Tuberculosis (TB) and HIV comorbidity remains a serious challenge to public health worldwide including in the European region [1,2]. On one hand, HIV is a strong risk factor for TB increasing the risk of progression to active TB and reactivation of latent TB . On the other hand, TB adversely affects the natural course of HIV infection in coinfected patients by increasing both viral replication and viral heterogeneity . Furthermore, the HIV epidemic may have contributed to the emergence of drug-resistant strains of TB . A meta-analysis showed that HIV-positive cases have higher risk of having multidrug-resistant (MDR) TB by 24% . The introduction of combination antiretroviral therapy (ART) was associated with a significant reduction in rates of AIDS and associated death in developed countries . However, limitations of ART in reducing TB risk have been observed, and TB rates in HIV-positive patients remain substantial even among those who initiated ART . In the European Union and European Economic Area (EU/EEA), limited data are available on the risk factors for TB/HIV coinfection. A systematic review carried out by Pimpin et al.  showed that coinfection was associated with male sex, adults, foreign-born person, the homeless, injecting drug users and prisoners. However this review indicated that only seven studies (from three countries: Spain, France and the Netherlands) of 61 studies included in the review provided risk factor information on TB/HIV coinfection, furthermore marginalized population was under-represented in the data .
In 1991, the 44th World Health Assembly set the international target for TB treatment success at more than 85% . In principle the treatment of TB in HIV coinfected patients should not be different from HIV-negative TB patients [11,12]. Early clinical response to therapy and the time to sputum culture conversion from positive to negative appear to be similar for those with HIV infection and those without HIV infection . However, the impact of HIV infection on TB treatment outcome at the population level appears inconclusive. Although some studies showed lower TB treatment success among HIV coinfected TB cases and demonstrated HIV infection as a risk factor for an unsuccessful TB treatment outcome [13–18], other studies reported comparable TB treatment success and observed no significant association of treatment outcome with HIV infection [19–24]. These studies were limited by a number of factors. Many of them were conducted in high-burden settings of TB and HIV with restricted access to ART [20–22], or had a small sample size [15,19,23]. Most of studies that reported similar TB treatment success rates in HIV-positive and HIV-negative cases had excluded cases still on treatment from the treatment outcome analysis [13,15,17,18]. This procedure might overestimate treatment success and can neglect the effect of HIV on the duration of TB treatment. Studies that concluded that TB treatment success was negatively associated with HIV infection did not assess confounding by MDR TB or the impact of the interaction between HIV and MDR TB on treatment success [20–23]. These studies may bias the effect of HIV as they do not distinguish between the effect of HIV and MDR status on treatment outcome.
Based on data from notifiable disease surveillance in Europe, we aimed to assess the impact of HIV infection on TB treatment success considering the interaction between HIV and MDR TB. Additionally, we investigated the impact of HIV on each treatment outcome category, comparing HIV coinfected TB cases with non-HIV infected TB cases.
Data source and case definitions
All EU/EEA countries report their available data on TB to the European Surveillance System (TESSy) hosted by the European Centre for Disease Prevention and Control (ECDC). Since 2010, TESSy data have included information on HIV status for TB cases. The cohort eligible for our analysis included TB cases reported to TESSy from EU/EEA countries that reported treatment outcome and HIV status for TB cases with at least one HIV-positive case in each year between 2010 and 2012.
Treatment outcomes of notified TB cases are reported 12 months after the start of treatment and 24 months after start of treatment for MDR TB cases. We categorized treatment outcomes in accordance with the joint World Health Organization Regional Office for Europe/ECDC surveillance and monitoring report 2015 .
- Cured: treatment completion and culture-negative samples taken at the end of treatment and on at least one previous occasion.
- Completed: treatment completed, but does not meet the criteria to be classified as cure or treatment failure.
- Successful outcome (treatment success): refers to the combined treatment outcome categories cured and completed.
- Died: death before cure or treatment completion, irrespective of cause.
- Still on treatment: patient still on treatment at 12 months without any other outcome during treatment and at 24 months for MDR TB cases.
- Failed: culture or sputum smear remaining positive or becoming positive again 5 months or later into the course of treatment.
- Defaulted: treatment interrupted for 2 months or more, not resulting from a decision of the care provider.
- Transferred out: patient referred to another clinical unit for treatment and information on outcome not available.
- Unknown: information on outcome not available, for cases not known to have been transferred.
