A Crisis for People Living With HIV/AIDS Worldwide
Globally, TB is the most common infection and a leading cause of death among people living with HIV.
Despite being curable, TB accounts for two million deaths each year. Thirteen percent of deaths among HIV-positive people are TB-related, and some autopsy studies have seen rates as high as 50%. TB disproportionately affects poor people; 95% of the disease is concentrated in the developing world. Of the estimated 14 million people coinfected with TB/HIV, 10 million reside in Africa. Insufficient resources, neglect, and challenges posed by TB/HIV coinfection have collectively contributed to a diagnostic emergency in tuberculosis, uniquely jeopardizing people with HIV.
HIV increases the risk of developing TB disease by 50% and is a primary driver in the global increase in TB prevalence, along with multi-drug resistant TB (bacterial strains resistant to isoniazid and rifampicin, the two most potent anti-TB drugs). The most frequently utilized TB diagnostics lack the sensitivity to consistently detect the bacteria in an HIV coinfected population. These tests are also incapable of identifying drug resistant strains of TB. Consequently, TB diagnosis is often delayed in coinfected people and people with MDR TB, resulting in needless illness and death. Excess mortality in HIV-positive people can range up to 33% in the first two months of TB treatment. Some individuals die of late-diagnosed tuberculosis, while others die from HIV-related complications. Effective TB control requires, among other advances, access to novel and improved diagnostic tools.
The increase in HIV-associated TB requires rethinking the global strategy for TB control: directly observed, short course therapy (DOTS). Introduced by WHO in 1993, DOTS is now used in 191 countries worldwide. This schematic for TB surveillance, treatment, and monitoring represents a dramatic improvement over the dismal days prior to 1993, when no global standard existed for TB. Since 1994, more than 17 million people have been treated under DOTS, of whom 80% have completed treatment. Despite its success, DOTS is limited by reliance on passive case finding, where individuals presenting with an unexplained cough lasting longer than three weeks receive a clinical exam and sputum smear microscopy. A central limitation is that these tools focus on TB in the lung, and hunt for bacilli in the sputum. Since HIV-positive people often have less bacilli in their sputum and are more likely to have extrapulmonary TB, the most commonly performed tests cannot consistently detect TB disease in HIV-positive people.
The availability of diagnostic tests is closely linked with access to various resources required to administer them, including trained personnel, clean water, electricity, budget for testing equipment and reagents, and equipment maintenance costs. Tests will be utilized less when fees are associated with their use. Furthermore, existing diagnostic recommendations (codified in decision-making flowcharts and algorithms), used to guide health care providers in the diagnosis of TB, are chiefly oriented toward smear microscopy and chest X-rays, and do not address the particular challenges posed by coinfection with HIV.
Common diagnostic tests can be categorized into the following three sets based on their respective mechanisms for identifying TB infection and disease: clinical examination based on symptoms; a measure of immune response to TB; and tests that detect the TB bacteria itself.
Clinical Examination and Symptom Assessment
Clinical examination remains an important initial screening step in TB control. A simple symptom questionnaire assessing the presence of chest pains, night sweats, weight loss, fever and other common symptoms should be administered routinely in settings where TB is endemic. Despite its simplicity, the combination of exam plus symptom questionnaire is surprisingly effective at raising the clinical index of suspicion. Many individuals with an unexplained cough lasting longer than three weeks will turn out to have pulmonary TB.
Immune Response Based Diagnostic Tests
The tuberculin skin test (TST), also called the Mantoux test, is one of the more common immune based diagnostic tests. TST involves injecting a substance called purified protein derivative (PPD), which is isolated from the mycobacterium tuberculosis (MTB) cell wall, under a person's skin. If the person is infected with MTB, immune cells such as macrophages and lymphocytes migrate to the injection site, causing a marked swelling (induration) in the skin, which appears within two to three days. The presence or absence of TB infection is judged based on size of the swelling; very large indurations are often associated with active TB.
