Epidemiology and outcome of HIV patients in Finland co-infected with tuberculosis 1998–2015

Background Tuberculosis (TB) is a major cause of death in HIV patients worldwide. Here we describe the epidemiology and outcome of HIV-TB co-infections in a high-income country with low TB incidence and integrated HIV and TB therapy according to European guidelines. Methods This study was based on the HIV cohort of the Helsinki University Hospital which includes all HIV patients in the Helsinki region with a population of 1.5 million. Totally, 1939 HIV-positives who have been under follow-up between 1998 and 2015 were included. Results TB was diagnosed in 53 (2.7%) of the HIV-patients. The TB incidence rate was higher in injecting drug users (IRR 3.15; 95% CI 1.33–7.52) and heterosexuals (IRR 3.46; 95% CI 1.64–7.29) compared to men having sex with men. The incidence rate was also higher in those born in Sub-Saharan Africa (IRR 3.53; 95% CI 1.78–7.03) compared to those born in Finland. There was a significant reduction in the total TB incidence rate of 59% per 6-year period between 1998 and 2015 (p < 0.001). In injecting drug users there was a reduction in incidence rate from 1182 to 88 per 100,000 (p < 0.001) and in people born in Sub-Saharan Africa from 2017 to 195 per 100,000 (p < 0.001). Among the 53 HIV-TB co-infected cases, one female and 15 males died during follow up. HIV was the primary cause of death in five patients but none of the deaths were caused by TB. Conclusion The incidence rate of tuberculosis among HIV-positives in Finland has been declining between 1998 and 2015. Among injecting drug users, the reduction is probably explained by harm reduction interventions and care in comprehensive care centers in Helsinki. The increased coverage of antiretroviral therapy is probably another main reason for the decline in TB incidence rates. Despite good treatment results for both HIV and TB, the all-cause mortality among Finnish males with HIV-TB was high, and common causes of death were intoxications and suicides.


Background
Tuberculosis (TB) is the most common opportunistic infection in HIV-positive patients. HIV-TB co-infection was estimated to affect 1.2 million people worldwide in 2015, and to cause 400,000 deaths [1]. HIV-positives are 20-40 times more likely to develop active TB infection compared to HIV-negatives [2]. The most important risk factors for developing active tuberculosis among HIV-positives are low CD4 count, living in high TB-incidence regions and absence of antiretroviral therapy [3][4][5].
High mortality has been reported in HIV-TB patients in Africa, particularly in patients with advanced disease [6]. In Africa, Asia and Eastern Europe the leading cause of death has been TB. Data about the outcome of HIV-TB co-infections in high-income countries has been limited. A multi-centre study showed that among patients from Western Europe and Argentina, 50% of the deaths during the first three months after the TB diagnosis were TB-related [7]. For patients who died at a later stage the cause of death was predominantly non-TB-related or unknown.
A Cochrane review of 12 randomized treatment trials of latent TB infection in HIV-positives showed a 32% reduction of the incidence of active TB [8]. The reduction was 62% in those with positive tuberculin skin test (TST). Overall, there was no evidence that TB preventive therapy versus placebo reduced all-cause mortality. The need for treatment of latent tuberculosis infection (LTBI) in high-income countries has remained controversial. The WHO [9] and US [10] guidelines recommend testing of all HIV-positives for LTBI and treatment of all patients with positive result in interferon gamma release assays (IGRA) or tuberculin skin test. EACS [11] and BHIVA guidelines [12] recommend IGRA-testing and medication only after risk assessment based on CD4 count, country of origin and length of previous antiretroviral therapy. Despite recommendations for treatment of LTBI, the implementation of this strategy has been limited in high-income countries [4].
The aim of this study was to describe in detail the incidence of TB among HIV-positives and the outcomes of HIV-TB co-infections in a high-income country with low tuberculosis prevalence.

Study participants
This is a retrospective register study based on the cohort of HIV-patients registered for follow up at the Infectious Disease Clinic of the Helsinki University Hospital. This is the only HIV clinic in the Helsinki region in Southern Finland with a population of 1.5 million people, where 63% of all HIV patients in Finland have been diagnosed. The treatment of HIV and tuberculosis is integrated and free of charge for patients living in Finland.
All 1939 patients in the Helsinki HIV Cohort between 1st January 1998 and 31st December 2015 were included in this study. Classified as HIV-TB co-infections were 53 patients diagnosed with an active TB infection in Finland between 1995 and 2015. We excluded four patients, whose tuberculosis diagnosis were made abroad before migrating to Finland.

Data sources
The

Genotyping of Mycobacterium tuberculosis isolates
Genotyping was performed with the spoligotyping technique as previously described [13]. The spoligotypes were assigned to international SIT types available in the SITVITWEB database [14] [15]. For spoligotypes for which a SIT code was not available, a local F (Finnish) code was given.

