Source: Wikimedia Commons, Janice Carr (CDC)

With 8.8 million new cases and 1.4 million deaths worldwide in 2010, TB remains an unacceptable burden of human suffering and loss, overwhelmingly borne by poor and vulnerable people living in low or middle income countries. The tools available for TB control are old, lack effectiveness, and are not readily accessible in many settings. In most highly affected countries the diagnosis of pulmonary TB still relies on sputum microscopy, a century old technology that only detects half of cases. Current treatment of tuberculosis, which was developed in the 1970s, demands close supervision, is difficult to use in people living with HIV, and cannot be used in patients infected with multi-drug resistant strains. The only TB vaccine (BCG), first used in 1922, is variable in its efficacy to protect adults from pulmonary TB. More effective and widely accessible tools are needed to make a greater impact on the global TB burden in order to reach the goal of eliminating TB by 2050, defined as less than one case per million population in the Global Plan to Stop TB 2011-2015.

Fortunately there is hope, thanks to notable progress in the development of new tools for TB control over the last decade. In diagnostics the recent introduction of Xpert MTB/RIF – a DNA-based molecular assay that can diagnose TB and the presence of rifampicin-resistance in 100 minutes – is a major breakthrough. For treatment, nine new drugs are currently in phases I to III clinical trials. For vaccines, four novel candidates are presently in phase II clinical trials and two have recently entered phase IIb trials.

These advance alone are, however, insufficient. A recent mathematical model suggests that to effectively control and eliminate TB by 2050 a combined and synergistic implementation of several novel strategies is needed. These strategies include improved diagnosis of drug-susceptible and drug-resistant TB, shorter treatment of overt TB cases, scaled-up treatment of latently infected persons, and mass vaccination campaigns using a more effective vaccine. This could be obtained only through massive synergistic efforts in all areas of research and development.

“What research is required to Stop TB?”

Research across the full continuum – from basic science for discovery, to development of new diagnostics, drugs and vaccines, and their optimal uptake for better TB control – is necessary to enable the revolution in TB control technology needed to achieve the goal of TB elimination by 2050. For this, we need to improve our understanding of the basic science that will fuel the development of new diagnostics, drugs and vaccines, and we need to ensure that the newly developed tools are acceptable and affordable to be effectively used where they are needed. To achieve these objectives all aspects of research must be properly addressed and funded in a harmonized way.

To support this, the TB Research Movement engaged in the development of a coherent and comprehensive roadmap for global TB research towards TB elimination that encompasses all aspects of research. This roadmap was developed through a coordinated process including a multidisciplinary Delphi consultation, a series of systematic reviews and an open web-based survey. It involved a multidisciplinary group of more than 150 scientists, TB experts, implementers, funders and community advocates from around the world. Critical research priorities were identified in the areas of epidemiology, fundamental research, research and development of new diagnostics, drugs and vaccines, and operational and public health research.  More than a simple research agenda, the International Roadmap for Tuberculosis Research outlines critical and priority areas for future scientific investment, with the aim of increasing and harmonizing funding across the research spectrum.

This roadmap provides an architecture on which transformational and outcome-oriented research areas can be constructed. It is intended to promote organization of cross-disciplinary teams and attract all research-related constituents to the field, especially those in BRICS countries, who have a vital role to play. It provides a common platform for donors, researchers, implementers, and advocates by identifying the most important research questions.

The roadmap appears at a critical moment, when funding for TB research has flattened for the first time since 2005.  A report released recently by the Treatment Action Group and the Stop TB Partnership found that in 2010 just US$ 617.1 million was spent on TB research and development globally, down 0.3% compared to 2009 funding levels – while the Global Plan to Stop TB 2011-2015 calls for at least US$ 9.8 billion in TB research funds over the plan’s five-year period. It is hoped that the research roadmap will serve as a framework for concrete actions to synergize TB research efforts globally and catalyse the development of new research collaborations to address difficult and as yet unanswered questions in TB.

Dr. Christian Lienhardt is Senior Scientific Advisor at the Stop TB Partnership and WHO and responsible for the TB Research Movement. He has been coordinating the development and production of the International Roadmap for Tuberculosis Research that is presented here.

