| Summary: | 博士 === 臺北醫學大學 === 公共衛生學系暨研究所 === 102 === Purpose
Tuberculosis (TB) and human immunodeficiency virus (HIV) are both the most important infectious diseases worldwide. According to the estimation by World Health Organization (WHO), there were 1.1 million HIV-positive new TB cases globally in 2012 and 320,000 people died of HIV-associated TB. Therefore, the WHO recommends adopting collaborative HIV/TB activities and strengthens the interventions needed to prevent, diagnose and treat TB in people living with HIV. After implementation of the “Mobilization Plan to Halve Tuberculosis Incidence in Ten Years” (national TB plan) since 2006, the number of new TB cases declined 7% annually, although Taiwan still belong to moderate TB burden country. On the contrary, the new and cumulative HIV-infected cases showed a rising trend, although still a low prevalence of HIV, but the risk of HIV and TB co-infection is increasing. What is the impact of such unique epidemiology on the HIV and TB co-infection needs further analysis. Persons co-infected with TB and HIV are 29.6 times (27.1 – 32.1) more likely to develop active TB disease than persons without HIV, and the risk of death are also higher among co-infected persons , 4-10 times, than persons without HIV. About 15 to 45% of co-infected patients would develop immune reconstitution inflammatory syndrome (IRIS) and some might resulted in death, make the treatment of TB complex in HIV-infected persons. Early initiation of HAART during TB treatment is strongly associated with the occurrence of IRIS. However, several observational studies found that deferral of HAART in TB treatments are associated with higher mortality. Therefore, the timing of HAART initiation during TB treatment is one of the important issues currently WHO identified the need to explore. Another important strategy to reduce the incidence of HIV-infected TB is screening and treatment of latent tuberculosis infection (LTBI). The tuberculosis skin test (TST) is the traditional method for the diagnosis of LTBI, but the test has low specificity due to cross reactions with the bacillus Calmette-Gue’rin (BCG) vaccine. Due to the low specificity, Tuberculin skin test (TST) may not be a good tool to screen LTBI in Taiwan due to high BCG vaccination coverage rate. Therefore, the appropriate LTBI screening protocol for HIV-infected persons in Taiwan need further study.
The first aim of this study is to compare the treatment outcome and fatality rate of TB cases in Taiwan, stratified by HIV sero-status, and further to elucidate risk factors related to death. The second is to understand the epidemiology of HIV and TB co-infection in Taiwan and hope to contribute to the understanding of the appropriate timing to initiate HAART in co-infected patients. The third is to evaluate the T-SPOT.TB (an IGRA) and the TST, for the diagnosis of LTBI and the predictive value of the development of subsequent active tuberculosis. We also offer isoniazid preventive therapy (IPT) for LTBI patients and observe the safety of the treatment. We tried to determine the clinical and epidemiological risk factors associated with positive results for the TST and the T-SPOT.TB test in HIV-infected individuals and recommend an appropriate protocol to better select HIV-infected individuals for IPT.
Methods:
The first part is retrieved from national TB registry dataset, collected the data of reported new TB cases from 2002/1/1 to 2007/12/31 for analysis. We further linked with HIV testing data from national health insurance dataset and national HIV registry data to classify the HIV status of TB patients as HIV-infected, HIV-uninfected and unknown HIV status. The second part was a retrospective study, through linkage of the HIV and TB registry in Taiwan CDC before 2007 to identify HIV/TB co-infected patients. All the medical and microbiologic records were reviewed by physician to obtain clinical information which included date of diagnosis; type of TB; antiretroviral drugs used before and after the diagnosis of TB; and the CD4+ lymphocyte and viral load closest to the date of TB diagnosis. The outcome of interest studied was all-cause mortality within 1 year following TB diagnosis and treatment. Cox Proportional Hazard model was used to evaluate the hazard ratio of variables (e.g. age, gender, HAART initiation timing, etc.) associated with one-year TB mortality between the groups. Variables associated with a p value < 0.15 were retained in the final multivariate model and use backward stepwise selection method. Results are expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). All comparisons were two-tailed and p value <0.05 was considered statistically significant.
The third part is to recruit HIV-infected individuals without clinical suspicion of active TB or a past history of TB from 1 January 2008 to 30 November 2010. Both T-SPOT.TB test and TST were offered to the participants whom were followed up prospectively until April 30, 2012 for development of TB. Multivariate logistic regression model was used to determine the risk factors for positive results. The concordance between the TST and T-SPOT.TB results was assessed using Cohen’s kappa (κ) coefficient. IPT was offered to recruited participants with positive TST reactions with free isoniazid, 300 mg daily for 9 months. All enrolled subjects were routinely followed up every 3-6 months in the HIV clinics until April 30, 2012; death; or the development of active TB, whichever was earliest. We used the Poisson distribution to calculate the relative risks (RRs) of incident TB between different tests and IPT or not.