For the purpose of our analysis, we defined ‘cases lost to follow-up’ as the combination of cases that defaulted, were transferred out, or had an unknown treatment outcome.
Categorical variables were described using absolute and relative frequencies and compared by the χ2 test regarding group differences. Continuous variables were described using medians with interquartile ranges (IQR) and compared by the Mann–Whitney U test for differences between groups. All tests were two sided and considered significant if P was less than 0.05.
To investigate the effect of HIV infection on TB treatment success, we used a multilevel logistic regression model involving two levels (TB cases nested within countries) corrected with a random intercept and a random slope for HIV effect at the country level . In this model, ‘cases lost to follow-up’ were excluded and treatment outcome was dichotomized as unsuccessful treatment (i.e. death, still on treatment, and treatment failure) vs. treatment success (i.e. cure, and treatment completion). Independent variables available in TESSy data (age, sex, geographical origin, MDR TB, major site of TB, previous treatment of TB, culture confirmation, microscopy result, and reporting year) were tested as possible confounders in the relationship between TB treatment success and HIV infection. Independent variables that led to a not less than 10% change in the HIV regression coefficient were considered as confounders and retained in the final multilevel multivariable model. We evaluated the interaction term between HIV and MDR TB at a P value of 0.1 . To illustrate the MDR-HIV interaction term, we calculated the odds ratios (OR) for each MDR TB strata separately , and graphed the adjusted probability of TB treatment success by HIV infection and stratified by MDR TB status .
A multinomial logistic regression model with adjusted relative risk ratio (RRR) was built to investigate the effect of HIV infection on each treatment outcome category (death, still on treatment, treatment failure, and loss to follow-up) relative to treatment success. To illustrate the results, we plotted the adjusted probability for each category of TB treatment outcome in relation to HIV infection and stratified by MDR status . All analyses were performed using STATA (version13, StataCorp, LP, College Station, Texas, USA) software.
The study was based on data collected on the basis of statutory notification in each EU country and reported anonymously to the ECDC on the basis of decision no. 2119/98/EC of the European Parliament and of the Council.
Between 2010 and 2012, nine EU/EEA countries (Belgium, Bulgaria, Czech Republic, Estonia, Ireland, Lithuania, Portugal, Romania, and Spain) reported treatment outcome and HIV status for their TB cases and had at least one HIV-positive case in each year between 2010 and 2012. These countries reported a total of 106 545 cases. Of these, 45 407 (42.6%) cases had an unknown HIV status and were therefore excluded (see table, Supplemental Digital Content 1, https://links.lww.com/QAD/A865).
Hence, a total of 61 138 cases with known HIV status were eligible for our analysis, including 3347 (5.5%) cases known as HIV positive. The cases’ characteristics stratified by HIV status are presented in Table 1.
Comparison of tuberculosis treatment outcome by HIV status
HIV coinfected cases had a lower TB treatment success rate compared with HIV-negative cases (56.9 vs. 78.7%, respectively; P < 0.001). Compared with HIV-negative cases, more HIV coinfected cases died while being treated for TB (13.5 vs. 6.2%, respectively; P < 0.001). Of the cases who died while on TB treatment, HIV coinfected TB cases tended to be younger compared with HIV-negative cases (median age: 38 vs. 61 years, respectively; P < 0.001). A higher proportion of cases ‘still on treatment’ was observed among HIV-positive cases compared with HIV-negative ones (7.4 vs. 1.9%, respectively; P < 0.001). Treatment failure was higher in HIV-negative cases compared with HIV-positive cases (2.4 vs. 1.5%, respectively; P = 0.001). A higher proportion of HIV coinfected cases were lost to follow-up compared with HIV-negative cases (20.2 vs. 10.2%, respectively; P < 0.001) (Fig. 1a).
After excluding cases that were lost to follow-up (i.e. defaulted, transferred or with unknown outcome), the proportion of successfully treated cases remained higher in HIV-negative cases compared with HIV coinfected cases (88.3 vs. 71.7%, respectively; P < 0.001) (Fig. 1b). The treatment success among HIV coinfected TB cases was lower than in HIV-negative ones in all subgroups and did not reach the global target of an 85% treatment success rate using different inclusion criteria (see Figure, Supplemental-Digital-Content 2, https://links.lww.com/QAD/A865).