Related Links:

• The International Roadmap for Tuberculosis Research and other publications from the StopTB Partnership can be downloaded here

• A related PLoS Medicine article describing the TB Research Movement can be accessed here

Image Credit: Sustainable sanitation

This week PLoS Medicine publishes three new articles, including a follow-up to a previously published manuscript.

A systematic review and meta-analysis by Kathrin Ziegelbauer and colleagues finds that sanitation is associated with a reduced risk of transmission of helminthiases to humans.

Learn more about the findings by Nayu Ikeda and colleagues on adult mortality in Japan by reading our most recent Media Release post.

Xavier Bosch and colleagues expand upon a recent analysis by Simon Stern and Trudo Lemmens in PLoS Medicine and outline areas in which authors participating in medical ghostwriting could be held legally liable.

Remember you can comment on, annotate and rate any PLoS Medicine article and see the views, citations and other indications of impact of an article on that articles metrics tab.

Image Credit: Alisha Vargas

The life expectancy of a person born in Japan is among the highest in the world (82.9 years) yet tobacco smoking and high blood pressure are still the major risk factors for death among adults in Japan, emphasizing the need to reduce tobacco smoking and to improve ongoing programs designed to help people manage multiple cardiovascular risk factors, including high blood pressure, according to a study published in this week’s PLoS Medicine.

In an analysis of available data led by Nayu Ikeda from the University of Tokyo in Japan, the authors found that in Japan in 2007, tobacco smoking and high blood pressure accounted for 129,000 and 104,000 deaths, respectively, among adults aged 30 years and over. Physical inactivity accounted for 52,000 deaths, high blood glucose and high dietary salt intake accounted for 34,000 deaths each, and alcohol use for 31,000 deaths. Furthermore, the authors found that life expectancy at age 40 would have been extended by 1.4 years for both sexes, if exposure to multiple cardiovascular risk factors had been reduced to an optimal level.

According to the authors, in order to sustain the trend of longevity in Japan for the 21st century, additional efforts in a variety of fields are required for decreasing adult mortality from chronic diseases and injuries. They say: “A first step will be to powerfully promote effective programs for smoking cessation.”

Tobacco smoking is deeply rooted in Japanese society, but the authors argue that health professionals can play a big role: “Health care professionals, including physicians, who are highly conscious of the harms of tobacco will play the primary role in treatment of smoking and creating an environment for implementation of stringent tobacco control policies.

As for high blood pressure, the authors say: “it is urgent to establish a monitoring system for management of high blood pressure at the national level. Further investigation through national health surveys will help understand factors that contribute to the inadequate control of blood pressure in the Japanese population.”

The authors conclude: “Measuring the quality of the care that is actually delivered by interventions will be of paramount importance in the assessment of current policies and programs for the treatment of multiple cardiovascular risks including hypertension. These concerted actions in research, public health, clinical practice, and policymaking will be the key for maintaining good population health in the aging society.”

CONTACT:

Nayu Ikeda
Department of Global Health Policy
Graduate School of Medicine
The University of Tokyo
Japan
ikedan@m.u-tokyo.ac.jp

This media release was distributed to our press list under embargo before the article was published.

Image Credit: hibino

Four new articles published this week in PLoS Medicine:

To learn about the new article by Thomas Smith and colleagues on malaria vaccines, visit our previous Media Release post.

Jay Berry and colleagues report findings from an analysis of hospitalization data in the US, examining the proportion of inpatient resources attributable to care for children with neurological impairment.

Grant Mackenzie and colleagues describe how they set up a population-based surveillance system to assess the impact of pneumococcal conjugate vaccines on invasive pneumococcal disease (IPD) and radiological pneumonia in children in The Gambia.

Vikram Patel, Judith Bass, and other global mental health leaders call for a special session of the UN General Assembly to discuss and debate action needed on mental health, which has been left off the international NCDs agenda.

Remember you can comment on, annotate and rate any PLoS Medicine article and see the views, citations and other indications of impact of an article on that articles metrics tab.

