Duration of infection with HIV increases the risk of injecting drug users developing active TB, independent of CD4 cell count, according to a study conducted in several European cities and published in the May 23rd 2003 edition of AIDS. However, the study also found that the risk of developing TB was greater for patients with severe immune damage and was also greater for HIV-positive drug users in southern Europe than northern Europe.
TB is the commonest AIDS-defining illness worldwide and unlike other AIDS-defining illness can occur in patients with relatively intact immune systems. How the risk of developing active TB varies with the duration of HIV infection is not known. Accordingly, investigators from six European countries collaborated on a study to see if the duration of HIV infection was associated with the risk of developing active TB in a cohort of HIV-positive injecting drug users, for whom the date of initial HIV infection was known.
The study population included 683 patients from seven European cohorts in six countries. The cohorts were started between 1982 and 1988 in Valencia, Edinburgh, Amsterdam, Geneva, Innsbruck and two French cities including Paris. All the patients had a confirmed HIV-negative and HIV-positive test result, giving a date of HIV infection. The patients were followed up at routine clinic visits for TB, with Amsterdam and Valencia contributing additional data from these cities enhanced TB control measures.
Investigators constructed a regression model to calculate the incidence of TB and the risk factors for developing the disease. Variables examined included study site, calendar period, sex, age at HIV seroconversion, CD4 cell count, and duration of HIV infection.
Patients had an average age of 25 at seroconversion, and two thirds of the sample were male. A total of 3350 patients years of follow-up were contributed to the study and 40 cases of TB were diagnosed. The majority of these, 25 cases (62%) were pulmonary TB. Average CD4 cell count at the time of TB diagnosis was 220 cells/mm3 (range 62 - 458), with CD4 cell counts higher in patients with pulmonary TB compared to patients with extrapulmonary TB (295 cells/mm3 versus 183 cells/mm3).
The incidence of TB varied between sites from 0 to 23.5 cases per 1000 patient years, with Valencia and Amsterdam having the highest rates.
In univariate analysis geographic location, a CD4 cell count below 100 cells/mm3, and the calendar period of 1996-97 were significantly associated with the risk of developing TB. Duration of HIV infection was not.
However, when the results were subjected to multivariate analysis calendar year ceased to be significant, but duration of HIV infection was revealed as a risk factor. Compared to the first three years of having HIV the risk ratio (RR) of developing TB was 2.8 (95% CI, 1.3-6.3) for years 4-6 of HIV infection, falling to 1.2 (95% CI, 0.3-4.2) in years 7-9, but increasing to 4.6 (95% CI, 1.4-15.0) in patients with HIV infection for nine of more years.
In further analysis, which excluded CD4 cell count but included site and duration of HIV infection, the RR for patients with HIV infection for over nine years increased from 4.8 to 6.7 (95% CI, 2.1-20.7).
The association with site and duration remained statistically significant for pulmonary TB, but not for extrapulmonary TB, however very few cases were available for inclusion in the analysis, and the investigators commented that their statistical analysis was "under-powered."
The investigators comment, "among IDU, we found that besides geographic location and CD4 T cell count, the risk of tuberculosis depends on the duration of HIV infection", particularly in years 4-6 of infection and even more so after nine years of HIV infection. They do not exclude the possibility, however, that TB risk increases "with any duration of HIV infection beyond four years", noting the wide value of the confidence interval for the 7-9 year period.
As both TB and HIV target the immune system, the two conditions could interact to cause disease progression, meaning that a patient's risk of developing TB may not be solely related to CD4 cell count.
The higher rates of TB detected amongst HIV-positive injecting drug users in Spain was expected by the investigators, given the high prevalence of TB in the general Spanish population. The results for Amsterdam however were surprising, and may be explained by Amsterdam having a good TB detection programme, but no policy of offering TB prophylaxis.
No "HAART effect" was found in the study; indeed in univariate analysis 1996-97, the first years HAART was available, represent peak years for TB cases. The investigators believe that this may be because many patients in the study had had HIV infection for a long time by this point and were therefore at increased risk of developing active TB. The investigators also assume that injecting drug users may have delayed starting HAART and were likely to have been less adherent to therapy.
The study concludes that duration of HIV infection, a CD4 cell count below 100 cells/mm3 and geographic region are the risk factors for HIV-positive drug users developing active TB.
Further information on this website
Tuberculosis - overview
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van Asten L et al. Tuberculosis risk varies with the duration of HIV infection: a prospective study of European drug users with known date of HIV seroconversion AIDS, 17, 1201-1208, 2003.