Isoniazid Preventive Therapy for Tuberculosis among HIV Patients: Comparison
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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][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][5][6]. For patients with latent TB, IPT can be beneficial, with the potential to reduce TB infection irrespective of HIV status [5,6][5][6] and protecting communities from [7,8,9][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][10][11][12][13][14][15][16][17][18]. Simultaneous administration of both IPT and ART reduced the incidence of TB by 80% [12][10], 93.7% [13][11], and 65% [14][19], 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][11]. IPT was associated with a significant change in CD4 count [15,19,20][12][16][17] and reduced all-cause mortality [14,17,19,20][14][16][17][19].（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[10][11][13][14][15][19][20],14,16,17,18,22], male [12[10][11][19][20],13,14,22], with a CD4 count of less than a 350 cell count/μL and those with opportunistic infections [15,16[12][13][14][15][18][20],17,18,21,22], children with delayed motor development [21][18] who did not take cotrimoxazole preventive therapy [18[15][18][20],21,22], use anti-pain [22][20], and have a hemoglobin level less than 10 mg/dL [16,21,22][13][18][20]. The risk of TB infection and death was lower in those who held good body weight [14,18,21,22][15][18][19][20] and referred to the hospital from other health facilities [14][19]. In some of the studies, the effects of age [14,21][18][19] and baseline CD4 count had a suboptimal effect on TB incidence or death [14][19].

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][21]. 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][22]. Additionally, clinician impressions that ruling out active TB among HIV patients is difficult was found to be a significant barrier to IPT uptake [25][23].
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]Mindachew et al., 2014 [22] 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]Yirdaw et al., 2014 [10] 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]Assebe et al., 2015 [14] 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)
            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]Nigusse et al., 2015 [13] 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]Ayele, 2015 [19] 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]Alemu et al., 2016 [18] 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]Teklay et al., 2016 [21] 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]Abossie et al., 2017 [12] 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%)
            Incidence of TB among IPT Plus ART RR 0.31 (95% CI 0.122, 0.49)
9. Semu et al., 2017 [13]Semu et al., 2017 [11] 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
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]Tiruneh et al., 2019 [15] 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]Gebremariam et al., 2020 [17] 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]Atey et al., 2020 [16] 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
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]Legese et al., 2020 [20] 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%)

References

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