The World Health Organization recommendations for tuberculosis (TB) control focus on curing patients presenting with their first episode of TB, with the aim of interrupting TB transmission. In countries with high TB incidence, recurrent TB accounts for a significant proportion of all cases [1,2], and HIV infection is a strong risk factor for recurrent TB [3–6] as are post-TB scarring, cavities, drug regimen used to treat the initial episode of TB and a low CD4 cell count [4–8]. In settings of lower TB incidence, recurrent TB occurs more commonly among HIV-infected patients, though the absolute difference in rates is small . Recurrent TB may result from either recrudescence of disease with the original infecting organism or reinfection with a new Mycobacterium tuberculosis strain [6,10]. Reinfection, with rapid progression to disease, has been shown to be an important cause of recurrence among HIV-infected individuals in settings with high rates of TB transmission .
Current international guidelines recommend TB preventive therapy for HIV-infected individuals who have never had TB previously (primary TB preventive therapy) . However, there is increasing evidence of the efficacy of secondary preventive therapy for HIV-infected individuals [12,13].
The present study examined the efficacy of secondary isoniazid preventive therapy (IPT) by comparing the TB incidence rates between two cohorts of HIV-infected gold miners in South Africa with a history of previous TB who had or had not received IPT.
Study population and site
The study was conducted at a single gold mining company in the Free State Province of South Africa. The mine hospital is the sole source of tertiary care for mine employees and manages the TB control programme. Clinics situated at most of the surrounding mine shafts provide primary health care to miners and dispense TB treatment and IPT.
TB control programme
The TB control programme includes directly observed rifampicin-based short-course chemotherapy regimens, use of combination tablets and active case detection using a miniature radiograph screening programme. Treatment regimens are in line with those recommended by the national TB control programme: four drugs are used for first episodes of TB, and regimens for drug-resistant disease are modified to ensure treatment with two or more drugs to which the isolate is sensitive.
Miners with suspected TB are investigated according to a standard protocol. Three sputum specimens are collected over 2 days. Smears are made from concentrated sputum and stained with auramine for fluorescence microscopy. Positive smears are confirmed with Ziehl–Neelsen staining. Following decontamination with 4% sodium hydroxide, sputum is inoculated onto Lowenstein–Jensen slopes and incubated for up to 8 weeks. An initial identification step for M. tuberculosis is carried out on these slopes with more than five colonies, using a colorimetric ribosomal RNA hybridization test (Accuprobe: M. tuberculosis complex probe kit, Gen-Probe, San Diego, California, USA). Positive cultures are sent to the National Health Laboratory for drug susceptibility testing of M. tuberculosis strains.
The study included miners with HIV infection and a history of previous TB with documented successful completion of TB treatment. Men who failed therapy for the previous TB episode or had an unknown treatment outcome were excluded from the study, as were men treated for non-tuberculous mycobacterial disease.
Participants receiving IPT (300 mg per day) were derived from a cohort of HIV-infected men receiving isoniazid and cotrimoxazole indefinitely as part of a clinical trial. The control cohort comprised men attending a routine HIV clinic who did not receive IPT because of a history of previous TB, an exclusion criterion in accordance with current international and local guidelines. Men in the control cohort received cotrimoxazole prophylaxis if their CD4 T cell count was < 250 × 106 cells/l if symptomatic or < 200 × 106 cells/l regardless of symptoms. The incidence of TB recurrence in the two cohorts was compared using a database listing all episodes of TB among company employees since 1979.
Time at risk
At the time of recruitment to their respective cohorts, men had blood taken for a CD4 cell count and were screened for TB using symptoms, chest radiography and sputum smears and cultures. In order to minimize the risk of including a case of TB diagnosed at the time of screening as a study case, the date of entry into this study was defined as 3 months after the date of TB screening. Men receiving TB treatment at the time of recruitment or who were diagnosed with TB at the time of screening entered time at risk after completing TB treatment. Time at risk was censored at the time of first TB episode during the study, death, loss to follow-up or end of study (31 December 2000 for the IPT cohort and 31 July 2001 for the control cohort).
