Clinical and prophylactic studies of human tuberculosis in a low-endemic setting

Sammanfattning: Sweden is a low burden country for tuberculosis (TB). New cases occur mainly among immigrants from countries with a higher TB prevalence. Most persons infected with TB (latent TB) will not develop disease (active TB). Prolonged treatment is necessary and can cause severe adverse drug reactions. A well-functioning TB program is essential to interrupt the transmission of infection in the community. The increasing global problem of resistant TBstrains necessitates development of a new tuberculosis vaccine that is more effective than the Bacillus Calmette Guerin (BCG) vaccination that has long been in use. Globally, human immunodeficiency virus (HIV) is the single strongest medical risk factor for active TB. The implementation of anti-retroviral treatment (ART) in 1996 completely changed the prognosis for persons living with HIV. By restituting the immune defense, ART has provided a strong protective effect against active TB. ART in combination with anti-TB treatment entails a higher risk of adverse drug reactions and this risk is even greater if ART is introduced during TB treatment. Sweden is a low burden country for HIV and more than 90% of all HIV-infected individuals in Sweden receive effective ART. In paper I we described the socio-demographic and clinical characteristics of the 127 HIVinfected persons that developed active TB in Stockholm County 1987–2013. The majority of the patients in the co-infected cohort were foreign-born (87%). After the introduction of ART in 1996 the success of TB treatment increased from 65% to 91%. In patients diagnosed with co-infection after 1996, treatment success was predicted by ART treatment (odds ratio (OR) 13.3, 95% confidence interval (CI) 1.5–114.8) and a CD4⁺ cell count at TB diagnosis >200 cells/μl (OR 17.2, 95% CI 1.2–236.6). Adverse reactions severe enough to lead to modification of anti-TB treatment occurred in 23% of the patients diagnosed with co-infection after 1996, and the risk of adverse events was significantly increased if ART was introduced after TB diagnosis (OR 13.3, 95% CI 1.6–112.4). BCG, the TB vaccine used since the 1920s, is most effective against active disease in children but does not give adequate protection in adults. In paper II we performed a phase 1 study, investigating the safety and the immunogenicity of the new vaccine candidate H4:IC31, consisting of a fusion protein of two TB antigens (Ag85B and TB10.4) and an adjuvant (IC31). In two randomized and double-blinded studies, conducted in Sweden and Finland, including BCG-vaccinated healthy individuals, 125 study subjects were immunized twice with different doses of antigen and adjuvant or placebo. The vaccine was well tolerated with only mild to moderate, mainly self-limiting adverse events: injection-site pain, myalgia, arthralgia, fever and post-vaccination inflammatory reaction at the site of screening tuberculin skin test injection. The vaccine triggered an antigen-specific and multifunctional CD4⁺ cell response and cytokine production, most prominent after two doses of 5, 15 or 50 µg of H4 combined with 500 µg of IC31. Latent TB infection (LTBI) is defined as a detectable immune response against TB without signs or symptoms of active disease. Treatment for LTBI is recommended by the Public Health Agency of Sweden to prevent active TB in persons with untreated HIV-infection. In contrast, the National Reference Group for Antiretroviral therapy in Sweden (RAV) recommends neither screening nor treatment for LTBI in this group, with reference to Sweden’s wellfunctioning HIV care; almost all HIV-infected persons are offered ART and if they nevertheless develop active TB the close follow-up of this group is considered sufficient for early detection and initiation of TB treatment. In paper III we studied the incidence of and risk factors for active TB in persons living with HIV in Stockholm County, 1996–2016. We observed an overall incidence rate of active TB of 6.2 cases (95% CI 5.1–7.6) per 1 000 personyears with a significant decline over the study period. Originating from a TB-endemic region was the only characteristic associated with a higher risk of active TB (Hazard Ratio (HR) 8.84 (95% CI 3.09–23.61). The number of patients needed to treat for LTBI to prevent one case of active TB among patients from TB-endemic regions was 22 (95% CI 26–47). Although the incidence of TB declined significantly during the study period, it was still 80 times higher than in the general population at the end of the study. Recurrence of infection after completed antibiotic treatment is reported to occur in around 2% of TB patients, in low-endemic settings. Recurrence can be caused by relapse of infection or reinfection by another TB strain. Molecular typing with whole genome sequencing (WGS) can distinguish relapse from reinfection with a high resolution. As an evaluation of current treatment strategies and treatment control, study IV was aimed to analyze the frequency of TB recurrence in Stockholm County, 1996–2016. Recurrence was defined as a new TB infection more than 180 days after successful treatment completion. The recurrence frequency was 0.7% in 2,552 patients diagnosed with culture-verified TB. With WGS analysis, 71% were classified as relapse cases. Drug-resistant TB was present in 50% of the patients with relapse. No acquired drug resistance was detected with WGS comparing the isolates in relapse cases. In conclusion, several interventions are needed to further reduce the incidence rate of TB in Sweden. The introduction of ART in 1996 has dramatically enhanced the success rate of TB treatment in patients co-infected with HIV and TB (Paper I). Since the introduction of ART, the incidence of active TB in persons living with HIV in Stockholm County has also declined significantly. However, our data indicate that the addition of screening and treatment of LTBI in persons with HIV could be expected to further decrease the incidence of TB in persons from TB-endemic regions (Paper III). Stockholm has a low TB relapse frequency, indicating a wellfunctioning TB care. Relapse occurs mainly among patients with resistant TB, which should be considered in the follow-up of these patients (Paper IV). The new vaccine candidate H4:IC31 is safe and immunogenic. Encouraging results from a phase 2 study of the vaccine candidate performed in South Africa were presented in 2018 (Paper II)