Statistics
For the statistical calculations, the SPSS Statistics software version 20 (IBM Corporation, NY, USA) and Stata 15.1 (StataCorp LLC, TX, USA) were used. Incidence rates and incident rate ratios and their 95% confidence intervals were calculated using Mantel-Haenszel methods. Score test was used to estimate trends of rates of change in incidence between the different 5-year periods. In the survival analyses of HIV-TB cases Log-rank test was used to calculate p-values for categorical variables and Wald test (Cox model) for continuous variables. Hazard ratios and their 95% confidence intervals were calculated using Cox model. Kaplan-Meier plots were used to show estimations of the probability of survival in different subgroups of patients with HIV-TB co-infection.

Epidemiology
In the patients of the Helsinki HIV cohort there were 53 active TB infections diagnosed in Finland between 1995 and 2015 (Fig. 1). The annual number of new HIV-TB co-infections have mainly been between 1 and 5 in the Hospital District of Helsinki and Uusimaa (HUS) with a population of 1.5 million inhabitants. The annual number of new HIV-infections in the same district has remained stable at a level of about 100 (Fig. 1). The new TB cases have slowly been decreasing from 150 to 100 annually (Fig. 1).

Baseline data
Between 1998 and 2015 there were 1939 HIV-positives on regular follow up in our cohort (Table 1). Among the HIV-TB cases, the place of birth was Finland in 25 cases and Sub-Saharan Africa in 12 cases. The countries of birth seen in those classified as others were Thailand in 9 cases, Estonia in two cases, Germany in one case, Lithuania in one case and Egypt in one case. The mean CD4 counts at the time of TB diagnosis for the different subgroups presented in Table 1

Incidence rates
The incidence rates of TB in different subgroups of HIV-positives are shown in Table 1. The incidence rates in the range of 100-700 cases per 100,000 population are very high compared to the current general TB  incidence rate of 5 cases per 100,000 in Finland. The TB incidence rate was higher in injecting drug users (IDU) and heterosexuals compared to men having sex with men (MSM). The incidence was lower in those born in Finland compared to migrants from Sub-Saharan Africa and other countries.
To analyze for temporal changes the TB incidence rates were analyzed in 5-year periods ( Table 2). This showed a statistically significant reduction in incidences with a 59% decrease per 5-year period, as the incidence rate dropped from 691 to 130 per 100,000. The incidence rate declined significantly in all subgroups, except for in females and in those with country of origin other than Finland or Sub-Saharan Africa. In IDUs, almost all of whom were men from Finland, there was a remarkable reduction in in the incidence rate from 1182 to 88 per 100,000 (p = 0.0009, score test for trend of rates).

Genotyping of M. Tuberculosis isolates
M. tuberculosis isolates were available for 38 of the 53 active TB cases, and were successfully genotyped ( Table 3). The most common spoligotypes were SIT53 and SIT42, with 7 and 5 cases each. Both of those included small clusters among IDUs born in Finland with active TB infection between years 2000-2003. Based on genotypes, most of the other TB infections were sporadic cases of activation of latent TB infection obtained in the country of origin. There were no signs that M. tuberculosis strains from Russia or Estonia would have caused transmission chains among HIV-positives in Finland.

Outcomes
The 53 HIV-TB co-infected patients were classified (Table 4) according to WHO's definition of tuberculosis treatment outcomes [1]. Three of the patients died during the TB treatment and 13 after the treatment. Classified as treatment completed or cured were 66.0% of the cases. In 22.6% of the cases data of outcome was not available due to transfer out or other reasons. The average length of TB treatment was 11.7 months.

Mortality and causes of death
In the Helsinki HIV cohort, 16 (30.2%) TB co-infected patients died during an average follow-up time of 8.8 years (Table 5). One female and 15 males died during follow-up and this difference was statistically significant (p 0.031, Log-rank test). There was a non-significant trend towards higher risk of death for cases born in Finland and in those who were diagnosed with TB more than 6 months after the moment of the HIV diagnosis.
Five of the HIV patients had both M. tuberculosis and nontuberculous mycobacterium (NTM) infection at the same time. Three of those were M. avium, one M. abscessus, and one M. malmoense. Two of the patients had M. avium cultured from the blood. M. malmoense was detected from sputum culture. M. abscessus was detected by culture from a lymph node biopsy sample. One of the patients with M. avium in sputum culture samples died during follow-up, the other four with NTM were alive at the end of follow-up.
To explore the reasons for death of the 16 HIV-TB co-infected patients, we analysed the ICD-10 diagnoses of the underlying cause of death from Statistics Finland. None of the deaths were directly related to the previous TB infection. Five patients had HIV as primary cause of death, with the direct cause of death being M. avium infection, pulmonary hypertension, pneumonia, and non-Hodgkin lymphoma for two patients. Seven patients had deaths caused by intoxication or suicide. One died of coronary disease, one of alcoholic liver cirrhosis, one of sub-arachnoid bleeding, and in one case the cause of death remained unknown. Thirteen of the 22 Finnish males with HIV-TB co-infection died during follow-up (59%). Six of these deaths were intoxications or suicides (46%).
The causes of deaths were also classified using the algorithms developed by the Coding of Death in HIV (CoDe) Project related to the EuroSIDA study [16]. Based on these algorithms, 4-6 of the 16 deaths were classified as AIDS-related, as compared to the 5 deaths with HIV as primary cause of death according to the ICD-10 diagnose in the death certificate.

