Female sex and discontinuation of isoniazid due to adverse effects during the treatment of latent tuberculosis

doi:10.1016/j.jinf.2013.07.015

Journal of Infection

Volume 67, Issue 5, November 2013, Pages 424-432

https://doi.org/10.1016/j.jinf.2013.07.015 Get rights and content

Summary

Objectives

To determine the rate of and risk factors for discontinuation of isoniazid due to adverse effects during the treatment of latent tuberculosis infection in a large, multi-site study.

Methods

The Tuberculosis Epidemiologic Studies Consortium (TBESC) conducted a prospective study from March 2007–September 2008 among adults initiating isoniazid for treatment of LTBI at 12 sites in the US and Canada. The relative risk for isoniazid discontinuation due to adverse effects was determined using negative binomial regression. Adjusted models were constructed using forward stepwise regression.

Results

Of 1306 persons initiating isoniazid, 617 (47.2%, 95% CI 44.5–50.0%) completed treatment and 196 (15.0%, 95% CI 13.1–17.1%) discontinued due to adverse effects. In multivariable analysis, female sex (RR 1.67, 95% CI 1.32–2.10, p < 0.001) and current alcohol use (RR 1.41, 95% CI 1.13–1.77, p = 0.003) were independently associated with isoniazid discontinuation due to adverse effects.

Conclusions

The rate of discontinuation of isoniazid due to adverse effects was substantially higher than reported earlier. Women were at increased risk of discontinuing isoniazid due to adverse effects; close monitoring of women for adverse effects may be warranted. Current alcohol use was also associated with isoniazid discontinuation; counseling patients to abstain from alcohol could decrease discontinuation due to adverse effects.

Introduction

There are an estimated 11 million people living with latent tuberculosis infection (LTBI) in the United States (US).¹ Reactivation of LTBI accounts for approximately 70% of tuberculosis (TB) cases in this country.2, 3 Therefore, targeted testing and successful completion of treatment for LTBI is a critical component of TB elimination in the US.⁴ The current standard treatment regimen for LTBI is daily isoniazid for 9 months.⁴ Completion rates for this regimen are low, ranging 30–64%, which is due in part to the long duration of the regimen as well as drug-related adverse effects.4, 5, 6, 7, 8, 9

One well-characterized adverse effect due to isoniazid is liver injury. A previous meta-analysis reported a rate of liver injury of 0.6% among patients taking isoniazid for LTBI treatment.¹⁰ More recent, large studies have reported lower rates of 0.1–0.3%.7, 11 However, fatalities due to isoniazid-associated liver injury have been reported.12, 13 Risk factors for isoniazid-associated liver injury include older age,7, 11, 13 regular alcohol use,¹³ chronic viral hepatitis,14, 15 and pregnancy or the post-partum period (particularly among Hispanic women).¹⁶ There is no clear evidence for a sex-related difference in the incidence of isoniazid-associated liver injury¹⁷; however, women may be at increased risk of death due to isoniazid-associated liver injury.¹⁸

Peripheral neuropathy is another adverse effect described during treatment with isoniazid. The incidence is dose-related and uncommon (<2%) with conventional dosing of 5 milligrams (mg)/kilogram (kg) daily.¹⁹ Risk factors include other conditions associated with nutritional deficiency including malnourishment, human immunodeficiency virus (HIV) infection, diabetes mellitus, renal failure, alcoholism, and pregnancy or breastfeeding.¹⁹ Pyridoxine supplementation is recommended during therapy with isoniazid among these high-risk groups.⁴

There is less known about the rate of and risk factors for the occurrence of other adverse effects during isoniazid LTBI treatment, particularly from programmatic field settings. In a retrospective study of 3788 patients starting isoniazid for LTBI treatment in San Diego County's TB Control Program, 52 (1.4%) stopped treatment early due to adverse effects.⁷ These included hepatotoxicity (50%), dizziness (35%), nausea or vomiting (9%), abdominal pain (5%), rash (4.6%), headache (2.4%), paresthesias (2.2%), and pruritus (1.7%). In adjusted analyses, female sex, increasing age, homelessness, and time spent in a correctional facility were associated with the occurrence of ≥1 adverse effect. The occurrence of ≥1 adverse effect, in turn, was associated with lower rates of completion of LTBI treatment. Excess alcohol use and injection drug use were not associated with adverse effects, although excess alcohol use was associated with lower completion rates. However, this study was retrospective and did not assess more detailed information on the timing, severity, or type of alcohol and substance use. Additionally, 19.3% of patients in this study were lost to follow-up and had no treatment outcome documented.

Injection drug use increases the risk for recent Mycobacterium tuberculosis infection20, 21 and progression to active disease.²² Therefore, injection drug users are a group of persons in whom the Centers for Disease Control and Prevention (CDC) recommends targeted testing and treatment for LTBI.⁴ Persons who use injection drugs are less likely to complete treatment for LTBI with rifampin and pyrazinamide,²³ but associations with isoniazid regimens have not been shown. It is unknown if the non-completion among this group is due to drug-related adverse effects, non-adherence, or both.

Regular alcohol use may increase the risk of infection with M. tuberculosis or progression to active disease; however, given the prevalence of other known risk factors among persons who abuse alcohol (e.g. tobacco use), it has been difficult to identify alcohol use as an independent risk factor.⁴ Persons who regularly use alcohol are less likely to complete isoniazid treatment for LTBI.7, 24 Regular alcohol use has also been shown to be a risk factor for isoniazid-associated liver injury,¹³ but has not been evaluated as a risk factor for non-hepatotoxic adverse effects.