Unfortunately, TST may be harder to interpret among individuals who were immunized with Bacillus Calmette-Guérin (BCG) vaccine, a live attenuated mycobacterial strain often administered to children under age five in order to prevent TB. The TST may also be non-reactive among individuals unreactive to skin tests. People successfully treated for tuberculosis will test positive using TST. Often, tests looking for signs of active TB disease (such as chest X-ray) are required to distinguish between latent and active TB infection following a positive TST result. Thus, while useful, TST requires follow up, and results are occasionally misleading, particularly among people with HIV and low CD4 counts.
Chest X-rays look for cavities and abnormalities in the lung, both of which are components of the immune response to pulmonary TB. Chest X-ray is a diagnostic tool frequently used to confirm active, pulmonary TB following positive immune based tests. Unfortunately, it is equally spotty in its ability to catch TB disease in HIV-positive people. TB infection and the accompanying immunologic response typically lead to holes in the upper portion of the lungs. In people with HIV, TB related cavities are either deficient or clustered instead near the middle chest region, often evading detection by lab workers trained to scrutinize the upper lung portions of chest film. Though these differences in TB-related lung disease between HIV-positive and negative people are well documented, diagnostic technicians in endemic areas are not routinely and consistently trained to hunt for them. The consequences can be fatal.
The Quantiferon-TB test (QFT) is a more recent method used to detect TB infection. QFT measures the amount of gamma interferon (a cell-mediated immunity associated cytokine) released in whole blood following stimulation with purified protein derivative (PPD). Approved by the FDA in 2001, the QFT test is not yet widely used in rich or poor countries, due to its costliness, technically demanding nature, and lack of guidelines about its specific usefulness relative to existing diagnostic tests.
Due to their collective reliance upon host ability to mount a cell-mediated immune response, immune-based tests for TB infection are of less utility in HIV-positive people, particularly among the more immunologically compromised, including persons with AIDS. Thus, this highly common method for diagnosing TB may be least useful among the people who are at greatest risk for TB related progression and death.
Diagnostic Tests That Detect TB Bacteria
Sputum smear microscopy is the most standard diagnostic recommended by DOTS. The method involves collecting three sputum samples over at least two days. Samples are then stained with a dye and washed with acid. This dye adheres to mycobacteria such as TB and other "acid-fast bacilli" (AFB) and remains visible under the microscope even after an acid wash. In order to detect the elusive acid-fast TB bacterium, laboratory workers must examine each slide using 100 different microscopic fields over a ten minute period. An individual is recorded as a "smear positive case of pulmonary tuberculosis" when technicians detect AFB in two of three samples collected. This time-consuming, tedious process dates to the discovery of Mycobacterium tuberculosis (MTB), announced by Robert Koch on March 24, 1882 -- the original world TB day.
Cumbersome methodology aside, smear microscopy frequently yields false negatives and is further limited by its singular focus on TB in the lung -- the most infectious form of disease. Evidence suggests that only 40-60% of pulmonary TB cases are AFB positive by sputum smear microscopy. Smear positive cases exemplify typical pulmonary TB, which causes cavitary lesions visible in chest X-rays. However, in the remaining half of cases evaluated using smear microscopy, TB is present in the lungs despite negative results on sputum samples. Additionally, TB can manifest as extra pulmonary disease, involving the lymph nodes, bones, joints, central nervous system tissue, or pleural space. Studies from Malawi and southeast Asia indicate that up to two thirds of HIV-associated TB cases are either sputum smear negative or extrapulmonary. Thus, even when available, sputum smear microscopy is inadequate for capturing the majority of HIV/AIDS-related TB cases. In addition, the method cannot detect TB in children, who constitute one-sixth of the global burden of disease and are generally under-diagnosed and under-treated.