Result
The first part: Among the 94,919 reported new TB cases between 2002 and 2007, 17.3% among them ever received 568(0.6%) were HIV-infected and 15,878(16.7%) were HIV-infected. Around 60% of HIV-uninfected and unknown HIV status TB patients were aged over 50 years old, but HIV-infected TB patients were significantly younger and over 60% were less than 50 years old. A total of 17,541 people died within one year after TB diagnosis, the overall TB mortality are 18.5% and no significant differences between the three HIV sero-status groups. However, HIV-infected individuals had significantly higher mortality rate when compared with HIV-uninfected and unknown HIV status in each age groups. HIV-infected cases had lower successfully treated and higher default rate, p<0.05. In multivariate analysis after adjustment with age, gender and sputum smear and culture status, HIV infection had a significantly higher risk of death than HIV-uninfected and HIV unknown status and the aHR was 3.70 (95% CI 3.01-4.51). Even those who have HAART, there is still a significantly higher risk of death and aHR was 3.15 (95% CI 2.48-4.00). In TB cases less than 50 years old, HIV infection was the most important factor on one-year TB mortality, aHR of 3.52 (95% CI 2.70-4.59), though the impact in aged over 50 years old was not significant.
The second part: Among the 13,013 reported HIV-infected persons in Taiwan by the end of 2006, 473 patients (3.6%, 489 episodes) developed TB infection. Extra-pulmonary involvement was common and accounted for 52.8%. Twelve month TB treatment outcomes of HIV infected individuals included 69.5% was successfully treated and 26.9% died. There are 64.5% among deaths were interpreted as tuberculosis-related deaths. On multivariate analysis, only increasing age at TB diagnosis and decreasing CD4+ lymphocyte counts was associated with TB mortality. Already on HAART at TB diagnosis showed better survival than those not on HAART, though not significant. In cases not on HAART during TB treatment, in addition to decreasing age and higher CD4 lymphocyte count, ever start HAART during TB treatment was significantly associated with better survival (adjusted Hazard Ratio was 0.11, 95% CI 0.06-0.21). As to the timing of HAART initiation, the TB mortality rate was highest among cases initiating HAART after 60 days of TB treatment, followed by within 15 days, 16-30 days and 31-60 days. Cases with HCV co-infection had significantly lower chance to initiate HAART during TB treatment than cases without or had unknown HCV status (p < 0.01); HBV co-infection did not show such findings. One third of the patients developed IRIS after initiation of HAART. Cases initiated HAART after 30 days had lower risk to develop IRIS than cases initiate HAART earlier. Cases with IRIS had significant higher rate of re-hospitalization (49% vs. 4%, p<0.001) and prolonged hospitalization (28 days vs. 18.5 days, p<0.01).
The third part: Among the 909 participants, 25% had positive TST reactions with cut-off point of 5 mm and 15% had positive TSPOT.TB and 9% had dual positive results. Increasing CD4+ lymphocyte counts and a history of contact with TB case were independently associated with a positive response in both tests. Increasing age and male gender independently predicted a positive T-SPOT.TB response, but not TST. Prison stay for over 6 months was associated with positive TST response. The overall agreement between the two tests was only fair (78.1%, κ = 0.32). There were 82 participants (92.1%) completed IPT, 11 persons ever interrupted due to adverse events and 10 persons (11.2%) experienced acute hepatitis, but only one participants (1.1%) discontinued IPT permanently. After a median follow-up of 2.97 years, there were 5 cases developed culture-confirmed active TB (all had dual positive TST and T-SPOT.TB results), and the incidence was 0.17 per 100 person-years. The relative risks (RRs) for subsequent active TB in HIV-infected individuals with positive TST results, positive T-SPOT.TB results and dual positive results compared with the risk for individuals with negative results were 40.6 (95% CI 2.1–767.9), 73.9 (95% CI 3.9–1397.7) and 226.5 (95% CI 12.0–4284), respectively. Among patients with dual positive results, there were 4 active TB cases among 32 untreated patients, compared with 1 TB case among 49 patients taking IPT (p<0.05 by the log-rank test), Dual positive TST and T-SPOT.TB results were associated with a 7.8-fold increased risk of active TB in patients who did not receive IPT.
Conclusion
Even in the era of HAART, HIV-infected individuals still experienced higher one-year TB mortality. In order to reduce the TB mortality rate of HIV-infected individuals is implementing HIV prevention program which include aggressive HIV screening program and case management program, thus enable HIV–infected persons can get HAART in time. As to persons not able to initiate HAART at TB diagnosis, we recommended that HAART should initiate during TB treatment. Early initiation of HAART during TB treatment demonstrated a non-significant better one-year survival than late initiation (60 days after TB treatment). Nevertheless, early initiation of HAART within 30 days appeared to increase the risk of IRIS. Deferring HAART to 31–60 days of TB treatment might be optimal after considering the risks and benefits. In addition, adopting positive results of the TST and T-SPOT.TB to screen LTBI among BCG-vaccinated HIV-infected individuals might be feasible. Number needed to treat for isoniazid therapy could be reduced significantly by using the dual positive strategy, thus can reduced adverse events and still can lower the future incident TB cases, further blocking the transmit ion. Therefore, we recommended all HIV-infected persons to initiate HAART timely when developed TB, can effectively reduce mortality; and screening for LTBI and offer IPT for cases without TB to reduce the incidence of TB. These two strategies in parallel could reduce the number of HIV and TB co-infection and related deaths in Taiwan.
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