Incidence, risk factors and mortality of tuberculosis in Danish HIV patients 1995-2007

The prognosis for Human Immunodeficiency Virus (HIV) infected patients has changed dramatically after the introduction of Highly Active Antiretroviral Therapy (HAART) [1]. In spite of the effect of HAART, tuberculosis (TB) is still one of the most frequently acquired immune-deficiency syndrome (AIDS) defining conditions worldwide [2]. Though effective, prevention of TB in HIV positive by tuberculin skin testing and targeted preventive treatments is of limited clinical success [3, 4]. In contrast, implementation of HAART has been the best preventive measure and incidence rates of TB co-infection have from Western World settings been reported to decrease from the pre- to late-HAART period. A European study reported incidence rates before September 1995 of 0.8/100 person-years of follow-up (PYR) decreasing to 0.3/100 PYR after March 1997 [5]. The identification of risk factors for development of TB is crucial for the design of strategies to control the TB epidemic in the HIV-infected population. Previously conducted studies in developed countries all present significant associations between both immigration from high-endemic TB regions and low CD4 cell counts and increased risk of developing active TB [2, 6‐8].

To our knowledge, no nationwide population-based studies have been conducted on the incidence, risk factors and prognosis of HIV-associated TB during the HAART era. The objective of the present study was to determine the incidence of TB in the Danish HIV-infected population during the pre-HAART (1995-1996), early HAART (1997-1999), and late HAART (2000-2007) periods and risk factors for developing TB. We further aimed to describe mortality after TB diagnosis.

From the Danish HIV Cohort Study we identified 2,668 patients diagnosed with HIV in the period 1995-2007 contributing with 14,711 person-years of follow up. The characteristics of the study population are shown in table 1. Due to HIV diagnosis prior to arrival in Denmark, 233 patients were excluded from the study of whom 6 developed TB after immigration to Denmark. In the study period, 120 patients met the criteria for a diagnosis of TB. Overall the incidence in the period 1995-2007 was estimated to 8.2/1,000 person-years of follow-up (PYR). Incidence rates decreased considerably from the pre- to the early- and late-HAART periods (table 2). The incidence of TB was highest in the first year after HIV diagnosis and stabilized in the following years (table 2).

The characteristics of patients diagnosed with TB are shown in table 3. There were 120 patients (4.5%) diagnosed with TB among the 2,668 study participants, of whom 69 (57.5%) had pulmonary TB, 38 (31.7%) had extrapulmonary TB and 13 (10.8%) had both. At time of the TB diagnosis 69 (67.0%) of the patients had a CD4 cell count less than 200 cells/μL. Only 28 (23.3%) patients had started HAART prior to their TB diagnosis, while 92 (76.7%) were diagnosed with TB before start of HAART. Among the 92 patients, 29 (31.5%) were diagnosed with TB simultaneous with the HIV diagnosis, 15 (16.3%) were diagnosed with TB after the HIV diagnosis and had a CD4 cell count of more than 200 cells/μL and among the remaining 48 (52.2%) patients the median time from HIV diagnosis to TB diagnosis was 10.5 days (IQR; 6.0 - 30.5). We found no major differences in the characteristics of patients diagnosed with TB in the periods 1995-1996, 1997-1999 and 2000-2007.

In univariate analysis the following factors were associated with an increased risk of TB diagnosis: Male gender (IRR: 2.1; 95% CI: 1.5-3.0; p-value < 0.001), age < 40 years (IRR: 1.5; 95% CI: 1.0-2.3; p-value 0.036), country/region of birth (Africa (IRR: 4.7; 95% CI: 3.1-7.0; p-value < 0.001) and Asia (IRR: 5.9; 95% CI: 3.5-9.8; p-value < 0.001)) route of HIV transmission (heterosexual (IRR: 3.9; 95% CI: 2.3-6.5; p-value < 0.001), IDU (IRR: 4.2; 95% CI: 2.1-8.4; p-value < 0.001) and other (IRR: 4.6; 95% CI: 2.3-9.1; p-value < 0.001)) and CD4 cell count ≤ 200 cells/μL at HIV diagnosis (IRR: 3.8; 95% CI: 2.4-6.0; p-value < 0.001). In the multivariate analysis only African (IRR: 4.3; 95% CI: 2.6-7.3; p-value < 0.001) and Asian (IRR: 5.7; 95% CI: 3.2-10.1; p-value < 0.001) origin, route of HIV infection (heterosexual (IRR: 1.9; 95% CI: 1.0-3.5; p-value: 0.048), IDU (IRR: 3.0; 95% CI: 1.5-6.2; p-value: 0.003) and other (IRR: 2.4; 95% CI: 1.2-4.9; p-value: 0.020)) and CD4 cell count ≤ 200 cells/μL at HIV diagnosis (IRR: 1.6; 95% CI: 1.1-2.2; p-value: 0.005) preserved a statistically significant association with increased risk of TB diagnosis. After start of HAART the unadjusted and adjusted IRR for TB respectively were 0.04 (95% CI: 0.03-0.07; p-value < 0.001) and 0.05 (95% CI: 0.03 - 0.08; p-value < 0.001) compared to the time period before initiation of HAART (table 4).

