Isoniazid Preventive Therapy for Tuberculosis among HIV Patients

Isoniazid Preventive Therapy for Tuberculosis among HIV Patients: History

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Subjects: Health Care Sciences & Services | Infectious Diseases

Contributor:

Dawit Getachew Assefa

Eden Dagnachew Zeleke

Delayehu Bekele

Dawit A. Ejigu

Wondwosen Molla

Tigist Tekle Woldesenbet

Amdehiwot Aynalem

Mesfin Abebe

Andualem Mebratu

Tsegahun Manyazewal

Tuberculosis (TB) is a major cause of morbidity and mortality in people living with HIV (PLWHIV). Isoniazid preventive therapy (IPT) prevents TB in PLWHIV, but estimates of its effects and actual implementation vary across countries. PLHIV who were on IPT, independently or simultaneously with ART, were less likely to develop TB than those without IPT. IPT interventions had a significant association with improved CD4 count and reduced all-cause mortality. IPT was less effective in people with advanced HIV infection. The major factors influencing IPT implementation and uptake were stock-outs, fear of developing isoniazid-resistant TB, patient’s refusal and non-adherence, and improper counseling and low commitment of HIV clinical care providers. IPT alone or in combination with ART significantly reduces the incidence of TB and mortality in PLHIV in Ethiopia than those without IPT. More research on safety is needed, especially on women with HIV who receive a combination of IPT and ART.

isoniazid prevention therapy (IPT)
HIV
tuberculosis

1. Introduction

Tuberculosis (TB) remains one of the top 10 causes of death globally and the primary cause of death from a single infectious agent [1]. In 2021, there were 10.6 million TB cases globally and 1.4 million deaths among HIV-negative people, and an additional 187,000 deaths among HIV-positive people [1]. Most people who acquired TB in 2021 were in the regions of South-East Asia (45%), Africa (23%), and the Western Pacific (18%) [1]. In Africa, a widespread scale-up of antiretroviral therapy (ART) strongly declines the incidence of TB [2]. Ethiopia is one of the top 14 triple burden countries for TB, TB/HIV, and MDR-TB [1]. An estimated incidence of all forms of TB in Ethiopia, in 2019, was 140/100,000 population, with 111,039 TB cases notified [1]. TB remains one of the major causes of morbidity and mortality in the country [3].

To prevent and reduce the incidence of TB in people living with HIV (PLHIV), the World Health Organization (WHO) recommended the use of isoniazid preventive therapy (IPT) as a mainstay of the “Three I’s” approach [4]. Per the WHO recommendation, IPT is administered at a daily dose of a maximum of 300 mg daily for 6–9 months in adults and adolescents and 5 mg/kg for children [5,6]. This chemoprophylaxis reduces the risk of an early episode of TB occurrence in people with latent infection or those exposed to infection, and reduces recurrent episodes of TB [5,6]. For patients with latent TB, IPT can be beneficial, with the potential to reduce TB infection irrespective of HIV status [5,6] and protecting communities from [7,8,9]. However, the emergence of drug resistance secondary to IPT administration is a potential risk that is understudied [5].

In Ethiopia, the National TB guideline recommends that IPT should be provided to all HIV-infected individuals who are unlikely to have active TB irrespective of CD4 count, ART status, pregnancy status, or history of treatment for a prior episode of TB before three years. Patients should be supported at home level either by local health extension workers or a family supporter to ensure daily administration of IPT. Patients should be given a one-month supply of isoniazid for six months, with a monthly scheduled follow-up integrated with other treatment services. IPT should also be administered for asymptomatic children under five who were exposed to TB within the past year.

