© 2005 American Thoracic Society doi: 10.1164/rccm.2504003
The Sound of One Hand ClappingTuberculosis and Antiretroviral Therapy in AfricaCenters for Disease Control and Prevention, Kenya, Nairobi, Kenya Efforts to increase access to antiretroviral therapy (ART) internationally dominate current discourse on the HIV/AIDS pandemic. In this issue of the Journal (pp. 123–127), Seyler and colleagues (1) examine tuberculosis incidence and risk factors in patients receiving ART in Côte d'Ivoire, highlighting persistent uncertainties in managing dually affected patients and stimulating reflection on the tuberculosis challenge in Africa. The authors monitored 129 patients receiving ART for a total of 270 person-years, finding an overall incidence of tuberculosis of 4.8/100 person-years (1). In patients with a prior history of tuberculosis, the incidence was 11.3/100 person-years compared with 3.0/100 person-years in those without prior tuberculosis (adjusted hazard ratio, 4.6) (1). These findings reemphasize that tuberculosis incidence and recurrence rates, even if reduced by ART, remain very high in HIV-infected patients accessing life-prolonging antiretroviral drugs (2). Tuberculosis recurrence after previous diagnosis and treatment results either from endogenous relapse or disease after reinfection with a different mycobacterial strain (3). Recurrence is significantly increased in HIV-infected persons; in South African gold miners, for example, recurrence was almost five times more common in those with HIV (4). Both reinfection and relapse play a part, with reinfection being more likely in HIV-infected than uninfected persons, especially in high transmission areas, as well as in persons in whom recurrence is more distant in time from initial treatment (5, 6). Nine percent of all tuberculosis cases in Malawi in 2000–2001 represented recurrences (3). Approaches to reducing tuberculosis recurrence in HIV-infected persons that were suggested in the pre-ART era included extending the continuation phase of the standard antituberculous treatment regimen (7) or providing secondary chemoprophylaxis after curative therapy (8, 9). Secondary prophylaxis with isoniazid in Haiti (8) and South Africa (9) reduced recurrence by 82 and 55%, respectively. Although the efficacy of secondary prophylaxis was not affected by the degree of immunosuppression, the potential number of cases averted is greatest in persons with advanced immunodeficiency, in whom the rates of recurrence are highest. Whereas extensive experience exists with primary chemoprophylaxis for tuberculosis in HIV-infected persons (10), there is only limited experience with secondary preventive therapy (8, 9), and little or none with preventive therapy in the context of ART. Seyler and colleagues (1) propose time-limited secondary prophylaxis in patients receiving ART until some threshold in CD4+ cell count is reached. It is possible, however, that the risk of recurrence will remain elevated despite ART-induced immune reconstitution and that protection may wane after chemoprophylaxis is discontinued. Assessing the efficacy and optimal duration of primary and secondary preventive therapy for tuberculosis in HIV-infected persons receiving ART remains an important research priority. Despite their importance, these specialized questions should not overshadow broader considerations of the current African tuberculosis disaster. In 2003, Africa's tuberculosis trends caused a 1% increase in global incidence despite stable or declining incidence elsewhere (11). In high HIV prevalence countries, where as many as 80% of patients with tuberculosis may be HIV infected, annual case notifications increased by up to 15% during the 1990s (11). With individual exceptions, African tuberculosis control programs yield low cure and high default rates (11). Despite increased international financing, there remain funding gaps, staff shortages, and lack of coordination in responding to the coepidemics of HIV/AIDS and tuberculosis (12). Aspirations that ART scale-up would substantially reduce tuberculosis incidence may be unrealistic because current guidelines initiate ART late in HIV disease, when much of the HIV-associated tuberculosis burden has already been experienced. ART could theoretically even aggravate long-term trends by keeping alive more persons with severe immunosuppression who are highly vulnerable to primary and recurrent tuberculosis. What is clear is that ART alone will not solve Africa's tuberculosis epidemic. A number of steps should be taken immediately in the context of ART rollout to improve care for African patients with or at risk for tuberculosis. First, universal HIV testing of patients with tuberculosis (and ideally of those with suspected tuberculosis) needs to be implemented (13). Second, all persons identified with HIV should have active tuberculosis excluded, and those eligible should ideally be offered preventive therapy. Third, HIV-infected patients with tuberculosis should be offered cotrimoxazole prophylaxis and linkage to long-term HIV/AIDS care (14). Finally, systems need to be built for HIV-infected patients with tuberculosis to access ART and long-term follow-up. Sustainability of safe ART and care will require that ART, like tuberculosis therapy itself, be considered a public good, provided free of charge to all who require it through national and international financing. A policy change required in Africa is the adoption of complete rifampin-based therapy for active tuberculosis. Evaluation of the widely used 8-month regimen providing ethambutol and isoniazid in the continuation phase showed that, compared with the standard 6-month rifampin-based regimen, treatment failure and relapse were significantly more frequent (15). Despite the challenges posed by rifampin-based therapy, including interactions with antiretroviral drugs, it is inconsistent to strive for ART access and other interventions to reduce tuberculosis recurrence yet persist with an inferior tuberculosis regimen. The tuberculosis establishment is potentially vulnerable in this regard to criticism from advocacy groups, demonstrated by analogous experience in malaria (16). The article by Seyler and coworkers (1) stimulates thought on short-term research and programmatic priorities. Of greater concern are the "big questions"—what is the future concerning Africa's tuberculosis epidemic and how should we best tackle it? Because tuberculosis incidence in Africa is driven by HIV, better performing tuberculosis programs alone, measured by increased case detection and tuberculosis cure rates, will not control tuberculosis (11), but neither will ART programs that ignore the HIV-uninfected sources of tuberculosis transmission. To avoid the analogy of one-handed clapping, programs should deliver combined and coordinated diagnostic, preventive, and therapeutic interventions for HIV/AIDS and tuberculosis, with ambitious assessment of the fiscal and especially human resources required. No matter how well implemented, AIDS treatment initiatives in Africa that do not fully embrace tuberculosis control miss a large part of HIV's medical impact and therefore limit their own success. FOOTNOTES Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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