Effect of HIV on treatment success of tuberculosis
Out of all statistically evaluated covariates (sex, geographical origin, MDR TB, major site of TB, previous treatment of TB, culture confirmation, microscopy result, and reporting year), only adding age to the model led to predefined change (≥10%) in the regression coefficient for HIV and therefore we retained age in the multivariable model as a potential confounder. The overall interaction between HIV and MDR TB was significant (P < 0.001) and therefore separate results regarding MDR TB status are reported (Table 2). In the adjusted model, HIV coinfected cases had a lower chance of treatment success compared with HIV-negative TB cases in all MDR strata [non-MDR TB: OR 0.24 CI (confidence interval) 0.20–0.29; unknown MDR TB status: OR 0.26 CI 0.23–0.30; MDR TB: OR 0.57 CI 0.35–0.91] (Table 2).
The age-adjusted probabilities of TB treatment success by HIV infection and stratified by MDR status are presented in Fig. 2.
HIV impact on each treatment outcome category of tuberculosis
In the multinomial regression model adjusted for age and corrected for clustering within countries, HIV-positive cases had significantly higher risk for death (non-MDR TB: RRR 4.30 CI 2.31–7.99; unknown MDR TB status: 5.55 CI 3.10–9.92; MDR TB: 3.59 CI 1.56–8.28) and ‘still on treatment’ (non-MDR TB: RRR 7.27 CI 3.00–17.6; unknown MDR TB status: 5.36 CI 2.44–11.8; MDR TB: 3.76 CI 2.48–5.71) relative to being successfully treated compared with HIV-negative ones. We did not find any significant association between HIV infection and TB treatment failure (non-MDR TB: RRR 0.50 CI 0.15–1.67; unknown MDR status: 1.51 CI 0.86–2.64; MDR TB: 0.51 CI 0.13–1.87). In HIV-positive cases, the relative risk of lost to follow-up over treatment success was significantly higher for both non-MDR TB cases (RRR 2.30 CI 1.71–3.10) and cases with unknown MDR status (RRR 2.84 CI 1.73–4.64), but not for MDR TB cases (RRR 0.85 CI 0.47–1.52) (Table 3).
Stratified by MDR status, the age-adjusted probabilities for each outcome category by HIV infection are presented in Supplemental Digital Content 3, https://links.lww.com/QAD/A865.
This study investigated the impact of HIV infection on TB treatment outcomes using European notification data. The strength of our work is that it is based on a large cohort from nine EU/EEA countries and applies a multilevel model in order to handle the correlation of TB cases within each country and therefore controlling for unobserved heterogeneity between countries . Additionally, a systematic statistical evaluation of potential confounders and the HIV/MDR interaction allowed us to close the level of incertitude of the findings from other studies and confirm with high precision that HIV infection is a risk factor for an adverse TB treatment outcome. We found that the adjusted probability of TB treatment success was significantly lower among HIV-positive compared with HIV-negative TB cases in all MDR strata. The unsuccessful TB treatment was mainly manifested by an increased risk of death and being ‘still on treatment’ (>12 months for non-MDR TB; >24 months for MDR TB) among HIV coinfected patients. We did not observe any statistically significant association between HIV infection and TB treatment failure.
The lower TB treatment success rate in HIV coinfected patients can be explained by difficulties in TB diagnosis and treatment in HIV coinfected patients. Alternation of the clinical manifestation of TB and lack of a rapid and sensitive TB diagnostic test in HIV coinfected patients might be responsible for delayed diagnosis and thus delayed treatment initiation, resulting in some of the negative treatment outcomes [11,29]. Treatment of TB in HIV coinfected patients presents with major challenges regarding the drug interactions between the rifamycins and some antiretroviral agents, overlapping toxic effects, and the occurrence of immune reconstitution inflammatory syndrome (IRIS) . Malabsorption of anti-TB drugs is common among patients with advanced HIV , leading to low serum concentrations of drugs and therefore to unfavorable treatment outcomes.
The probability of TB treatment success was much lower among MDR TB compared with non-MDR TB both for HIV-negative and HIV-positive cases in our study population. In Europe, MDR TB cases are known to have lower treatment success and there is an inverse association between TB treatment outcome and MDR TB status . This effect can be explained largely by the fact that treatment regimens for MDR TB are less efficient and less well tolerated, in consequence, making treatment adherence difficult for patients .
