Efficacy and safety of different regimens in the treatment of patients with latent tuberculosis infection: a systematic review and network meta-analysis of randomized controlled trials

Tuberculosis (TB) remains the leading cause of morbidity and mortality from a single infectious disease [1], with one-fourth of the global population, approximately 2 billion persons, estimated to be infected with TB [2, 3]. The occurrence of latent tuberculosis infection (LTBI)—a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB – is impeding the effort to prevent and control TB [2, 4-6]. Treatment of LTBI is effective in preventing progression to TB disease while approximately 5%–10% of persons with LTBI progress to active TB disease if untreated [7-9]. The probability of progression to active TB disease is higher in specific risk groups including people living with HIV, receiving dialysis, preparing for an organ or hematological transplant, prisoners, health workers, immigrants, homeless, silicosis, diabetes, and drug addicted [10-14].

WHO recommends TB preventive treatment (TPT) a key approach to end TB. The current TPT treatment consists of the preferred three rifamycin-based preferred regimens: 3 months of once-weekly isoniazid plus rifapentine, 4 months of daily rifampin, or 3 months of daily isoniazid plus rifampin [3, 4]. Some studies reported that rifamycin-based regimens are effective and safe for treatment of LTBI, with higher treatment completion rates [15-20]. Some other studies reported that regimens isoniazid monotherapy, daily for 6–9 months, is efficacious but with a higher risk of toxicity and a lower treatment completion rates compared to rifamycin-based regimens with shorter treatment durations [21, 22]. Studies also demonstrated that 3 months of once-weekly isoniazid plus rifapentine is non-inferior to other regimens, but with slightly higher adverse events [21-25]. A recent study also showed a beneficial effect of one month daily isoniazid and rifapentine combination-therapy [26]. There are concerns about pragmatic and long-term aspects of TPT, including adherence, potential emergence of drug resistance, and cost-effectiveness in resource-constrained settings [27]. Several systematic reviews as well as network meta-analyses have yet been documented about treatment of LTBI [8, 28-30]; however, majority focused on effectiveness of different regimens that did not provide information about the indirect relative (comparision of different TPTs with one another indirectly) safety of the TPT regimens. Also, these studies have provided separate information about the efficacy of TPT among people living with HIV, immigrants, children, and people who had Tb cotact history. We belive that there is a need for an updated and more comprencive evidence regarding the efficacy and safety of TPTs for different population groups.

We, therefore, conducted this systematic review and network meta-analysis of randomized controlled trials (RCTs) using the frequentist model to provide an up-to-date summary and analysis of previously published studies that have evaluated LTBI regimens and made informative comparisons of their relative efficacy and adverse event profiles.

The protocol for this systematic review and network meta-analysis has been registered at the International Prospective Register of Systematic Reviews (PROSPERO) database, ID: CRD42022334163 [31]. The PRISMA statement extension for systematic reviews incorporating network meta-analysis (PRISMA-NMA) was used to review and report this research [32].

Ttreatment of individuals with LTBI is considered a fundamental strategy for the control of TB. Prevention of TB by treating individuals with LTBI is a cost-effective intervention when directed at those with the greatest likelihood of TB, such as recently infected cases, individuals with untreated residual lesions or immuno suppression, children, and recent immigrants from highly endemic regions [59]. Globally, tuberculosis is the principal cause of death in up to one third of people dying who have HIV infection [60-62]. Patients with human immunodeficiency virus (HIV) infection and latent tuberculosis are at substantial risk for the development of active tuberculosis [59]. Many people living with HIV are still dying from TB, despite the availability of ART and measures to control opportunistic infections such as TB are especially important. The prevention of tuberculosis in people with HIV infection has both clinical and public health importance [59].

