Risk of TB doubles in first year of HIV infection

The risk of developing tuberculosis doubles within the first year of testing HIV positive, according to a large retrospective study published in the January 15^th issue of The Journal of Infectious Diseases. This risk further increased in subsequent years.

Although HIV increases the risk of TB it has long been assumed that this was primarily due to falling CD4 cell counts seen with advancing HIV disease progression. The early effect seen in the study, conducted by researchers from the London School of Hygiene and Tropical Medicine, was largely unexpected.

The retrospective study analysed data drawn from the medical records of 23,874 workers from four South African gold mines. The mines provided the perfect opportunity to assess how HIV affects the risk of tuberculosis over time. The mines have a stable population, provide regular medical care and keep good medical records. There is a well-established TB control programme and a confidential database of all HIV test results of the mine workers has been kept since 1989. HIV test results could therefore be linked to routinely collected TB and demographic data.

At the beginning of the study, 3371 miners were HIV-positive (these are referred to as having “prevalent HIV”) and 20,503 were HIV-negative. Over the course of several years, many of the workers had subsequent HIV tests. Of these, 2737 received positive HIV results (these cases are referred to as having “incident TB”) — 1962 (72%) within two years or less of a previous HIV negative result.

A total of 740 cases of pulmonary TB (first episode) were analysed during a seven-year period. TB was found to be at least three times more common in those who were HIV-positive. The incidence of pulmonary TB was 2.9 cases per 100 patient years at risk (pyar) in the HIV positive workers [95% confidence interval {CI}, 2.5–3.4] and 0.8 cases/100 pyar in the HIV negative workers.

Investigators then assessed the relative risk (RR) of developing TB by age and calendar period (1991-92, 93-94, and 95-9) and according to when workers tested HIV positive. Age and calendar were significantly associated with an increased risk of TB (Ps ≤ .0001). Interestingly, the incidence of TB per pyar doubled during the last time period, with an adjusted case rate ratio of 2.21 (95% CI1.65–2.95). This could reflect the impact that the HIV pandemic was having on the overall incidence of TB in the southern African region.

The relative risk (RR) of developing TB was greater in those who were HIV-positive when the study began, which is to be expected as they had been infected longer and their immune systems would be less able to fight off TB. But what was not expected, as mentioned earlier, was the increase in incidence of pulmonary TB so soon (within a year) after seroconversion, with an adjusted case rate ratio of 2.11 (1.45–3.09).

An editorial accompanying the article in JID suggested that there could have been a small bias in detecting TB in patients with HIV because “HIV-positive miners may present to medical facilities more frequently because of the development of HIV-related clinical symptoms of illness, thus potentially biasing toward greater evaluation for, and detection of, TB among HIV-positive miners.” However, the study authors state that “We do not believe that TB is more likely to be diagnosed in HIV-positive than in HIV-negative miners;” because TB is so very common in this setting that all workers are closely monitored for TB.

Minor differences aside, the editorial writers believe the study provides sufficient data to demonstrate the doubling of the incidence of TB within the first year of HIV seroconversion.

The editorial suggests two possible explanations for the increased TB risk 1) the profound immune dysregulation that occurs soon after [HIV] infection or 2) that those patients who develop tuberculosis within the first year of HIV infection have a rapidly progressing form of HIV disease.

High levels of HIV seen during acute seroconversion or the immune response to HIV could also activate latent TB infections in some patients. If TB is activated in this setting, any CD4 cell response to could be quickly wiped out by HIV leaving the patient defenceless.

Investigators evaluated whether the increased risk of TB early during the course of HIV infection is due to reactivation or to a newly acquired M. tuberculosis infection by performing molecular fingerprinting on available isolates. Unique isolates are more likely to have been due to reactivated TB acquired before working in the mines, while the isolates of TB acquired in the mines would be the same.

Among HIV seroconverters, unique TB isolates were present in 57% (8/14) of miners who developed TB within 2 years of HIV seroconversion, compared with 20% (3/15) who developed TB later. The finding is intriguing though numbers are too small to draw any firm conclusions. However, it suggests that patients with latent TB are more likely to develop pulmonary TB within the first year of seroconversion.

The study’s findings have a number of major implications for TB and HIV control programmes. The editorial points out that while current models for TB control do factor an increase in TB incidence where there is a high adult HIV prevalence, they do not account for the increased risk of TB early during the course of HIV infection. “Reframing these models in the context of these new data is likely to affect the calculated burden of TB—and not just for HIV-positive persons, but for the general community as well.”

It is also important to note that TB that occurs later in HIV disease is usually not centred in the lungs but is extrapulmonary. This study showed a doubling in pulmonary TB — which is far more infectious.

Another issue that the study brings up is whether treatment of latent M. tuberculosis infection may be the most feasible way to reduce the risk of TB. Isoniazid prophylaxis is not routinely administered in all developing world settings, partly because of the high risk of re-infection with TB and partly because of the difficulty in excluding active TB infection.

Finally both teams agree that there is an immediate need to expand reliable and affordable HIV testing services in areas where TB is endemic and, conversely, to improve surveillance for TB among patients testing positive for HIV.