It is important to determine the rates of discontinuation of isoniazid treatment for LTBI due to all adverse effects, not just liver injury. Moreover, identification of risk factors for adverse effects may lead to the identification of persons in need of closer monitoring or persons in whom interventions such as treatment for alcohol or substance abuse should be pursued in conjunction with treatment for LTBI. We report data from a large, prospective, multi-site study to determine the rate of adverse effects resulting in drug discontinuation during isoniazid treatment for LTBI. We also examine risk factors for discontinuation of isoniazid due to adverse effects, including the severity, timing, and type of alcohol and substance use.

Section snippets

Patient population

The Tuberculosis Epidemiologic Studies Consortium (TBESC) conducted a prospective cohort study from March 2007–September 2008 among adults initiating isoniazid for LTBI treatment at 12 sites in the US and Canada. Details regarding this consortium are described elsewhere.²⁵ Participants were eligible if they were ≥18 years old, tested positive for LTBI by a tuberculin skin test, and accepted self-administered isoniazid as treatment for LTBI. Participants were ineligible for study enrollment if

Results

From March 2007 to September 2008, 1323 participants were determined eligible and enrolled in this study. Participants were excluded from this analysis if they accepted, but never initiated isoniazid treatment (n = 17). Of 1306 who initiated isoniazid, 617 (47.2%, 95% confidence interval [CI] 44.5–50.0%) completed isoniazid treatment; 595 (96.4%) completed a planned 9-month course and 22 (3.6%) a planned 6-month course. There were 196 (15.0%, 95% CI 13.1–17.1%) who discontinued isoniazid due to

Discussion

In this study, the rate of completion of isoniazid for LTBI treatment was 47.2% (95% CI 44.5–50.0%). This isoniazid completion rate is consistent with previously reported rates ranging from 30 to 64% depending on the population studied.4, 5, 6, 7, 8, 9

The rate of discontinuation of isoniazid due to adverse effects was 15.0% (95% CI 13.1–17.1%). In a previous study of 3788 patients starting isoniazid for LTBI treatment in San Diego County's TB Control Program, there were 672 (17.7%, 95% CI

Funding information

This study was supported by the Centers for Disease Control and Prevention, Contract Number 200-2001-00082 and National Institutes of Health K24 AI 65298 (ACP, TRS).

Financial/nonfinancial disclosures

All authors report no conflicts of interest relevant to this article. Dr. Sterling reports receiving research grant funding from Bristol-Myers Squibb and Pfizer for HIV observational studies. Dr. Sterling is also a member of a data safety monitoring board for Otsuka.

Acknowledgments

Author Contributions: A.C.P. had full access to all of the data and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: A.C.P., J.B., P.W.C., Y.H., T.R.S. Acquisition of data: J.B., P.W.C., Y.H., T.R.S. Analysis and interpretation of data: A.C.P., J.B., P.W.C., Y.H., T.R.S. Drafting of the manuscript: A.C.P. All authors were involved in critical revision of interim drafts and approved the final version of the manuscript.

Other

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While some studies have found no significant sex differences (Ting et al., 2014; Teklu et al., 2018; Ncayiyana et al., 2016), others appear to show higher rates of LTBI in men (Reichler et al., 2020; Sabri et al., 2019; He et al., 2015; de Souza et al., 2014; Chen et al., 2015). Further analyses found that men were more likely to receive (Fiske et al., 2014) and complete LTBI treatment (Hirsch-Moverman et al., 2015) and have less antitubercular medication toxicity (Pettit et al., 2013). Of note, several of these studies were in specific populations such as healthcare workers, and only the Tuberculosis Epidemiologic Studies Consortium Task Order-2 Team evaluated large numbers of close contacts with active TB disease (Reichler et al., 2020; Fiske et al., 2014).
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Several studies have reported risk factors associated with non-completion of LTBIT. In the USA and Canada, Pettit et al. observed that among adults who initiated INH, female sex and alcohol use were independently associated with LTBIT discontinuation due to drug intolerance.23 In another study, Horsburgh et al. identified the following as risk factors for non-completion of LTBIT: nine months treatment with INH, living in a nursing home, shelter, or prison; illicit drug use, age ≥15 years, and being a health care professional.9
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Correlation of N-acetyltransferase 2 genotype and acetylation status with plasma isoniazid concentration and its metabolic ratio in ethiopian tuberculosis patients
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Influence of sex on the exposure to isoniazid in patients with pulmonary tuberculosis
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^☆: Notation of Prior Abstract Presentation: These results were presented in part at IDWeek 2012, October 17–21, 2012, San Diego, CA, Abstract #36105.

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Female sex and discontinuation of isoniazid due to adverse effects during the treatment of latent tuberculosis☆

Summary

Objectives

Methods

Results

Conclusions

Introduction

Section snippets

Patient population

Results

Discussion

Funding information

Financial/nonfinancial disclosures

Acknowledgments

Chest

Chest

Am J Gastroenterol

Tubercle

Chest

Hepatology

Prevalence of tuberculosis infection in the United States population: the national health and nutrition examination survey, 1999–2000

Am J Respir Crit Care Med

Changes in the transmission of tuberculosis in New York City from 1990 to 1999

N Engl J Med

The epidemiology of tuberculosis in San Francisco. A population-based study using conventional and molecular methods

N Engl J Med

Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society

MMWR Recomm Rep

Priorities for the treatment of latent tuberculosis infection in the United States

N Engl J Med

Tuberculosis contact investigations: outcomes in selected areas of the United States, 1999

Int J Tuberc Lung Dis

Use of isoniazid for latent tuberculosis infection in a public health clinic

Am J Respir Crit Care Med

Adherence to treatment for latent tuberculosis infection: systematic review of studies in the US and Canada

Int J Tuberc Lung Dis

Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic

J Am Med Assoc