Recurrent TB was defined as definite if there were compatible clinical features and sputum or tissue culture was positive for M. tuberculosis; probable if there were compatible clinical features and two sputum smears were positive for acid-fast bacilli, or sputum or tissue culture was positive for mycobacteria that were not further speciated, or histological examination was positive (acid-fast bacilli present or granulomatous disease); and possible if there were compatible clinical features and a response to treatment with antituberculous drugs.
Grading of silicosis and post-treatment scarring
The standard-sized chest radiographs of study participants, taken at the time of recruitment to their respective cohorts, were assessed for the presence and grade of silicosis using a modified International Labour Organization scoring system. For the purposes of this study silicosis was categorized as none (0/0 or 0/1) or definite (category 1/0 and above). The radiological extent of post-treatment scarring was determined by dividing the lung on each side into three equal zones and allocating a score according to the total number of zones involved. The presence or absence of cavities was also noted.
Data were analysed with STATA 6.0 software (STATA Corporation, College Station, Texas, USA). Differences between categorical variables were investigated using the chi-square test or Fisher's exact test where appropriate. The differences in length of follow-up between the two groups were assessed using the Wilcoxon rank-sum test. Poisson regression was used to calculate univariate and adjusted TB incidence and mortality rate ratios for different variables. Overall significance, tests for trends for ordinal variables with more than two categories and tests for effect modification were determined using the likelihood ratio test.
Ethical approval for the clinical trial from which the IPT cohort was drawn was obtained from the Anglogold Health Services and UNAIDS Ethical Review Boards; all participants gave informed consent. The evaluation of the routine health service clinic from which the control cohort was drawn was given ethical approval by the Ethics Committees of Anglogold Health Service and London School of Hygiene and Tropical Medicine.
All study participants were HIV-infected black male miners; the IPT cohort comprised 338 men and the control cohort 221 men. The characteristics of the two cohorts are presented in Table 1. The two cohorts were similar with respect to age, CD4 cell count, number of previous TB episodes, silicosis grade, presence of cavitation and extent of post-treatment scarring. The control cohort had their preceding episode of TB significantly longer before study entry than did the IPT cohort and had a shorter duration of follow-up within the study (median 0.41 versus 0.91 years). Recruitment to the IPT cohort began and ended a year earlier than recruitment to the control cohort.
A record was kept of all treatment dispensed to the primary health care clinic and collected by the study participants on a monthly basis: 76% (256/338) of men in the IPT cohort collected at least 80% of the isoniazid dispensed and 19/28 (68%) of the patients with TB in the IPT cohort collected at least 80% of their prescribed isoniazid. IPT was interrupted, and then restarted, in four patients because of skin rash (two), abdominal pain (one) and nausea (one). IPT was stopped and not restarted in a further three patients, all because of skin rash. There were no episodes of hepatitis or peripheral neuropathy.
During the study period, 51 cases of TB were diagnosed, 28 (8.3%) among the IPT cohort and 23 (10.4%) among the control cohort. The recurrent TB cases in the two groups were similar with respect to the proportion classified as definite, site of disease and CD4 cell count at baseline (Table 2). There was no significant difference in the prevalence of isoniazid resistance between the IPT and control cohorts [20% (2/10) and 23% (3/13), respectively, P = 1.0].
Results of incidence rates (IR) of recurrent TB, unadjusted incidence rate ratios (IRR) and 95% confidence intervals (CI) are presented in Tables 3 and 4. There was a significantly lower incidence of TB among the IPT cohort compared with the control cohort (IRR, 0.45; 95% CI, 0.26–0.78). There was no difference in efficacy of IPT when adjusted for age, silicosis, extent of post-treatment scarring or presence of cavitation, CD4 cell count and time since completion of treatment for previous TB episode (adjusted IRR, 0.45; 95% CI, 0.26–0.79). The effect of IPT on TB incidence remained significant when the analysis was restricted to TB cases defined as probable or definite (Table 3). Likewise, the effect of IPT remained highly significant if the analysis was restricted to those in whom the previous TB episode had been culture positive for M. tuberculosis (IRR 0.19; 95% CI, 0.09–0.42; Table 4).
