Incidence of active tuberculosis in HIV-infected individuals not receiving universal tuberculosis preventive treatment

To the Editor: Tuberculosis (TB) is the leading cause of death in people living with HIV (PLWH) globally. Given the increased risk of TB infection, TB preventive therapy (TPT) is recommended for PLWH to prevent TB activation and to reduce relevant mortality. However, the implementation of TPT remains weak with only 21% of eligible PLWH initiated on TPT globally in 2021,[1] primarily due to the implementation challenges in developing countries. The low completion rate of TPT may be attributed to various reasons, including socio-economic factors, individual behaviors (medication adherence, lack of knowledge, etc.), unstable supply chain of anti-TB drugs, and insufficient understanding of TB treatment guidelines. China has always been regarded as a region with high TB burden. Therefore, conditional TB prophylaxis has been recommended in national guidelines for HIV-infected patients since 2006, with emphasis on those with CD4+ T count <200 cells/μL, or those with positive tests of latent TB screening, preferred using interferon γ release assay (IGRA). Since 2021, universal TB prophylaxis strategy has been recommended following the World Health Organization (WHO) guidelines. However, in real practice, HIV-infected individuals seldomly receive universal TPT when initiating antiretroviral therapy (ART) in most centers. Nevertheless, there is little report on the incidence of active TB development following ART initiation of HIV-infected individuals in China. In addition, whether a universal prophylaxis strategy would benefit the population also depends on the population-based prevalence of TB activation, as well as therapeutic cost and drug-related adverse events. Therefore, we here aim to compile the prevalence of active TB of PLWH in the first five years of initiating ART in one comprehensive referring center in Beijing China, providing real-world data for a more individualized TPT in HIV-infected individuals. The study obtained ethical review and approval from the Institutional Review Board of Peking Union Medical College Hospital (No. K23C3931). Before the commencement of this study, informed consent was obtained from all PLWH. We retrospectively enrolled a total of 940 eligible HIV-infected individuals from January 2000 to May 2023. 1.7% of this cohort tested positive on purified protein derivative (PPD) skin tests, while all individuals who have undergone chest X-rays showed normal results. During the first five years after ART, a total of 23 HIV-infected individuals developed active TB [Supplementary Table 1, https://links.lww.com/CM9/C232]. The majority of them had pulmonary TB (19 [83%]), with only four affected with extrapulmonary TB. Among all participants, the cumulative incidence of active TB infection over 5 years was about 2.4% [Figure 1A]. The incidence density was about 7 per 1,000 person-years (95% confidence interval [CI]: 4–10). Notably, during the 5-year follow-up, PLWH with baseline CD4+ T count <200 cells/μL had a prominently higher incidence of active TB compared to those with baseline CD4+ T count ≥200 cells/μL (P = 0.006) [Figure 1B]. The median time of active TB occurrence was 3 months (IQR: 1–16) [Supplementary Table 1, https://links.lww.com/CM9/C232]. The peak for active TB was within the first 3 months of ART, with an incidence rate of 1.4% (13/940). However, occurrence of active TB was infrequent after 3 years of ART [Figure 1C], when the average CD4+ T count remained stable and consistently close to 500 cells/μL [Figure 1D].Figure 1: (A) Cumulative incidence of active TB in follow-up five years. (B) The cumulative probability of active TB occurrence in PLWH with baseline CD4+ T count <200 cells/μL group and CD4+T count ≥200 cells/μL group. (C) Active TB incidence of the study population at different follow-up time. (D) Changes of CD4+T count of participants within the first five years of ART. ART: Antiretroviral therapy; TB: Tuberculosis.We further observed the characteristics before ART of individuals co-infected with HIV and active TB. Most participants had an undergraduate educational background. Compared with the study population, they had a lower median baseline CD4+ T count (86 cells/μL vs. 303 cells/μL) and a higher HIV-1 viral load (VL) (5.1 log10 copies/mL vs. 4.7 log10 copies/mL). About 65% (15/23) of individuals had a baseline CD4+ T count <200 cells/μL. PLWH with baseline CD4+ T count <50 cells/μL accounted for 39.1% (9/23), CD4+ T count 50–100 cells/μL for 17.4% (4/23), and CD4+ T count 100–200 cells/μL for 8.7% (2/23), respectively [Supplementary Figures 1A,B, https://links.lww.com/CM9/C232]. No significant difference was observed in the baseline CD8+ T count between PLWH who developed active TB and those who did not (P = 0.316), but the CD4+/CD8+ ratio was lower in the active TB group (P <0.0001) [Supplementary Figures 1C,D, https://links.lww.com/CM9/C232]. All individuals infected with TB received anti-TB treatment. Of them, one person experienced drug-related adverse effects. No deaths were recorded due to active TB infection [Supplementary Table 2, https://links.lww.com/CM9/C232]. Furthermore, Cox regression suggested that baseline CD4+ T count and baseline HIV-1 VL were risk factors contributing to active TB infection of the HIV-infected individuals, with lower CD4+ T count and higher HIV-1 VL associated with greater likelihood of developing active TB [Supplementary Table 3, https://links.lww.com/CM9/C232]. TB is the most common and life-threatening opportunistic infection in PLWH in China and other developing countries. The widespread use of ART has significantly reduced the risk of active TB infection.