Image Credit: Daniel Paquet

In the event that a vaccine for the prevention of malaria is licensed and ready for use (such as the research malaria vaccine RTS,S, which currently looks promising), distributing and giving the vaccine to three-month old infants via the World Health Organization’s Expanded Programme on Immunization (EPI) will be the most efficient mechanism in high transmission areas but for lower transmission areas, mass vaccination every 5 years might be a more efficient vaccination strategy, a new study has found.

In a modelling study led by Thomas Smith from the Public Health Institute in Basel, Switzerland, and published in this week’s PLoS Medicine, the authors used 14 different models that simulated the transmission of the parasite that causes malaria (P. falciparum) in thousands of hypothetical individuals through different stages of malaria infection. The authors used each model to predict the health benefits over 14 years of the potential malaria vaccine RTS,S given by different vaccination strategies and found that the predicted benefits of  giving the malaria vaccine using the EPI strategy were modest and similar over a wide-range of settings. However, EPI with an initial catch-up phase averted the most deaths per vaccine dose in individuals who had over 10 infectious malaria bites a year but in areas where people typically have two or less infectious mosquito bites a year, the authors’ model found that mass vaccination strategies substantially reduced transmission leading to much greater health effects per dose than other strategies, even at modest coverage.

This study only reports the first stages of using ensemble modelling to predict the health effects of RTS,S vaccination, so future studies will need to combine the outputs of multiple models with economic analyses to provide a rational basis for the design of vaccine-containing malaria control and elimination programs.

The authors say: “The ensemble modeling approach provides more robust outcomes than single models, and our analyses suggest that such an approach produces greater confidence in predictions of health effects for lower malaria transmission settings than for higher ones.”

The authors continue: “This study suggests that targeted mass vaccination with RTS,S in low transmission settings may be more efficient than national-level introduction via EPI programs, but there remains a need to analyze the feasibility and economics of such strategies and the circumstances in which vaccination will avert epidemics.”

CONTACT:

Thomas Smith
Swiss Tropical & Public Health Institute
Basel, Switzerland
thomas-a.smith@unibas.ch

Guest blogger Dr Michael Ekuoba Gyasi discusses trachoma, and the implications of two trials recently published in PLoS Medicine evaluating the treatment of minor trichiasis.

Trachoma is caused by Chlamydia trachomatis and is a leading cause of infectious blindness. In endemic communities the disease normally runs a chronic course with two distinct stages. The active stage occurs mainly in children under ten years who experience inflammation of the eyelids and discharge from the eye. The second stage occurs mostly in female adults. This is believed to be due to their close association with children, who serve as the reservoir for C. trachomatis, leading to cycles of re-infection and healing. With the ensuing chronic inflammation of the tarsal conjunctival tissues the lid margins turn inwards (entropion) and the lashes eventually touch and rub the surface of the globe (trichiasis) leading to corneal opacification and visual impairment.

Trachoma has been eliminated in most parts of the developed world but the disease remains a major cause of avoidable blindness in many developing countries.  At the global level the disease is concentrated in hot, dusty, and dry parts of the world stretching from Africa, through the Middle East to the Indian sub-continent and Asia with some pockets in Latin America. In endemic countries, it is found in rural areas that are economically underdeveloped with limited access to water and generally low level of personal and environmental hygiene.

As an infectious disease, trachoma clusters at the household and community levels with different severity and different potential for blindness. Ocular discharges containing the Chlamydia organism are the main sources of infection, which is transmitted through fomites (any inanimate object capable of carrying an infection), contaminated fingers and, more importantly, the eye-seeking common housefly, muscae sorbens.

The World Health Organization currently estimates that Trachoma accounts for 3.6% of global blindness burden and a control program, the SAFE strategy is being implemented in affected countries under the tenets of Vision 2020, the Right to Sight initiative. While there has been considerable success in the control of active trachoma in many endemic countries, the same cannot be said of the vision-threatening inactive form of the disease. The many reasons for this include inadequate number of surgeons trained to perform lid-rotation surgery, high recurrence of operated cases, low acceptance of corrective surgical procedures and socio-cultural issues among others. It is in this light that any attempts aimed at increasing surgical uptake, improving success and exploring alternative solutions should be commended.

