March 23, 2009
Tuberculosis: New Faces of an Old Disease (page 2)

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Continued from page 1.

“The Perfect Storm”: When TB drug-resistance and HIV/TB co-infection collide

Treating MDR-TB and HIV simultaneously is incredibly frustrating because of drug interactions and the potential for many strong side effects, let alone the number of pills patients have to take every day. With the tools we have today, we're fighting a losing battle in places where we see a lot of HIV/AIDS. The risk of MDR-TB spreading like wildfire is a terrifying but all too likely prospect.

Dr. Liesbet Ohler, MSF, Kenya

When drug-resistant TB emerges in vulnerable populations also infected with HIV the elements of a “perfect storm” are created. The results are catastrophic. The world woke up to this threat in 2006 after a hospital in KwaZulu-Natal in South Africa reported that 52 out of 53 patients co-infected with HIV and extensively drug-resistant strains of TB had died before their diagnosis could be confirmed and they could be put on treatment.21

MSF first encountered drug-resistant TB in eastern Europe and the former Soviet Union, where the problem of MDR-TB first emerged and the medical infrastructure was already in place for treating TB.

However, with the spread of TB across increasing numbers of HIV positive populations in sub-Saharan Africa, the picture is now completely different. The medical infrastructures in these countries – already swamped by HIV, (for instance the estimated 5.5 million people living with HIV in South Africa)22, let alone other diseases – are ill-equipped to cope.

Patient isolation – a counterproductive strategy

Some countries – such as South Africa – have adopted the policy of isolating DR-TB patients from the community as the national strategy. Diagnosed patients are admitted to regional, specialized treatment centers for at least six months, usually into congregate wards. The main argument is around the need to reduce community transmission by ‘isolating’ patients. However, there is little evidence that prolonged hospitalization improves adherence and prevents transmission, and there are even indications to the contrary. In addition, this policy raises difficult ethical questions. There are several reasons why isolation cannot continue to be the norm for all patients.

Firstly, under-resourced and overburdened health services can’t provide the required facilities, with the result that many patients are kept waiting without treatment.

Secondly, there is now evidence that patients within the confines of such health facilities will actually pass on the disease to their fellow in-patients and health staff, even while they are receiving second-line therapy.23

But the overwhelming reason for not pursuing this blanket policy of hospitalization is that so many patients will simply not be able to tolerate the isolation in far-away specialized hospitals. They may lose their economic livelihoods and separation from their normal support networks makes treatment unbearable. This could result in many patients defaulting from such hospitals with dire consequences for themselves and with the risk of spreading infection back in the community. Furthermore, isolation could discourage people from being diagnosed and therefore drive the epidemic underground, leading to increased community transmission. 24

Out in the community: MSF pilots integrated care project

For these reasons, in Khayelitsha, a township outside Cape Town in South Africa, MSF and local health authorities have been developing a community-based approach to treatment of patients infected with drug-resistant TB – most of whom are also infected with HIV.

This model of care brings with it its own challenges including the need to train local health staff, give peer adherence support to patients, adapt patients’ housing conditions to reduce transmission risks for family members, boost the rapid tracing of patients who default on treatment, and raise awareness more widely about the disease, how it can be treated and its spread limited.

It is hoped that through this model of care more patients will be diagnosed and successfully treated if they are supported to follow treatment in their homes and communities. In addition, building treatment capacity at the primary care level will allow more patients to access care.

Dr. Cheryl McDermid is the team leader for MSF’s drug-resistant TB (DR-TB) pilot project in Khayelitsha, South Africa

Once a patient is diagnosed with TB, we offer counseling so that the patient understands the disease. We educate patients about TB, make them aware that they can be cured, and explain how they can prevent transmitting the disease to others. An MSF counselor and a peer educator provide this support. Both are former DR-TB patients themselves, and are therefore able to counsel patients based on first-hand experience.

A second counseling session ideally takes place at the patient’s home with family members present. Again, we explain the disease, its transmission and treatment and how the risk of transmission at home can be reduced. Sometimes MSF assists the family by providing a separate sleeping space for the patient or installing a window. Ironically, many of the corrugated iron shacks in Khayelitsha provide adequate ventilation because of the gaps left in the buildings as a result of poor construction.

All patients are invited to join a support group which meets weekly. These groups are excellent for encouraging patients just starting on treatment – they can meet people who have been on treatment for much longer, and learn how others cope with taking their TB drugs. An MSF counselor visits patients in hospital at least once every fortnight. These visits reduce feelings of abandonment and neglect and the counselor acts as a link between patients and families.