In this study, the incidence of TB among people living with HIV who have taken 3RH as TPT was lower followed by 6H. However, 3HP shows a significant reduction on the incidence of TB among HIV negative patients who had TB contact history. In terms of preventing TB among PLWHIV, while initiating TPT, it is necessary to consider potential harm such as hepatotoxicity and development of drug resistance, and acceptability of the selected regiment by the patient [3, 30]. A previous network meta-analysis has reported that all regimens of interest except 9H showed significant benefits in preventing active TB compared to placebo [29]. On the contrary, another previous network meta-analysis reported that 6 to 12 months of isoniazid were no more efficacious in preventing microbiologically confirmed TB than rifamycin-containing regimens [30]. But, a previous meta-analysis also reported that prolonged regimens (prolonged H and 6H) were more effective in preventing TB [63-65]. However, a 12-dose regimen of once-weekly isoniazid and rifapentine has been shown to be noninferior to 9 months of daily isoniazid in a large and well conducted clinical trial [66]. It has also showed a significant benefits in preventing the development active TB among patients who had a household TB contact history, immigrant population, and old people [16, 19, 67]. Perhaps, those studies which assessed the efficacy of prolonged isoniazid regimens, followed the patients for a short period of time after treatment; thus, the incidence of TB cases detected are only those patients who developed TB while on treatment or shortly after. Yet, difference on the post-treatment follow up time could also have an impact on the incidence of TB among patients. Other factors including the setting where the patients were living (e.g., places where TB incidence were higher), tuberculin skin test positive (ie, ≥ 5 mm induration) at enrolment, high fat intake with TPT regimens, low CD4⁺ cell count, drug addiction, and high ART coverage could also be a confounding factors [3, 30, 65, 68-70].

In order to enhance the potential benefit of TPT and achieve the anticipated efficacy level, patients’ adherence to TPT needs to be higher. The efficacy, adherence, and safety of TPT depends in treatment regimen selection [59]. In this study, patients’ adherence to TPT was higher among patients who have taken 4R followed by 3RH. According to the result from previous network meta-analysis, even if the definitions of regimen completion varied across studies, regimens of 3–4 months were associated with a greater likelihood of adequate completion [29]. Consistently, a previous study [21] reported that, compared with the 9H regimen, the 3HP regimen had a higher completion rate with lower hepatotoxicity and well-tolerated adverse drug reaction [18]. Most of the previous studies associated higher compliance rate with shorter duration of regimen, drug tolerability, self-limiting adverse drug reactions (ADRs), directly observed administration, and dosing schedule, these factors could affect the completion rate [18, 71]. Other factors such as difference in population group (e.g., prisoners and other marginalized communities), precarious social and economic situation, the diagnosis resulting from screening, which suggests a lack of patient motivation, as there was no known TB focus could also have an impact on the completion rate. In immigrant population, precarious employment, economic difficulties, lack of family support and language and cultural barriers all make patient follow-up more difficult. As this was a healthy population that had immigrated with the intention of working, worrying about their health was not a priority.

The proportion of subjects who permanently discontinued a study drug because of adverse event were higher in patients who has taken 3RH. The frequency of nausea and vomiting were higher among patients who have taken 3HP, followed by two months twice a week combination of HP. However, a previous study reported that, compared with 9H and 3HP had associated with low hepatotoxicity and well-tolerated adverse drug reaction [18, 72]. Furthermore, the risk of grade 3 and 4 liver toxicity was significantly higher among patients who have taken 12H, followed by 2RZ. The risk of hepatotoxicity could be related to prolonged isonizide therapy [18, 30] and combination of isoniazid either with rifampicin [73], age, female sex, white race, non-Hispanic ethnicity, decreased body mass index, alcohol consumption, and elevated baseline AST [16, 74, 75]. Other factor such as frequent liver monitoring and symptom-driven monitoring for hepatotoxicity, could also affect the result [21, 23, 74]. In addition, Heptitis C Virus (HCV) infection was also associated with hepatotoxicity when controlling for other factor [76]. Consistently, a previous study also reported that the risk of hepatitis in patients receiving pyrazinamide/rifampin for prevention of latent tuberculosis is increased threefold as compared to patients receiving isoniazid [75].

From this review, it can be concluded 3RH and 6H has a significant impact on the reduction of TB incidence among PLWH and 3HP among HIV negative people who had TB contact history. However, combinations of rifampicin either with isoniazid were significantly associated with adverse events which resulted permanent discontinuation among adult patients. Furthermore, Grade 3 and 4 kiver toxicity was more common in patent’s who have taken 9H, 1HP, and 6H. This may support the current recommended TPT regimen of 3HP, 3RH, and 6H.