Discussion
During the last 20 years, the HIV incidence in Finland has been slightly increasing, mainly because of immigration from Africa and Asia. The tuberculosis incidence has been gradually decreasing, as the number of elderly people with exposure in childhood has declined.
The decline in the incidence of tuberculosis among HIV-infected shown in this study was expected. A comprehensive care center for marginalized HIV-infected IDUs was started in December 2000 [17]. The outbreak of HIV among IDUs in the Helsinki region was contained in a couple of years after the start of the care center [18]. A symptom-based interview of the clients of the care center was carried out in 2002 after the fourth case of tuberculosis among IDUs was identified. The interview yielded one additional case of tuberculosis.
We do not have a definite explanation for the decline in tuberculosis incidence among people from Sub-Saharan Africa. However, the increase in antiretroviral therapy coverage may have played a central role. The coverage of antiretroviral therapy among people from Sub-Saharan Africa in our clinical database has been rising continuously, in 1998 63%, in 2005 65%, in 2010 74%, and in 2015 93% (unpublished data).  The rate of successful treatment of TB was 66% in our Finnish cohort. This can be compared to WHO's global numbers of treatment success rate of 88% for HIV-negative and 74% for HIV-positive TB-patients [1]. In Europe, the success rate for all TB treatments has increased from 67 to 75% between 1995 and 2012. For new HIV-positive TB-cases registered in Europe in 2013 the TB treatment success rate was 47% in a cohort of 9504 patients. In both the European region and the Region of the Americas, 19% of HIV-positive TB patients died during treatment, compared with just over 5% of HIV-negative TB patients.
A study from Uganda with 302 HIV-TB co-infected enrolled 2007-2009 reported an all cause mortality of 20% during an average follow up time of about one year [6]. Among our 11 HIV-TB coinfected patients from Sub-Saharan Africa only one died, despite longer follow up times. This could be explained by early initiation of ART, which was shown to be the strongest factor protecting from death in the study from Uganda.
There was a rather high number of loss to follow-up seen in the HIV-TB patients in this cohort. Probable reasons were that a substantial part of the subjects were migrants living only temporary in Helsinki. Also IDUs might have a more unregular living situation compared to other residents.
The average duration of TB treatment was nearly 1 year. This cannot be explained by drug resistance, as only two cases of MDR TB were diagnosed. Instead, this seems to reflect the fact that most of the TB cases were treated before year 2006, when the first national Finnish guideline for TB treatment was published, which recommended shorter treatments than earlier. Until that there had been a tradition of long treatment durations in Finland.
The small number of deaths in each subgroup has to be considered when interpreting factors affecting mortality. The all-cause mortality of HIV-TB co-infections in our cohort during an average follow up time of 9 years is 30%. However, none of these 16 deaths were directly related to TB. Among the 16 fatalities, 14 were Finnish males. The all-cause mortality of Finnish males with HIV-TB co-infection was 59%. The reason for this high mortality rate is most likely an accumulation of other risk factors of early death, such as heavy alcohol consumption, smoking, injecting drug use and psychiatric illness. To reduce the mortality rate in this group, active follow-up and multidisciplinary social and psychiatric support could be useful. On the other hand, among HIV-positive females and migrants,  The outcomes of the TB treatment of the HIV-TB co-infected patients in our cohort presented according to WHO's definitions TB-infection does not seem to affect their long-term survival.
The benefits of isoniazid preventive therapy (IPT) for latent tuberculosis has remained controversial as most of the randomized trials showing efficacy of this strategy where conducted in Africa before the beginning of highly active antiretroviral therapies [19][20][21]. The recent TEMPRANO study from Ivory Coast showed that 6 months of IPT has a durable protective effect in reducing mortality in HIV-infected, even in people with high CD4 cell counts and who have started ART [22,23]. HIV cohort studies from Switzerland and the UK have shown a significant reduction in incidence of active TB after treatment of latent TB [4,5]. However, the number needed to treat to avoid one case of active TB was 15 and among those with ART as high as 35 [4]. During the time period of our study, IPT was not routinely used to prevent TB in our center.

Conclusions
To reduce the negative health effects of HIV-TB co-infections in Finland and similar high-income countries, the most important means are early diagnosis and treatment of both HIV and tuberculosis. It is important to identify those HIV-patients with high TB-risk to be able to detect active TB infections as early as possible based on symptoms, chest x-ray, sputum samples and biopsy of enlarged lymph nodes. The treatment results of TB and the long-term prognosis are generally good. However, for non-migrant males with HIV-TB co-infection, the all-cause mortality is unacceptably high and special efforts are needed to address this problem. Funding This work was supported by grants from Tampereen tuberkuloosisäätiö, Finska läkaresällskapet and Stifltelsen Perkléns minne. The funding bodies did not have any role in the design of the study or collection, analysis, or interpretation of data or in writing the manuscript.