2. Incidence of TB

Among PLHIV, the incidence of TB after administration of IPT independently or simultaneously with ART shows a significant reduction in the incidence of TB as compared to patients who were on ‘ART only’ and ‘No intervention’ [12,13,15,16,17,18,19,20,21]. Simultaneous administration of both IPT and ART reduced the incidence of TB by 80% [12], 93.7% [13], and 65% [14], respectively. Completion of IPT showed a significant protective effect against the occurrence of active TB for 3 years when compared to IPT non-exposed patients [13]. IPT was associated with a significant change in CD4 count [15,19,20] and reduced all-cause mortality [14,17,19,20].（Table 1）

3. Factors Associated with TB Incidence among PLWHIV Who Took IPT

The risk of developing TB or dying was significantly higher in PLHIV on WHO stage III and above at baseline [12,13,14,16,17,18,22], male [12,13,14,22], with a CD4 count of less than a 350 cell count/μL and those with opportunistic infections [15,16,17,18,21,22], children with delayed motor development [21] who did not take cotrimoxazole preventive therapy [18,21,22], use anti-pain [22], and have a hemoglobin level less than 10 mg/dL [16,21,22]. The risk of TB infection and death was lower in those who held good body weight [14,18,21,22] and referred to the hospital from other health facilities [14]. In some of the studies, the effects of age [14,21] and baseline CD4 count had a suboptimal effect on TB incidence or death [14].

4. Barriers in the Implementation of IPT

A significant number of HIV clinical care providers reported that several barriers hinder IPT coverage and its effective implementation, including isoniazid stock-outs, fear of developing isoniazid resistance, patient’s refusal and non-adherence, and improper counseling and low commitment of HIV clinical care providers [23]. Lack of patient empowerment and proper counseling on IPT, weak patient/healthcare provider communication, information gaps, low commitments from health administrators and other stakeholders to effectively run the IPT program, and underlying mental health issues resulting in missed or irregular patient adherence to IPT were also reported as barriers for effective implementation of IPT in Ethiopia [24]. Additionally, clinician impressions that ruling out active TB among HIV patients is difficult was found to be a significant barrier to IPT uptake [25].

Table 1. Characteristics of included studies.