A recently published high-powered control study by Rajak and co-workers has shown that using absorbable sutures (polyglactin-910) for tracomatous entropion surgery is as good as using conventional non-absorbable silk sutures.  Using the same surgical techniques, the authors found no difference in recurrence rate between the two sutures, even though there have been previous reports favouring lower recurrences for polyglactin. Since polyglactin sutures are absorbable and thus can be left in-situ, they offer major advantages in the operational sense; removing sutures is less of a burden for patient and surgeon freeing time to move on with other surgeries. It also allows surgeons enough time to assess surgical outcome and potential for recurrence. The main drawback however, is the cost and availability of polyglactin sutures in many of these impoverished countries where trachoma is endemic. Control programs will have to make budget allocation for this or persuade the manufacturer (Ethicon) to make donations in the same way as Pfizer and others do for azithromycin.

While surgical management of entropion is the gold standard for preventing cornea opacification and visual impairment, high recurrence rate, limited access, economic and socio-cultural barriers prevent many trachoma patients from accepting surgery in all cases. An alternative approach that is effective, easy to deliver and culturally acceptable therefore becomes important. This is why a sister article by Rajak and colleagues looking into the inferiority of self-epilation to standard surgical management of mild trichiasis is worth reading. Though inconclusive, there is enough evidence that self-epilation could be a viable alternate approach to the prevention of trachomatous corneal blindness.

Dr. Michael Ekuoba Gyasi is Medical Director of the North Western Eye Centre and Head of Clinical Care and Research at the Emmanuel Eye Centre in Accra, Ghana.

Image Credit: e-Magine Art

Four new articles were published in PLoS Medicine this week:

Using a simulation model, Andrea Ciaranello and colleagues find that the latest WHO PMTCT guidelines plus better access to PMTCT programs, better retention of women in care, and better adherence to drugs are needed to eliminate pediatric HIV in Zimbabwe.

Reed Beall and Randall Kuhn describe their analysis of the use of compulsory licenses for pharmaceutical products by World Trade Organization members since 1995.

Linda Flinterman and colleagues report on the long-term mortality rate for individuals who have experienced a first venous thrombosis or pulmonary embolism, describing an ongoing elevated risk of death compared to controls for up to eight years after the event.

Jason Nickerson and Amir Attaran examine the vast inequities in medical pain relief around the world and argue that the global control of licit narcotics be shifted from the International Narcotic Control Board to WHO.

Remember you can comment on, annotate and rate any PLoS Medicine article and see the views, citations and other indications of impact of an article on that articles metrics tab.

Visceral leishmaniasis (VL), a protozoan disease transmitted by sandflies, is the second-biggest parasitic killer worldwide (after malaria). In Ethiopia, the host country for the ICASA 2011 conference, VL and especially HIV/VL co-infection are major public health problems: more than one in three Ethiopian patients with VL is also HIV-positive, the world’s highest co-infection rate.

Treatment of HIV/VL patients presents serious challenges. The two diseases create a vicious spiral: HIV infection increases susceptibility to VL more than 2000-fold, and infection with VL accelerates progression to AIDS. VL is much more difficult to treat in patients with HIV, and even when initial treatment succeeds, patients usually relapse. While there are various drugs available for treating VL, all have drawbacks—for example, sodium stibogluconate (SSG) is highly toxic, particularly in HIV/VL patients (16-33% mortality during treatment) [1,2]; miltefosine is teratogenic; and resistance to drugs is a growing problem, especially when using monotherapy. Liposomal amphotericin B (L-AmB, currently registered as AmBisome®) is safe but must be given intravenously, and is prohibitively expensive for many settings. All these drugs show lower efficacy in HIV/VL patients.

As a physician with Médecins Sans Frontières (MSF) I spent two years living and working in Ethiopia, first in Humera, a hot, dusty border town, where MSF teams treated thousands of people with VL and HIV over the program’s 11 years.

Migrant workers in Humera, working and sleeping unprotected from the sandflies.

