

Those items will be on the agenda tomorrow, along with data about the virulent threat of drug-resistant TB, at a Capitol Hill briefing entitled, “Bringing Methods to Scale: New Perspectives in the Changing World of TB.”

The briefing will feature a top official from the WHO’s Stop TB Department, who will detail the latest WHO data on MDR/XDR TB; Dr. Rachel Nugent, deputy director for global health at the Center for Global Development, who will address ways in which MDR-TB can inform larger concerns about drug resistance; and Dr. Celine Gounder, an IDSA member and director for deliverables for CREATE, who will discuss the twin epidemics of TB and HIV.

The briefing will begin at 10 a.m. in the Hart Senate Office Building, Room SH-902. Please stop by and join the discussion!

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The Center for Strategic and International Studies yesterday unveiled  a new “must-read” report for global health advocates, “Smart Global Health Policy.” While a panel at the Congressionally-chartered Institute of Medicine, made up primarily of scientists, issued recommendations on US global health policy last year, the CSIS panel is the first to involve high-level business leaders and sitting members of Congress.

The report drew on observations made during a study trip to Kenya, but it is unclear if consultation in developing countries went beyond that, for instance to include global representatives of affected communities and of developing country civil society, such as those on the boards of UNITAID and the Global Fund.

The report and the webcast of the launch event are available online.  Here are a few highlights:

The report makes a strong case that it is in the interest of the United States to continue and increase  our investment in global health and that the issue should matter to all Americans. It calls for keeping funding for AIDS, TB and malaria on a “consistent trajectory,” doubling spending on maternal and child health to $2 billion a year, forging a collaborative response to emerging heath threats, establishing strong coordination of global health policy across US agencies, and increasing support for multilateral efforts.

In 2009 there was a massive drop off in the expansion of treatment by US programs, and the report notes that AIDS advocates are “particularly anxious” at the slowing growth rate, a stalling that could also impact health systems.  The report suggests that funding is a concern for treatment advocates, yet, in fact, HIV prevention advocates have also been quite alarmed at the essentially flatline funding picture.

Despite World TB Day (March 24) being just a few days away, no mention is made in the report of immediate tuberculosis funding concerns, lowered TB targets in the 6-year Global Health Initiative or USAID’s role in responding to TB.  Instead, the report includes TB within a much longer timeframe, stating that “we can accomplish great things in the next 15 years:  We can cut the rate of new HIV infections by two thirds, end the threat of drug-resistant tuberculosis, and eliminate malaria deaths.”

In terms of overall funding, the report calls for less spending in the near term than either the IOM panel or the Global Health Initiative coalition did; instead, the CSIS document endorses the President’s proposed funding of $63 billion by 2014.  While the IOM called for specific increased funding levels on AIDS, TB and malaria consistent with Lantos-Hyde, the CSIS report does not delve into specific funding levels, with the exception of maternal and child health.  Instead, taking the long view, it calls for $25 billion in annual spending by 2025.

One exciting aspect of the CSIS report is that it endorses innovative financing as a means of raising funds for global health.  The report does not touch on the concept of innovative taxation for health, recently championed by maternal health advocates at Family Care International and many other groups. However, it identifies some specific mechanisms, such as borrowing the money needed through an international finance facility, and it urges the US National Security Council to review the most promising ideas on innovative financing and develop a US position.

Admiral William J. Fallon kicked off the launch event, stating that global health is a “bipartisan enterprise… which can unite US citizens in collective action.”  He stated the importance of maintaining forward momentum, noting that “we do not want to coast or slide backward.”  Helene Gayle said that global health efforts are showcasing the American spirit of generosity and said “we need forward momentum even in a period of constrained resources.”

Jack Lew, the top State Department official developing the US Global Health Initiative, spoke about the Administration’s goals in developing the new strategy. He said that the Administration’s aim was to “challenge a way of doing business by moving beyond a primary focus on disease treatment.”  He said the goal was “not to do harm to existing programs.”

Advocates for effective HIV prevention have felt stymied in recent weeks by the lack of specific HIV/AIDS guidances from the Administration to the field and have noted that Kenya’s Partnership Framework with the US even appears to rule out family planning integration.  Family planning came up at the event when Dr. Michael Merson, of Duke University, criticized the Canadian government’s rejection of the inclusion of family planning as a part of its maternal health initiative.

