By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC

Professor of Internal Medicine, Northeast Ohio Medical University; Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, OH

Dr. Watkins reports no financial relationships relevant to this field of study.

SYNOPSIS: A health system cost comparison showed that four months of rifampin was safer and less expensive than nine months of isoniazid in high-income countries, medium-income countries, and African countries.

SOURCE: Bastos ML, Campbell JR, Oxlade O, et al. Health system costs of treating latent tuberculosis infection with four months of rifampin versus nine months of isoniazid in different settings. Ann Intern Med 2020;173:169-178.

Latent tuberculosis (TB) infects approximately one in four humans and is a major global health concern. Monotherapy with nine months of isoniazid (INH) became the standard therapy for latent TB in the 1960s. Recently, multiple studies have shown that rifamycin-containing regimens are safer, better tolerated, and can be given for four months instead of nine. However, many policymakers require economic analyses before new treatment regimens are adapted widely. Therefore, Bastos et al compared healthcare and other costs between nine months of INH and four months of rifampin for the treatment of latent TB. The study included adults and children enrolled in two randomized clinical trials. Inclusion criteria were a positive tuberculin skin test or interferon-γ release assay, a clinical or epidemiologic risk factor associated with an increased risk for developing active TB, and a treating physician’s recommendation for treatment of latent TB. Participants underwent a baseline evaluation that included a medical visit, chest X-ray, and routine laboratory tests. In the first month, the authors recommended all participants undergo repeat blood tests. Follow-up visits occurred monthly for the first two months, then at least every eight weeks thereafter.

All participants’ healthcare use was tabulated, which included all activities related to the initial medical evaluation, study drugs, follow-up visits, and management of adverse events or active tuberculosis. Direct costs were estimated from the perspective of the country’s healthcare system. These included Indonesia, Ghana, Benin, Guinea, Australia, Brazil, South Korea, Canada, and Saudi Arabia. The costs were adjusted using local inflation indices and converted to U.S. dollars as of 2017.

There were 6,012 adults and 829 children included in the modified intention-to-treat analysis. The treatment completion rate was 82% for children and 71% for adults. Participants from Africa logged more follow-up visits compared to other sites, while those from the high-income countries underwent more laboratory tests. In the adult population, those who received nine months of INH recorded twice as many follow-up visits and four times the number of laboratory tests as participants who received four months of rifampin.

The total costs among adults who received rifampin were significantly lower than among those who received INH. In high-income countries, the average cost was $549 for rifampin and $725 for INH. In African countries, it was $112 for rifampin and $140 for INH. Furthermore, costs for adverse event care were lower for rifampin in all settings compared to INH. The rifampin regimen also was less expensive in the pediatric population. Notably, in African countries, the 100-mg INH pill is used, which is more expensive than the 300-mg pill and raised costs in the INH group. In a multivariate analysis, the total health system cost for rifampin was $340 cheaper than the INH regimen (95% CI, $330 to $350), a relative savings of 38%.

COMMENTARY

The effect of economics on the healthcare system carries important implications for patient care. Strictly speaking, a four-month supply of rifampin costs more than a nine-month supply of INH. However, this is only part of the equation. Multiple studies have shown four months of rifampin is noninferior to nine months of INH for latent TB — and safer, with a greater likelihood that patients will complete the course of therapy. Indeed, the recent CDC guidelines for latent TB recommend four months of rifampin as the primary regimen.1 The study by Bastos et al provides another important reason to prescribe rifampin over INH: lower overall healthcare system cost. Thus, the higher cost of the pills should not prevent the adoption of four months of rifampin in latent TB programs, especially in resource-limited settings.

There were some limitations to the study. First, the clinical trials required a minimum number of follow-up visits that might be regarded as excessive in real-world settings. However, multiple guidelines recommend monthly follow-up visits for latent TB. Second, the costs were not standardized across the sites, and the investigators had to use some judgment in deciding the true cost in each country. Third, there were few children enrolled from high-income sites, thus reducing the generalizability of the results for the pediatric population in high-income countries. Finally, costs were not estimated from patients’ perspectives (e.g., time lost for appointments, travel expenses, and time to refill medication).

Rifampin now carries another advantage over INH for latent TB: cheaper costs. Treating patients with INH for latent TB should be the exception, not the rule.

REFERENCE

  1. Sterling TR, Njie G, Zenner D, et al. Guidelines for the treatment of latent tuberculosis infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020. MMWR Recomm Rep 2020;69:1-11.