Here and elsewhere we worked towards better treatment for HIV/VL patients, and in a late-breaker oral presentation at ICASA I presented new data on outcomes of an alternative drug combination regimen and gave an overview of MSF’s experience managing HIV/VL patients in Ethiopia.

A combination treatment that improves on monotherapy
The main news was hopeful. In 2010 MSF introduced a new combination treatment, after evaluation of high dose L-AmB monotherapy in HIV/VL patients showed disappointingly limited effectiveness in HIV co-infected patients (32% parasitological failure) [3] and unacceptable mortality (16%) during “rescue” treatment of these patients with SSG. But in 50 patients treated with L-AmB (30 mg/kg) plus miltefosine (28 days), results were significantly better: initial cure rates of HIV/VL relapse, which is notoriously difficult to treat, were 87%, compared to 38% with L-AmB monotherapy (p<0.001). In 2012, MSF and several partners [4] will launch a randomized trial of the 2-drug combination, as well as higher-dose (40 mg/kg) L-AmB monotherapy, in co-infected patients.

Impact of ART on outcomes
Cellular immunity is vital for suppressing remaining parasites after VL treatment. While I was in Ethiopia, we demonstrated that ART in HIV/VL patients improves CD4 cell reconstitution only partially. Patients who had a VL relapse fared worst [5]: their CD4 levels never increased above 100 and VL relapses kept coming. Based on these findings, MSF now starts HIV/VL patients on ART as soon as possible after (first) VL treatment, regardless of CD4 count. Because ART alone is not adequate to prevent VL relapse, MSF and partners will soon begin a prospective study of secondary prophylaxis using monthly pentamidine injections.

Implications for HIV programs
MSF’s experience with VL and HIV/VL patients has important implications for HIV programs in VL-endemic countries. Donors and national HIV programs in these regions should include interventions that scale up VL prevention (e.g., impregnated bednets), diagnosis and optimal treatment. Access to early ART for those most vulnerable to VL, including rural migrant laborers and migrated populations, should be improved. In HIV-positive patients infected with the VL parasite but still asymptomatic, early use of ART may be the best way to prevent re-activation of latent VL. SSG should be avoided (due to its extreme toxicity) and high-dose L-AmB-based combination treatments given until parasitological cure is achieved, with ART added as soon as possible. And VL-endemic countries should add VL as in indication for ART initiation, irrespective of CD4 count.

Access to treatment
Access to L-AmB is a major challenge, mainly due to its high price. The recent AmBisome® donation agreement is significant in that it helps advance immediate treatment for one of the world’s most neglected diseases in four least-developed countries. But much more is needed to ensure long-term affordability and widespread availability, including more competition from similar products (for example, to reduce price) and registration of miltefosine and other VL drugs in more East African endemic countries, which otherwise cannot import them.

Rachel ter Horst is a Dutch physician who has worked for Médecins sans Frontières since 2003. She is currently serving as medical advocacy advisor, based in Amsterdam.

1. Ritmeijer K, Veeken H, Melaku et al. Ethiopian visceral leishmaniasis: generic and proprietary sodium stibogluconate are equivalent; HIV co-infected patients have a poor outcome. Trans R Soc Trop Med, 2001, 95;668-72.

2. Ritmeijer K, Dejenie A, Assefa Y, et al. A comparison of Miltefosine and Sodium Stibogluconate for treatment of Visceral Leishmaniasis in an Ethiopian population with high HIV-prevalence. Clin Infec Dis, 2006, 43 (3): 357-64.

3. Ritmeijer K, ter Horst R, Chane S, et al. Limited effectiveness of high-dose liposomal amphotericin B (AmBisome®) for treatment of visceral leishmaniasis in an Ethiopian population with high HIV prevalence. Clin Infect Dis 2011: Dec;53(12):e152-8. Epub 2011 Oct 19.

4. Drugs for Neglected Diseases initiative (DNDi), Gondar University, Ethiopia, and the Institute of Tropical Medicine (ITM) in Antwerp, Belgium.

