In a post-hoc analysis of patients who had initiated ART, we found that those who developed TB were more likely to have discontinued ART at their last clinic visit (27 versus 6% of those without TB, P < 0.001, Supplementary Table 4, http://links.lww.com/QAD/B155). ART initiation rates and time from the most recent clinic visit to the end of the study were similar for MSM, heterosexuals and PWID.
There was no substantial difference in the age, sex, ethnicity/country of birth, route of HIV infection or CD4+ cell count of patients with missing data on any of the following variables: route of HIV infection, CD4+ cell count, IMD decile and country of birth. Patients with missing route of infection were less likely to be diagnosed with TB; however, there were no substantial differences for patients missing data on any other variable.
Sensitivity analyses were conducted as follows: excluding 241 individuals who acquired HIV infection through mother-to-child transmission, excluding 595 individuals with TB whose probabilistic matching scores (linking to their HIV record) were in the lowest quartile, excluding 137 individuals with TB who were matched to their HIV record using the three lowest ranked deterministic criteria, excluding 424 individuals diagnosed with TB 92–182 days after HIV diagnosis, including IMD score and excluding data on 12 432 individuals missing IMD score. All analyses provided consistent results with the main model (Supplementary Tables 1–3, http://links.lww.com/QAD/B155).
People who acquired HIV infection through IDU (largely UK-born patients) had a high risk of TB following their HIV diagnosis, with incidence rates comparable with those in black Africans born in high TB incidence countries; almost five-fold more than MSM after accounting for other factors including starting ART. Consistent with previous research [3,6], declining CD4+ cell count was associated with higher TB rates.
The current study benefits from the very large national HIV-positive cohort, providing comprehensive results for England, Wales and Northern Ireland. The algorithm linking patients with TB and HIV utilizes ethnicity, year and country of birth; all variables with very high completeness: 97.3, 99.9 and 90.5%, respectively.
We found no substantial differences in the demographics or proportion of TB in patients missing data on each of these variables; however, patients missing data on one variable were more likely to have other missing data. In addition, patients missing data for multiple variables were less likely to be linked to a TB notification, and therefore, we may have underestimated TB incidence rates; it is likely that the low incidence of TB in patients with ‘unknown’ route of HIV infection is a symptom of this and patients with extensive missing data may be more likely to be from populations at high risk for TB. In addition, the record linkage algorithm is less sensitive to non-English names ; therefore, we may have underestimated TB incidence in foreign populations.
One limitation was missing CD4+ cell count data for approximately a third of patients, who were therefore excluded from the risk factor analysis. This is partly due to difficulties linking data, and partly because some large hospitals do not supply CD4+ cell count data to HARS. However, we found no evidence that patients with missing CD4+ cell count data were systematically different to our analysis cohort. As our sample size remained very large, and there was no evidence that patients missing data were systematically different, we chose not to use multiple imputation due to the complexity of the dataset as a result of using time-updated CD4+ cell count and ART initiation. Data were available on ART discontinuation but were of poor quality and could not be included in the model. Consequently, we may have underestimated the association between starting ART and lower TB incidence by assuming all individuals remained on treatment for the duration of our study.
Individuals entered the study cohort 92 days after HIV diagnosis or first presentation to UK health services; therefore, we may have underestimated TB incidence in people diagnosed abroad who were at risk prior to entering the United Kingdom, as we would have missed TB cases diagnosed during the initial period following HIV diagnosis when TB incidence is highest. A recent study of PLHIV had 18% loss to follow-up over 4 years, and 14% of TB cases diagnosed more than 91 days after HIV diagnosis were amongst these patients . As TB and HIV are sometimes treated (and usually reported) separately in the United Kingdom, dropping out of HIV care does not prevent notification of a TB diagnosis. We therefore used passive censoring, continuing follow-up until 31 December 2014 rather than the date last seen for HIV care. Consequently, migration out of the United Kingdom may mean we underestimated TB incidence.
A limitation of the Poisson regression model was censoring due to competing risks, specifically deaths from non-TB causes. However, few patients died (3%) and median time to death was 3.4 years, substantially longer than median time to TB diagnosis (1.8 years); therefore, any impact of censoring is likely to be minimal.
Although PWID represented less than 2% of PLHIV, they accounted for 3% of TB cases in this population and more than 4% of cases diagnosed more than 91 days after HIV diagnosis. TB incidence in PWID in our study (876/100 000 person-years in men and 605/100 000 in women) was substantially higher than that in a cohort of German PLHIV , possibly because this cohort utilized active rather than passive follow-up and excluded patients who did not present to care for 6 months or more, who may be more likely to develop TB disease than patients who remain engaged with care. PWID are typically diagnosed with HIV late , have slower rates of linkage to care and lower rates of viral suppression , all of which may contribute to increased risk of TB. We found ART initiation and the time from the last clinic visit to the end of the study were comparable for MSM, heterosexuals and PWID, and that PWID did not have higher rates of ART discontinuation at their last clinic visit prior to study end (Supplementary Table 4, http://links.lww.com/QAD/B155). Consequently, it seems high rates of TB among PWID are caused by difficulties in linking to care and not lack of engagement with health services once linked. Many PWID have other comorbidities which may cause immunosuppression, make HIV care more challenging, or be associated with increased risk of TB . In addition, there are high rates of alcoholism and homelessness, and living in hostels is common . These, in addition to injecting drugs in shared social settings, may drive close mixing of people with similar risk factors for TB disease, driving transmission. High rates of smoking may also have impacts on both local lung immunity and TB transmission. Further studies are needed to explore the impact of these factors and to design effective interventions. The British HIV Association (BHIVA) guidelines currently recommend testing and treating latent TB infection (LTBI) among PLHIV using criteria based on CD4+ cell count, time on ART and country of birth . As the incidence of TB among PWID was comparable with that of black African patients born in countries with high TB incidence, we suggest that additionally screening and treating PWID for LTBI should be considered.