Most patients with DR-TB do not need complex hospital care. To provide an alternative to sub-acute care, we are establishing a small inpatient facility with 12 beds. This will offer outpatient services but also allow us to treat inpatients for several weeks at a time in a healthcare environment that is closer to patient’s family and friends. For patients whose treatment options have run out, the facility will give them the option to receive palliative care and spend the end of their lives close to loved ones.

Our approach aims to allow patients to stay in or near their own homes and, to the greatest extent possible, to maintain a normal, autonomous life.

Of the nearly 6,000 people diagnosed with TB in Khayelitsha in 2008, 196 have been diagnosed with DR-TB to date. 74 percent of patients with DR-TB were also infected with HIV.

Conclusions and recommendations

We’re still simply not seeing the necessary urgency and major investment into research and development that is needed to make sure the basic science of TB gets translated into newer drugs that can shorten and improve treatment, and diagnostic tests that can be used in resource-poor settings.

Dr. Tido von Schoen-Angerer
MSF Campaign for Access to Essential Medicines

MSF calls for increased access to treatment

We need a massive effort to ensure more patients have access to appropriate treatment. This means:

Boosting access to better diagnostic methods

Until a new easy-to-use and sensitive point-of-care diagnostic test for TB is developed, there is no alternative but to boost access to existing diagnostic tools. Additional TB culture facilities must be set up wherever possible. Significant international and national efforts to build the capacity of laboratory facilities will also be necessary if the WHO recommendation to screen patients at risk of DR-TB for drug resistance is to be implemented successfully. MDR-TB rates in many areas of the world are high enough to justify routine DST testing in all new TB patients. For people living with HIV, DST should be performed at the start of TB treatment, as far as possible, to avoid mortality due to unrecognized DR-TB. Rapid DST methods should be used whenever feasible for the initial screening of DR-TB. 25

Prioritizing TB and scaling-up drug-resistant TB treatment programs

Current scale-up of TB treatment programs is far too slow to achieve the global target to treat 1.6 million MDR- and XDR-TB patients by 2015.26 What’s more, this global target does not even include all new patients with MDR-TB: with more than one million people already with MDR-TB today and an additional 490,000 new cases emerging each year, many more will need treatment. The goal of treatment scale-up is unrealistic with the tools at our disposal today. Greater efforts are needed to accelerate scale up.

Like tobacco control, MDR-TB requires an international response. An international agreement on TB with a specific focus on control and treatment of MDR-TB could strengthen the WHO’s role towards countries that are not on track to control the MDR-TB epidemic. It would also draw the attention of policy makers to the MDR-TB problem.

New treatment models, including patient follow up at community level, are needed in particular in high burden MDR-TB / HIV contexts. The current centralized, hospital-based model will not be replicable in many health systems.

Removing the barriers preventing the supply of second-line drugs

To reduce drug costs and improve the supply of second-line drugs, it is necessary to identify more than one quality-assured producer for each of the drugs needed in a second-line regimen. A global scale-up of MDR-TB treatment should increase volumes sufficiently to attract further drug producers and to reduce the price thanks to economies of scale and competition.

WHO leadership is needed to ensure that the drugs it recommends for second- and third-line treatment continue to be delivered to MDR-TB programs, even when no regulatory indication for TB treatment exists.

Integrating TB and HIV care

TB treatment is falling dramatically behind where it matters most: Africa. Routine HIV testing and care must be made available to TB patients and all HIV patients must be screened and have access to early diagnosis and treatment of TB.

MSF calls for an end to the neglect of TB research and a new framework for innovation and access

Many of the formidable obstacles we face in treating and detecting TB today are due to the inadequacy of the tools at our disposal.

Not enough is being done. Despite the presence of new actors and initiatives working in the field of TB diagnosis research, current research and development efforts are still woefully insufficient to deliver the diagnostic tests that answer the most urgent medical needs. We need tests that are more accurate than culture or microscopy, that give results fast and are simple enough to be used in remote settings.

Although the situation has significantly improved in the last decade, the TB drug pipeline is also relatively weak. About 40 compounds are currently in the global TB drug pipeline.27 This might sound promising, but if we compare it to the 171 and 371 drugs currently in clinical development respectively for pain management28 and cardiovascular diseases29 and developed only by US pharmaceutical companies, the size of neglect for TB research and development becomes evident.