Among men with only one previous episode of TB, the incidence of recurrent TB in the IPT cohort was significantly lower than in the control cohort (Table 3). Among men with more than one previous episode of TB, recurrences occurred more often in those on IPT, though the difference was not statistically significant (Table 3). The interaction between the number of previous TB episodes and the efficacy of IPT was significant overall (Pinteraction, 0.03), when the analysis was restricted to those cases classified as probable or definite (Pinteraction, 0.02) (Table 3) and when the preceding TB episode was culture positive for M. tuberculosis (Pinteraction, 0.001) (Table 4). The effect of IPT was strongest in men with only one previous episode of TB that was culture positive for M. tuberculosis, among whom there was an 89% reduction in incidence of recurrent TB (IRR 0.11; 95% CI, 0.04–0.27).
The effect of IPT was not significantly modified by time since completion of previous TB treatment (Pinteraction, 0.86) or by CD4 cell count category (Pinteraction, 0.55) (Table 3). However, the incidence of recurrent TB increased with decreasing CD4 cell count (CD4 cell count ≥ 500 × 106 cells/l, 6.9/100 person-years; 200–499 × 106 cells/l, 8.6/100 person-years; < 200 × 106 cells/l: 18.8/100 person-years; Ptrend, 0.008) and hence the number needed to treat to prevent a case of recurrent TB was substantially lower for individuals with lower CD4 cell counts (The number of person-years on IPT required to prevent one case of recurrent TB was 10 overall, 5 for CD4 cell count < 200 × 106 cells/l and 19 for CD4 cell count ≥ 200 × 106 cells/l).
Overall mortality was not significantly lower among the IPT cohort compared with the control cohort (mortality rate ratio 0.7; 95% CI, 0.39–1.24) (Table 5). In order to control for any possible effect of cotrimoxazole on mortality, the analysis was restricted to those men with a CD4 cell count of ≤ 200 × 106 cells/l who were taking cotrimoxazole, but this did not affect the result (mortality rate ratio 0.73; 95% CI, 0.39–1.38).
The concept of TB preventive therapy was developed in the pre-HIV era based on the idea that treatment of asymptomatic latent or recently acquired TB infection would reduce the risk of developing active TB disease . In industrialized countries, the contribution of exogenous reinfection to active disease was declining in the mid-20 century , and preventive therapy was thought to have no effect among those who had been previously treated for TB ; secondary preventive therapy was, therefore, not recommended. The clinical trials that demonstrated the efficacy of TB preventive therapy among HIV-infected individuals were based on this same principle and hence only included individuals who had no history of previous TB. However, with the development of molecular ‘fingerprinting’ techniques, it has become clear that recurrent TB may occur either as a result of recrudescence of disease from the original infecting organism (relapse) or from reinfection with a new strain of M. tuberculosis, particularly in settings with a high rate of TB transmission [6,10].
In this study, in a setting where the prevalence (and hence also the risk of transmission) of TB is high, secondary IPT was associated with a 55% reduction in the incidence of recurrent TB among HIV-infected individuals. The results are consistent with small prospective randomized trials of secondary IPT from Haiti  and Abidjan  and a study from the Democratic Republic of Congo, which demonstrated a reduction in TB recurrence among HIV-infected individuals in whom treatment was extended by 6 months with twice weekly isoniazid and rifampicin .
The effectiveness of secondary preventive therapy is likely to be limited to communities with high rates of TB transmission, such as the South African gold mining industry, where there are high rates of TB recurrence following documented cure, particularly among HIV-infected individuals [4,6]. DNA fingerprinting data suggest similar rates of relapse between HIV-infected and HIV-uninfected individuals, but higher rates of reinfection with rapid progression to TB disease among HIV-infected individuals . In this setting, secondary preventive therapy may prevent acquisition of new infection or may treat recently acquired infection that has occurred following completion of treatment of the previous TB episode.
Our study suggests that the effectiveness of secondary IPT may be limited to HIV-infected individuals with only one previous episode of TB. This may be because individuals who have had more than one recurrence of TB are more likely to have drug-resistant TB ; the number of individuals in this study with isoniazid-resistant TB was too small to provide data supporting this hypothesis. Limiting secondary preventive therapy to individuals who have only had one previous episode of TB seems rational but requires additional studies to confirm a lack of benefit in those individuals with more than one previous TB episode.