S. No	Study ID	Design	Setting	Age	Follow Up	Subjects		Patient Important Outcome
1.	Mindachew et al., 2014 [24]	Qualitative	Hospital	N/A	N/A	12 heath professional		barriers	Lack of patient empowerment and proper counseling on IPT, weak patient/healthcare provider relationship, lack of patient information, low reinforcement by health officials and stakeholders to strengthen IPT uptake and adherence forgetfulness, patient IPT non-adherence, and non-disclosure of HIV zero-status.
2.	Yirdaw et al., 2014 [12]	Retrospective cohort	Hospitals (n = 5)	Mean (30 years)	2 years	5407 patients		IPT before ART	aHR = 0.18, 95% CI = 0.08–0.42
								IPT before ART’	HR = 0.25, 95% CI = 0.11–0.59
								IPT and ART	aHR = 0.20,95% CI = 0.10–0.42
								IPT and ART	HR = 0.36; 95% CI = 0.17–0.74
								IPT only	HR = 0.24, 95% CI = 0.13–0.44
								IPT after ART	HR = 0.19, 95% CI = 0.11–0.34
								TB incidence	295
3.	Assebe et al., 2015 [17]	Retrospective cohort study	Hospital	N/A	Mean 24.1 months	588		Overall TB incidence	49
						IPT 294	No IPT 294	Overall TB incidence	3.78 cases per 100 PY (95% CI: 2.85, 4.99 cases per 100 PY)
						IPT 294	No IPT 294	Incidence of TB among IPT Plus ART	2.22 cases per 100 PY (95% CI: 1.29, 3.82 cases per 100 PY)
								Incidence of TB among ART alone	5.06 cases per 100 PY (95% CI: 3.65, 7.02 cases per100 PY)
								Incidence of TB among IPT Plus ART	aHR 2.02 (95% CI: 1.04–3.92)
4.	Nigusse et al., 2015 [16]	Retrospective follow up study	Hospital	Median 38 (IQR: 31.2–42)	5 years	480		Overall TB incidence	70
								Overall TB incidence	3.59 per 100 PY
								TB incidence among IPT	aHR = 0.49, 95% CI = 0.26–0.94
5.	Ayele, 2015 [14]	Retrospective cohort study	Hospital	Range 15–99 years	839 days	1922 (374 received IPT)		Overall TB incidence	258
								Incidence of TB/death among IPT plus ART	HR = 0.35; 95% CI (0.16, 0.77)
								Incidence of TB/death among ART alone	HR = 1.22; 95% CI (0.45, 3.28)
								Incidence of TB/death among IPT plus ART	aHR = 0.40; 95% CI (0.18, 0.87)
								Incidence of TB among IPT plus ART	5.20 per 100 PYs
								Incidence of TB among ART alone	8.05 per 100 PYs
6.	Alemu et al., 2016 [21]	Retrospective cohort study	Hospitals (n = 2), Health centers (n = 6)	Median (IQR) 6 (3.5–9.00) years	N/A	645		Overall TB incidence	79
								Overall TB incidence	4.2: 95% CI (3.4, 5.3) PY
7.	Teklay et al., 2016 [23]	Qualitative study	Hospitals (n = 11)	Mean (±SD) 30 (±6) years	N/A	50 health providers		Barriers	Isoniazid stock out
									Fear of creating isoniazid resistance Problems in patient acceptance Lack of commitment of health managers
8.	Abossie et al., 2017 [15]	Hospital-based retrospective study	Hospital	Mean (±SD) 31.27 (+12.0)		271		Incidence of TB among IPT Plus ART	12 (8.7%)
						IPT 138	No IPT 133	Incidence of TB among ART alone	37 (27.8%)
						IPT 138	No IPT 133	Incidence of TB among IPT Plus ART	RR 0.31 (95% CI 0.122, 0.49)
9.	Semu et al., 2017 [13]	Retrospective cohort	Public health institutions	Mean (±SD) 34.9 (±9.1) years	5 years	2524 patients		TB Incidence Rate among IPT	0.21/100 PY
9.	Semu et al., 2017 [13]	Retrospective cohort	Public health institutions	Mean (±SD) 34.9 (±9.1) years	5 years	2524 patients		TB-incidence Rate among at IPT completion	aIRR 0.037 (95% CI, 0.016–0.072)
								overall TB incidence	6.7/100 PY
								TB incidence	277
								Incidence of TB among IPT-with-HAART	0.42/100 PY
								Incidence of TB among IPT-with-HAART	aIRR = 0.063 (95% CI 0.035–0.104)
								Incidence of TB among alone HAART	7.83 cases/100 PY
10.	Tiruneh et al., 2019 [18]	Retrospective cohort study	Hospital and health center	Mean (±SD) 33 years (±9) years	Median 26 months	600
						IPT 200	No IPT 400	Overall TB Incidence	53 (8.8%)
								Overall TB Incidence	57 cases per 100 PY
								Incidence of TB among IPT group	1.98 per 100 PY
								Incidence of TB among non-IPT group	4.52 per 100 PY
								Incidence of TB among IPT group	aHR 0.45, 95% CI 0.219–0.920
								Incidence of TB among IPT group	HR 0.397, 95% CI 0.203–0.774
11.	Gebremariam et al., 2020 [20]	Retrospective cohort study	Hospitals (n = 2)	N/A	5 years	968 patients		Incidence of TB among ART plus IPT	8 (0.5 cases/100 PY)
						IPT 484	No IPT 484	Incidence of TB among ART plus IPT	aHR 0.17; 95% CI 0.08–0.35
								Incidence of TB among ART alone	49 (3 cases/100 PY)
								Deaths on ART plus IPT	12 (0.5 cases/100 PYs)
								Deaths on ART alone	35 (2.1 cases/100 PYs)
								Death reduction among ART plus IPT	aHR 0.48; 95% CI 0.24–0.97
12.	Atey et al., 2020 [19]	Retrospective Cohort Study	Hospitals (n = 5)	N/A	N/A	1863		Incidence of TB among IPT Plus ART	28
						IPT 621	No IPT 1242	Incidence of TB among ART alone	272
						IPT 621	No IPT 1242	Overall incidence	300
								Incidence rate of mortality among IPT Plus ART	440 per 100,000 PYs
								Incidence rate of mortality among ART alone	1490 per 100,000 PYs
13.	Legese et al., 2020 [22]	Institutional based cross-sectional	Hospital	Mean (±SD) 37.94 (±12.15)	6 months	372 (231 on IPT)		Overall incidence of TB among IPT group	13 (3.5%)

This entry is adapted from the peer-reviewed paper 10.3390/ijerph20010621

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