But Lew’s presentation did not delve into details — and there was no opportunity at the event for questions from the floor.  He stated that program integration was crucial to meet the needs of women, and he commented on the importance of having family planning and HIV/AIDS services in one location.

The report is particularly noteworthy for the very strong focus on measurement for accountability in delivering services. Business leaders at the event decried the reporting burden on health programs and, along with Dr. Merson, called for a common set of impact indicators.

Rajeev Venkayya, Director of Global Health Delivery at the Bill and Gates Melinda Foundation, said that measurement matters because it allows us to maximize efficiency and stretch dollars while identifying what works and what doesn’t.  In addition, measurement allows us to hold accountable institutions, organizations, and even individuals, which in turn allows for greater project improvement.  Exxon Mobil Chairman and CEO Rex Tillerson agreed, and cited a Lancet article which said that evaluation must be a top priority for global health.

Robert Rubin, former US Treasury Secretary and former head of Citigroup and Goldman Sachs, told the audience that global health leaders “face wrenching choices” as a result of US fiscal problems.  He asked two members of Congress, Rep. Keith Ellison and Senator Jeanne Shaheen, whether global health is an issue that can “break through the mire” on Capitol Hill.

Senator Shaheen said that the issue can succeed, but it is crucial to explain to Americans that international affairs spending is only a tiny fraction of the US budget, much less than people realize.   She said it was cheaper to spend on global health than on war, noting Bill Clinton’s recent statement about the appreciation of PEPFAR expressed by Muslim residents of Tanzania.  She also said the current committee structure in Congress is an impediment and endorsed the recommendation included in the report for a consultative body that would work across committees.

Congressman Ellison also voiced strong support for greater US action on global health, stating that “infectious diseases know no borders.”  He said that while in Kenya, he made good progress in persuading Kenyan leaders of the necessity of stepping up their own contributions.  He suggested that by reducing US spending on outmoded weapons systems the US could improve its budget outlook and make global health spending easier.

Gayle Smith, the NSC official leading the development of the US Global health Initiative, was the concluding speaker at the event. She said global health was a bipartisan issue and that in fact President Obama specifically directed that the achievements of the previous Republican Administration be recognized.  She praised the CSIS report, and said that its ideas were remarkably congruent with those of the Administration.

She said the Administration’s commitment to fighting global HIV/AIDS was “absolute” and, she added, “this will grow over the life of the initiative.” She said the Administration’s plans for the Global Health Initiative “include an ambitions set of targets in terms of outcomes.”

She did not respond to concerns submitted to the Administration by the Global Center, TAG, the Global Health Council, and the GHI Working Group that the Administration’s targets regarding tuberculosis contradict a directive from Congress approved in 2008 as a part of Lantos-Hyde.  In fact, it was surprising that the event unfolded without  reference  to the consultative process which numerous NGOs have engaged in regarding the US Global Health Initiative or to the detailed analyses these groups have submitted to the Administration.

There were a range of reactions from health NGOs to the event.  Eric Friedman at Physicians for Human Rights noted the “surprisingly little attention in the report to human resources for health and health systems, and no mention of including civil society in the development of country compacts.” He praised the report for “proposing that the Administration develop a long-term, 15-year framework for making progress in and committing the United States to improving global health, a good idea so long as it does not set the stage for underambition, and is flexible to respond to changes in the years ahead. ” He also would have liked to see “a recommendation that the United States should deliberately integrate a right to health approach throughout U.S. global health programs, including the consistent focus on equality, accountability, and participation that this entails.”

Matt Kavanagh at Health GAP praised what he heard from the report, which included an emphasis on keeping up the fight against HIV/AIDS, especially important for the health of African women. But he noted with concern that “some of the Administration comments that seemed to favor prioritizing ‘cheap’ interventions that do not work in the long term, such as single dose nevirapine instead of treatment for HIV positive mothers, an approach abandoned long ago as ineffective in wealthy nations.”

The American Medical Students Association’s Farheen A. Qurashi said that the report “takes a bold, but necessary, approach to U.S. global health planning by insisting upon a 15-year comprehensive plan.”  She said, “Unfortunately, the Commission’s report does not appear to specify the need for scaling-up of PEPFAR investments versus the dangers of flat-funding, and instead uses language that suggests that a continuation of current levels of funding without annual growth is sufficient.”

On health systems, she said that “though integration and health systems strengthening is mentioned in general terms, and the need for training and retention of health care workers is noted, there is no detailed analysis of the measures, funding, and support necessary to establish and retain adequate numbers of health professionals and other health care workers.”