Furthermore, ‘attrition’ rates mean that this is in fact falling far short of what is needed – on average only one compound out of 20 makes it through the development stages, while the other 19 are abandoned.30

TB vaccine research has made progress and today we have some candidate vaccines in the pipeline. However, they are all in the early stage of development and clinical testing will not be completed before the next seven to eight years. Moreover, after the vaccines are tested singularly, further clinical research will need to be conducted to identify the most effective combination of priming and boosting vaccines. Therefore, an effective vaccine for TB is still years away and sustained funding will be necessary to reach this goal.

We need a massive push to get new tools for TB.

This means:

New tools that respond to needs

Currently many different research agendas co-exist, and the most urgent needs don’t necessarily attract the most investment. For diagnostics, for example, the needs of patients that are falling through the net must be prioritized. We need tools that work for children, for HIV positive patients, for all forms of active TB, and that can determine drug resistance. This may mean using samples other than sputum, which is so problematic for many patients.

Looking at the peripheral level

Diagnostic developers need to focus on the peripheral level. They must concentrate on developing tools that can be used as close as possible to a patient’s bedside. This would allow diagnosis to be carried out at the places where the majority of patients are seen and ensure that patients are immediately enrolled into appropriate treatment, avoiding the spread of disease.

Boosting clinical trial capacity

More clinical trials are needed for the validation of tests and new drugs. Yet only US$20 million is spent annually worldwide for clinical trials for TB drugs compared to around US$300 million for HIV drugs in the US alone.31 In order to get more clinical trials done, funding needs to be fast tracked, and building of clinical trial capacity in endemic countries must become a priority. This requires a concerted effort of its own.

Boosting clinical trials for MDR-TB drugs

Improvements in MDR-TB treatment are critically urgent not only because of the current desperate situation in MDR-TB treatment but also because an entirely new first-line regimen for TB that would also address the problem of drug-resistant TB is many years away. . New drugs that are developed for TB should undergo trials in MDR-TB patients. A series of trials will be necessary to identify the best regimens and to integrate any new compound in the MDR-TB treatment regimen. A new initiative, Research Excellence to Stop TB Resistance (RESIST-TB) has been created to address this gap, but lacks crucial funding. This must change.

Ensuring access to knowledge

Cooperation among different research projects must be encouraged, and access to knowledge and others’ research facilitated, for example through promising open source initiatives.

Spending more money now

TB predominantly affects developing countries. As a result, TB research has been neglected through a lack of market incentives for pharmaceutical companies to invest in this area. The shortfall is colossal. Funding needs are estimated at around US$2 billion,32 yet barely US$400 million is spent today. European countries’ contributions are particularly weak.33

Supporting alternative mechanisms to finance research and development and support access

The current system for stimulating and rewarding research into and development of medicines, diagnostics and vaccines relies predominantly on the high prices that can be secured for health products developed, notably through granting monopoly and other intellectual property rights.

It is no secret that the system is broken. Alternative mechanisms that stimulate research and development into neglected diseases, but also ensure that any products developed remain affordable and accessible to those in need, must be explored.

We need a combination of larger and more sustainable ‘push’ funding through grants to researchers and academics, and ‘pull’ funding, through mechanisms such as a prize fund.

Backing a TB diagnostic test prize fund

Prize funds that separate the cost of research from the price of the finished product mean that any developed drug or diagnostic test can be priced more affordably for developing countries. They also allow donors to steer research towards areas of priority needs by determining in advance what medical innovation deserves to be rewarded.

In April 2008, at an expert roundtable discussion convened by MSF, TB researchers, economists and campaigners showed considerable interest in a proposal for a prize fund that would encourage the development of an easy-to-use, point-of-care TB diagnostic test.

The governments of Barbados and Bolivia subsequently made such a proposal to the WHO. They suggested exploring multiple prizes: for the development of a low-cost rapid diagnostic test for TB; for new treatments for Chagas disease; for a priority medicines and vaccines prize fund to reward mechanisms for new cancer treatments in developing countries; and for a licensed products prize fund for donors.

Putting patents into a patent pool

The idea behind a patent pool is that different patent-holders, such as companies, universities and research institutes, make their patents and other relevant intellectual property available to others on a voluntary basis through the pool. The pool then acts like a one-stop patent shop and allows other companies and researchers to access those patents in exchange for a fair royalty payment to the patent-holders.

