Incidence of TB infection despite HAART and treatment in coinfected patients

In an observational cohort study, Moreno and colleagues looked at the incidence of TB in just over 1800 HIV-positive patients who had received HAART at the Hospital Ramón y Cajal. Madrid. Sixty percent of the cohort had acquired through IV drug us and a quarter had a previous AIDS diagnosis. 339 patients (19%) had a positive TB skin test (TST) and TB had been diagnosed in 243 patients (13%) prior to starting HAART.

Median follow-up was just over 14 months. During the follow-up period 45 cases of TB were observed (1.9 cases per 100 person years follow up, PYFU). Incidence of TB was 4.26 and 1.02 per 100 PYFU amongst patients with a positive-TST compared to negative-TST respectively.

Mean CD4 count were 165 cells/mm3 for patients who developed TB compared to 258 cells/mm3 for those who did not develop TB. Both positive-TST and CD4 count were independently associated with risk of developing TB.

The researchers concluded that recommendations to treat all HIV+ patients with positive TST irrespective of CD4 count or use of HAART was reinforced by the results of this study.

Comment

Tuberculosis is the commonest opportunistic mycobacterial infection in the era of HAART in Western Europe. Latent TB (LTB) is defined as a positive Tuberculin Skin Test (TST) in the absence of signs and symptoms of active tuberculosis. Many of these individuals are at risk of re-activating tuberculosis in later life. However, in order to produce a positive TST a relatively intact immune system is required and patients with very low CD4 counts may not demonstrate a positive TST despite LTB, or for that matter, active tuberculosis.

Patients with HIV are particularly at risk of re-activation of LTB and acquisition of new TB infection with progressive immune suppression.

In areas of low prevalence, as in the study above, the incidence of TB was higher amongst patients with a positive TST re- enforcing the risk of re-activation of LTB rather than exposure to new infections as the primary source of TB in these countries. This study also demonstrates that despite HIV-induced immune suppression, the TST remains a valuable tool for assessing risk of active TB in HIV-positive patients.

There has been adequate demonstration both in low and high-prevalence areas that HAART associated immune restitution will protect against LTB re-activation. However, as shown in this study, the level of CD4 restoration required to protect against this phenomenon may need to be well above 200 cells/mm³ and perhaps closer to 300 cells/mm³. The issue of treating LTB in patients starting HAART remains controversial. This study suggests an increased risk of LTB re-activation despite HAART particularly in patients with low CD4 counts. Moreover, there has recently been data suggesting an ‘unmasking’ effect of HAART, particularly in asymptomatic patients with TB and low CD4 counts (Breen R et al 2005).

As suggested in this study, one option for patients with a positive TST is to treat whilst one waits for the CD4 counts to rise above 250 cells/mm³. Treatment is usually with isoniazid monotherapy, although this is associated with its own risks; peripheral neuropathy and hepatitis (especially in patients with HBV or HCV co-infection). Furthermore, there is now increasing incidence of isoniazid resistance, so this may not be an ideal therapy for many patients.

Moreno S et al, Development of tuberculosis in HIV-infected patients treated with Highly Active Antiretroviral Therapy (HAART). 3rd IAS Conference on HIV Pathogenesis and Treatment, Rio de Janiero, July 2005. Abstract TuPe7.1C15.