ART reduces TB incidence, but some risk persists

While antiretroviral therapy (ART) substantially reduces the incidence of tuberculosis (TB) and restores immunity to TB mycobacteria (mTB), a recent review of epidemiological, clinical and laboratory data in the July 22^nd issue of AIDS suggests that the immune restoration from ART is incomplete and that most people with HIV will continue to have a heightened risk of TB that will persist with long-term treatment. The study’s authors believe these findings could have significant implications for TB control programmes.

Background

Existing TB control strategy is based upon directly observed treatment of infectious TB, which is detected by sputum smear microscopy (see news story). But while this approach has contained the spread of TB in most of the world, it has failed to control the rise in TB cases in countries where HIV infection is common. This is primarily because HIV makes TB detection more difficult, and because people with HIV who are exposed to TB are far more likely to develop active disease and relatively soon after exposure (see news story).

So in an attempt to improve TB control wherever HIV-coinfection is common, the World Health Organization (WHO) has developed a strategic framework with the goal of integrating TB and HIV/AIDS control programmes. One of the elements of this framework is the hope that the widespread use of ART will prove an effective tool in TB control at the community level.

However, the authors of this study contend that this has yet to be demonstrated and that “the extent to which [ART] will have an effect on TB control will be determined, in part, by the rate and extent to which functional immune responses to mTB are restored.”

The effect of ART on TB-specific immune responses

Unlike other AIDS-related opportunistic infections, TB often occurs before CD4 cell counts fall below 200 copies/mm³, and there is a continued risk of TB when CD4 cells rebound in ART-treated patients. The AIDS study summarises the available epidemiological, clinical and laboratory data that describe ART effect on a person’s immune response to MTB:

• ART reduces the incidence of TB by 70 to 90% in treated patients, whether living in settings with high or low TB incidence
• ART restores skin test (hypersensitivity responses) to TB (these are often lost in untreated patients with advanced HIV)
• ART increases the proportion of patients who have typical x-ray features of pulmonary TB (X-rays are frequently ‘atypical’ in patients with advanced HIV)
• Immune reconstitution disease (or immune reconstitution inflammatory syndrome, or IRIS) that is associated with TB reflects a rapid though somewhat out-of-control restoration of TB-specific immunity in the first three months of ART
• ART restores both the quantity and function of antigen-specific T-cells. But, even among the small proportion of patients whose CD4 cell counts become normal, there are persistent phenotypic and functional defects
• The lower the CD4 cell count is when ART is started, the more limited the extent of immune restoration that is possible
• The incidence of TB during ART remains higher than that among HIV non-infected individuals.

Study discussion

Despite the partially restored immune responses to TB in ART-treated patients, the authors conclude that ART “is unlikely to play a prominent role as a TB control measure.” Their reasoning is that while ART may reduce frequency of TB in ART-treated patients, it also greatly increases their longevity which “means that patients will have a chronically heightened TB risk over a greatly increased life-span.”

However, their analysis does not really address the other aspects of why TB and HIV/AIDS control programmes should be more closely integrated. While ART may not completely eliminate TB, bi-directional referral between TB and HIV programmes should lead to more rapid case detection and treatment for both diseases. Furthermore, ART treatment may lead to increased diagnosis of active TB in patients — which (with the exception of TB-associated IRIS) should follow a more ‘typical’ (and thus more easily diagnosed) course than in patients with more advanced disease.

The authors are not arguing against the integration of TB and HIV/AIDS control programmes — they are simply calling for a greater emphasis on “strategies to optimise restoration of TB-specific immune function during ART.” In particular, the “identification and treatment of patients before they develop advanced immu-nodeficiency may be critical in this respect.”