Some tests diagnose tuberculosis by detecting the presence of TB causing bacteria, bacterial proteins (antigens), or bacterial nucleic acids (DNA or RNA). Two examples include the sputum smear microscopy test for acid fast bacilli (AFB) and the nucleic acid amplification tests (NAAT). At times, HIV infection can complicate interpretation of these diagnostics as well. As discussed above, HIV-positive people are less likely to have abundant bacilli in their sputum (possibly leading to false negative on smear microscopy); and often have extra-pulmonary TB disease. Culture tests, which sample infected tissue or fluid from an individual and then culture the TB organism in a test tube, diagnose TB with far great accuracy, even among HIV-infected people. The disadvantage is that cultures are time-consuming, requiring four to eight weeks -- an unacceptable long window of time for coinfected TB/HIV patients, who may die waiting. Faster tests that use liquid media can grow the culture in as short a period as 12 days. Paradoxically, these tests have far greater efficiency and sensitivity but are expensive, technically demanding, and less widely available in resource-poor settings. Yet, despite both time and expense required, a clear advantage to culturing TB is that results also provide drug susceptibility profile of the bacilli, enabling the detection of drug resistant TB. For these reasons, it is imperative that liquid culture tests become available as a component of treatment for patients with MDR TB. While such culture-based diagnostics are a vast improvement over smear microscopy in terms of accuracy, their utility is currently limited due to the length of time they take and the amount of resources they require.
Policy and Advocacy Issues
The solution to the current diagnostic crises is two-pronged. At a bare minimum, currently available technologies must become more accessible in resource poor countries. This includes broader use of CXR, PPD, rapid culture, and nucleic acid amplification technology. Meanwhile, there is an urgent need for heightened investment in the development of cheaper, easier-to-use diagnostic tools capable of detecting (with greater sensitivity) sputum smear negative, extrapulmonary, pediatric, and/or multi drug resistant TB. Such tests must be designed for use at the point of care in resource-constrained settings of the developing world. Additionally, diagnostic algorithms must be modified to hasten the accurate diagnosis of TB in people living with HIV/AIDS, children, and others. A clear advantage to culturing TB is that results also provide drug susceptibility profile of the bacilli, enabling the detection of drug resistant TB.
Continued success of TB control programs depends on thorough and meaningful community education and empowerment. Community involvement can significantly contribute to earlier detection of TB and higher treatment completion rates, thereby reducing transmission, morbidity, and mortality. Advocacy on the part of people living with HIV and TB is vital to ensure that:
basic, applied, and operational TB research is adequately funded;
education and support is available for people in treatment or at risk for TB infection;
algorithms are adapted;
diagnostics are improved; and
access to these tests is expanded.
Finally, the discovery and development of TB diagnostics requires consistent, adequate funding to support TB research, including basic science research to enhance our understanding of the bacilli, develop new methods for distinguishing between latent and active TB, and identify characteristics that predict conversion from latent to active TB.
Despite recent, significant increases in resources for TB research and control (including from the Gates Foundation and the Global Fund to Fight AIDS, TB, and Malaria), the field of TB diagnostics continues to be drastically under funded. In 2004, the NIAID had just eight grants focused on TB diagnostics. In its January 2006 Global Plan to Stop TB, the Stop TB Partnership -- a global network of 400 public and private institutions working to develop a global TB control strategy -- identified a very modest resource gap of 163 million for TB diagnostics over the next ten years (2006-2015). Such projections, which influence funding allocations, must increase to reflect the true cost of scaling up current diagnostics, as well as costs associated with developing new diagnostics capable of being used in the settings where they are most needed. Additionally, there is a need to develop consistent regulatory standards to ensure high quality TB diagnostics. Nascent coordination efforts have begun through the public-private partnerships such as the Foundation for Innovative New Diagnostics (FIND). However, we need to address this matter with far greater urgency, and people living with TB and HIV must play a central role in pushing the agenda forward.
TB is a preventable and curable disease that still kills one person every 15 seconds, yet it has failed to receive due political and financial attention. The inadequacy of current diagnostics contributes to great illness and death, especially among people living with HIV and AIDS. Active engagement is needed on the part of all people of conscience in order to change this situation. Networks of people living with HIV must assume a leadership role, given that TB is a leading cause of death among us. Sadly, TB has not been consistently prioritized on the HIV advocacy agendas to date. It is imperative that civil society and activists, especially people living with HIV, engage this issue in order to ensure that TB -- a disease which has been with us since before the time of the ancient Egyptians -- finally becomes history.
There is an urgent need for heightened investment in the development of easier-to-use diagnostic tools capable of detecting sputum smear negative, extrapulmonary, pediatric, and/or multidrug resistant TB.