Rifampicin plus isoniazid for the prevention of tuberculosis in an immigrant population.

Int J Tuberc Lung Dis. 2013 Mar;17(3):326-32.

Jiménez-Fuentes MA, de Souza-Galvao ML, Mila Augé C, Solsona Peiró J, Altet-Gómez MN.

Unidad de Prevención y Control de la Tuberculosis de Barcelona, Servei d’Atenció Primària Suport al Diagnóstic i al Tractament, Institut Català de la Salut, Barcelona, Spain. ajimenezf.bcn.ics@gencat.cat

 

Abstract

OBJECTIVES: To compare the tolerance, adherence and effectiveness of two approaches for the treatment of latent tuberculosis infection (LTBI): 6 months of isoniazid (6H) vs. 3 months of isoniazid plus rifampicin (3RH).

POPULATION: Immigrants with LTBI.

METHODS: Participants were enrolled in a controlled, randomised clinical trial in Barcelona, Spain, from April 2001 to April 2005. Monthly follow-up was done to assess tolerance, side effects and adherence. Effectiveness was evaluated at 5 years.

RESULTS: In the 590 subjects enrolled, the rate of adherence was greater in the 3RH than in the 6H arm (72% vs. 52.4%, P = 0.001). No differences between study arms were observed with respect to hepatotoxicity or side effects. Variables associated with non-adherence were diagnosis by screening (OR 1.88, 95%CI 1.26-2.82, P = 0.001), illegal immigration status (OR 1.48, 95%CI 1.01-2.15, P = 0.03), unemployment (OR 1.91, 95%CI 1.28-2.85, P = 0.0008), illiteracy (OR 1.73, 95%CI 1.04-2.88, P = 0.02), lack of family support (OR 3.7, 95%CI 2.54-5.4, P = 0.001) and the 6-month treatment regimen (OR 2.45, 95%CI 1.68-3.57, P = 0.0001). None of the patients who completed either treatment developed tuberculosis.

CONCLUSIONS: The 3RH regimen facilitates adherence to LTBI treatment and offers a safe, well-tolerated and effective alternative.

PMID: 23407221

MA. JIMENEZ FUENTES-1

Suplementary

Tuberculosis (TB) is one of the leading causes of death worldwide. The World Health Organisation estimates that one third of the world population is infected with Mycobacterium tuberculosis, the causative bacterium of TB. Treatment of individuals with latent M. tuberculosis infection (LTBI) is considered a fundamental strategy for the control of TB1. Prevention of TB by treating individuals with LTBI is a cost-effective intervention when it is directed at those with the greatest likelihood of TB, such as recently infected cases, individuals with untreated residual lesions or immunodepression, children under 5 years  and recent immigrants from highly endemic regions.

The traditional preventive chemotherapy regimen, which consists of administering isoniazid for 6 to 12 months, has demonstrated its effectiveness and efficacy. Nonetheless, patient adherence is poor, primarily due to the long treatment duration.

The development of shortened protocols began at the end of the 1970s with the introduction of rifampicin, associated with isoniazid or other tuberculostatic drugs13. Various regimens have been tested, such as rifampicin plus pyrazinamide, rifampicin monotherapy and isoniazid plus rifampicin or rifapentine. A shorter regimen would be of special interest in groups with a high risk of disease, such as immigrants, a group that has demonstrated scant adherence to treatment. The use of a shorter regimen might improve effectiveness by facilitating adherence, but few studies have compared this approach with the classic strategy.

Our work has shown that the shortened regimen combining rifampin plus isoniazid for three months (3RH) in the treatment of LTBI is better than the traditional pattern (6H) in terms of adherence and there are no differences regarding tolerance, side effects, liver toxicity and effectiveness. Studies in the general adult population in our context and in those coinfected with HIV have reported results similar to ours. There are no studies comparing the usefulness of this regimen in recent immigrants from areas with high prevalence of TB.

A total of 590 immigrants with LTBI and candidates for preventive chemotherapy were recruited in Barcelona. Immigrants came from 59 countries, all of them in geographic areas with TB rates higher than those of the local population. The demographic characteristics of the study sample were representative of the immigrant population: young, mostly male and having a geographic origin with high TB prevalence as their only risk factor for the development of TB.

Even under the best conditions, adherence to preventive chemotherapy is low. Although multiple strategies have been tested to improve adherence, directly observed therapy coupled with short treatment protocols is the only measure that yields better results.

In our study the shorter regimen had significantly better adherence, 72% versus 52.4% for the 6H regimen. The factors related to non-adherence in our study were primarily related to a precarious social and economic situation, the length of the treatment and the diagnosis resulting from a screening, which suggests a lack of patient motivation, since there was no known disease focus.

With respect to drug tolerance and the presence of adverse effects, there were no differences between study arms, 12.1% for the 3RH regimen versus 13.2% in the 6H arm. The secondary effects were primarily gastrointestinal, mild in nature and without leading to the withdrawal of any patient. There also were no significant differences in hepatic toxicity cases, which were very few — 9.1% in the 6H arm and 6.7% in the 3RH arm — and serious in only one case; this could be a result of the low alcohol consumption in this population and the young and healthy population profile. In our experience both approaches are equally effective: none of the patients who completed treatment developed the disease, and only two cases of pulmonary TB were diagnosed in patients who abandoned treatment.

Studies with alternative protocols have typically been conducted in populations at high risk of developing TB, such as patients with silicosis or who are HIV-positive, to reduce sample size and length of follow-up. Very few studies have focused on special populations in developed countries, such as recent immigrants from areas with high TB prevalence, despite evidences of an increase of TB cases in the early years after immigration. Our research in the recent immigrant population has demonstrated that the 3RH resulted in better adherence with no differences in tolerance, hepatic toxicity, secondary effects or effectiveness. Therefore, we consider the 3RH regimen to be the first choice in a population with a problematic family, employment and social integration status.

Further research on pharmaceutical regimens and strategies that facilitate TTBI adherence in patients at high risk of developing TB should be a priority in policies to control TB.

 

In memoriam

To Dr. José Alcaide Megias, teacher and inspiration for this project, who passed away before it came to full fruition.

Funding

This work was made possible by a grant from the Spanish Society of Pneumology and Thoracic Surgery, SEPAR 2002.

Contact

María Angeles Jiménez Fuentes.

Unitat de Prevenció i Control de la Tuberculosi Vall Hebrón-Drassanes.

Programa Especial de Enfermedades Infecciosas.

Hospital Universitario Valle de Hebrón.

Barcelona, Spain.

Mail:  m.jimenez@vhebron.net.

 

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