The statistically significant interaction between MDR TB and HIV on treatment success in our data suggests that considering the interaction is necessary when investigating the effect of HIV infection on TB treatment outcome in order to obtain a correct estimation. Our data show that HIV infection impacts the treatment success of MDR TB cases to lesser extent than in non-MDR TB cases but nevertheless significantly. This could be due to the fact that coinfection with HIV and MDR TB may result in more care and adherence support to the patients. Existing data on treatment outcome of MDR TB have shown inconsistent findings regarding the effect of HIV. In some studies, HIV was a predictor for poor treatment outcome among MDR TB cases [34–36], whereas others did not indicate any association [37–40]. Age was a confounder in the relationship between HIV and treatment success in our analysis. It is well known that increased age is a risk factor for an inadequate treatment outcome in the general population in the EU/EEA , and HIV coinfected TB cases were significantly younger compared with HIV-negative TB cases in our data. Also, delay in TB diagnosis and more advanced disease at presentation are common among elderly and contribute to increased mortality among them .
The probability of death during TB treatment was significantly higher among HIV coinfected TB cases than among HIV-negative TB cases. It is well documented in both developed and developing countries that HIV coinfected TB cases suffer of high mortality while on TB treatment [13,15,21,22]. A study from Southern Ethiopia found that there was no significant difference in the risk of death regarding HIV status during the intensive phase of TB treatment, but the risk was significantly higher among HIV coinfected cases in the continuation phase . This increased mortality can be due to the fact that TB progresses more rapidly in HIV coinfected patients resulting in some excess mortality among them . Immunological studies have also shown that TB is associated both with increased HIV viral load and HIV diversity, leading to accelerated HIV disease progression and early mortality . However, many clinical and observational studies attributed a high proportion of death among HIV coinfected TB cases to HIV-related complications other than TB [21,22,30,42,44]. A meta-analysis showed that receiving ART reduces the mortality during TB treatment for HIV-positive TB cases by between 44 to 71% . In EU/EEA, it was estimated that more than 85% of those diagnosed with HIV received ART in 2012 . Data available on the TB/HIV coinfected patients on ART are limited. According the WHO Global Tuberculosis Report 2013, three of the nine countries included in our analysis provide information on ART coverage among TB/HIV coinfected patients including Estonia, Portugal and Romania with 62, 100 and 90%, respectively .
Our data show that the risk of being ‘still on treatment’ (>12 months for non-MDR TB; >24 months for MDR TB) was significantly higher among HIV coinfected patients than HIV-negative patients. The treatment of TB in HIV-positive patients may be intermittent and extended due to intercurrent diseases frequent in individuals infected with HIV, concerns of treatment failure or relapse, potential drug interactions, clinical deterioration from IRIS, overlapping side-effects and high pill burden compromising treatment adherence . A study from the United States demonstrated that HIV was a risk factor for failing to complete TB treatment in time (≤12 months) , and in a French study HIV was associated with extensively long treatment of TB . In Zaire, an observational study showed a high relapse rate after one year of standard TB therapy among HIV coinfected cases , whereas a clinical trial showed that extending TB treatment from 6 months to 12 months significantly reduced the rate of relapse among HIV coinfected cases . A meta-analysis showed that longer duration of rifamycin therapy (at least 8 months) might be associated with better outcomes . As the majority of studies on TB treatment outcome excluded cases ‘still on treatment’ from the analysis, there are only limited data that provide evidence for the effect of treatment duration on treatment outcome. The World Health Organization recommends that TB patients who are living with HIV should receive at least the same duration of TB treatment as HIV-negative TB patients acknowledging that the data quality of the studies included in the evidence base was low . Thus very basic questions on treatment of active TB in HIV coinfected patients, including duration of treatment remain unresolved, and future randomized clinical trials are urgently needed .
No statistically significant difference in the risk of treatment failure was observed between HIV-positive and HIV-negative TB cases. This is consistent with other findings from studies that showed that treatment failure of TB was not related to HIV infection [21,54]. Among non-MDR TB cases, the risk of loss to follow-up was higher among HIV-positive cases than HIV-negative ones. That can be attributed to some underlying factors correlated with HIV infection such as intravenous drug use (IDU) as indicated in a study done in Spain .