Of the 120 TB patients, 19 died during the study period. Five deaths were recorded as related to TB, eight deaths were recorded as related to HIV and six died of other causes not related to HIV or TB or the cause of death was unknown. 16 of the 19 patients died within the first two years after HIV diagnosis. 9 (47%) of the 19 patients had a CD4 cell count < 200 cells/μl and 7 (37%) had a CD4 cell count < 50 cells/μl at time of death. The mortality was highest in the first two years after TB diagnosis with a two year probability of survival of 85% (95% CI; 78% - 92%), Figure 1. The five year probability of survival was 81% (95% CI; 74% - 89%).

In this nationwide, population-based cohort study, we found that the incidence of TB in HIV-infected individuals peaks during the first year after HIV diagnosis and decreased markedly after the introduction of HAART. African and Asian origin, low CD4 cell count at HIV diagnosis, lack of HAART and heterosexual and IDU route of HIV transmission were risk factors for being diagnosed with TB. To our knowledge this study is the first to present a comprehensive, nationwide analysis of incidence, risk factors of TB and prognosis of TB in HIV infected individuals. Further, the study design allowed long and nearly complete follow-up with the inclusion of only patients diagnosed with HIV in the study period after arrival to Denmark. Of importance our study population was incident concerning HIV and TB diagnosis.

The TB diagnosis was included in our analysis regardless of the patient being classified with presumptive or definite TB. Some patients may therefore have been misclassified leading to overestimation of the incidence. However, due to the complexity of diagnosing TB among HIV-positive individuals, presumptive TB, being clinical symptoms and/or paraclinical findings suggestive of TB, is by the majority considered sufficient for further measures and initiation of TB treatment [5, 13]. Unfortunately our study does not include data on immune restitution inflammatory response (IRIS) which has been reported in up to 7-36% in HAART-naive HIV patients co-infected with TB [14].

Despite our large sample size and relatively long period of observation, only 120 cases of TB were diagnosed, which limits the strength of the multivariate analyses. To obtain an incident cohort of HIV and TB we excluded 233 patients diagnosed with HIV before arrival in Denmark. Of these patients, 6 were found to have TB. With regard to our findings on risk factors for TB, the omission of these patients may have altered our conclusions. The small number of deaths did not allow us to identify risk factors for death among the HIV patients with TB.

We chose to adjust for alcohol abuse using alcohol related discharge diagnoses as registered in the Danish Hospital Database, knowing that this is an incomplete measure giving rise to unmeasured and residual confounding.

We found a high incidence rate of TB among HIV positive patients in Denmark of 8.2/1,000 PYR in the period 1995-2007. The incidence of TB was remarkably high the first year after being diagnosed with HIV - irrespective of the time period studied. Hereafter the incidence rates declined steadily over time. Other studies from regions with low TB incidence have found similar incidence rates; Girardi et al. found an overall incidence of 4.7 cases per 1,000 PYR in Europe and North America in a study conducted in the HAART era [15]. In HIV patients from the United States, Markowitz et al. found an incidence of 7 TB cases per 1,000 PYR [16], a figure similar to that found in the EuroSIDA cohort, which estimated an incidence of 8/1,000 PYR [5].

Interestingly, the incidence of TB declined significantly with time after HIV-diagnosis, independently of the time periods (pre-, early or late- HAART). Within the first year of HIV-diagnosis we found an incidence of 39.9 TB cases per 1,000 PYFU, a number approaching that seen in Ethiopia and South Africa. In South Africa, however, the high incidence persists after 5 years, being 10-fold of that found in our study five years after HIV-diagnosis, probably due to high prevalence of latent TB infection and advanced immune suppression in a population where HAART is not widely implemented or by other co-morbidity [17, 18]. Likewise, in our study the decline in incidence of TB with time after HIV diagnosis is most likely attributed to immunological restitution due to HAART. Initiation of HAART and immunological restitution may "unmask" TB as a part of IRIS which probably also partially explains the high incidence of TB in the first year after HIV diagnosis. Besides this, TB is the most frequent AIDS defining disease and in many African countries more than half of the TB patients are diagnosed with HIV when diagnosed with active TB. This bias may also contribute to the extremely high incidence rate of TB seen in connection with the HIV diagnosis and explain the rapid decline after diagnosis.

Concerning risk of a TB diagnosis, observational studies conducted both in low- and high-income countries have shown that the risk of TB has decreased 50-90% under HAART, yet not approaching that in the general population [2, 18]. Our study supports this finding with a more than 90% decreased risk of TB after initiation of HAART. However, some subgroups still remain at a higher risk of developing TB than others. Findings similar to ours have been established in Brazil where baseline CD4 cell counts of ≤ 200 cells/μL and lack of HAART treatment both were independently associated with increased risk of TB [18]. In a study cohort from the United States, IDU, heterosexual contact, CD4 cell counts ≤ 100 cells/μL and lack of antiretroviral therapy were important risk factors for TB [16]. Not surprisingly patients from high TB burden countries are at greater risk of TB than others due to reactivation of latent TB [8]. This may explain the finding of a higher risk of TB among heterosexually HIV infected as this is the most likely route of HIV transmission for the majority of African and Asian immigrants [19, 20].

The mortality was increased in the first two years after the TB diagnosis, presumably due to a high degree of immunodeficiency among the TB patients. The prognosis was good after the first two years. The five year probability of survival was comparable to that of other studies [17, 18, 21].

We conclude that although the risk of TB has decreased after the introduction of HAART it is still high and substantially higher in the first year after HIV diagnosis and associated with African and Asian origin, low CD4 count and non-homosexual route of HIV infection. The mortality is high in this patient population in the first 2 years after TB diagnosis.