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HIV Spread Threatens Decade's Tuberculosis Treatment/Prevention Success

tagline 2002 July

New Challenges, Questions

TB researchers and policy-makers from around the world gathered on 3-5 June 2002 in Washington, D.C., at the 4th World TB Congress (the 3rd was held ten years ago) to mark progress and map out the next stages of the global campaign to STOP TB, which is led by the World Health Organization (WHO). Daniel Raymond prepared this report for TAGline.

Mycobacterium tuberculosis (TB) is the leading killer of people with AIDS around the world. Immune systems weakened by HIV are more susceptible to the ravages of TB, which itself speeds up progression to AIDS. Like HIV, TB is preventable and treatable, but unlike HIV, it is also curable. An uncomplicated case of drug-susceptible pulmonary tuberculosis can usually be cured with a six month regimen consisting of four drugs taken for two months, followed by two drugs taken for four months. Because many people stop taking their medications after their TB symptoms disappear, the favored approach to TB treatment involves directly-observed therapy (DOT), which increases the cure rate and reduces the incidence of multi-drug resistant (MDR) TB.

Worldwide, infection with tuberculosis is, along with HIV and malaria, the leading infectious killer. Moreover, the HIV pandemic has caused an upsurge in worldwide TB-related disease and death, in spite of a massive scale-up over the past ten years which has led to significant advances in the treatment and prevention of tuberculosis in resource-poor settings.

The Congress marked the culmination of a decade of astonishing advances and success, while ushering in a period filled with new challenges and questions. A concerted international effort, coordinated by the WHO, has led to the wide-scale adoption of DOTS (Directly Observed Therapy, Short Course), whose key elements include:

  1. Sustained national political commitment to TB control;

  2. Passive case detection of active TB disease via sputum microscopy;

  3. Standardized short-course (six months) chemotherapy;

  4. Reliable procurement and distribution systems for quality-assured drugs; and

  5. A surveillance and reporting system documenting individual patient outcomes.

The DOTS strategy -- devised in the early 1990s and now adopted by 148 countries -- is a global public health priority due to the fact that one third of the world's population harbors TB infection, of whom 8.4 million people develop active tuberculosis, from which nearly two million die each year. Multidrug-resistant TB cases are rising in many areas, while the HIV epidemic is fueling a resurgence of TB in many high HIV prevalence areas, particularly sub-Saharan Africa and parts of Southeast Asia and the former Soviet Union. Indeed, tuberculosis accounts for at least one third of all HIV-related mortality worldwide.

Mario Raviglione from the WHO STOP TB Program reviewed developments over the last decade that spurred a renewed global commitment to fighting TB. He noted that widespread media coverage surrounding outbreaks of MDR-TB in urban settings in the developed world in the early 1990s (including New York and San Francisco) reversed two decades of decline in global concern during which TB was largely controlled in the West while in developing countries dedicated TB funding and staff were folded into broader infectious disease programs. Raviglione cited the World Bank's 1993 World Development Report as critical in establishing the cost effectiveness, and hence feasibility, of treating TB even in resource-poor settings, using the DOTS strategy.

In 1991 the World Health Assembly set targets of 70% detection of active cases and 85% cure rate of those cases. The momentum from this revived focus on TB control led to the establishment of multi-sectoral working groups, including the Stop TB Partnership, the Global Alliance on TB Drug Development, and the Global TB Drug Facility, as well as groups focusing on MDR-TB and vaccine and diagnostics development. Over the past decade WHO successfully persuaded health and finance ministers in 148 countries to implement DOTS. Ten million cases of TB disease have been treated under DOTS, and seven million people have been cured.

In contrast to the mood of optimism in TB research -- including progress towards the development of new drugs and effective vaccines -- the conference sessions addressing the impact of HIV on the TB epidemic had a more somber tone. People with HIV are more susceptible to TB infection and much more likely to develop active TB. In some sub-Saharan countries, which account for 70% of the world's HIV/TB coinfection cases, 40-60% of people with active TB disease are HIV positive. Peter Godfrey-Fausett from the London School of Hygiene and Tropical Medicine noted that "no country with a severe HIV epidemic is controlling TB," including those with established, well-functioning national TB control programs.