The majority of PWID were white (51%) and born in the United Kingdom or low TB incidence countries (72%). It is therefore likely that most TB in this group was acquired in the United Kingdom, meaning these cases may be preventable by diagnosing HIV sooner and ensuring prompt ART initiation. We could also do more to diagnose TB cases sooner; the impact of active case finding in PLHIV should be evaluated. In contrast, heterosexuals were typically black African (61%) and born in high TB incidence countries (69%), both populations which also have high rates of TB among HIV-negative people. Consequently, they are likely to have acquired TB abroad, limiting our ability to prevent these TB infections if they present with clinical TB at the time of HIV diagnosis . As more than 60% of heterosexuals were diagnosed with TB simultaneously or prior to HIV diagnosis, greater efforts to diagnose these HIV infections and initiate ART would reduce TB in this population. A greater focus on screening and treating LTBI could also prevent these cases . There is little data available on the prevalence of LTBI and the use of preventive therapy among PLHIV in the United Kingdom. Rates of LTBI screening and uptake of preventive therapy vary substantially between HIV clinics [32,33], and a survey of UK HIV healthcare providers providing care to 90% of PLHIV in the United Kingdom found that only 54% offered LTBI screening and preventive therapy . Health economics evaluations would be useful to determine the most effective screening measures for these populations.
Over half of all TB cases (55%) were diagnosed simultaneously with HIV infection, and of the 39% diagnosed later, the probability of a TB diagnosis was highest in the first year following HIV diagnosis (Fig. 1). This suggests that TB disease is largely the result of TB infection acquired prior to HIV diagnosis. This could result from late diagnosis of existing active TB, particularly in migrants who have recently moved to the United Kingdom from high-burden countries and whose TB is largely attributable to reactivation of remotely acquired infection . In addition, the incidence of TB amongst migrants decreases with time since entry to the United Kingdom, as new TB infection is less likely in the United Kingdom than their country of origin. Other factors which could explain this trend are increased surveillance for opportunistic infections following HIV diagnosis, or ‘unmasking-type’ immune reconstitution inflammatory syndrome as a consequence of ART. Although TB incidence was lower after the first year since HIV diagnosis (Table 1), 25% of all TB cases occurred more than 1 year after HIV diagnosis. These cases can certainly be attributed to reactivation of LTBI and could be preventable with LTBI treatment.
Patients who had initiated ART had greatly reduced rates of TB compared with those who had not (Table 3); however, time-updated CD4+ cell count and ART initiation status interacted within our model. Higher rate ratios for TB at low CD4+ cell count in people on ART may be attributable to late ART start (i.e. long periods of low CD4+ cell count prior to initiating ART and then little time on ART prior to TB diagnosis), or due to ART discontinuation. The Strategies for Management of Antiretroviral Therapy trial demonstrated an association between stopping ART and increased risk of opportunistic disease and death . Our post-hoc analysis of patients who had started ART demonstrated that patients who went on to develop TB were more likely to have discontinued ART at their last study visit than individuals who remained TB-free (Supplementary Table 4, http://links.lww.com/QAD/B155). This suggests ART discontinuation could leave patients at risk of new TB disease.
In England, Wales and Northern Ireland, PLHIV who acquired HIV by injecting drugs had higher rates of TB after their HIV diagnosis than MSM, comparable with black Africans born in countries with high TB incidence. High rates of TB in PWID are likely to result from transmission within the United Kingdom. ART is highly protective against TB, but the majority of TB diagnoses were in people who have never started ART. ART discontinuation rates were much higher in people who subsequently developed TB than those who did not. Quicker initiation of ART, as per the recently updated BHIVA guidelines , and improving retention in care and ART continuation should decrease incident TB in PLHIV.
J.R.W. is funded by a UCL IMPACT studentship. This report is independent research supported by the National Institute for Health Research (Postdoctoral Fellowship, H.R.S., PDF-2014-07-008). I.A. acknowledges funding from NIHR (NF-SI-0616-10037 and SRF-2011-04-001), MRC and the Wellcome Trust. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.
Author contributions: J.R.W. designed the study, linked the TB and HIV surveillance datasets, conducted the analysis and drafted the article. H.R.S. and C.J.S. designed the study, analysed and interpreted the data and critically revised the article. A.E.B., M.K.L., A.S., H.L.T., Z.Y. and P.K. gave input on the study design, collected the data, linked the datasets, interpreted the results and critically revised the article. V.D. and I.A. designed the study, collected, linked, analysed and interpreted the data and revised the article. M.L. and A.P. interpreted the results and critically revised the article. All authors approved the final version of the article for publication.
The article utilized two surveillance datasets collected by the respiratory (Tuberculosis section) and HIV departments in the National Infections Service at Public Health England. In light of the work involved in collecting and linking these two datasets, and designing a study utilizing both of them, we have listed 13 authors for this article.
Conflicts of interest
J.R.W., A.E.B., M.K.L., M.L., A.S., P.K., Z.Y., H.L.T., V.D. and I.A. have no conflicts of interests to declare. H.R.S. declares funding from the National Institute for Health Research, UK during the conduct of the study; and, outside of the submitted work, grants and personal fees from Otsuka Pharmaceutical, nonfinancial support from Sanofi, and other support from the WHO. Outside the submitted work, C.J.S. reports personal fees from Gilead Sciences and ViiV Healthcare. A.P. is chair of the BHIVA TB guidelines committee. J.R.W. had full access to all the data in the study and had final responsibility for the decision to submit for publication.
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cohort studies; coinfection; HIV; observational study; risk factors; tuberculosis
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