UNITAID is currently setting up a medicines patent pool. The pool will initially focus on HIV and seek to boost access to new antiretroviral drugs in developing countries and to stimulate follow-on innovation such as the development of fixed-dose combinations or pediatric formulations. Once established, the patent pool could be extended to TB. Companies should collaborate with UNITAID with a view to voluntarily contribute their patents.

Glossary of terms

Active tuberculosis. A form of TB characterised by active growth and multiplication of bacteria in the infected part(s) of the body, leading to the destruction of infected tissues and organs. As opposed to latent TB it needs immediate treatment.

Adherence. A patient is fully adherent to a treatment if the drugs are taken at the right dose, at the right time for the whole duration of the treatment course; if no doses are missed; if no appointments for follow up are missed; and if the patient feels co-responsible for his or her treatment. For TB, one patient out of two will have difficulties in following the treatment course. Poor adherence may lead to treatment failure, the development of drug resistance, and increases the threat of transmitting the disease to others.

Ambulatory treatment. Also called outpatient treatment, ambulatory treatment for TB is delivered and directly observed by a caretaker (see DOT), but without keeping the patient hospitalised. Patients living near a health centre will go to the centre on a daily basis to collect their treatment. Patients living further away will be visited by a community health worker who will deliver treatment to the patients’ home.

Combination therapy. Therapy characterised by the simultaneous administration of two or more drugs.

Completion. A type of treatment outcome used to determine the success (or lack of success) of treatment for individual patients. Treatment completion applies to patients who have undergone a whole treatment course but for whom there is no confirmation of cure. This can either be because the absence of M. tuberculosis from the patient’s sputum was not correctly verified or because the patient was not able to produce sputum. This definition will also be used for patients who initially enrolled as smear negative, as in their case a negative sputum sample is not a confirmation of a specific response to treatment.

Culture. Bacterial culture is a laboratory method to multiply bacteria in order to assess their presence or not in a patient’s sample. This is done by letting the bacteria grow in predetermined culture media under controlled laboratory conditions, outside the natural environment where they usually grow (e.g. for TB, the human body).

Culture medium. A liquid or solid substance with a composition that supports the growth of micro-organisms or cells outside the natural environment where they usually grow.

Default. A patient who defaults has interrupted treatment for over two months. Defaulters who eventually return to access healthcare will usually be re-started on treatment, but the treatment regimen used will be stronger, with initially five (instead of four) drugs, as the patient might have developed resistance by virtue of defaulting.

DNA. Deoxyribonucleic acid. This is the molecule that encodes the genetic information that determines the development and functioning of living organisms and some viruses.

DOT. Directly-Observed Treatment. As opposed to self-administered treatment (SAT), DOT involves a patient taking medication in front of a healthcare or community worker, in order to ensure that the lengthy regimen is taken in full by the patient.

DOTS. Directly-Observed Treatment, Short-course is WHO’s recommended strategy for detection and cure of TB. DOTS combines five elements: political commitment, access to microscopy services for diagnosis of TB, reliable drug supplies, surveillance and monitoring systems and use of highly efficacious regimes with direct observation of treatment.

Drug resistance. When a drug used to treat tuberculosis is in fact ineffective against a strain of M. tuberculosis, the bacteria is said to be resistant to the drug (as opposed to drug-susceptible or drug-sensitive).

Drug sensitivity testing. Sometimes also called antibiogram, Drug Sensitivy Testing, or DST, is a technique to determine which drugs work and which don’t. It is done by exposing the TB bacilli to a culture-medium enriched by the antibiotic: if the bacteria are able to grow, the antibiotic is ineffective and the bacteria are resistant to the drug. If there is no growth, the antibiotic is proven to be effective, and the bacteria are sensitive or susceptible to the drug.

Drug-susceptible TB. Bacteria are said to be sensitive to a drug when the drugs are effective in killing or stopping the multiplication of bacteria in the body and can therefore clear the infection. The strains of TB which are sensitive to all first-line drugs are called drug-susceptible.

Extra-pulmonary TB. Form of TB where M. tuberculosis infect parts of the body other than the lungs. This is most commonly the lymph nodes, bones, central nervous system, cardiovascular and gastrointestinal systems.