[2] Due to the high risk of TB reactivation in PLWH, WHO has recommended universal TPT in HIV-infected individuals, which has also been echoed in Chinese HIV/AIDS Guidelines since 2021. However, completion of TPT in PLWH was poor in China, making it necessary to re-assess the best implementation mode in areas with varying TB burdens and practical problems. In this study, we retrospectively investigated the incidence of active TB infection in PLWH after ART initiation in a referring medical center in Beijing, and found the incidence of TB reactivation with a 5-year follow-up was approximately 2.4%, with pulmonary TB as the major clinical type. The incidence density was about 7 per 1000 person-years. Our study revealed that PLWH with baseline CD4+ T count <200 cells/L experienced dramatically higher cumulative incidence of active TB compared to those with baseline CD4+ T count ≥200 cells/μL. Lower baseline CD4+ T count and higher HIV-1 VL were the potential risk factors of active TB infection. These findings suggested a role of TPT in PLWH in China, and a primary targeted TPT strategy focused on more advanced HIV-infected individuals should be considered. Although WHO has recommended universal TPT for HIV-infected individuals, the practice of TPT in real-world remains irresolute, especially given the changing TB prevalence, well-received early ART concept, and concerns regarding the costs, potential adverse effects, and drug interactions between anti-tuberculosis treatment and ART. Studies showed that TPT with fewer drugs and shorter duration compared with standard therapy, showed survival benefit especially in advanced HIV-infected individuals, as indicated by the REALITY trial[3] and the TEMPRANO trial[4]. However, most relevant studies were carried out in Africa, and situations may differ in other areas. Nevertheless, there seems to be no doubt that early ART initiation and TPT in advanced HIV-infected individuals could significantly improve the outcome. Our results also showed little occurrence of active TB after 3 years of ART, indicating that consistent ART can significantly reduce the incidence of opportunistic infections. However, a universal TPT plan seems a bit far from current Chinese practice, and a stepwise mode may be more practical. Our study found that lower CD4+ T count and higher HIV-1 VL were the risk factors of active TB during ART. Specifically, PLWH with a stable CD4+ T count of close to 500 cells/μL or ART for over three years seldomly experienced active TB. Therefore, closer attention should be paid especially to PLWH with low baseline CD4+ T count and higher HIV-1 VL, and TPT in such patients may be more cost/benefit efficient. Our findings may serve as a specific reference for the future implementation of TPT in China. The true considerations underlying the current low rate of TPT in PLWH need to be further explored. Our study has some limitations that should not be ignored. Firstly, it is a retrospective investigation with inevitable retrospective bias. Meanwhile, this is a single-centre study with a relatively small sample size with limited predictive power. We are unable to further establish a delayed ART group or a non-HIV infection group as controls for comparison or to substantiate our conclusions. Due to the low implementation rate of TPT among PLWH globally for various reasons, especially in resource-limited settings including China, we lack a comparison with PLWH who have undergone TPT to further clarify the specific benefits of TPT for clinical PLWH. Additionally, the substantial missing baseline data of PPD skin test and limited completion of baseline IGRA tests due to unaffordability, have made it hard to get more detailed analysis of PLWH at risk for active TB during ART, though such tests have reduced power in immunocompromised populations including PLWH. Finally, while this study identified risk factors for active TB occurrence during ART, providing insights for enhancing clinical management of HIV-infected individuals in China and prompting further investigation, it is crucial to note that these findings need to be re-evaluated, especially in future interventional or prospective cohort studies. In conclusion, our study indicates that the overall incidence of active TB largely depends upon PLWH immune status, more prominent in those with advanced HIV status. A stratified strategy for TB prophylaxis in different disease statuses should be considered as a preliminary and practical option in current clinical practice in China. Lower baseline CD4+ T counts and higher viral load are identified as risk factors for active TB occurrence post-ART initiation. Initiating TPT in HIV-infected individuals with low baseline CD4+ T count and high baseline HIV-1 VL in parallel with ART offers clinical benefits, and could be considered a practical preliminary option. However, further investigations through interventional or prospective cohort studies are required for the TPT strategy in current China. Conflicts of interest None.