Introduction

Settings with a high prevalence of the human immunodeficiency virus (HIV) have experienced dramatic increases in tuberculosis incidence [1]. Alternative approaches are necessary to reduce the risk of HIV associated tuberculosis in such settings. Approaches promoted by the World Health Organization (WHO) include antiretroviral therapy and its 3Is strategy of isoniazid preventive therapy (IPT), intensified case finding (ICF) and infection control [1]. IPT was provided to almost 450,000 newly enrolled into HIV care in 2011, up from 201,000 in 2010, yet still far lower than the total number newly enrolled in HIV care and potentially eligible for IPT (estimated at 1.5 million in 2010) [1]. In 2011, the WHO released simplified guidelines for IPT and ICF, recommending that all people living with HIV should be regularly screened for tuberculosis using a clinical algorithm of any of cough, night sweats, weight loss and/or fever. Those without any of these symptoms and without further contraindications to IPT should be enrolled on IPT [2]. The Global Plan to Stop TB (2011-2015) has set a target of universal IPT coverage for all eligible persons living with HIV by 2015, assuming that half of all people living with HIV will be eligible [3]. However, the actual percentage that would be eligible for IPT under these new guidelines it is not known and this has clear implications for the required scale-up and subsequent impact.

The South African gold mines have experienced a dramatic increase in tuberculosis case notifications, to greater than 4% per year [4], caused in part by high prevalences of HIV (29%) and silicosis [5,6]. This has happened despite implementation of the World Health Organization’s DOTS (Directly Observed Therapy, Short course chemotherapy) strategy and routine radiological screening for tuberculosis. “Thibela TB” is a cluster randomised study, in the South African gold mines, evaluating the impact of community-wide tuberculosis screening followed by IPT, in addition to standard of care, on tuberculosis incidence [7]. Understanding the eligibility profile of those who consented to be screened for suitability to start IPT as part of the Thibela TB intervention will thus inform both future roll-outs of IPT and contextualize the results of the study. The aim of this analysis was to determine the proportion, reasons and factors associated with ineligibility among those who consented to Thibela TB.

Methods

Results

Between July 2006 and May 2009, 27,126 individuals consented to take part in the Thibela TB study in the eight intervention clusters. Reflecting the general gold mining workforce, they were 94.7% male, median age 41 years (inter-quartile range: 32-47 years), median years of employment 16 years (inter-quartile range: 5-25 years), 98.1% were black, 59.5% were South African and 55.4% lived in hostels (Table 2). 12.2% reported previous tuberculosis, 0.6% reported ever taking IPT and 2.5% reported currently being on antiretroviral therapy.

At the enrolment visit, 1,249 of the 27,126 (4.6%) who consented were classified as permanently ineligible, 3,111 (11.5%) as temporarily ineligible and 22,766 (83.9%) were immediately eligible to start IPT. The most common reasons for being classified as permanently ineligible were: excessive alcohol consumption (427, 1.6%); being on tuberculosis treatment (241, 0.9%); contraindicated medications (226, 0.8%); history of convulsions (136, 0.5%); pregnancy, planning on becoming pregnant or unwillingness to use contraceptives while taking IPT (107, 0.4%); all other reasons were given by fewer than fifty participants, including those already on IPT (47, 0.2%). Participants with missing data (48, 0.2%) were considered as ineligible.

1,879 of 27,126 (6.9%) participants were classified as tuberculosis suspects, based on symptom screen or radiographic abnormalities, regardless of other reasons for ineligibility. Of these suspects, 665 were culture positive (35.4% of all tuberculosis suspects), of whom 343 (51.6%) were MPB64 positive for Mycobacterium tuberculosis and two did not have the test done. An additional 40 were culture negative (or contaminated) and smear positive. Among the 383 who were culture positive for M. tuberculosis or smear positive, only 150 (39.2%) were symptomatic, with the remaining 233 investigated because of compatible abnormalities on their chest radiograph. A further 1,281 participants were temporarily ineligible while their current chest radiograph was compared to a previous one, but were then classified as not having evidence of tuberculosis i.e. were not classified as tuberculosis suspects.

There were 126 participants initially classified as temporarily ineligible for reasons other than tuberculosis, regardless of other reasons for ineligibility: 58 had rash consistent with hypersensitivity, 40 were temporarily ineligible while reliable contraception was arranged, 12 had symptoms suggesting hepatitis and 20 for other reasons. 55 of the 126 (43.7%) returned for their review visit, at which 10 were reclassified as permanently ineligible (7 due to unresolved rash consistent with hypersensitivity, 2 had not started contraceptive use and 1 due to both of these).

In total, 24,430 of the 27,126 (90.1%) who consented were finally classified as eligible to start IPT, of whom 23,659 started IPT (87.2% of all those who consented). There were 971 tuberculosis cases (positive smear and/or culture, on tuberculosis treatment at screen or starting tuberculosis treatment while temporarily ineligible), while a further 734 were ineligible due to suspected tuberculosis. Ineligibility was associated with the following factors: older age, female gender, non-Mozambican, with longer duration in the workforce, prior history of tuberculosis, in “HIV care” and of lower weight (Table 2). However, even among those with prior history of tuberculosis, the sub-group with the highest percentage ineligible, 78.4% (95% confidence interval: 76.9%, 79.8) were eligible for IPT (Table 2).

Discussion

This study found that 90.1% of participants screened were eligible to start IPT. The commonest reason for ineligibility was a positive smear and/or culture (705 of 27,126 consenting [2.6%]), underscoring the importance of tuberculosis screening prior to starting IPT.