Current World Health Organization recommendations regarding TB preventive therapy for HIV-infected individuals in resource-poor settings have not been widely implemented . In sub-Saharan Africa, the majority of HIV-infected individuals are unaware of their HIV status  and many discover their status only when an opportunistic infection, often TB, is diagnosed, at which point it is too late for primary preventive therapy. Furthermore, because of limited eligibility criteria and logistical difficulties of excluding active disease prior to commencing preventive therapy, there is a high attrition of patients during the screening process . Consequently, the number of patients who start primary preventive therapy compared with the number screened is small. Secondary preventive therapy may be easier to implement than primary preventive therapy. HIV testing should have been offered at the time of TB diagnosis; a tuberculin skin test and chest radiograph are not required and exclusion of active TB at the end of treatment, by sputum smear examination, is done routinely according to World Health Organization TB control programme guidelines. For these reasons, it seems logical to offer secondary preventive therapy to HIV-infected individuals in settings of high TB prevalence where primary TB preventive therapy is being offered.
In this study, the risk of recurrent TB increased significantly with declining CD4 cell count, but the relative effect of IPT was not significantly modified by CD4 cell count. Hence fewer patients with advanced HIV disease would need to be treated to prevent a case of TB compared with the situation in patients with less-advanced HIV disease. It may be more cost- effective to target IPT to those with advanced HIV disease, based on CD4 cell count or clinical staging. Of note, absolute numbers needed to treat depend on TB incidence; hence, where TB incidence is lower, the numbers needed to treat will be higher.
In other studies [12,17], the effectiveness of secondary preventive therapy was evaluated in the immediate post-treatment period . Our study demonstrated effectiveness of secondary IPT regardless of the interval between the previous TB episode and commencing IPT. We, therefore, propose no restriction by time since previous episode for offering secondary preventive therapy to HIV-infected individuals.
Although secondary IPT significantly reduced the incidence of TB recurrence in this study, the rate of recurrence in the IPT cohort remained unacceptably high (8.6/100 person-years) and mortality was not significantly reduced. In resource-poor settings, secondary IPT may be a safe and, at less than $10 per person per year, affordable way to reduce morbidity among HIV-infected individuals with a history of previous TB. Antiretroviral therapy is likely to have a greater effect in reducing morbidity and mortality from TB and AIDS-defining conditions in this group of patients [21,22]. However, TB incidence remains high among individuals on antiretroviral therapy with low CD4 cell counts living in communities with endemic TB ; therefore, TB preventive therapy will remain an important intervention for individuals receiving antiretroviral therapy in these settings.
In this study, we were able to include a relatively large number of individuals with a large number of events. Since this was not a randomized controlled trial, there could have been differences between the two cohorts that could not be controlled. However, we had access to detailed data on potential confounding factors, and the two cohorts had similar baseline characteristics. Although the two cohorts differed in terms of time since last TB episode, there was no difference in efficacy of IPT when adjusted for time since last TB episode. The risk of recurrent TB in the IPT cohort may have been greater because of the longer duration of follow-up and hence increased chance of disease progression. If so, we may have underestimated the efficacy of IPT.
Secondary IPT was administered indefinitely in this study, which contrasts with current international guidelines of 6–9 months of isoniazid for primary preventive therapy [11,23] and other studies of secondary preventive therapy [12,13]. Further work is needed to determine the optimum duration of both primary and secondary TB preventive therapy in settings with high rates of TB transmission, and to establish how best to target preventive therapy.
There is a growing body of evidence of the efficacy of secondary TB preventive therapy for HIV-infected individuals in communities with a high incidence of TB. HIV-infected individuals may benefit from secondary preventive therapy, and international recommendations need revision to take this into account.
We would like to thank the staff of Aurum Health Research and Ernest Oppenheimer Hospital, particularly those from the laboratory and radiology departments, and of the TB and prevention clinics for their assistance in conducting this study. We acknowledge Anglogold Health Service for their permission to publish the data.
Sponsorship: The study from which the IPT cohort was derived was funded by UNAIDS. Anglogold funded the evaluation of the routine HIV preventive therapy clinic. E. L. Corbett was funded by a Wellcome Trust Training Fellowship in Clinical Tropical Medicine.