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This afternoon, Dr. Mel Spigelman, president and CEO of the Global Alliance for TB Drug Development, and other leading TB advocates will join with FDA Commissioner Margaret Hamburg to launch a new initiative designed to accelerate the development and approval of life-saving new treatments for tuberculosis. There are now at least 9 promising new TB drugs in the pipeline. This project aims to shave decades off the time it takes to bring dramatically improved TB treatments to the millions of patients who die unnecessarily from TB.  These drugs are desperately needed tools in the battle against TB, an epidemic that claims 1.8 million lives each year.  We spoke with Dr. Spigelman about the implications of this new initiative, called the Critical Path to TB Drug Regimens (CPTR).

Dr. Mel Spigelman

Q: I know there are 9 new TB drugs in the pipeline and this initiative will allow them to be tested together and earlier in development. Can you tell me exactly how this process will work—what steps will be skipped and where and how will these drugs be tested?

Dr. Spigelman: What’s important to realize is that the CPTR is not about skipping steps, but rather streamlining processes and creating more efficient pathways to accomplish one goal—to dramatically speed the time it takes to bring new TB drug regimens to patients.

That’s important because developing new drug regimens is an extremely long process. Traditionally, new regimens are developed by successively substituting one new drug at a time into the existing regimen. Each substitution usually takes a minimum of 6 to 8 years.  Therefore, for a completely new regimen, substituting one drug at a time, it could take at least a quarter of a century. That’s too long to wait, when nearly 2 million patients die each year from TB.

 CPTR allows combination testing of new–as well as existing–drugs at once, reducing the time it takes to develop novel regimens to as little as 6 to 8  years. The CPTR has put together a regulatory science consortium, led by the Critical Path Institute, which will play a key role in validating the regulatory science that will back this process.

Preclinically, compounds will undergo the same battery of tests an individual drug is subjected to, as well as additional combination tests that will generate information that to be used to identify which drug combinations display the most promise. The fastest-acting and most effective combinations will move toward the clinic.

Q: Ever since the first human trials of the first-ever drug used to treat TB, streptomycin, in 1947, Mycobacterium tuberculosis has proven its ability to dodge our medical weaponry by developing resistance to these drugs. There’s a concern that if we continue to introduce new TB drugs one at a time, we will end up repeating history. What, if anything, does this project do to address those concerns?

Dr. Spigelman: You’re right–developing drugs one by one does increase the risk that resistance to therapies will develop. Under the conventional paradigm, by the time a second new drug is introduced into a regimen, resistance could have begun to mount against the first drug.

CPTR will fight the development of resistance in two important ways. First, CPTR regimens will have the potential to markedly shorten the duration of treatment needed to cure TB. This, in and of itself, is absolutely key to turning off the faucet of new drug-resistant cases. Shorter and simpler treatment means better adherence, which cuts down on the development of resistance.

Second, introducing multiple novel compounds at one time means that fewer elements of the regimen are accompanied by pre-existing, widespread resistance.   

Q: Why did it take so long to streamline the regulatory process for TB drug approval? Hasn’t the FDA been doing with this with HIV drug candidates for years?

Dr. Spigelman: To make dramatic progress in fighting the TB epidemic, a novel TB regimen is needed. However, as recently as 10 years ago — prior to the inception of the TB Alliance — there were no TB drug candidates under development. In fact, even as recent as four or five years ago, the global TB drug portfolio just wasn’t mature enough to realistically conceive of implementing a CPTR approach to TB drug development. There just weren’t enough drugs. 

Now, however, we have multiple new drugs in clinical development, which makes pursuing the CPTR initiative practical and feasible. There is also much greater industry commitment to new TB drugs than there has been in decades. There’s widespread recognition that to make an impact, companies, among a wide variety of constituencies, must work together if they want to impact the TB epidemic. The nexus of these commitments has enabled CPTR.  

The FDA has helped streamline the process of developing and registering HIV drugs in the past, but not in the way the CPTR initiative will function. This is in many ways a groundbreaking endeavor.  (more…)

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If ever there was a time to be getting more vigilant, not less, about combating tuberculosis, it is now, as strains of this ancient bug are becoming more virulent and better able to dodge our medical weaponry.

Take this disconcerting new study from researchers at the Johns Hopkins Bloomberg School of Public Health and colleagues in China, which found a strain of TB that actually “thriveson rifampin, a front-line drug in the treatment of TB. The patient, a 35-year-old Chinese man, grew increasingly ill when doctors tried to treat him with a regimen that included rifampin. He was eventually cured when they switched to a different set of medicines, according to the study, which can be found here.