First-line drugs. The drugs used as the first resort to treat a disease. In the case of TB, the following five drugs are usually chosen: isoniazid (H), rifampicin (R), ethambutol (E), pyrazinamide (Z) and streptomycin (S). These drugs are highly effective in drug-susceptible TB and patients usually tolerate them well.

Latent TB. A form of TB characterised by the presence in the body of M. tuberculosis in a “dormant” state. In other words, they are not actively growing or multiplying. This form of the disease is not contagious. As opposed to active TB, most of the time, no treatment is needed.

MGIT. MGIT stands for Mycobacterium Growth Indicator Tube. A diagnostic technique that contains a liquid medium releasing fluorescence when Mycobacteria are growing. The fluorescence is detected by a machine. The huge benefit of MGIT is the shorter time lag until a positive result can be obtained (8-10 days compared with 4-6 weeks for conventional culture media). But MGIT requires a well equipped laboratory, constant power supply and well trained staff.

Microscopy. Microscopy is currently the most commonly used technique to diagnose TB. Two to three sputum samples are taken from the patient and the sample will be stained and later read under the microscope. If TB bacilli are present, they occur in the form of small red rods, while the rest of the sample is blue.

Mycobacteria. Types of bacteria, of the genus Mycobacterium, that cause diseases such as TB and leprosy.

Mycobacterium tuberculosis or M. tuberculosis. A pathogenic bacterial species of the genus Mycobacterium and the causative agent of most cases of TB. First discovered in 1882 by Robert Koch.

Outpatient treatment. See ambulatory treatment.

Pathogen. Any disease-producing agent (e.g. virus, bacteria, fungi).

Peripheral level. In the organisation of health systems, the peripheral level represents the first point of contact of a person who is unwell with the health services. In low- and middle-income countries, peripheral health facilities are often located in rural and remote areas.

Point-of-care testing. Testing at the point-of-care means that diagnosis is carried out as close as possible to the site of patient care. The driving notion behind point-of-care testing is having a test as convenient to the patient as possible and giving immediate results that can lead to prompt initiation of treatment.

Pulmonary TB. Form of TB where M. tuberculosis bacteria are infecting the lungs.

Push and pull mechanisms. ‘Push’ financing mechanisms are those that invest upfront in research to stimulate the development of new products. ‘Push’ programmes provide direct funding through, for example, grants to universities or government laboratories. In contrast, ‘pull’ mechanisms are economic devices designed to create or secure a market, thereby improving the likelihood of a return on financial investments and thus making such investment more attractive.

Reagent. A chemical agent used for chemical reactions. Reagents are used in medical laboratories to facilitate reactions which than can confirm or reject a diagnosis.

Second-line drugs. Second-line drugs are used when the first-line drugs are no longer effective to cure a patient. They are less effective against M. tuberculosis and have many more side-effects than first-line drugs.

Sputum smear-positive or smear-negative TB. We speak about sputum smear-positive TB when M. tuberculosis bacteria can be identified in the sputum of patients through examination with a microscope. Sputum smear-negative TB, on the contrary, is when bacteria can not be identified in the sputum of patients.

TLA. Thin layer agar. A solid culture medium used to facilitate the rapid culturing of M. tuberculosis. The TLA method is cheaper and easier to handle than MGIT and therefore a promising technique for more remote settings.

21. Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. The Lancet 2006;368(9547):1575-80.  
22. UNAIDS. AIDS epidemic update: Joint United Nations Programme on HIV/AIDS (UNAIDS) and World Health Organization (WHO), 2007.  
23. Cox HS, et al. Emergence of extensive drug resistance during treatment for multidrug-resistant tuberculosis. The New England Journal of Medicine, 2008. 359(22): p. 2398-400; Andrews JR et al. Exogenous reinfection as a cause of multidrug-resistant and extensively drug-resistant tuberculosis in rural South Africa. Journal of Infectious Diseases, 2008. 198(11): p. 1582-9.  
24. Goemaere E, et al. XDR-TB in South Africa: detention is not the priority. PLoS Med, 2007. 4(4): p. e162.  
25. WHO. Guidelines for the programmatic management of drug-resistant tuberculosis. Emergency update 2008. Geneva: World Health Organization, 2008, WHO/HTM/TB/2008.402  
26. WHO, Stop TB Partnership (2007). The Global MDR-TB & XDR-TB response plan 2007-2008.  
27. Working group on new TB drugs. Working Group TB Drug R&D Portfolio 2008.  

© 2013 Doctors Without Borders/Médecins Sans Frontières (MSF)