The eligibility criteria in “Thibela TB” were deliberately wide as the safety profile of isoniazid is well characterised and the risk of tuberculosis in this mining population is very high in all subgroups [5,9-11]. There were no restrictions on IPT use with antiretroviral therapy, previous tuberculosis treatment, previous IPT use, silicosis, age or moderate alcohol use, consistent with the 2011 WHO and 2010 South African Department of Health guidelines for IPT (Table 1) [2,12]. Despite these wide eligibility criteria, and the use of self-report for initial assessments rather than laboratory tests or medical record review, the safety profile of isoniazid in this nurse-delivered study was good [13], validating the choice of criteria to maximise the uptake of IPT.

In this analysis, differences in ineligibility between sub-groups were due to these groups acting as proxies for exclusion criteria. The factors associated with ineligibility were similar to those associated with tuberculosis [9], such as for increasing age and years in the workforce, country of origin, previous tuberculosis and being in HIV care. This was unsurprising as active tuberculosis made up a substantial proportion of the reasons for ineligibility. In contrast, women were more likely to be ineligible, despite being at lower risk for undiagnosed tuberculosis, due to the exclusion criteria of pregnancy, planning on becoming pregnant or unwillingness to use contraceptives.

Eligibility in this study was higher than observed in studies screening for IPT among HIV-infected adults [14-17]. A randomised trial comparing six months versus 36 months of IPT among adults accessing antiretroviral therapy in Botswana used a two-stage screening process [15]. The first stage applied the exclusion criteria from the Botswana National IPT programme to 4,018 consenting participants; this excluded 27% of those screened, predominantly due to illness, recent history of tuberculosis and prior IPT (66%, 9% and 8% respectively). The second stage applied study specific exclusion criteria to the remaining 2,934 participants; this excluded a further 776 (26%), most commonly due to chest radiographs compatible with tuberculosis (296 of 776 [36%]). Another randomised trial comparing six months IPT to 36 months isoniazid and ethambutol screened 1,095 HIV-infected persons in India, of whom 268 (24.5%) were excluded for study-specific and 144 (13.2%) for non-study specific criteria (29 culture positive, 115 other unspecified criteria) [16]. A randomised trial of four preventive regimens screened 1,528 tuberculin-positive, HIV-infected adults in South Africa, of whom 324 were ineligible (21.2%), including 141 (9.2% of 1528) who would be ineligible under current guidelines (90 active tuberculosis, 39 chest radiograph compatible with tuberculosis, 4 on tuberculosis treatment and 8 other) [17]. A retrospective evaluation of intensified tuberculosis case finding and IPT among newly diagnosed HIV infected adults in a Voluntary Counselling and Testing clinic in Uganda found 5% had active tuberculosis and a further 37% were excluded from IPT, predominantly because of distance from the clinic, stage 4 HIV disease and previous history of tuberculosis (45%, 30% and 27% respectively) [14]. Under the wider eligibility criteria of “Thibela TB”, many of those excluded in these other studies would have been eligible for IPT, either immediately or following further tuberculosis investigations. In addition, populations with relatively high proportions of people with later stage HIV disease, where it is more difficult to exclude active tuberculosis, are likely to have a higher proportion ineligible. As HIV testing is scaled up and individuals are enrolled into care at earlier stages of HIV disease, the proportion eligible for IPT may increase as the prevalence of symptoms and undiagnosed tuberculosis will be lower.

The generalisability of these results to other settings were IPT is being rolled out at scale may be thought to be limited, as the study investigated community-wide rather than the more common approach of targeted IPT, and was conducted in the mining industry with a predominance of men and possibly a “healthy worker effect”. However, although this strategy of community-wide IPT, which was conducted irrespective of HIV status, is more likely to find healthy, asymptomatic people than targeting HIV infected persons, the scale up of HIV testing is likely to result in increasing proportions of healthy, asymptomatic people entering HIV care. A “healthy worker effect” may result in a population with less severe HIV disease among those who are HIV infected than among those HIV infected in the general population, but this is likely to be true of other settings where community-wide IPT could be implemented, for example, similar workforces and the military. Although women were not well represented in this study, the results presented here show that the vast majority of women were eligible for IPT, which is generalisable. In addition, the main reasons for increased ineligibility among women in this study were the study-specific exclusion criteria of pregnancy or risk of pregnancy. However the 2011 WHO guidelines have made it make clear that these should not be reasons for excluding IPT in a routine setting (Table 1 [2]) and so, eligibility may be higher among women than reported here. Most studies conducted in health care settings have a predominance of women, so one advantage of this study is the large amount of data provided for men.

Conclusions

This community-wide, nurse-delivered intervention found that the vast majority of individuals assessed were eligible for IPT. As HIV testing is scaled up, particularly community-based testing, and more people with early HIV disease are identified, a high proportion will be eligible for IPT, supporting immediate scale up of HIV testing and IPT.

Acknowledgments

We thank the thousands of mine employees who consented to take part in this study. We also thank the many stakeholders for their support for the study to be implemented, particularly: the National Union of Mineworkers, Solidarity and United Unions of South Africa; Anglogold Ashanti, gold Fields and Harmony mining companies; the South African Chamber of Mines; the Mine Health and Safety Council; and the South African government Departments of Minerals and Energy, Health and Labour. We thank the large study team for their commitment and persistent efforts to ensure that the study is successfully implemented. We thank the members of our scientific advisory group for their input: Prof Richard Chaisson, Prof Richard Hayes, Prof Peter Godfrey-Faussett and Dr Elizabeth Corbett.