1. Churchyard GJ, Kleinschmidt I, Corbett EL, Mulder D, De Cock KM. Mycobacterial disease in South African gold miners in the era of HIV infection. Int J Tuberc Lung Dis
2. Weyer K, Kleeberg HH. Primary and acquired drug resistance in adult black patients with tuberculosis in South Africa: results of a continuous national drug resistance surveillance programme involvement. Tuber Lung Dis
3. Pablos-Mendez A, Raviglione MC, Laszlo A, Binkin N, Rieder HL, Bustreo F, et al. Global surveillance for antituberculosis-drug resistance, 1994–1997. World Health Organization-International Union against Tuberculosis and Lung Disease Working Group on Anti-Tuberculosis Drug Resistance Surveillance. N Engl J Med
4. Mallory KF, Churchyard GJ, Kleinschmidt I, De Cock KM, Corbett EL. The impact of HIV infection on recurrence of tuberculosis in South African gold miners. Int J Tuberc Lung Dis
5. Banda H, Kang'ombe C, Harries AD, Nyangulu DS, Whitty CJ, Wirima JJ, et al. Mortality rates and recurrent rates of tuberculosis in patients with smear-negative pulmonary tuberculosis and tuberculous pleural effusion who have completed treatment. Int J Tuberc Lung Dis
6. Sonnenberg P, Murray J, Glynn JR, Shearer S, Kambashi B, Godfrey-Faussett P. HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers. Lancet
7. Pulido F, Pena JM, Rubio R, Moreno S, Gonzalez J, Guijarro C, et al. Relapse of tuberculosis after treatment in human immunodeficiency virus- infected patients. Arch Intern Med
8. Johnson JL, Okwera A, Vjecha MJ, Byekwaso F, Nakibali J, Nyole S, et al. Risk factors for relapse in human immunodeficiency virus type 1 infected adults with pulmonary tuberculosis. Int J Tuberc Lung Dis
9. Sterling TR, Alwood K, Gachuhi R, Coggin W, Blazes D, Bishai WR, et al. Relapse rates after short-course (6-month) treatment of tuberculosis in HIV-infected and uninfected persons. AIDS
10. Van Rie A, Warren R, Richardson M, Victor TC, Gie RP, Enarson DA, et al. Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Engl J Med
11. World Health Organization. Preventive therapy against tuberculosis in people living with HIV. Wkly Epidemiol Rec
12. Fitzgerald DW, Desvarieux M, Severe P, Joseph P, Johnson WD, Jr., Pape JW. Effect of post-treatment isoniazid on prevention of recurrent tuberculosis in HIV-1-infected individuals: a randomised trial. Lancet
13. Haller L, Sossouhounto R, Coulibaly IM, Dosso M, Kone M, Adom H, et al. Isoniazid plus sulphadoxine-pyrimethamine can reduce morbidity of HIV- positive patients treated for tuberculosis in Africa: a controlled clinical trial. Chemotherapy
14. Rieder HL. Interventions for Tuberculosis Control and Elimination.
(Monograph). Paris: International Union Against Tuberculosis and Lung Disease; 2002.
15. Canetti G, Sutherland I, Svandova E. Endogenous reactivation and exogenous reinfection. Their relative importance in the outbreak of nonprimary tuberculosis. Bull Int Union Tuberc
16. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. A general review. Adv Tuberc Res
17. Perriens JH, St Louis ME, Mukadi YB, Brown C, Prignot J, Pouthier F, et al. Pulmonary tuberculosis in HIV-infected patients in Zaire. A controlled trial of treatment for either 6 or 12 months. N Engl J Med
18. Kritski AL, Rodrigues de Jesus LS, Andrade MK, Werneck-Barroso E, Vieira MA, Haffner A, et al. Retreatment tuberculosis cases. Factors associated with drug resistance and adverse outcomes. Chest
19. Colebunders R, Lambert ML. Management of co-infection with HIV and TB. Br Med J
20. Aisu T, Raviglione MC, van Praag E, Eiriki P, Narain JP, Barugahare L, et al. Preventive chemotherapy for HIV-associated tuberculosis in Uganda: an operational assessment at a voluntary counselling and testing centre. AIDS
21. Harries AD, Hargreaves NJ, Kwanjana JH, Salaniponi FM. Recurrent tuberculosis: definitions and treatment regimens. Int J Tuberc Lung Dis
22. Badri M, Wilson D, Wood R. Effect of highly active antiretroviral therapy on incidence of tuberculosis in South Africa: a cohort study. Lancet
23. American Thoracic Society/Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med