The convergence of these two epidemics has worsened the impact of each: in countries with high HIV prevalence, people are often reluctant to seek out TB treatment as they fear being tarred with the social stigma of "TB-AIDS." In some areas TB drugs such as rifampin used to treat TB are being taken to manage opportunistic infections, increasing the risk of developing MDR-TB. Moreover, while isoniazid ("INH") therapy -- used as TB prophylaxis to prevent active disease -- may prevent active TB, some research suggests that it does not reduce overall mortality after two to three years of follow-up -- either because of TB re-exposure and reinfection or because of other HIV related causes of mortality.

Discussing the prospects of linking antiretroviral therapy to TB treatment in Africa, Nicola Hargreaves from the Malawi National TB Control Program observed that rifampin has known interactions with some antiretroviral medications, notably protease inhibitors and nevirapine. She also described a reactivation, or immune reconstitution, syndrome experienced by some patients with latent TB infection upon initiating HAART, which may lead to serious complications. Furthermore, she cited figures indicating that almost 60% of HIV+ people who die of TB despite treatment die in the first two months of TB treatment. Given these considerations, she suggested a model for treating patients presenting with both active TB and HIV:

  • CD4 count below 50: Initiate antiretroviral therapy during the first two-month intensive phase of TB treatment

  • CD4 count between 50 and 200: Initiate antiretroviral therapy during the subsequent six-month continuation phase of TB treatment

  • CD4 count above 200: Initiate antiretroviral therapy after TB treatment

She acknowledged that this algorithm presumed access to CD4 testing which is generally unavailable in resource poor settings. Nevertheless, Hargreaves called for a package of TB and HIV care that explicitly included ART, noting the preliminary successes of pilot ProTEST programs in South Africa and elsewhere which using voluntary counseling and testing for HIV as an entry point into various services including TB screening, opportunistic infection prophylaxis with cotrimoxazole (Bactrim), treatment of sexually transmitted diseases (STDs) and safer sex counseling, and psychosocial support services.

Some speakers and audience members questioned whether ART would have an impact on TB control, given that many people with HIV develop active TB when their CD4 counts are still well above 200, a time when most would not be on antiretroviral therapy. Peter Godfrey-Fausett remarked when TB and HIV were treated concurrently, it would be more difficult if not impossible to identify the cause of drug-related side effects such as hepatotoxicity and neuropathy which might lead some patients to discontinue prematurely their TB regimens.

David Cohn of the Denver Department of Public Health and University of Colorado argued that initiating antiretroviral therapy during TB treatment increased the risk of side effects, adherence problems, drug interactions, and paradoxical reactions (immune reconstitution syndrome). He called for carefully designed pilot studies with an operational research component. Support for the impact of antiretroviral therapy on TB rates came from a timely article appearing in the Lancet after the World TB Congress, showing that among HIV+ patients in South Africa, HAART reduced the incidence of TB by over 80%. The effect of HAART on TB was most pronounced in people with a CD4 count below 200.

Christopher Dye from WHO presented compelling data that called into question the long-term success of current strategies utilizing vertical approaches based on DOTS. While DOTS implementation has proven successful in some areas at increasing cure rates to the 85% target, the goal of 70% case detection has proven more elusive.

According to Dye's models, even with expanding DOTS to provide full coverage across the world, case detection rates will level off at about 40% of all active TB cases. Many of the "missing" cases are presumably people seeking care outside of public health systems. Cure rates are much lower in the private health care sector, which may help account for the rise in MDR-TB in some places. Dye stated that it would be necessary to broaden case-finding to the private sector, possibly by providing incentives to private providers, or to try other means of broadening the cadre of physicians who understand the DOTS approach.

The managerial discourse dominating discussions of TB control underlies the aversion towards health sector reform approaches, which raise the specter for National TB Control Programs (NTPs) of loss of budget control, disruption of lines of communication and supervision, and net loss of TB expertise and specialized experience.

The management paradigm may also explain the almost total absence of discussion during the conference of strategies for community involvement and mobilization. Ample evidence from the field and the literature indicates that people with TB take an active role in managing their health. NTPs rely on passive case finding -- typically patients presenting for care with a persistent cough -- but many people with TB are clearly making choices about their health care that don't necessarily lead them to NTPs. While more research is needed on the health management strategies of people with TB, it would be a mistake to frame this phenomenon solely as a "management problem" for NTPs, rather than an opportunity to develop methods to engage communities in actively participating in TB control.