“Rifampin-dependent tuberculosis is an unrecognized and potentially serious treatment issue,” said Ying Zhang, MD, PhD, senior author of the study and Hopkins professor said, according to this news release.  “Rifampin resistance is ominous. Our study highlights the potential dangers of continued treatment of MDR-TB with rifamycins that occur frequently due to delayed or absent drug susceptibility testing in the field.”  

Against that backdrop, there was this story in Monday’s San Francisco Chronicle about potentially devastating cuts to that city’s TB control program. 

“If we have five multi-drug resistant cases in San Francisco this coming year, we’re not going to have enough funding to manage them,” Dr. L. Masae Kawamura, director of San Francisco’s TB Control Section, told the paper. He said the TB section lost six employees this year to funding cuts. “We’ve already changed our operations to be lean, mean and efficient, but there’s a point where you’ve done everything you can, and that’s where we are now.”

Two days later, the SF Chronicle ran this piece about a man with drug-resistant TB who was allowed to board a flight from Philadelphia to San Francisco.

Taken together, these items do not paint a reassuring picture about the threat, or the response, to global TB.

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In a small new study, researchers found that linezolid, an antibiotic first approved in 2000, may be an effective component in the treatment of multidrug-resistant drug-resistant tuberculosis. But as previous research of this drug has suggested, linezolid is far from a perfect cure for the global epidemic of drug-resistant TB, and the findings reinforce the need for a ramped-up research and development effort to combat this deadly germ.

The most recent study, published in Clinical Infectious Diseases, involved 30 patients in California who were diagnosed with MDR-TB. Most of the patients were successfully cured. But nine patients experienced side effects, with symptoms including peripheral and optic neuropathy, anemia, rash, and diarrhea. Three patients stopped therapy.

The results are an indication that linezolid needs to be used carefully, the researchers concluded. “While receiving linezolid, patients should be closely monitored for signs or symptoms of bone marrow toxicity and peripheral and optic neuropathy,” the scientists write in the CID article.

“We found that linezolid … can play an important role in the management of MDR-TB, as long as it is used carefully and with appropriate monitoring, while we wait for better and less toxic drugs,” lead investigator Dr. Gisela F. Schecter said, according to a Reuters Health story. “Use of this drug has allowed the treatment and cure of patients who might otherwise have been deemed incurable.”

In another caveat, the authors note in CID that none of the patients in their study were known to have HIV infection and that more research was needed to investigative the efficacy and tolerability of linezolid in HIV-positive persons.  That is particularly crucial given the deadly syngery of the HIV and TB epidemics.

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An estimated 8 million tuberculosis-related deaths have been averted over the last 15 years through aggressive global efforts to combat this ancient and deadly epidemic, according to a new report released today by the World Health Organization.

Dr. Mario Raviglione, of the World Health Organization, highlights success in treating TB

 The epidemiological report, which provides more up-to-date figures than usual, says there were an estimated 9.4 million new cases of tuberculosis in 2008, a slight increase from the 9.3 million new cases in 2007. The disease claimed more than 1.8 million lives last year, including .5 million women.

Despite the continued global threat posed by TB, and reflected in the report’s new numbers, WHO officials said significant strides have been made in treating the disease. Over the last 15 years, an estimated 36 million patients have been cured of TB, Dr. Mario Raviglione, director of WHO’s Stop TB Department, said at a Congressional briefing to unveil the WHO report.

“We are now getting to the level of very high success rates,” Dr. Raviglione said of treatment under the DOTS strategy, or Directly Observed Therapy Short-Course. An estimated 87 percent of patients globally were successfully treated using DOTS, he said, marking the first time the global 85 percent treatment goal was surpassed since being set in 1991.

He noted that even in some countries with a high HIV burden, which fuels the TB epidemic, TB treatment has been successful. “That’s partly due to antiretrovirals being used abundantly in those countries,” he said. Still, in some parts of Africa, up to one percent of the population gets TB every year, “which is extraordinary,” Dr. Raviglione said.

Rep. Eliot Engel, D-N.Y., who also spoke at the briefing, said Congress must not falter in its commitment to fighting TB.

Rep. Eliot Engel, D-N.Y., called it "reprehensible that we allow over a half a million women to die each year of a preventable, treatable disease."


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