Understanding the Decline of Incident, Active Tuberculosis in People With Human Immunodeficiency Virus in Switzerland

Abstract

Background: People with human immunodeficiency virus type 1 (HIV-1) (PWH) are frequently coinfected with Mycobacterium tuberculosis (MTB) and at risk for progressing from asymptomatic latent TB infection (LTBI) to active tuberculosis (TB). LTBI testing and preventive treatment (TB specific prevention) are recommended, but its efficacy in low transmission settings is unclear.

Methods: We included PWH enrolled from 1988 to 2022 in the Swiss HIV Cohort study (SHCS). The outcome, incident TB, was defined as TB ≥6 months after SHCS inclusion. We assessed its risk factors using a time-updated hazard regression, modeled the potential impact of modifiable factors on TB incidence, performed mediation analysis to assess underlying causes of time trends, and evaluated preventive measures.

Results: In 21 528 PWH, LTBI prevalence declined from 15.1% in 2001% to 4.6% in 2021. Incident TB declined from 90.8 cases/1000 person-years in 1989 to 0.1 in 2021. A positive LTBI test showed a higher risk for incident TB (hazard ratio [HR] 9.8, 5.8-16.5) but only 10.5% of PWH with incident TB were tested positive. Preventive treatment reduced the risk in LTBI test positive PWH for active TB (relative risk reduction, 28.1%, absolute risk reduction 0.9%). On population level, the increase of CD4 T-cells and reduction of HIV viral load were the main driver of TB decrease.

Conclusions: TB specific prevention is effective in selected patient groups. On a population level, control of HIV-1 remains the most important factor for incident TB reduction. Accurate identification of PWH at highest risk for TB is an unmet clinical need.

Figure 1.

Depiction of the study design, showing workflow of the analysis, and chosen subpopulations with its patient number. Abbreviations: HIV, human immunodeficiency virus; LTBI, latent TB infection; PWH, people with HIV; SHCS, Swiss HIV Cohort study; TB, tuberculosis.

Figure 2.

A Incident active TB incidence in PWH enrolled in the SHCS. Incidence per 1000 person y of incident TB, that is, at least 6 months after SHCS enrollment. B, Time from SHCS enrollment until incident TB. C, Prevalent active TB, active TB, that is, within 6 months after SHCS enrollment. Shown as prevalence among PWH newly enrolled in the SHCS. D, TB infection prevalence in the SHCS between 1988 and 2022 diagnosed by tuberculin skin test or interferon gamma release assay. Abbreviations: LTBI, latent TB infection; HIV, human immunodeficiency virus; PWH, people with HIV; SHCS, Swiss HIV cohort study; TB, tuberculosis.

Figure 3.

Adherence to TB management in PWH with latent (LTBI) or active TB in the SHCS. A, PWH with incident active TB stratified by their prior received LTBI test and its result. B, PWH with a positive or borderline LTBI test stratified by received preventive treatment and occurrence of incident active TB. C, Proportion of incident active TB based on adherence to LTBI test and treatment strategies. Stratified by SHCS enrollment before 1996, between 1996 and 2007, and after 2007. D, Numerical solution of a statistical model, comparing improvements in sensitivity of LTBI testing compared to adherence to preventive treatment initiation in their ability to prevent cases of incident active TB. Above the line sensitivity is higher, whereas below, initiation is higher. The dot indicates overall performance in the SHCS. Abbreviations: HIV, human immunodeficiency virus; LTBI, latent TB infection; PWH, people with HIV; SHCS, Swiss HIV cohort study; TB, tuberculosis.

Figure 4.

Comparison of CD4 T-cell count and LTBI test results/availability and the time to occurrence of incident active TB in people with HIV. LTBI test was at enrollment into the SHCS. TB is defined as TB at least 6 months after SHCS enrollment. LTBI test is defined as a positive/borderline or negative TST or IGRA or no available test within six months of SHCS enrolment. CD4 T-cell count is defined as the nadir measurement within six months of SHCS enrolment. A, Kaplan-Meier plot comparing the time until incident active TB, stratified by LTBI test results/availability. B, CD4 T-cell count stratified by LTBI test result/availability. C, CD4 T-cell count stratified by LTBI test result/availability among PWH without subsequent incident TB. Abbreviations: HIV, human immunodeficiency virus; LTBI, latent TB infection; PWH, people with HIV; SHCS, Swiss HIV cohort study; TB, tuberculosis; TST, tuberculin skin test; IGRA, interferon gamma release assay.

Figure 5.

A. The hazard ratios for acquiring incident active TB, in PWH in the SHCS, using time updated uni-/multivariable Cox proportional hazard regression. B, Multiple mediation analysis, showing how increase of CD4 T cells, decrease of HIV-1 RNA viral load, preventive treatment efficacy, and LTBI testing improvements mediate the effect of time on incident active TB. All confidence intervals are clipped at ± 100%. Abbreviations: BMI, body mass index; CI, confidence interval; HIV-1, human immunodeficiency virus type 1; HR, hazard ratios; LTBI, latent TB infection; PWH, people with HIV; SHCS, Swiss HIV cohort study; TB, tuberculosis.