5. Ter Horst R, Collin S, Ritmeijer K, et al. Concordant HIV infection and visceral leishmaniasis in Ethiopia: the influence of antiretroviral treatment and other factors on outcome. Clin Infect Dis 2008:46;1702-9.

“Finally, someone is talking about this.” I heard this refrain frequently at the recent ICASA conference in Addis-Ababa, Ethiopia after telling people about the satellite session hosted by Doctors Without Borders/Médecins Sans Frontières (MSF). The difficult topic: false positive HIV tests.

In resource-limited settings, HIV diagnosis is done with rapid diagnosis tests (RDT) using two or three different RDTs in either a serial or parallel algorithm (according to national guidelines). Rapid tests allow scale up and decentralization of treatment, both of which are essential to saving lives. Yet RDTS are screening tests –they were not designed for definitive diagnosis [1]. They work well for screening blood transfusions and identifying people who need further tests, but are known to yield false positive results due to serological cross-reactivity (or to inadequate quality control and human error (e.g. mislabeling of specimens). I first came across this unpleasant reality in Bukavu, DRC while working as a medical coordinator for MSF in 2005. We were running the first program offering ART to the province and had tested nearly 6000 people. But late in 2004 we came to realize that some people in our program did not have HIV, so we re-tested a number of them—and identified almost 50 who were suspect for false positive HIV diagnosis. This news was devastating, considering the consequences a false diagnosis can have on people’s lives.

We immediately worked to put stricter quality control protocols in place to eliminate errors in the testing process, and we reviewed all aspects of the program. Then we piloted a confirmation test for people who screen positive on two RDTs, using a test that is simple to use and interpret, requires no special equipment, and yields results in less than two hours [2] . All patients with a suspected false diagnosis were counseled and re-tested using the confirmation test. The reaction of those identified as false-positive varied. One woman said that her husband had divorced her, and she had remarried someone from the HIV+ peer support group. A pastor was immensely relieved to hear that he was HIV-negative, since he could never figure out how he got infected. Some felt it was a miracle from God, or evidence that the latest magic potion on the market cured HIV. Since people in the community were dying from lack of access to testing, we were very concerned about the potential consequences if people lost confidence in the testing program. But in fact we saw no decrease in uptake of testing or loss of confidence in our program. In fact, we learned that many local people were encouraged to come to MSF for testing due to the additional guarantees our program introduced.

At the MSF satellite session on HIV testing, we presented an interim analysis of our data from Ethiopia. The 2 study sites initially showed a 7% false positive rate using the national algorithm, which relies on 2 out of 3 positive tests (“tie-breaker” algorithm). Using an improved algorithm (with the confirmation test) the number of false positives dropped to zero. The UNHCR (UN Refugee Agency) presented its experience in Uganda: after recognizing problems with testing in its PMTCT programs, they adopted new measures to improve quality control and accuracy of the tests. Audience members shared similar experiences from their programs in several countries. Many spoke of policy makers’ reluctance to allow re-testing of people already under care, even if a problem with false positives was identified, or to openly acknowledge the issue.

Given the vital importance of testing and getting people on life-saving treatment, these testing problems are arguably outweighed by the greater good RDTs bring for scaling up access to care. However, it’s not either-or: there are feasible solutions that virtually eliminate the problem, such as improving the test algorithm, adding a simple confirmation test, and improving quality control.
In this era of initiating treatment earlier and scaling up community and door-to-door testing, confidence in the test algorithms is more important than ever. Fortunately for those still waiting to be tested, there are good solutions. It’s just a matter of putting them in place.

Leslie Shanks is a Canadian physician working for Médecins sans Frontières since 1994. She currently works in the position of Medical Director based in Amsterdam.

The author has completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declares: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.

[1]  Greenwald JL, Burstein GR, Pincus J, Branson B. A Rapid Review of Rapid HIV
Antibody Tests. Curr Infect Dis Rep. 2006 Mar;8(2):125-31

[2]  Klarkowski, D.B et al. The evaluation of a rapid in situ HIV confirmation test in a program with a high failure rate of the WHO HIV two test diagnostic algorithm. PLoS ONE February 2009 4 (2): e4351