Anti-HIV treatment reduces TB incidence in Spain

Antiretroviral therapy and tuberculosis (TB) control measures have helped reduce the incidence of tuberculosis in Spain in recent years, according to data from GEMES, the Spanish Multicenter Study Group of HIV Seroconverters published in the November 30^th 2007 edition of AIDS.

HIV increases the risk of TB disease through reactivation of latent infection as the immue system declines or by accelerating the progression of recently acquired infection. Therefore the availability of effective antiretroviral therapy since the mid-1990s is likely to have had an impact on the epidemiology of TB in HIV-infected individuals.

Although this are good data about the incidence of TB in resource-limited countries, there is less information about the incidence of the infection in industrialised countries.

Spain has a high incidence of HIV compared to other countries in Western Europe and intravenous drug use (IDU) has been a major route of HIV transmission. Before the HIV epidemic, Spain had the second highest TB rate of Western Europe in the general population. IDUs, irrespective of their HIV status, are also exposed to high levels of TB infection. As a result of this, Spain has seen a large overlap of both the HIV and TB epidemics leading to high rates of HIV–TB co-infection.

Using data from GEMES, an established Spanish nation-wide cohort of HIV-infected individuals with well known dates of seroconversion from the 1980s to the present day, researchers analysed the incidence and determinants of tuberculosis in HIV-seroconverters before and after the introduction of effective antiretroviral therapy. Furthermore, all HIV-infected persons with clotting disorders (PCD) from three of the largest haemophilia units in Spain were analysed.

Information on sociodemographic characteristics (age, sex) as well as clinical and immunological data (number and type of AIDS events, antiretroviral treatments prescribed, lymphocyte CD4 cell count, HIV viral load, vital status and cause of death) were collected. All transmission categories were included: IDU, men who have sex with men (MSM), heterosexuals and PCD/people with haemophilia.

Calendar year at risk was divided into three periods (before 1992, between 1992–1996 and 1997–2004) reflecting the availability of different antiretroviral therapies before the introduction potent anti-HIV therapy in Spain in 1996. Between 1992 and 1996 only AZT, ddC, 3TC, d4T and ddI were available for the treatment of HIV and AIDS. Incident tuberculosis was calculated as cases per 1000 person-years. In this study TB diagnoses were culture proven in 85% of cases.

The proportional hazard model was used to determine the factors associated with the risk of developing TB taking into account the following variables: gender, exposure category, age at seroconversion, and calendar period.

Data from 2238 HIV-seroconverters (1874 men and 364 women) between the 1980s and 2004 were analysed. Overall, 51.9% were infected with HIV via IDU, 27.4% were PCD and 20.6% were infected by sexual transmission, of which 14.7% were heterosexuals.

By December 2004, 173 (7.7%) patients had developed TB (55.5% pulmonary, 35% extra-pulmonary and 10% in both locations) giving an overall rate of 7.3 cases per 1000 person-years (95% confidence interval [CI], 6.3–8.5). TB was the first AIDS-defining condition in 147 patients (85%), second in 19 cases (11%) and third in six cases (3.5%). Median time from HIV seroconversion to TB disease was 5.6 years.

The median CD4 cell count at TB diagnosis was 80 cells/mm³, indicating a profound state of immune suppression. After the introduction of effective antiretroviral therapy, the median was 182 cells/mm³. The majority (106; 61.2%) of the patients that developed TB had not received any antiretroviral treatment and 135 out of 173 (78%) were IDUs.

Incident tuberculosis was higher in IDUs, 12.3 per 1000 person-years compared with persons infected sexually, 3.8 per 1000 person-years (P < 0.001), and persons with clotting disorders (PCD), 2.7 per 1000 person-years (P < 0.001).

Highest tuberculosis rate, 44 per 1000 person-years, were observed prior to 1997 in IDUs infected with HIV for eleven years.

A decreasing tuberculosis incidence trend was observed from 1995 in all categories. TB rates in the era of effective anti-HIV therapy (5.6 per 1000 person-years) were significantly lower than before 1997 (8.9 per 1000 person-years). TB rates before and after the introduction of potent antiretroviral therapy were 18.09 and 8.68 cases per 1000 person-yers for IDUs, 8.18 and 2.22 cases per 1000 person-years for sexually transmitted HIV and 3.43 and 0 cases per 1000 person-years for PCD, respectively. The reductions in the hazard of TB for each of the transmission categories were 48%, 27% and 100%, respectively. For PCD, no new TB cases were observed after 1997.

The study showed a 69% reduction in the incidence of TB among HIV-seroconverters from all transmission categories from 1997 onwards, (RH, 0.31; 95% CI, 0.17–0.54; P < 0.001). Before 1997, the risk of tuberculosis increased with time since HIV seroconversion, whereas it remained nearly constant in the era of potent anti-HIV therapy. After 1997, TB did not increase with longer duration of HIV infection but peaked around the fifth to seventh year in the IDU and sexually transmitted HIV groups, and decreased thereafter.

Among the 65 TB cases observed since the introduction of effective anti-HIV therapy, 52 (80%) were IDU and 41of the 65 (63%) were not taking antiretroviral therapy. The remaining 24 patients developed TB despite having started anti-HIV therapy.

Women had a 38% lower risk of TB compared to men. IDUs showed a three times higher risk of developing TB and PCD had a 60% lower risk in comparison with people infected through sexual transmission.

The authors conclude, “Our results suggest that in the period between 1997 and 2004, improvements in the immune status among those receiving HAART and/or a reduction in the environmental risk of TB transmission must have taken place. Forty percent of patients from GEMES cohorts had been initiated on HAART, so it is likely that antiretroviral therapy may be responsible for a large proportion of the observed reductions in TB, as it has been for other AIDS-defining conditions.”

As the decreasing trends in TB were observed just before the introduction of effective anti-HIV therapy in Spain they also note that TB control programmes may have also played a part.