Our data show that the treatment success of TB among HIV coinfected cases in EU/EEA settings was markedly low and did not reach the global target of 85% treatment success rate; the application of different inclusion criteria did not change this result. This confirms that, even in settings like the EU/EEA where ART is available and accessible, the TB/HIV coepidemic presents a serious threat to public health. As such patients are treated for two diseases, special case management is strongly recommended in order to achieve the optimal outcome in terms of treatment response and prevention of drug resistance for both diseases . However, our data showed that the treatment success among HIV-negative cases was also below the global target. A current study evaluating the TB treatment outcome in the EU/EEA over 10 years showed the overall treatment success was 78% and none of the EU/EEA countries included in the study reached the global target in any years between 2002 and 2011 .
There are some limitations to this study. Early initiation of ART among coinfected patients is known to decrease mortality,  and ART during TB treatment can be a protective factor against default from TB treatment . Due to the unavailability of information on ART we could not assess its effects on our findings. However, by using multilevel model corrected with a random slope we could control for the different relationship between HIV and TB treatment outcome for the different countries (among other factors also the unobserved heterogeneity of ART coverage and availability between countries) and therefore enhance the generalizability of our findings. Also, we could not explore whether CD4+ cell count, HIV viral load, homelessness, alcoholism, drug use, or comorbidities were associated with TB treatment outcome as these data are not collected at the EU/EEA level. According to a study from Spain, drug use substantially affects mortality and many HIV-positive patients were also drug users ; hence, drug use might be a potential confounder in the analysis for which we could not correct. Collecting information on risk factors such as comorbidities, substance use and social determinants are necessary to increase our understanding, empower tailored interventions and develop targeted responsive strategies . Our study included data from nine of 31 EU/EEA countries which represent 49% of all TB cases reported to the ECDC from EU/EEA for the period 2010–2012 . Therefore, our data pertain to our nine EU/EEA countries and are not necessarily generalizable to the whole of EU/EEA. Finally, 41% of the cases reported from the nine EU/EEA countries in our analysis were of unknown HIV status and therefore excluded. As the reason for the absence of a HIV test result is unknown, it is not possible to hypothesize how this affects our findings. Notably, the proportion of cases of foreign origin was twofold higher in TB cases with known HIV status (included cases) than in cases with unknown HIV status (excluded cases). However, it is known that the treatment success rate was slightly higher among native cases than among cases of foreign origin in the EU/EEA .
In conclusion, this large study confirms that, even in EU/EEA settings where ART is available, HIV infection is a strong risk factor for an adverse TB outcome in all MDR TB strata. Our findings strongly reinforce the evidence that HIV infection is associated with higher mortality in TB coinfected patients than HIV-negative TB patients. Additionally, an increased risk of still being on treatment (>12 months for non-MDR TB; >24 months for MDR TB) is another indicator of less successful TB regimens in HIV-positive patients. This result encourages future studies including randomized clinical trials to investigate the optimal duration of TB treatment in HIV coinfected individuals.
The authors would like to acknowledge the work of the ECDC national surveillance focal points and the TB national surveillance network who make EU/EEA TB surveillance possible. The authors would like to thank Talei Lakeland for linguistic revision of the manuscript. The authors acknowledge the nominated national operational contact points for tuberculosis Peter Henrik Andersen, Delphine Antoine, Trude Margrete Arnesen, Thorsteinn Blondal, Domnica Ioana Chiotan, Edita Davidavičienė, Irene Demuth, Raquel Duarte, Sabine Erne, Walter Haas, Alexander Indra, Jerker Jonsson, Ourania Kalkouni, Maria Koliou, Maria Korzeniewska – Kosela, Gábor Kovács, Joan O’Donnell, Analita Pace Asciak, Maria Grazia Pompa, Elena Rodríguez Valín, Erika Slump, Hanna Soini, Ivan Solovič, Petra Svetina, Lucy Thomas, Tonka Varleva, Piret Viiklepp, Kate Vulāne, Jiří Wallenfels and Maryse Wanlin for providing the surveillance data used in this analysis.
Source of funding: No external funding was received for this project.
Author's contributions: Concept and design (B.K., W.H.), literature search (B.K.), statistical analysis (B.K.), interpretation of the data (B.K., W.H., G.K., S.C., Mvd.W., V.H.), drafting the manuscript (B.K.) and critical revision of the manuscript for important intellectual content (B.K., W.H., G.K., S.C., Mvd.W., V.H., O.H.). All authors have read and approved the final manuscript.
Conflicts of interest
There are no conflicts of interest.
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